· Web viewSodium-glucose co-transporter 2 inhibitors (SGLT2i) exposure and outcomes intype 2 diabetes: a systematic review of population-based observational studies . Thomas M

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Sodium-glucose co-transporter 2 inhibitors (SGLT2i) exposure and outcomes in type 2 diabetes: a systematic review of population-based observational studies

Thomas M Caparrotta1,2, Andrew M Greenhalgh2,3, Karen Osinski2, Robert M Gifford2,3,4, Svenja

Moser1, Sarah H Wild5, Rebecca M Reynolds4, David J Webb4, Helen M Colhoun1,6

Affiliations:

1Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South,

Edinburgh, EH4 2XU, United Kingdom

2NHS Lothian, Edinburgh Royal Infirmary, 51 Little France Crescent, Edinburgh EH16 4SA,

United Kingdom

3Defence Medical Services, Whittington Barracks, Whittington, Lichfield WS14 9PY, United

Kingdom

4University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen’s

Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom

5Usher Institute, University of Edinburgh, Old Medical School, Teviot Place, Edinburgh, EH8 9AG,

United Kingdom

6NHS Fife, Department of Public Health, Hayfield House, Hayfield Rd, Kirkcaldy KY2 5AH

Word count: 5,742

Keywords:

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Abstract

Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) are licensed for the

treatment of type 2 diabetes (T2D) and more recently for heart failure with or without diabetes.

They have been shown to be safe (from the cardiovascular (CV) perspective) and effective (in

terms of glycaemia, and in some cases, in reducing CV events) in extensive randomised

controlled trials (RCTs). However, there remain concerns regarding the generalisability of these

findings (to those ineligible for RCT participation) and about non- CV safety. For effectiveness,

population-based pharmacoepidemiology studies can confirm and extend RCTs’ findings to

broader populations and explore safety, for which RCTs are not usually powered, in more detail.

Method: A pre-planned and registered ((International PROSPEctive Register Of Systematic

Reviews) PROSPERO registration: CRD42020165720) systematic review of population-based

studies investigating SGLT2i effectiveness and safety, following Meta-analyses Of Observational

Studies in Epidemiology (MOOSE) guidelines was conducted.

Results: 37 studies were identified (total n = 1,300,184; total follow-up 910,577 person-years,

exposures: SGLT2i class, canagliflozin, dapagliflozin and empagliflozin) exploring CV disease

(CVD) outcomes, acute kidney injury (AKI), lower limb amputation (LLA), diabetic ketoacidosis

(DKA), bone fracture, urinary tract infection (UTI), genital mycotic infection (GMI),

hypoglycaemia, pancreatitis and venous thromboembolism. For CV and mortality outcomes,

studies confirmed the associated safety of these drugs and correlated closely with the findings

from RCTs, which may extend to primary CVD prevention (major adverse cardiovascular events

point estimate range (PER): hazard ratio (HR) 0.78-0.94; hospitalised heart failure PER HR 0.48-

0.79). For safety outcomes, SGLT2i exposure was not associated with an increased risk of AKI

(PER HR 0.40-0.96), fractures (PER HR 0.87-1.11), hypoglycaemia (PER HR 0.76-2.49) or UTI

(PER HR 0.72-0.98). There was a signal for increased association for GMIs (PER HR 2.08-3.15),

and possibly for LLA (PER HR 0.74-2.79) and DKA (PER HR 0.96-2.14), but with considerable

uncertainty.

Conclusion: In T2D, SGLT2is appear safe from the CV perspective and may have associated

benefit in primary as well as secondary CVD prevention. For safety, they may be associated with

an increased risk of GMI, LLA and DKA although longer follow-up studies are needed

[Word Count = 258]

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Introduction

Sodium-glucose co-transporter 2 inhibitor (SGLT2i)s are licensed for the treatment of type 2

Diabetes Mellitus (T2D) when diet and lifestyle have not improved glycaemic control. They have

also recently been licensed by both European Medicines Agency (EMA) and Food and Drug

Administration (FDA for the treatment of heart failure (HF) with reduced ejection fraction in

those with or without diabetes. In diabetes, they improve glycaemic control by causing

glycosuria, natriuresis and osmotic diuresis. Their effect is independent of insulin and they are

thought to exert beneficial effects through pleiotropic mechanisms beyond improved glycaemia,

including favourable haemodynamic changes.1

The clinical development programmes for these agents assessed the efficacy, cardiovascular

(CV) safety and preliminary non-CV safety of the SGLT2is in T2D. Many have subsequently been

assessed for cardiovascular disease (CVD) safety in large trials and have been shown to be non-

inferior, and sometimes superior, to usual care in this respect.2–6 Both canagliflozin5 and

empagliflozin2 reduce major adverse cardiovascular events (MACE) but dapagliflozin3 does not.

All three agents reduce heart failure in those with T2D2,3,5 and dapagliflozin reduces heart failure

in those without diabetes4. Almost all outcomes’ trial participants were on background

metformin.

It remains unclear, however, whether the CV benefits of these medicines extend to people who

were ineligible for the trials. Furthermore, safety concerns have emerged, either during trials or

through post-marketing surveillance.2,3,5–26 It is also unclear whether the beneficial effects

extend to the SGLT2i class as a whole or whether this is limited to individual agents. For non-CV

safety, population-based observational pharmacoepidemiology allows for rare, but severe,

adverse events to be detected.

Population-based studies present more generalisable data which can expand upon the findings

from randomised controlled trial (RCT)s but the lack of randomisation and blinding increases

the risk of bias and confounding. However, population-based database studies, when properly

designed and analysed, are associated with fewer systematic distortions, such as selection bias,

compared to other forms of observational pharmacoepidemiology.27

This study describes a pre-planned and prospectively registered impartial systematic review of

population-based, observational studies examining effectiveness and safety of SGLT2is in T2D

((International PROSPEctive Register Of Systematic Reviews) (PROSPERO) registration:

CRD42020165720, 16th January 2020). It must be noted that there is a broad diversity in

outcomes, particularly for CVD, as well as the definitions of pre-existing CVD, which makes

interpretation challenging.

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The hypothesis was that the studies included in this review would show a treatment

effectiveness or safety estimate associated with SGLT2i exposure of a similar direction and

order of magnitude to that reported in RCTs (or, for safety, pharmacovigilance studies).

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Methods

We followed Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines for

reporting. In brief, two search methodologies were employed (maximal and targeted search) of

the following citation databases: Web of Science, OVID, Excerpta Medica dataBASE (EMBASE)

and PUBMED using the search criteria listed in the supplementary material, which were

agnostic to specific outcomes (Supplementary Table S1). Searches were conducted for studies

published between November 2012 (date of licensing: dapagliflozin) and December 2020.

Duplicates were eliminated using each study’s unique identifier. Two (medically-qualified)

reviewers (AG and TC) independently applied the inclusion and exclusion criteria (table S2)

first to the title and subsequently to the abstracts. We searched European Network of Centres

for Pharmacoepidemiology and Pharmacovigilance (ENCePP), ClinicalTrials.gov and the

European Union (EU) Post-Authorisation Studies (PAS) registers to identify further studies.

Studies were excluded that only reported continuous clinical outcomes (e.g. blood pressure) or

studies that only reported adherence or tolerability. We only included English language

publications due to resource limitations.

Each reviewer checked 10% of the other’s title and abstract screening with a pre-specified

decision that <95% agreement would mean that the entire list would be re-screened. Third

party arbitration of disputes was planned in the event of <95% agreement. There was 100%

agreement of included/excluded studies and arbitration was not necessary.

A standardised data extraction template was used to collect study data (table S3).

The studies eligible for inclusion were scored for quality (using the Downs and Black Checklist

for Non-Randomised Studies28), which has been shown to have good inter-rater reliability, but

no score cut-off for inclusion/exclusion was employed (table S4).29 Score discrepancies were

handled in conference with the reviewers, with 3rd party arbitration planned if agreement was

not achieved but this latter step was not necessary.

The references of included studies were searched manually to identify studies which may not

have been included in original searches. All reported outcomes were included.

Studies were subsequently tabulated by outcome to compare effect estimates and relevant

subgroup analyses (so studies may appear in multiple tables). Effect estimates and relevant

subgroup analyses were compared between studies in separate tables for each outcome. Forest

plots were used to compare safety outcomes.

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We chose to describe studies with <5000 participants as small; 5000-20,000 participants as

medium-sized; and >20,000 as large. Confidence intervals (CIs) widths are described

qualitatively. The associated effect estimate is neutral when no effect can be discerned, and as

an associated increase/decrease in risk when the bound of the CI does not cross unity.

Meta-analysis was not performed due to breaching meta-analytic standards (Berlin et al.30).

Study design heterogeneity, low study numbers for individual outcomes and multiple

representation of data sources influenced this decision. A funnel plot was considered to assess

the risk of publication bias but there were too few studies per outcome to undertake this

(Cochrane Library recommends >10 studies per outcome31) Thus, we present the findings of a

narrative systematic review.

This article is based on previously conducted studies and does not contain any new studies with

human participants or animals performed by any of the authors.

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Results

The search and application of inclusion/exclusion criteria identified 37 individual studies

within the dates specified (Figure 1: = Preferred Reporting Items for Systematic Reviews and

Meta-Analyses (PRISMA) diagram) including n = 1,300,184 persons; total follow-up 910,577

person-years. Of these, 21 were funded by academic institutions, public bodies or charity/non-

profit organisations32–52 and 16 were funded by pharmaceutical companies53–68. We found six

studies that had been prospectively registered with either https://clinicaltrials.gov/ (five

studies56,58,63,65,67, with two sharing a registration number56,58) or EU PAS Register (one study52).

Table S4 reports the quality score agreed by two independent reviewers (TC and AG). The

scores ranged from 10-22 (the maximum achievable score would have been 29/31 as none of

the studies was randomised). None of the study designs as described appeared to have affected

by immortal time bias arising from an inappropriate start date to follow-up.

There was a preponderance of studies of the earliest SGLT2is to achieve market authorisation

(dapagliflozin, empagliflozin, canagliflozin), with SGLT2is licensed later (ipragliflozin (licensed

only in Japan) and ertugliflozin) only included in SGLT2i class studies.

Table S5 describes the Comparative-Effectiveness of Cardiovascular Outcomes in New-Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-Real) programme.

Tables 1-9 describe the studies in more detail. Tables S6-S10 and S14-S22 give the study

characteristics and effect estimates.

Here we compare (and tabulate) the composites/outcomes together, grouped by exposure and

comparator, to allow head-to-head contrasts to be drawn.

Cardiovascular disease

Non 3-point MACE cardiovascular composites

All-cause mortality (ACM) and hospitalised heart failure (HHF) composite

Three studies explored the association of SGLT2i class exposure on the composite of ACM and

HHF versus (vs.) oral anti-hyperglycaemic drugs (OADs) as a primary56,66 and secondary

outcome58. All three studies were associated with a reduction in the composite and each

component alone (tables 1.1, 1.4, 1.6, S6.3, S6.4 and S6.5). There was less prevalent ischaemic

heart disease (IHD) compared to the cardiovascular outcome trial (CVOT)s (~13.0%58 and

~26.7% 56 established IHD (not reported in66) compared to 45-75%2,3,5) and in two studies the

association remained consistent when secondary CVD prevention was examined alone in

subgroup analysis56,66.

https://clinicaltrials.gov/

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Myocardial infarction (MI) and stroke composite

Two studies investigated the composite of MI and stroke. For the SGLT2i class pairwise (head-

to-head) vs. sulphonylurea (SU)s and DPP4is as a primary outcome there was an associated

reduction in the composite for both comparisons (established CVD ~12% compared to 45-

75%2,3,5 in the CVOTs, tables 1.9, S6.1).37 For canagliflozin pairwise vs. DPP4is, glucagon-like

peptide-1 receptor antagonist (GLP1Ras) and SUs there was a neutral effect on a CVD composite

and for the individual components in all three comparisons (established CVD ~11% vs. 73%5 in

the CVOT, tables 1.14, S6.6, S11, S12).45 There was also a neutral effect in the expanded

composite and in secondary CVD prevention subgroup.

Other composites

For SGLT2i class vs. DPP4is, a study explored the composite of HHF, IHD, stroke and peripheral

arterial disease (PAD) as a primary outcome (baseline CVD 4.3-5.5% compared to 45-75%2,3,5 in

the CVOTs) and reported a neutral association in the population overall, and in

primary/secondary CVD prevention (tables 1.8 and S6.2).62

Dapagliflozin exposure was compared in four studies to OAD49, non-users59, insulin61 and head-

to-head with empagliflozin47. Versus OAD, exposure was associated with a neutral effect on an

incident CVD composite as a secondary outcome (MI, IHD, stroke/TIA. HHF and left ventricular

dysfunction; baseline IHD 13.2-14.8% compared to 40.5%3 in the CVOT; tables 1.18 and S6.8.) in

a low-risk of CVD population (~primary prevention).49 Versus non-users, exposure was

associated with a neutral effect on a composite of IHD, cerebrovascular disease, HHF, cardiac

arrhythmias or coronary revascularisation, as a secondary outcome (baseline IHD not reported,

tables 1.20 and S6.9).59 Versus insulin, exposure was associated with a reduction of the

composite of fatal and non-fatal CVD as a primary outcome (MI, stroke, UA, HHF and CVD death;

prior MI 9% vs. 40.5% any atherosclerotic history 3from the CVOT, tables 1.17 and S6.7).61.

Head-to-head with empagliflozin, exposure was associated with a neutral effect on the

composite (as a primary outcome) of MI, stroke and HHF (baseline IHD 14.3% vs. 40.5%3 in

CVOT, tables1.15 and S6.10).47

MACE

MACE was defined as a composite of mortality (we allowed the mortality definition to be both

CV mortality and ACM), non-fatal MI and non-fatal stroke (+/- other outcomes, reported

separately).

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Three studies explored the association with MACE for the SGLT2i class in patients with lower

baseline CVD (6-25%44,54,66) than the CVOTs (45-75%2,3,5) but with inconsistent findings. One

study (vs. OAD) showed a surprising associated reduction in the primary CVD prevention

subgroup but not in the secondary prevention subgroup or the population overall, where the

largest expected benefit might be in those with pre-existing CVD (tables 1.3, S7.2).54 Versus OAD

(SGLT2i non-users) exposure was associated with a reduction in MACE (secondary outcome) in

both the intention-to-treat (ITT) and on-treatment analysis and also in primary/secondary CVD

prevention subgroups (tables 1.6, S7.3).66 Versus DPP4is, there was an associated reduction in

MACE in the on-treatment but not in the ITT analysis (consistent in primary/secondary CVD

prevention) (tables 1.10, S7.1).44

For dapagliflozin versus dipeptidyl peptidase-4 inhibitor (DPP4i) (CVD-REAL sub-analysis, 23%

pre-existing CVD), a reduced association for MACE was demonstrated (and for the expanded

composite) in both the ITT and on-treatment analyses (tables 1.16, S7.4).64 Versus OAD (a CVOT

inclusion/exclusion emulation for dapagliflozin, but with 10%-less established CVD), exposure

was associated with a reduction in MACE in the on-treatment, but not the ITT, analysis, driven

by a reduction in CV mortality (tables 1.19, S7.5).60

Myocardial Infarction MI was always a composite component.

For the SGLT2i class vs. OAD (CVD-REAL sub-analysis, 13% established CVD), exposure was

associated with a decrease in MI events (on-treatment and ITT analyses) with benefit in

primary/secondary CVD prevention (tables 1.2, S8.6).57 This contrasts with another CVD-REAL

sub-analysis (SGLT2i vs. OAD) with a neutral association on MI (tables 1.3, S8.5).54 There was a

reduced association in CVD-REAL 2 (geographically distinct to CVD-REAL, vs. OAD, 27%

established CVD at baseline) for MI in the ITT, on-treatment and adjusted analyses (overall and

in primary/secondary CVD prevention) (tables 1.4, S8.4).56 A further study revealed a neutral

association, vs. OAD, for MI (secondary outcome) in ITT (but reduced in on-treatment analysis),

and stable in primary/secondary CVD prevention subgroup (tables 1.6, S8.7).66 Versus DPP4i

there was a neutral association in two studies44,62 for MI/IHD; for one study both in both ITT

(tables 1.10, S8.2) and on-treatment analyses44; and for the other study the association

remained stable regardless of baseline glycated haemoglobin (HbA1c) and metformin use

(tables 1.8, S8.1)62. Whereas versus DPP4i or SUs, there was a negative association for MI in

both comparisons, persisting in primary/secondary CVD prevention subgroups but the <65s

benefitting more (tables 1.9, S8.3).37

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For canagliflozin vs. DPP4i, GLP1RAs and SUs there was a neutral association for MI in all

pairwise comparisons (tables 1.14, S8.10, S11, S12).45

For dapagliflozin (vs. DPP4i, CVD-REAL sub-analysis) there was a neutral association with MI

(tables 1.16, S8.9)64, and similar in another study, vs. OADs, where there was neutral association

in all analyses (tables 1.19, S8.18)60 A head-to-head comparison vs. empagliflozin showed a

neutral association with MI (tables 1.15, S8.11).47

Stroke

Non-fatal stroke was always a composite component.

For SGLT2i class vs. OADs (CVD-REAL sub-analysis) there was an associated reduction in stroke

(ITT and OT analysis, tables 1.2, S9.6)57 although another CVD-REAL sub-analysis suggests a

neutral association (tables 1.3, S9.5)54 For CVD-REAL 2 study, vs. OADs, there was a reduced

association for stroke (all analyses) (tables 1.4, S9.4)56 Versus OADs, there was a neutral

association (ITT analysis, marginally beneficial in the on-treatment) (tables 1.6, S9.7)66

Versus DPP4i and SUs, for class exposure, there was a reduced association for stroke for both

comparisons, persisting in subgroup analysis (tables 1.9, S9.1).37 Versus DPP4i, exposure was

associated with a neutral effect for primary/secondary CVD prevention (tables 1.8, S9.2)62, a

finding replicated in another study with the same comparison (both ITT and OT analysis)

(tables 1.10, S9.3)44.

For canagliflozin (versus DPP4i, GLP1RA and SUs, pairwise) a neutral association with stroke

was observed (tables 1.14, S9.10, S11, S12)45

For dapagliflozin head-to-head with empagliflozin there was a neutral association with stroke

(tables 1.15, S9.11) 47 Versus DPP4is, there was a neutral association with stroke risk, stable in

subgroup/sensitivity analysis (tables 1.16, S9.9)64 Versus DPP4i (CVD-REAL sub-analysis) a

neutral association for stroke was observed 64, which was similar in another study (vs. OADs,

ITT and OT) (tables 1.19, S9.8)60.

Heart Failure

HF was explored either alone, as part of a composite or with proxies.

For SGLT2i class, vs. OAD, both CVD-REAL and CVD-REAL 2 main analyses showed an associated

reduction in HHF, holding in sensitivity/subgroup analysis (tables 1.3, S10.10; tables 1.4, S10.9;

tables 1.1, S10.7)54,56,58 Versus OADs there was an associated reduction in HHF (in both those

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with and without baseline HF, tables 1.6, 4,6)66 As a proxy for HF, versus OAD, there was an

associated reduction in incident loop-diuretic prescriptions following exposure but not for dose

change/prescription cessation (tables 1.11, S10.8).51

Versus DPP4is, SGLT2i class exposure (13.7% baseline atherosclerosis) was associated with a

reduction in HHF (population overall, the ≥65s and those with pre-existing diabetes

complications; tables 1.5, S10.4)55 and in the same comparison in another study (~60% baseline

HF) for both primary/secondary HF prevention (after ≥3y in the former, tables 1.7, S10.5)40.

This pattern repeated in another study (vs. DPP4i, all analyses) with the greatest associated

reduction in the ≥65s (tables 1.10, S10.2)44 Compared to DPP4is (and SUs) there was a reduced

association in both comparisons for HHF (12.6% baseline IHD, and for primary/secondary CVD

prevention, tables 1.9, S10.1)37 Versus DPP4is (with lower baseline CVD, 5.5%), a neutral

association was observed in both primary/secondary HF prevention, static in sensitivity

analysis (tables 1.8, S10.3)62.

For empagliflozin, vs. sitagliptin (25% prevalent CVD), an associated reduction was

demonstrated for HHF (primary outcome, tables 1.12, S10.12)63

For canagliflozin (compared to all hyperglycaemic drugs (including injectable therapies)

(AHDs), 0.3-1.4% prevalent HF), the was an associated reduction in HHF vs. non-SGLT2i drugs

but not head-to-head with other SGLT2is (tables 1.13, S10.16, S13)65 Versus DPP4is, GLP1RAs

and SUs, pairwise, canagliflozin was associated with reduced HHF (all analyses) (tables 1.14,

S10.12, S11, S12)45

Head-to-head, dapagliflozin vs. empagliflozin was associated with a reduced risk of HHF in all

analyses and adjustments (tables 1.15, S10.14)47 Versus DPP4Is, exposure was associated with

reduced HHF (CVD-REAL sub-analysis)(tables 1.16, S10.11)64 and also compared to OADs

(tables 1.19, S10.13)60, in all analyses.

MortalityCVD mortality was always a composite component. ACM was reported as part of a composite

and also alone as an outcome.

SGLT2i class exposure, vs. OAD (CVD-REAL sub-analysis), was associated with a reduction in

CVD mortality (main driver of MACE reduction; tables 2.2, S14.4)54 Versus DPP4is, SGLT2i

exposure was associated with a neutral effect on CVD mortality (tables 2.5, S14.1)44 Compared

to OAD, there was an associated reduction in ACM in four studies, in two as a primary outcome

(tables 2.2, S14.4; tables 2.1, S14.3) 54,58, and for two as a component of a composite in all

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analyses (tables 2.4, S14.6; tables 2.3, S14.5)56,66 Compared to DPP4is, SGLT2i exposure was

associated with a reduction in the risk of ACM in two studies (tables 2.6, S14.2; tables 2.5,

S14.1)34,44

For canagliflozin (vs. DPP4i, GLP1RA and SUs, compared pairwise), exposure was associated

with a neutral effect on CVD mortality across all comparisons (tables 2.7, S14.9, S11, S12)45

Compared to DPP4i, GLP1RAs and SUs there was a neutral association with ACM as a primary

outcome in all pairwise comparisons.45

Compared to empagliflozin, dapagliflozin exposure was associated with a neutral effect on CVD

death (tables 2.12, S14.12)47 and also vs. DPP4is (tables 2.11, S14.8)64 and OADs (tables 2.10,

S14.7)60.

Dapagliflozin was associated with a reduction in ACM compared to DPP4is in a CVD-REAL sub-

analysis64 and compared to non-dapagliflozin controls (in both the high and low-risk of CVD

populations; tables 2.9, S14.11)49, compared to insulin (in both on-treatment and ITT analyses;

tables 2.8, S14.10) 61and compared to OADs, as part of a composite, in both the ITT and on-

treatment analysis (tables 2.10, S14.7).60

Renal outcomes (acute kidney injury)For SGLT2i class vs. OADs exposure was associated with a reduction of acute kidney injury (AKI)

in the unadjusted models but this effect attenuated in the adjusted models (stable when the

analysis was repeated for individual agents and for both AKI definitions, kidney disease

improving global outcomes (KDIGO) and international classification of diseases (ICD); tables

3.3, S15.3) 43 Versus GLP1RAs, there was a neutral association of SGLT2i exposure (ICD

definition, adjusted and unadjusted models) reduced in those with baseline CVD in sub-analysis

(tables 3.1, S15.1)50 SGLT2i exposure vs. DPP4i was associated with a reduction in the

composite renal outcome (hospitalisation for AKI, starting dialysis or sustained reduction in

estimated glomerular filtration rate (eGFR) <15mL/min/1.73m2) but with no association in

deterioration of chronic kidney disease (CKD) category (tables 3.2, S15.2)34

The renal benefit of SGLT2i exposure, demonstrated in RCTs, appears to be replicated in these

studies, with no elevation in association with AKI34,43,50, although the CIs were wide and all

crossed unity and follow-up time was short, suggesting these studies may be underpowered.

Figure 2 shows the forest plots for these outcomes.

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AmputationFor the SGLT2i class four studies have a point estimate suggesting an increased association with

amputation but with considerable uncertainty. Compared to OADs subgroup analysis (ITT)

suggests an elevated association in men, those on insulin, those not exposed to GLP1RAs, those

with ≥2 CVD risk factors and those with pre-existing renal disease (tables 4.7, S16.7)66. Versus

GLP1RAs, there was an associated elevated risk with subgroup suggesting pre-existing CVD as a

risk factor (but not in other subgroups; tables 4.6, S16.6)50 Compared to DPP4is (but not SUs )

exposure was associated with an increased risk of lower-limb amputation (LLA) (mainly toe and

metatarsal loss), with baseline amputation, insulin use and CKD highlighted as particular risk

factors (tables 4.2, S16.2)52 Versus DPP4is and GLP1RAs there was a neutral association with

LLA (tables 4.5, S16.5). Exposure was associated with an elevated risk of vascular ulcers,

osteomyelitis and peripheral vascular disease (PVD) (proxies for amputation, vs. metformin,

thiazolidinedione (TZD)s and SUs, but not DPP4is/GLP1RAs, data not shown (DNS)) 35 The

remaining three SGLT2i class studies suggest a neutral association with amputation compared

to DPP4i (tables 4.3, S16.3; tables 4.1, S16.1; tables 4.4, S16.4)33,37,44 with previous amputation

being a risk factor for future amputation in one study 33.

Canagliflozin was compared to non-SGLT2i agents, which showed a neutral association,

although follow-up was short (tables 4.8, S16.8)68 For dapagliflozin compared to non-

dapagliflozin controls, exposure was associated with a neutral association for LLA (but the 95%

CIs were wide) (tables 4.9, S16.9)59

For amputation, four comparisons had a neutral or reduced association37,52,68, but only one study

(vs. SU) did not cross unity37. Eight comparisons yielded an effect estimate suggesting an

increased association of SGLT2i exposure with amputation32,35,44,50,52,59, with two comparisons not

crossing unity (vs. DPP4i52 and vs. GLP1RA50). Many of the CIs were wide, suggesting the studies

may have been underpowered. On balance, there appears to be a signal for elevated LLA risk

following SGLT2i exposure, but with significant uncertainty, which may be modulated by

baseline characteristics and comparator drug chosen.


Diabetic ketoacidosisTwo studies found an increased association with SGLT2i exposure on diabetic ketoacidosis

(DKA) (vs. GLP1RAs tables 5.1, S17.150 and vs. DPPIVI, as a supplemental analysis, tables 5.3,

S17.344). In the former study, no subgroup was at elevated risk except the <65s50.

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Other studies found a neutral association with DKA exposure vs. DPP4i (with neutral but higher

hazard ratio (HR)s in those with microvascular disease and on diuretics; tables 5.2, S17.2)41 and

compared to OADs (tables 5.4, S17.4)67.

Finally, for dapagliflozin (vs. non-dapagliflozin controls) a neutral association was observed for

DKA but with wide 95% Cis (tables 5.5, S17.5) 59

Only one study (vs. GLP1RA) showed an increased association for DKA but with very wide

confidence intervals.50 Of the other four studies, three had an effect estimate suggesting positive

association44,59,67 and one suggesting negative association41, three44,59,67 of these had wide CIs

suggesting the studies may be underpowered.


FractureFour studies explored the association of SGLT2i exposure on fracture risk.38,46,48,50

For SGLT2i class, vs. OADs, a neutral association was observed on fractures overall and in

subgroup analysis (tables 6.2, S18.2)46 Versus GLP1RAs, SGLT2i exposure was associated with a

neutral effect on all fractures and also major osteoporotic fractures (tables 6.1, S18.1)50 For

canagliflozin (vs. GLP1RA) there was a neutral association with fracture risk stable in all

analyses, although follow-up was short (tables 6.3, S18.3)38 For dapagliflozin (vs. unexposed

controls) a neutral association was observed on all fractures and also fragility fractures (tables

6.4, S18.4)48

All of the confidence intervals crossed unity.


Genitourinary infections

Urinary tract infections

For SGLT2i class (vs. GLP1RAs), a neutral association was observed on urinary tract infection

(UTI) risk across all subgroups (tables 7.1, S19.1)50

A study comparing the association of UTI risk of SGLT2i exposure to GLP1RAs and DPP4is found

a neutral association compared to GLP1RA but a reduced risk compared to DPP4is (tables 7.2,

S19.2) 36 Compared to DPP4is alone, SGLT2i exposure was also associated with a neutral risk of

UTI (tables 7.3, S19.3)39 However, another analysis comparing SGLT2i exposure to DPP4i (in

older people) found a reduced association for UTI in both men and women (tables 7.4, S19.4)42

15

Finally, for canagliflozin (vs. non-canagliflozin controls), a neutral association was observed for

UTI and also in sensitivity analysis (tables 7.5, S19.6)53


Genital mycotic infections

For the SGLT2i class, vs. DPP4i, exposure was associated with an increased risk of genital

mycotic infection (GMI) (tables 7.6, S19.3)39 In the same comparison in a different study,

exposure was associated with an increased risk in both men and women, which persisted over

time (tables 7.7, S19.4)42 In a prescription symmetry analysis (using anti-fungal prescriptions as

a proxy for GMI), SGLT2i class exposure was associated with an increased risk of receiving a

prescription for treatment of GMI in both men and women over time but with women receiving

more treatment prescriptions (with the strongest association for canagliflozin) (tables 7.8,

S19.5)32

For canagliflozin, vs. non-canagliflozin controls, there was an elevated association of exposure

with GMI overall, but when men and women were analysed separately only women had an

elevated association (tables 7.9, S19.6)53

All three studies which explored GMI showed a significantly elevated association of SGLT2I

exposure with GMI.39,42,53 There appears to be an increased association for both men and women,

although women may be at greater risk.


HypoglycaemiaFor the SGLT2i class, compared to OAD, exposure was associated with a reduced risk of

hypoglycaemia (tables 8.1, S20.1)54 For dapagliflozin, compared to insulin, the association was

neutral although the CIs were wide(tables 8.4, S20.4)61. However, when compared to DPP4is

(table 8.2, S20.2)64and OAD (tables 8.3, S20.3)60 the associations observed were neutral.


16

PancreatitisAlthough T2D itself raises the risk of pancreatitis, the one study we identified exploring the of

SGLT2i exposure compared to GLP1RA (which may be associated with increased risk) a neutral

association was observed in all analyses (tables 9.1, S21)50

Venous ThromboembolismDue to the diuretic effect of SGLT2i agents, it had been proposed that exposure may lead to

haemoconcentration, and hence to elevated risk of venous thromboembolism (VTE). The one

study we found exploring SGLT2i exposure (compared to GLP1RAs) on VTE risk found a neutral

association in the population overall and in all subgroups (tables 10.1, S22)50

17

Discussion

This study adds rich data on the CVD effectiveness of SGLT2i agents for T2D in broad

populations, including people ineligible for CVOT participation, and examines a wide variety of

safety outcomes. The CVOTs compared SGLT2i exposure to placebo (usual care). However,

many of the studies we identified enable exploration of head-to-head comparative effectiveness.

There was broad heterogeneity in outcomes, comparators and study design.

In order to contextualise the discussion Table 11 contains the evidence generated from RCTs (or

other sources) related to the outcomes reported.

Quality scores ranged widely (10-22/31). No studies reported blinding their data analysts and

few had power calculations. It was also often unclear whether subgroup analysis had been pre-

planned or done post-hoc.

Cardiovascular disease and mortality

From RCT data, empagliflozin and canagliflozin reduce MACE, but dapagliflozin does not.2,3,5

None of the agents reduce non-fatal MI or stroke. 2,3,5 Only empagliflozin reduces CV mortality

and ACM, the other agents reduce neither.2,3,5 All three agents reduce HHF. 2,3,5

No studies we found were associated with an increased risk of CVD, suggesting CV safety. The

studies we found were either associated with a reduction in CVD or a neutral effect. Multiple

(but not all) studies suggest that this benefit might extend to primary as well as secondary CVD

prevention (a key area of uncertainty in the CVOTs).54,57,58 The majority of studies we identified

exploring HF/HHF suggest that SGLT2i exposure is associated with a reduction in this outcome.

These findings confirm and extend HF reduction as a major benefit of SGLT2i exposure to

populations with broader baseline HF and CVD risk profiles. It follows that the effect of SGLT2i

on CVD is differential depending on the outcome being observed, where almost all studies

exploring HF/HHF reported a negative association with this outcome whereas only half the

studies exploring MI showed an associated reduction. However, this is not unexpected, where

RCT data shows that all SGLT2i reduce HHF whereas none reduce MI.

Whilst it is challenging to infer what proportion of the populations, in the studies we found,

would have been eligible for inclusion in the CVOTs, examination of the baseline IHD suggests

that the studies identified included a larger proportion of people at lower CVD risk.

18

The studies we identified suggest a neutral or reduced association with mortality (CV and ACM).

An area of controversy is whether or not the CVD benefits of SGLT2 inhibition extends to those

with better glycaemic control than the inclusion criteria in the CVOTs. The DAPA-HF trial

showed CV benefit in those with and without T2D.4 However our included studies which

adjusted for baseline HbA1c returned neutral associations for CVD outcomes45,49,62, except one34.

We were unable to assess whether SGLT2i ought to be introduced earlier in the treatment of

T2D as no studies explored this, likely because SGLT2is are still recommended as ‘>1st-line’

therapy.

Safety outcomes/adverse eventsThe current regulatory position on SGLT2i safety is as follows. EMA has issued SGLT2i class-

wide warnings for DKA and amputation.69,70 Medicines and Healthcare products Regulatory

Agency (MHRA) and FDA have issued class-wide warnings for Fournier’s gangrene.71,72 FDA has

recently removed a warning for amputation from canagliflozin73 (the only SGLT2i with this

warning) but continues to warn about AKI for dapagliflozin and canagliflozin only74 and for DKA

and UTI class-wide75. The British National Formulary (BNF) recommends monitoring renal

function before and periodically after SGLT2i treatment initiation.76

The studies we found did not suggest an increased risk of AKI (in any definition of AKI

employed).34,43,50

On balance, there appears to be a signal for elevated LLA risk following SGLT2i exposure, but

with considerable uncertainty.32,35,37,44,50,52,59,68 Studies with longer follow-up are needed to

address this uncertainty and to better identify subgroups at risk of amputation harm, if at all.

Since LLA can occur at different levels and be a recurrent event, which in some cases might

occur in quick succession in the same individual, amputation can be a challenging outcome to

capture. However, most studies we identified either explored incident events35,59,66,68,77 (and

censored on amputation occurrence) or conducted sensitivity analysis excluding prevalent

amputation (which did not change the effect estimate)33,50,52. Only one study included prevalent

amputation and did not adjust for this (but did include prior amputation in the propensity

score).44 We believe that both users and clinicians should remain vigilant for, and regulators

should continue to warn about, this adverse event.

From the studies identified41,44,50,59,67 there is considerable uncertainty as to the association of

SGLT2is with DKA and clinicians and users ought to have a high index of suspicion for this

outcome particularly in hospitalised patients (MHRA currently recommends ‘interrupt

19

treatment with SGLT2i in patients who are hospitalised for major surgery or acute serious

illnesses’78). The gold standard for identification of DKA is through biochemical parameters, but

the studies we identified used ICD or Systematized Nomenclature Of MEDicine clinical terms

(SNOMED) codes giving rise to the possibility of misclassification. The role of incomplete DKA

case ascertainment, intercurrent illness and insulin exposure (especially rapid dose reduction

following post-SGLT2i exposure) ought to be explored further as must the possibility of cases

being misclassified as type 1 Diabetes Mellitus (T1D). We believe regulators should continue to

warn about this adverse effect.

Although an association of SGLT2i with fractures cannot be ruled out, the evidence we found is

reassuring.38,46,48,50 However, if the mechanism of fracture is due to reduced bone mineral

density10 (rather than falls caused by hypovolaemia, which would occur rapidly after exposure)

then it remains possible that insufficient person-years’ exposure have accumulated to detect

fragility fractures.

Although diabetes itself appears to elevate the risk of UTI79, the associated risk following SGLT2i

exposure appears minimal from the studies we found. 36,39,42,50,53

On the basis of these data, SGLT2i exposure does appear to be associated with increased risk of

GMI in both men and women, likely due to the glycosuria caused by SGLT2is. 39,42,53 Users should

be warned of the risk of this adverse effect.

Given that SGLT2i agents are insulin-independent, it is not surprising that they do not appear to

be associated with hypoglycaemia. 54,60,61,64 However, it is important to understand, when

SGLT2i agents are added to therapy that do cause hypoglycaemia (e.g. insulin and SUs), whether

exposure increases or decreases the risk and this question remains unanswered by the data we

found.

Strengths and limitationsTo our knowledge, this is the first systematic review of population-based observational studies

looking at effectiveness in terms of CV/mortality outcomes and safety of SGLT2i agents in T2D.

We identified studies from many countries and involved informationists to use appropriate

search terms. The quality of the included studies is reported.

Given the heterogeneity of the studies both in terms of outcome definition, population,

confounding control and analysis method, making generalised conclusions about these data is

challenging.

20

As with all observational data exploring interventions, the studies included may be subject to

unmeasured confounding and bias, particularly misclassification bias.27 Observational

pharmacoepidemiology is also subject to allocation bias/confounding-by-indication, although

most of the included studies used modern methods to control for this (e.g. propensity score-

matched (PSM)). Nevertheless, the effectiveness estimates may be biased or confounded both in

terms of direction and order of magnitude and in some cases may be entirely explained away by

these; cautious interpretation is required.

For effectiveness studies, when observational pharmacoepidemiology studies conflict with RCT

data, they should be viewed as hypothesis-generating and the trial results preferred. RCTs often

do not include a hypothesis for harm, nor are they powered to detect safety.27 For safety,

observational pharmacoepidemiology remains an important tool to enumerate the risks,

especially when RCTs allude to an increased risk of harm due to numerical imbalances (which

could be true or due to chance).

There was over representation of certain data sources, e.g. Truven Health Analytics, which

depending on the comparison and analysis methods chosen sometimes yielded different results

for the same outcome, e.g. 33,35

A major challenge was the variety of composite end-points in the studies identified, particularly

for CVD, making comparisons challenging. While composite primary end-points are useful for

increasing the power of a study to detect change (by increasing the events counted towards the

primary end-point) it would be helpful if future studies emulated the composite outcomes

reported in the cardiovascular outcomes’ trials.80 This would be useful for comparing identified

studies between each other and also to RCT data.

We identified studies with potentially useful data in the form of letters to journals, which was

one of our exclusion criteria (as it is unclear if these studies underwent peer-review).81–83 In the

case of Dave’s letter, this identifies Fournier’s gangrene as a potential complication of SGLT2i

exposure.82 This adverse event is warned about by both MHRA and FDA.71,72 We deliberately

excluded disproportionality reporting ratio studies based on interrogating adverse event

reporting databases due to the high-risk of bias, especially once an adverse event becomes

known. However, skin photosensitivity84 and Fournier’s gangrene85 both emerged as potential

harms from disproportionality reporting ratio studies and should continue to be monitored for.

There were a lack of studies identified exploring bladder and breast cancer, which are known

concerns regarding SGLT2i exposure.86

Many of the studies were commercially funded, which raises the possibility of commercial bias.

21

Despite considerable effort on our part to identify eligible studies systematically (including the

manual searching of references), it remains possible that we overlooked potentially suitable

studies and we omitted non-English language publication due to resource limitation. Although

the search terms we employed should detect observational studies conforming to the

‘Strengthening The Reporting of OBservational studies in Epidemiology’ (STROBE) items on

publication title and abstract, studies not conforming would be missed (although non-

conforming could be considered a marker of poor quality).

Meta-analytic methods were not utilised in this study because due to axiomatic breaches of the

assumptions underpinning these, such as diversity of comparators, studies undertaken in the

same data sources (leading to double counting of events) and a wide variety of methodologies

rendering the associated treatment effect estimate uncombinable. We were keen not to give a

false illusion of precision.

This systematic review provides a comprehensive view of the association of SGLT2is on a wide

variety of CV/motality effectiveness and safety outcome in broad and unselected populations,

generalisable to day-to-day practice. This should be of extensive interest to people living with

T2D, their care providers and healthcare policy makers.

AcknowledgementsWe would like to thank Ruth Jenkins at the University of Edinburgh Library and the Information

and Resource Department of the Defence Medical Academy for their assistance with searching.

TC acknowledges the support of Diabetes UK via his ‘Sir George Alberti’ fellowship: 18/005786.

RMR acknowledges the support of the British Heart Foundation (RE/18/5/34216). Compliance

with Ethics Guidelines: This article is based on previously conducted studies and does not

contain any new studies with human participants or animals performed by any of the authors.

No funding or sponsorship was received for this study or publication of this article. The Rapid

Service Fee will be paid for out of funds from the University of Edinburgh set aside for this

purpose. All data generated or analysed during this study are included in this published

article/as supplementary information files.

Author Contribution Statement TMC and AMG conceived, designed and executed this study. KO and SM provided critical

manuscript revision and restructuring, figure and table construction and approved the final

version. RMG helped conceive the study question, contributed to the methods, provided critical

input to the manuscript and approved the final version. SHW and RMR critically reviewed the

draft manuscript and approved the final version. DJW provided manuscript review/editing,

22

expert clinical pharmacology opinion and research supervision. HMC provided expert

pharmacoepidemiology opinion and research supervision.

Disclosures/Conflicts of InterestThe authors report disclosures or no conflicts of interest.

23

References1 Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-

of-the-art review. Diabetologia 2018; 61: 2108–2117.

2 Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM 2015; 373: 2117–2128.

3 Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. NEJM 2019; 380: 347–57.

4 McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. NEJM 2019; 381: 1995–2008.

5 Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. NEJM 2017; 377: 644–657.

6 Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. NEJM 2019; 380: 2295–2306.

7 Alba M, Xie J, Fung A, Desai M. The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus. Curr Med Res Opin 2016; 32: 1375–1385.

8 Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med 2013; 11: 43.

9 Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier gangrene associated with sodium–glucose cotransporter-2 inhibitors. Ann Intern Med 2019; 170: 764–769.

10 Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab 2016; 101: 44–51.

11 Cefalu WT, Leiter LA, Yoon K-H, Arias P, Niskanen L, Xie J et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. The Lancet 2013; 382: 941–950.

12 Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2012; 2: e001007.

13 Girman CJ, Kou TD, Cai B, Alexander CM, O’Neill EA, Williams-Herman DE et al. Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes. Diabetes Obes Metab 2010; 12: 766–771.

14 Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013; 27: 473–478.

15 Khouri C, Cracowski J-L, Roustit M. SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect? Diabetes Obes Metab 2018; 20: 1531–1534.

24

16 Kohler S, Kaspers S, Salsali A, Zeller C, Woerle HJ. Analysis of fractures in patients with type 2 diabetes treated with empagliflozin in pooled data from placebo-controlled trials and a head-to-head study versus glimepiride. Diabetes Care 2018; 41: 1809–1816.

17 Kumar S, Costello AJ, Colman PG. Fournier’s gangrene in a man on empagliflozin for treatment of Type 2 diabetes. Diabet Med 2017; 34: 1646–1648.

18 Ljunggren Ö, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab 2012; 14: 990–999.

19 Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med 2012; 44: 375–393.

20 Nauck MA, Prato SD, Meier JJ, Durán-García S, Rohwedder K, Elze M et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34: 2015–2022.

21 Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care 2009; 32: 834–838.

22 Nyirjesy P, Zhao Y, Ways K, Usiskin K. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin 2012; 28: 1173–1178.

23 Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium–glucose cotransporter 2 inhibition. Diabetes Care 2015; 38: 1687–1693.

24 Tang HL, Li DD, Zhang JJ, Hsu YH, Wang TS, Zhai SD et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 2016; 18: 1199–1206.

25 Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016; 101: 157–166.

26 Wilding JPH, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin. Ann Intern Med 2012; 156: 405–415.

27 Caparrotta TM, Dear JW, Colhoun HM, Webb DJ. Pharmacoepidemiology: Using randomised control trials and observational studies in clinical decision making. ‐ Br J Clin Pharmacol 2019; : bcp.14024.

28 Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1979- 1998; 52: 377–384.

25

29 Hootman JM, Driban JB, Sitler MR, Harris KP, Cattano NM. Reliability and validity of three quality rating instruments for systematic reviews of observational studies. Res Synth Methods 2011; 2: 110–118.

30 Berlin JA, Crowe BJ, Xia HA, Evans SJW. The Use of Metaanalysis in Pharmacoepidemiology. In: Pharmacoepidemiology. John Wiley & Sons, Ltd, 2019, pp 897–947.

31 Chapter 13: Assessing risk of bias due to missing results in a synthesis. Cochrane Train. https://training.cochrane.org/handbook/current/chapter-13 (accessed 29 Jul2020).

32 Adimadhyam S, Schumock GT, Calip GS, Marsh DES, Layden BT, Lee TA. Increased risk of mycotic infections associated with sodium–glucose co-transporter 2 inhibitors: a prescription sequence symmetry analysis. Br J Clin Pharmacol 2019; 85: 160–168.

33 Adimadhyam S, Lee TA, Calip GS, Marsh DES, Layden BT, Schumock GT. Risk of amputations associated with SGLT2 inhibitors compared to DPP-4 inhibitors: A propensity-matched cohort study. Diabetes Obes Metab 2018; 20: 2792–2799.

34 Cahn A, Melzer-Cohen C, Pollack R, Chodick G, Shalev V. Acute renal outcomes with sodium-glucose co-transporter-2 inhibitors: Real-world data analysis. Diabetes Obes Metab 2019; 21: 340–348.

35 Chang H-Y, Singh S, Mansour O, Baksh S, Alexander GC. Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes. JAMA Intern Med 2018; 178: 1190–1198.

36 Dave CV, Schneeweiss S, Kim D, Fralick M, Tong A, Patorno E. Sodium-glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections. Ann Intern Med 2019; 171: 248–256.

37 Dawwas GK, Smith SM, Park H. Cardiovascular outcomes of sodium glucose cotransporter-2 inhibitors in patients with type 2 diabetes. Diabetes Obes Metab 2019; 21: 28–36.

38 Fralick M, Kim SC, Schneeweiss S, Kim D, Redelmeier DA, Patorno E. Fracture risk after initiation of use of canagliflozin: A cohort study. Ann Intern Med 2019; 170: 155.

39 Gadzhanova S, Pratt N, Roughead E. Use of SGLT2 inhibitors for diabetes and risk of infection: Analysis using general practice records from the NPS MedicineWise MedicineInsight program. Diabetes Res Clin Pract 2017; 130: 180–185.

40 Kim Y-G, Han SJ, Kim DJ, Lee K-W, Kim HJ. Association between sodium glucose co-transporter 2 inhibitors and a reduced risk of heart failure in patients with type 2 diabetes mellitus: a real-world nationwide population-based cohort study. Cardiovasc Diabetol 2018; 17: 91.

41 Kim Y-G, Jeon JY, Han SJ, Kim DJ, Lee K-W, Kim HJ. Sodium-glucose co-transporter-2 inhibitors and the risk of ketoacidosis in patients with type 2 diabetes mellitus: A nationwide population-based cohort study. Diabetes Obes Metab 2018; 20: 1852–1858.

42 Lega IC, Bronskill SE, Campitelli MA, Guan J, Stall NM, Lam K et al. Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: A population-based study of older women and men with diabetes. Diabetes Obes Metab 2019; 21: 2394–2404.

26

43 Nadkarni GN, Ferrandino R, Chang A, Surapaneni A, Chauhan K, Poojary P et al. Acute kidney injury in patients on SGLT2 inhibitors: a propensity-matched analysis. Diabetes Care 2017; 40: 1479–1485.

44 Pasternak B, Ueda P, Eliasson B, Svensson A-M, Franzén S, Gudbjörnsdottir S et al. Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study. BMJ 2019; 366: l4772.

45 Patorno E, Goldfine AB, Schneeweiss S, Everett BM, Glynn RJ, Liu J et al. Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. BMJ 2018; 360: k119.

46 Schmedt N, Andersohn F, Walker J, Garbe E. Sodium-glucose co-transporter-2 inhibitors and the risk of fractures of the upper or lower limbs in patients with type 2 diabetes: A nested case–control study. Diabetes Obes Metab 2019; 21: 52–60.

47 Shao S-C, Chang K-C, Hung M-J, Yang N-I, Chan Y-Y, Chen H-Y et al. Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study. Cardiovasc Diabetol 2019; 18: 120.

48 Toulis KA, Bilezikian JP, Thomas GN, Hanif W, Kotsa K, Thayakaran R et al. Initiation of dapagliflozin and treatment-emergent fractures. Diabetes Obes Metab 2018; 20: 1070–1074.

49 Toulis KA, Willis BH, Marshall T, Kumarendran B, Gokhale K, Ghosh S et al. All-cause mortality in patients with diabetes under treatment with dapagliflozin: a population-based, open-cohort study in The Health Improvement Network database. J Clin Endocrinol Metab 2017; 102: 1719–1725.

50 Ueda P, Svanström H, Melbye M, Eliasson B, Svensson A-M, Franzén S et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ 2018; 363: k4365.

51 Weeda ER, Cassarly C, Brinton DL, Shirley DW, Simpson KN. Loop diuretic use among patients with heart failure and type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors. J Diabetes Complications 2019; 33: 567–571.

52 Yang JY, Wang T, Pate V, Gower EW, Crowley MJ, Buse JB et al. Sodium-glucose co-transporter-2 inhibitor use and risk of lower-extremity amputation: Evolving questions, evolving answers. Diabetes Obes Metab 2019; 21: 1223–1236.

53 Amos TB, Montejano L, Juneau P, Bolge SC. Healthcare costs of urinary tract infections and genital mycotic infections among patients with type 2 diabetes mellitus initiated on canagliflozin: a retrospective cohort study. J Med Econ 2017; 20: 303–313.

54 Birkeland KI, Jørgensen ME, Carstensen B, Persson F, Gulseth HL, Thuresson M et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol 2017; 5: 709–717.

55 Gautam S, Agiro A, Barron J, Power T, Weisman H, White J. Heart failure hospitalization risk associated with use of two classes of oral antidiabetic medications: an observational, real-world analysis. Cardiovasc Diabetol 2017; 16: 93.

27

56 Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J et al. Cardiovascular events associated with sglt-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL 2 study. J Am Coll Cardiol 2018; 71: 2628–2639.

57 Kosiborod M, Birkeland KI, Cavender MA, Fu AZ, Wilding JP, Khunti K et al. Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: Results from the CVD-REAL study. Diabetes Obes Metab 2018; 20: 1983–1987.

58 Kosiborod Mikhail, Cavender Matthew A., Fu Alex Z., Wilding John P., Khunti Kamlesh, Holl Reinhard W. et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs. Circulation 2017; 136: 249–259.

59 McGurnaghan SJ, Brierley L, Caparrotta TM, McKeigue PM, Blackbourn LAK, Wild SH et al. The effect of dapagliflozin on glycaemic control and other cardiovascular disease risk factors in type 2 diabetes mellitus: a real-world observational study. Diabetologia 2019; 62: 621–632.

60 Norhammar A, Bodegård J, Nyström T, Thuresson M, Nathanson D, Eriksson JW. Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE-TIMI 58 trial: A nationwide observational study. Diabetes Obes Metab 2019; 21: 1136–1145.

61 Nyström T, Bodegard J, Nathanson D, Thuresson M, Norhammar A, Eriksson JW. Novel oral glucose-lowering drugs are associated with lower risk of all-cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes. Diabetes Obes Metab 2017; 19: 831–841.

62 O’Brien MJ, Karam SL, Wallia A, Kang RH, Cooper AJ, Lancki N et al. Association of second-line antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes. JAMA Netw Open 2018; 1: e186125–e186125.

63 Patorno Elisabetta, Pawar Ajinkya, Franklin Jessica M., Najafzadeh Mehdi, Déruaz-Luyet Anouk, Brodovicz Kimberly G. et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation 2019; 139: 2822–2830.

64 Persson F, Nyström T, Jørgensen ME, Carstensen B, Gulseth HL, Thuresson M et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study. Diabetes Obes Metab 2018; 20: 344–351.

65 Ryan PB, Buse JB, Schuemie MJ, DeFalco F, Yuan Z, Stang PE et al. Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab 2018; 20: 2585–2597.

66 Udell Jacob A., Yuan Zhong, Rush Toni, Sicignano Nicholas M., Galitz Michael, Rosenthal Norman. Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor. Circulation 2018; 137: 1450–1459.

28

67 Wang Y, Desai M, Ryan PB, DeFalco FJ, Schuemie MJ, Stang PE et al. Incidence of diabetic ketoacidosis among patients with type 2 diabetes mellitus treated with SGLT2 inhibitors and other antihyperglycemic agents. Diabetes Res Clin Pract 2017; 128: 83–90.

68 Yuan Z, DeFalco FJ, Ryan PB, Schuemie MJ, Stang PE, Berlin JA et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. Diabetes Obes Metab 2018; 20: 582–589.

69 Anonymous. SGLT2 inhibitors - DKA. Eur. Med. Agency. 2018.https://www.ema.europa.eu/en/medicines/human/referrals/sglt2-inhibitors (accessed 14 Oct2020).

70 Anonymous. SGLT2 inhibitors (previously canagliflozin) - Amputation. Eur. Med. Agency. 2018.https://www.ema.europa.eu/en/medicines/human/referrals/sglt2-inhibitors-previously-canagliflozin (accessed 14 Oct2020).

71 Research C for DE and. FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. FDA. 2019.https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes (accessed 14 Oct2020).

72 SGLT2 inhibitors: reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum). GOV.UK. https://www.gov.uk/drug-safety-update/sglt2-inhibitors-reports-of-fournier-s-gangrene-necrotising-fasciitis-of-the-genitalia-or-perineum (accessed 14 Oct2020).

73 Research C for DE and. FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). FDA. 2020.https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin (accessed 14 Oct2020).

74 Research C for DE and. FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). FDA 2019.https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-kidney-warnings-diabetes-medicines-canagliflozin (accessed 3 Jul2020).

75 Research C for DE and. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. FDA. 2020.https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious (accessed 14 Oct2020).

76 BNF: British National Formulary - NICE. https://bnf.nice.org.uk/ (accessed 14 Oct2020).

77 Dawwas GK, Smith SM, Park H. Cardiovascular outcomes of sodium glucose cotransporter-2 inhibitors in patients with type 2 diabetes. Diabetes Obes Metab 2019; 21: 28–36.

78 SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis. GOV.UK. https://www.gov.uk/drug-safety-update/sglt2-inhibitors-updated-advice-on-the-risk-of-diabetic-ketoacidosis (accessed 19 Oct2020).

29

79 Ribera MC, Pascual R, Orozco D, Pérez Barba C, Pedrera V, Gil V. Incidence and risk factors associated with urinary tract infection in diabetic patients with and without asymptomatic bacteriuria. Eur J Clin Microbiol Infect Dis 2006; 25: 389–393.

80 Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol 2016; 183: 758–764.

81 Abrahami D, Douros A, Yin H, Yu OHY, Azoulay L. Sodium–glucose cotransporter 2 inhibitors and the risk of fractures among patients with type 2 diabetes. Diabetes Care 2019; 42: e150–e152.

82 Dave CV, Schneeweiss S, Patorno E. Association of sodium-glucose cotransporter 2 inhibitor treatment with risk of hospitalization for fournier gangrene among men. JAMA Intern Med 2019; 179: 1587–1590.

83 Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an sglt2 inhibitor (letter). http://dx.doi.org.ezproxy.is.ed.ac.uk/10.1056/NEJMc1701990. 2017. doi:10.1056/NEJMc1701990.

84 Raschi E, Parisotto M, Forcesi E, La Placa M, Marchesini G, De Ponti F et al. Adverse events with sodium-glucose co-transporter-2 inhibitors: A global analysis of international spontaneous reporting systems. Nutr Metab Cardiovasc Dis 2017; 27: 1098–1107.

85 Fadini GP, Sarangdhar M, Ponti FD, Avogaro A, Raschi E. Pharmacovigilance assessment of the association between Fournier’s gangrene and other severe genital adverse events with SGLT-2 inhibitors. BMJ Open Diabetes Res Care 2019; 7: e000725.

86 Scheen AJ. An update on the safety of SGLT2 inhibitors. Expert Opin Drug Saf 2019; 18: 295–311.

87 Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. The Lancet 2019; 393: 31–39.

88 Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M et al. Empagliflozin and progression of kidney disease in type 2 diabetes. NEJM 2016; 375: 323–334.

89 Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 2017; 19: 348–355.

30

TablesTable 1: CVD study summary

Exposure/Study Number

Study Summary

SGLT2i Class

1.1 The large, 2017 main CVD-REAL cohort study explored the association of SGLT2i class exposure vs. OADs on HHF (primary

outcome and composite component).58. SGLT2i exposure was associated with a reduction in the CVD composite of ACM and

HHF (table S6.3) and with ACM (table S14.3) and HHF (table S10.7) composite components alone with narrow CIs and

authors suggest benefit may extend to primary prevention of HHF (although subgroup analysis on the basis of pre-existing

CVD was not presented).

1.2 A large 2018 CVD-REAL sub-analysis explored the association of SGLT2i class vs. OAD on stroke and MI events.57 SGLT2i

exposure was associated with a reduction in the risk of stroke in all analyses (table S9.6) and a neutral association the risk of

MI (reduced in the on-treatment cohort but not in the ITT cohort, table S8.6) and suggests that the benefit may extend to

primary prevention of these outcomes (although this subgroup analysis is not presented). The CIs were narrow.

1.3 A further large 2017 CVD-REAL sub-analysis investigated the effect of SGLT2i class vs. OADs on CVD.54. SGLT2i exposure was

associated with a reduction in MACE (primary prevention-only, table S7.2) and HF (primary and secondary prevention, table

S10.10), and a neutral association in non-fatal stroke and non-fatal MI (table S9.5 and table S8.5) with no effect on the

negative control, atrial fibrillation. The MACE benefit appeared greatest in those ≥65y (DNS) and CIs were narrow for all

outcomes.

31


Study Summary

1.4 CVD-REAL 2 was a large 2018 cohort study exploring the association of SGLT2i class exposure vs. OADs on HHF, MI and

stroke.56 SGLT2i exposure was associated with a reduction in HHF (table S10.9), MI (table S8.4), stroke (table S9.4) and the

composite of HHF and death (table S6.4) in all analyses. The CIs were narrow. The effect remained consistent in pre-planned

subgroup analysis of those without pre-existing CVD (DNS).

1.5 A small 2017 American cohort study explored the association of SGLT2i class vs. DPP4i exposure on HHF.55 SGLT2i exposure

was associated with a reduction in HHF in the PS-matched, IPTW and MSM models with narrow CIs (table S10.4). This

association was driven mainly by findings among people ≥65y and/or with pre-existing diabetes complications (DNS).

1.6 A medium-sized 2018 American cohort study explored the association between SGLT2i class vs. non-SGLT2i AHDs on MACE,

HHF, non-fatal stroke and non-fatal MI.66 SGLT2i exposure in the ITT analysis was associated with a reduction the primary

composite outcome of ACM and HHF (table S6.5), the HHF component alone (table S10.6) and the secondary outcome of

MACE overall (table S7.3) but a neutral association with the non-fatal MI (table S8.7) and non-fatal stroke (table S9.7)

components when analysed individually. The associated effects reported in the ITT analysis were amplified in the on-

treatment analysis (DNS). All CIs were narrow. The results remained consistent in all the pre-planned subgroup analyses,

including with and without pre-existing CVD, suggesting an associated benefit in both primary and secondary prevention

(DNS).

1.7 A large 2018 South Korean cohort study investigated the association of SGLT2i class exposure vs. DPP4i on HHF.40. SGLT2i

exposure was associated with a reduction in HHF in all time periods analysed up to 3 years post-initiation in the whole

population and in the secondary prevention population with varying CI width (a duration response-effect) but not in the

32


Study Summary

primary prevention population with the associated reduction in HHF only apparent in time periods >1-year post-exposure

(lagged duration response-effect) (table S10.5).

1.8 A medium-sized 2018 American cohort study explored the association of SGLT2i class vs. DPP4i on HHF, stroke, IHD and

hospitalised PVD (negative control: schizophrenia).62 SGLT2i exposure was associated with a neutral effect for all outcomes

including negative control (table S6.2, S10.3, S9.2, S8.1). The CIs were wide. These findings remained stable irrespective of

baseline HbA1c and prior metformin-use and also in the maximally-adjusted and time-varying model (DNS).

1.9 A large 2019 American cohort study explored the association of SGLT2i class vs. SUs and DPP4is.37. Versus SUs, SGLT2i

exposure was associated with a lower risk of MI, HHF and stroke with a reduction also observed in the composite of MI and

stroke. Versus DPP4is, SGLT2i exposure was associated with a reduction in HHF, MI, stroke with a reduction also observed in

the composite of MI and stroke, all CIs were narrow (all comparisons in tables S6.1, S10.1, S9.1, S8.3). The associated effect

persisted in sensitivity analyses in the <65s but not the ≥65s, but the associated reduction in CVD and HHF remained when

the primary/secondary CVD prevention groups and individual agents were analysed separately (DNS).

1.10 A medium-sized 2019 Scandinavian cohort study explored the association of SGLT2i class vs. DPP4i on primary/secondary

prevention of MACE, HHF, incident MI and stroke.44 SGLT2i-use in the ITT analysis was associated with a reduction in the risk

of HHF (in those with and without a history of HF but only in those with pre-existing CVD, when analysed separately) an also

an associated neutral effect on MACE and its components (in both primary/secondary CVD prevention)(tables S10.2, S9.3,

S8.2, S7.1). CIs were narrow. The on-treatment analysis was associated with a reduction in MACE, but not in AMI and stroke

(driven by a reduction in CVD mortality) while the reduction in HF was amplified (DNS). ≥65y individuals saw an associated

33


Study Summary

reduction in both MACE and HHF versus <65s (DNS), who did not.

1.11 A small 2019 American cohort study explored the association of SGLT2i class vs. OAD in those with a diagnosis of HF, using

loop-diuretic prescriptions as a proxy for HF symptomatic severity.51. SGLT2i exposure was associated with a reduction in

new loop-diuretic use but no change in diuretic-use in those already exposed (table S10.8).

Empagliflozin

1.12 A medium-sized 2019 American cohort study explored the association of empagliflozin vs. sitagliptin on HHF.63 In the

population overall there was a reduction in HHF associated with empagliflozin exposure, greater in the broad definition of

HHF (HHF mentioned anywhere on discharge, DNS) compared to specific one (HHF in primary position of discharge, table

S10.15). In subgroup analyses (pre-existing CVD, HF, sex and empagliflozin dose), the associated reduction for the broad

HHF definition remained stable and demonstrated a dose response-effect but not for the specific definition (CVD subgroups

in table S10.15, other DNS). The CIs were wide. There was no association with negative control outcome, seasonal flu

vaccination.

Canagliflozin

1.13 A large 2018 American study investigated the association of canagliflozin exposure vs. all non-SGLT2i-users and also vs.

select non-SGLT2i (DPP4i, GLP 1RA, TZD, SU and insulin) and head-to-head with other SGLT2is (followed by other all ‐SGLT2is vs. non-SGLT2i) on the association with HHF.65 supplementary table S13 for baseline characteristics in each of the

datasets. In the on-treatment analysis, a reduced association with HHF was observed in canagliflozin vs. all non-SGLT2i

comparison (primary outcome) with narrow CIs, canagliflozin vs. select non-SGLT2is comparison and SGLT2is vs. non-

34


Study Summary

SGLT2is but not for canagliflozin head-to-head with other SGLT2is (table S10.16). This attenuated in the ITT analysis (DNS).

In those with established CVD (75% of the post-index events), there was also an associated reduction with canagliflozin vs.

AHDs but not head-to-head with other SGLT2is, suggesting a class effect (DNS).

1.14 A medium-sized 2018 American cohort study explored the association of canagliflozin vs. DPP4i, GLP1RA and SUs (analysed

separately) on HHF (primary event-based outcome and diuretic-use as a proxy) and a CVD composite of MI and

stroke(secondary outcome)(supplementary tables S11 and S12).45. Canagliflozin was associated with a risk reduction for HHF

(table S10.12) and diuretic-use in all comparisons and a neutral effect for the composite CVD end-point (table S6.6) and the

individual components of the composite (MI table S8.10; stroke table S9.10, other DNS) in both primary and secondary CVD

prevention. The CIs were narrow. The on-treatment and baseline HbA1c-adjusted analyses yielded the same results (DNS).

Dapagliflozin

1.15 An unmatched medium-sized 2019 Taiwanese cohort study explored the association of dapagliflozin head-to-head with

empagliflozin on the composite of CV mortality, MI, stroke and HHF (negative control: incident AF).47 Dapagliflozin exposure

was associated with a neutral effect on the composite (table S6.10), MI and stroke, but was associated with a reduction in

HHF compared with empagliflozin (MI table S8.11; stroke table S9.11; HHF table S10.14). This associated reduction remained

stable in standardised mortality analysis, the low dose group and also when adjusting for CVD risk, regardless other CVD

drug exposure (DNS). Both drugs showed a neutral effect on the negative control. The composite CI was narrow, but the

other outcomes CIs were of varying width.

1.16 A medium-sized 2018 CVD-REAL sub-analysis investigated the association of dapagliflozin vs. DPP4i on MACE.64 The on-

35


Study Summary

treatment analysis showed dapagliflozin was associated with a reduced risk of MACE (table S7.4), MACE, unstable angina and

HHF expanded composite (DNS) and HHF alone (table S10.11). For the MACE components there was a neutral effect on non-

fatal MI (table S8.9) and non-fatal stroke (table S9.9). The CIs were narrow throughout. There was also a reduced association

with incident AF. The results remained stable in the ITT analysis but primary/secondary CVD prevention groups were not

analysed separately (DNS).

1.17 A medium-sized 2017 Swedish cohort study explored the effect of dapagliflozin vs. insulin’s association with non-fatal CVD.61

Dapagliflozin exposure was associated with a reduction of non-fatal CVD in the PS-matched and the adjusted model (DNS),

for both the on-treatment (PSM table S6.7) and ITT analyses (DNS). The CIs were narrow. Primary/secondary CVD

prevention was not analysed.

1.18 A small 2017 UK cohort study explored the association between dapagliflozin and unexposed controls on incident CVD

(secondary outcome).49 A neutral association (table S6.8) on incident CVD in the low-risk (of CVD) population was observed

(incident CVD in the overall population not assessed). The CIs were narrow.

1.19 A medium-sized 2019 Swedish cohort study examined the association of dapagliflozin vs. OADs on MACE, HHF, MI, stroke and

AF.60 Dapagliflozin was associated, in the ITT analysis, with a lower risk of HHF (table S10.13) but a neutral association on

MACE (table 7.5,), MI (table S8.8), stroke (table S9.8) and AF. The CIs were narrow. The associated on-treatment effect was

amplified such MACE reduction became significant (DNS).

1.20 A medium-sized 2019 Scottish cohort study explored the association of dapagliflozin exposure vs. non-exposure on CVD

36


Study Summary

(coronary/cerebrovascular disease). 59 This was a secondary analysis. Dapagliflozin was associated with a neutral effect with

narrow confidence intervals on incident CVD in the dose-response analysis (table S6.9).

1.20 A medium-sized 2019 Scottish cohort study explored the association of dapagliflozin exposure vs. non-exposure on CVD

(coronary/cerebrovascular disease). 59 This was a secondary analysis. Dapagliflozin was associated with a neutral effect with

narrow confidence intervals on incident CVD in the dose-response analysis (table S6.9).

37

Table 2: Mortality study summary


Study Summary

SGLT2i class

2.1 The main large 2017 CVD-REAL cohort study explored the association of SGLT2i class exposure vs. OADs on ACM.58

SGLT2i exposure was associated with a reduction in ACM alone with narrow CIs (table S14.3) and also in the composite

with HHF (table S6.3), stable geographically.

2.2 A large 2017 Scandinavian study (CVD-REAL sub-analysis) explored the association of CVD mortality and ACM in

SGLT2i class-exposed vs. OADs. 54 Authors report an association of lower CVD mortality in those exposed to SGLT2i

(table S14.4) in those with and without established CVD, with a greater reduction in the >65s (DNS). There was also a

reduced association with ACM (table S14.4). The CIs were narrow.

2.3 A large 2018 American cohort study explored the association between SGLT2i class vs. non-SGLT2i AHAs on ACM.66

SGLT2i exposure was associated with a reduction in ACM (and also in the composite of ACM and HHF, table S6.5) in the

ITT cohort (table S14.5), stable in the pre-planned subgroup analysis (DNS). The CIs were narrow.

2.4 The large 2018 CVD-REAL 2 cohort study exploring the association of SGLT2i class exposure vs. OADs on ACM.56

SGLT2is were associated with a reduction in the ITT (table S14.6) and on-treatment analyses, in those with and

without established CVD groups (DNS) for ACM alone (table S6.4). The CIs were narrow.

2.5 A medium-sized 2019 Scandinavian cohort study explored the association of SGLT2i class vs. DPP4i on CVD mortality.44

38


Study Summary

SGLT2is showed a neutral association with CVD mortality in the population overall in the ITT analysis (table S14.1) but

a reduced association in the on-treatment analysis (DNS). For ACM, SGLT2i-use was associated with a reduction in the

risk of ACM in the ITT (table S14.1) and on-treatment groups (DNS). The CIs were narrow.

2.6 A medium-sized 2019 Israeli case-control explored the association of SGLT2i class exposure vs. DPP4i on ACM.34 This

study showed an associated reduction in the odds of ACM in both the crude (DNS) and the adjusted model for SGLT2is

(secondary analysis, table S14.2). The CIs were wide.

Canagliflozin

2.7 A medium-sized 2018 American cohort study comparing canagliflozin exposure pairwise with DPP4i, GLP1RAs and

SUs showed a neutral effect of CVD mortality in all comparisons (table S14.9). These associations remained stable

when adjusted for baseline HbA1c level (DNS).45 For ACM, there was a neutral association with canagliflozin (part of

CVD composite) overall (table S14.9) and in primary/secondary CVD prevention. These associations remained stable

when adjusted for baseline HbA1c level (DNS). The CIs were wide for all comparisons.

Dapagliflozin

2.8 A medium-sized 2017 Swedish study explored the effect of dapagliflozin vs. insulin’s association with ACM.61

Dapagliflozin exposure was associated with a reduced risk of ACM in both those with, with narrow CIs, and without

pre-existing CVD, with wider CIs than those with CVD (table S14.10).

39


Study Summary

2.9 A small 2017 UK cohort study explored the association between dapagliflozin and unexposed controls on ACM.49 There

was an associated reduction in ACM in the both the low-risk (of CVD) population and the population overall for

dapagliflozin with narrow CIs (including those with prevalent CVD) (table S14.11).

2.10 A medium-sized 2019 Swedish cohort study examined the association between dapagliflozin vs. non-SGLT2i OADs on

CVD mortality and ACM.60 Dapagliflozin exposure was associated with a lower risk of CVD mortality (MACE

component) in both the ITT (table S14.7) and on-treatment groups (DNS). For ACM, dapagliflozin was associated with

a lower risk of ACM in both analyses (ITT, table S14.7). The CIs were narrow.

2.11 A medium-sized 2018 CVD-REAL sub-analysis investigated the effect of dapagliflozin vs. DPP4i on CVD mortality

(MACE component) and ACM (single outcome).64 This study showed a neutral association on CVD mortality in the on-

treatment analysis (table S14.8). For ACM there was a reduced association (table S14.8). The results for both outcomes

remained stable in subgroup/sensitivity analysis (DNS). The CIs were narrow.

Dapagliflozin head-to-head with empagliflozin

2.12 A medium-sized 2019 Taiwanese cohort study explored the association of dapagliflozin head-to-head with

empagliflozin for CVD mortality.47 Dapagliflozin showed a neutral association with CVD mortality ((table S14.12) as

part of a composite outcome), with wide confidence intervals, (stable in sensitivity analyses, DNS). The CIs were wide.

40

Table 3: Renal outcomes summary


Study Summary

SGLT2i class

3.1 A medium-sized 2018 Scandinavian study using Sweden and Denmark’s population registers, analysed separately

explored SGLT2i class vs. GLP1RAs’ (only Sweden for the maximally-adjusted model) association with AKI.50 Both the

unadjusted and maximally-adjusted HR showed a neutral association for AKI in those exposed to SGLT2i but both

confidence intervals were wide (table S15.1, figure 2). The CIs were moderately wide. In subgroups analysis, the effects

remained stable except in those with pre-existing CVD, which was associated with a reduction in AKI (DNS).

3.2 A medium-sized 2019 Israeli study explored the deterioration of CKD status and hospitalisation for AKI in those

exposed to SGLT2i class vs. DPP4i.34 SGLT2i exposure was associated with a reduced odds of the composite of

hospitalisation with AKI, initiation of dialysis and sustained eGFR <15 but with no effect on deterioration of CKD

category (table S15.2, figure 2). The CIs were narrow.

3.3 A small 2017 American cohort study compared the use of SGLT2i class vs. OAD, in two separate datasets, analysed

separately, on the association with AKI.43 Two definitions of AKI (KDIGO and ICD) were used and SGLT2i exposure was

associated a reduction AKI in the MS dataset (adjusted and unadjusted) but not the smaller GHS dataset, where the

associated effect attenuated in the adjusted model. (table S15.3, figure 2) The CIs were narrow. These results remained

stable when SGLT2i drugs were analysed individually.

41

Table 4: Amputation study summary


Study Summary

SGLT2i class

4.1 A large 2019 American cohort study compared SGLT2i class exposure vs. DPP4is and SUs on the risk of LLA.37 This

study reported that compared to SUs, SGLT2i-use was associated with a lower risk of LLA but neutral compared to

DPP4is (table S16.1, figure 3). The CIs were narrow.

4.2 A medium-sized 2018 American cohort study compared the hazard of LLA associated with SGLT2i class exposure vs.

DPP4is and SUs.52 The study reports an elevated association of LLA compared to DPP4i and a neutral association

compared to SUs in all analyses with wide CIs for both comparisons . 83% of the overall amputations were of the toe

and metatarsal (table S16.2, figure 3). In subgroup analysis, characteristics associated with an increased LLA risk were

history of amputation, baseline insulin-use and history of CKD in both analyses (but metformin-use and history of CVD-

only in the SU comparison, DNS). Results remained stable in sensitivity analysis, expect for canagliflozin alone, which

had a higher HR (DNS).

4.3 A medium-sized 2018 American cohort study investigated the association of SGLT2i class vs. DPP4i with LLA.33 The

maximally-adjusted HR suggests SGLT2i exposure was associated a neutral effect on risk of LLA (table S16.3, figure 3).

The CIs were wide. Three-quarters of detected amputations occurred at the level of partial foot. In subgroup analysis,

there was a neutral association for increased risk in those ≥65s, with pre-existing PVD or with at ≥1 vascular

complication of diabetes (‘high-risk group’, DNS). The risk of amputation was higher in the dapagliflozin or

42


Study Summary

empagliflozin group than the canagliflozin group and the results remained stable in sensitivity analysis (DNS).

4.4 A medium-sized 2019 Scandinavian study compared association of LLA (as a supplementary analysis) in SGLT2i class

vs. DPP4i. 44. The study reports a neutral association (table S16.4, figure 3). The CIs were wide.

4.5 A medium-sized 2018 American study investigated the association of SGLT2i class vs. GLP1RAs and DPP4i with LLA

with a neutral association in both comparisons (table S16.5, figure 3).35 The CIs were wide. Compared to users of older

T2D drugs (metformin, TZDs and SUs), SGLT2i exposure was associated with an increased risk of vascular ulcers,

osteomyelitis and PVD but not compared to DPP4is/GLP1RA (DNS). Results remained stable in sensitivity analysis,

except that when those with prior amputation were included SGLT2i exposure was associated with increased risk

(DNS).

4.6 A medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP1RA for LLA.50 There was an

increased associated risk of amputation overall (but not toe and metatarsal amputation) in both the whole population

(Sweden and Denmark) and the maximally-adjusted model (Sweden only) (table S16.6, figure 3). The CIs were wide. In

subgroup analysis, the associations remained stable geographically and for sex, although there was an associated

increased risk in <65s and in those with pre-existing CVD (but not previous amputation, DNS).

4.7 A large 2018 American cohort study investigated the association of SGLT2i class vs. non-SGLT2i-initiators with incident

BKA.66 There was an associated increased risk of BKA in the ITT group (DNS) and a neutral association risk of BKA in

the on-treatment group, although the CIs were wide (table S16.7, figure 3). Subgroup analyses suggest an associated

43


Study Summary

elevated risk of BKA in men, those on insulin, those not exposed to GLP1RA, those with ≥2 CV risk factors and in those

with pre-existing renal disease (CIs wider still, DNS).

Canagliflozin

4.8 A large 2018 American cohort study investigated the association between canagliflozin vs. OAD (excluding metformin)

on BKA.68 Authors report a neutral association for risk of amputation (table S16.8, figure 3). The CIs were wide. The

results remained stable in sensitivity analysis (DNS).

Dapagliflozin

4.9 A medium-sized 2019 Scottish study cohort study sought to determine a dose response-effect of dapagliflozin exposure

(vs. non-exposure) on LLA.59. Dapagliflozin was associated with a neutral risk of amputation but with wide CIs (table

S16.9, figure 3).

44

Table 5: DKA study summary


Study Summary

SGLT2i class

5.1 A medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP1RA on DKA.50 SGLT2i

exposure was associated with a neutral risk of DKA in both unadjusted (Sweden and Denmark) and the maximally-

adjusted population (Sweden-only) but with very wide CIs (table 11.1, figure 4). In subgroup analysis, <65s appeared

to be at increased risk of DKA vs. older-users (DNS).

5.2 A large 2019 South Korean study comparing SGLT2i class exposure vs. DPP4i on DKA risk.41 Authors report neutral

association for DKA (with no evidence of a duration response effect, table S17.2, figure 4) and narrow CIs. Subgroup

analysis in those with microvascular disease and those exposed to diuretics had a higher associated HR but remained

non-significant (DNS).

5.3 A medium-sized 2019 Scandinavian study also explored the association of SGLT2i class vs. DPP4i on DKA

(supplementary analysis).44 There was a positive association with DKA (table S17.3, figure 4). The CIs were wide.

5.4 A medium-sized 2017 US study compared SGLT2i class vs. OADs (excluding metformin) on DKA.67 There was a neutral

association for DKA but with extremely wide CIs (broad definition, DNS), which attenuated with a more specific

definition of T2D (table S17.4, figure 4). The specific definition attempted to exclude possible T1D; this reduced the

analysis population by 10% but DKA events by >50%. In the per-protocol sensitivity analysis, SGLT2i exposure was

45


Study Summary

associated with a significant risk of DKA under the broad definition but not in the specific definition (DNS).

Dapagliflozin

5.5 A medium-sized 2019 Scottish study explored the association of dapagliflozin vs. non-exposure on the rates of DKA,

king a dose response effect.59 There was an associated neutral DKA risk but the CIs were wide (table S17.5, figure 4).

46

Table 6: Bone fracture study summary


Study Summary

SGLT2i class

6.1 A medium-sized 2018, Scandinavian study investigated the association of SGLT2i class vs. GLP1RAs on fracture risk.50

Both the unadjusted (Sweden and Denmark) and the maximally-adjusted population (Sweden-only) data showed an

associated increased fracture risk, with narrow CIs (table S18.1, figure 5). This association remained stable when

hospitalised fractures and osteoporotic fractures were analysed separately (DNS).

6.2 A medium-sized 2019 German nested, 1:40 matched, case-control study explored the association of metformin +

SGLT2i class vs. metformin + any OAD on upper- and lower-limb fracture.46 There was a neutral association in both the

crude (DNS) and adjusted analysis (table S18.2, figure 5), with narrow CIs. Subgroup analysis by fracture site, SGLT2i

dose, falls and CVD remained stable (DNS).

Canagliflozin

6.3 A large 2019 American cohort study assessed the association between canagliflozin vs. GLP1RAs on the risk of

fractures in two data sources combined.38 Canagliflozin was associated with a neutral risk of fracture, both when the

data sources were analysed separately (DNS) and combined (table S18.3, figure 5) with narrow CIs. There was a

neutral association with an elevated risk of fracture in subgroup/sensitivity analysis (DNS).

Dapagliflozin

47


Study Summary

6.4 A small 2018, UK study cohort study investigated the association of dapagliflozin exposure vs. dapagliflozin-unexposed

persons on any fracture risk.48 The study reported a neutral association of dapagliflozin on fragility fractures (defined

by site: vertebral, humerus, proximal femoral, distal radius; DNS) and all fractures (table S18.4, figure 5). The CIs were

narrow. The results remained stable in sensitivity analysis in those at higher risk of fracture (DNS).

48

Table 7: Genitourinary infections (UTI/GMI)

Outcome/Exposure/Study Number

Study Summary

Urinary tract infection

7.1 A medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP1RA on UTI. 50 There was a

neutral association for UTI in whole population and also in the maximally-adjusted (Sweden-only) population with

narrow CIs (table S19.1, figure 6), stable in all subgroup analyses (DNS).

7.2 A large 2019 American cohort study explored the association of SGLT2i class vs. GLP1RA and DPP4i on UTI.36

SGLT2is were associated with lower risk of UTI vs. GLP1RA but neutral vs. DPP4is with narrow CIs (table S19.2,

figure 6), consistent in subgroup and sensitivity analysis (DNS).

7.3 A small 2017 Australian cohort study, explored the association of SGLT2i class vs. DPP4i exposure on UTI.39. There

was a neutral association for UTI (table S19.3, figure 6) with moderately wide CIs.

7.4 A medium-sized 2019 Canadian cohort study explored the association for UTI in older people comparing SGLT2i

class exposure vs. DPP4i, king a duration response-effect.42 There was a reduced association with UTI at 30-, 90-and

120-days post-initiation overall, with narrow CIs (table S19.4, figure 6; 120 days, other DNS) and in both men and

women when analysed separately (DNS).

Canagliflozin

7.5 A medium-sized 2017 American cohort study, explored the association of canagliflozin exposure vs. non-

canagliflozin AHAs on the risk of UTI.53 There was a neutral association of canagliflozin on UTI with narrow CIs

49


Study Summary

(table S19.6, figure 6), stable in sensitivity analysis (DNS).

Genital mycotic infection

SGLT2i class

7.6 A small 2017 Australian study investigated the association of SGLT2i class vs. DPP4i exposure on GMI.39 There was

an increased association for GMI (table S19.3, figure 7) but with wide CIs.

7.7 A medium-sized 2019 Canadian study explored the association of SGLT2i class vs. DPP4i on GMI, king a duration-

response effect.42 There was an elevated associated risk of GMI, sustained over time, in the overall population with

narrow CIs (table S19.4, figure 7; 120 days, other DNS) and in both men and women when analysed separately,

stable in sensitivity analysis (DNS).

7.8 A medium-sized 2018 American study explored the (within-person) association of SGLT2i class with GMI using a

prescription symmetry analysis (anti-fungal prescription rates as proxy for GMI) before and after SGLT2i initiation.32

There was an associated increased risk of anti-fungal prescription at 30-, 60-, 90-, 180- and 365-days post-initiation,

suggesting sustained risk (table S19.5 for 365 days, other DNS). The association remained in subgroup analysis for

both men and women (but women at higher risk, DNS). Canagliflozin was associated with a higher risk of an anti-

fungal prescription compared to dapagliflozin and empagliflozin exposure (individual drug analysis, DNS).

Canagliflozin

7.9 A medium-sized 2017 American cohort study explored the association of canagliflozin vs. non-canagliflozin controls

50


Study Summary

with GMI.53 There was an increased association overall for GMI (table S19.6, figure 7) but when analysed separately,

the association remained for women but not for men (DNS). The CIs were narrow.

51

Table 8: Hypoglycaemia study summary

Exposure/Study Number Study Summary

SGLT2i class

8.1 A large 2017 Scandinavian CVD-REAL sub-analysis explored the association of SGLT2i class vs. other OAD.54 This

study showed that compared to OADs, SGLT2i exposure-use was associated with a lower risk of hospitalised severe

hypoglycaemia (table S20.1, figure 8). The CIs were narrow.

Dapagliflozin

8.2 A medium-sized 2018 Scandinavian CVD-REAL sub-analysis explored the association of dapagliflozin vs. DPP4i

exposure for hospitalised severe hypoglycaemia (as sub-analysis).64 There was a neutral association with

hypoglycaemia (table S20.2, figure 8). The CIs were narrow.

8.3 A medium-sized 2019 Scandinavian study examined the association between dapagliflozin vs. OADs for hospitalised

severe hypoglycaemia (as sub-analysis).60 There was a neutral association for hypoglycaemia (table S20.3, figure 8),

with narrow CIs.

8.4 A medium-sized 2017 Swedish study explored the association of dapagliflozin vs. insulin on hospitalised severe

hypoglycaemia (sub-analysis).61 There was a neutral association in both the PSM (table S20.4, figure 8) and the

multivariate-adjusted model (DNS). The CIs were wide.

52

Table 9/10: Pancreatitis and venous thromboembolism study summary study

Outcome/Exposure/Study Number Study Summary

Pancreatitis

9.1 One medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP1RA

exposure on the pancreatitis.50. There was a neutral association with pancreatitis in the whole

population (Sweden and Denmark, DNS), the maximally-adjusted population (Sweden-only) with

wide CIs (table S21) and in subgroup analysis (DNS).

Venous Thromboembolism

10.1 One medium-sized 2018 Scandinavian study explored the effect of SGLT2i class vs. GLP1RA for

VTE.50 This study showed a neutral association for VTE in the whole population (Sweden and

Denmark, DNS), the maximally-adjusted population with narrow CIs (Sweden-only, table S22) and

subgroup analysis (DNS).

53

Table 11: Current RCT and other evidence related to outcomes

Outcome RCT evidence summary

Major adverse cardiovascular events

Both empagliflozin and canagliflozin reduce cardiovascular morbidity and mortality in patients with T2D at high CVD risk, on the basis of CVOT

data.

For MACE:

empagliflozin, HR 0.86 (95.02% CI 0.74, 0.99)

canagliflozin, HR 0.86 (96% CI 0.75, 0.97)

dapagliflozin, HR 0.93 (95% CI 0.84, 1.03) does not improve these outcomes. 2,3,5

Myocardial Infarction For non-fatal MI, none of the CVOTs showed a significant reduction in this component of the MACE composite: empagliflozin, HR 0.87, (95%CI

0.70, 1.09)

canagliflozin, HR 0.85 (95% CI 0.69, 1.05)

dapagliflozin, HR 0.77 (95% CI 0.77, 1.01))

This was not a primary outcome meaning the trials were not specifically powered to detect this.2,3,5

Stroke For non-fatal stroke, all of the CVOTs showed a neutral effect on this component of the MACE composite,

Empagliflozin, HR 1.24, (95%CI 0.92, 1.67)

canagliflozin, HR 0.90 (95% CI 0.71, 1.15),

dapagliflozin, HR 1.01 (95% CI 0.84, 1.21))

There was a trend towards an increased risk in the case of empagliflozin; this was not a primary outcome and the trials were not powered to detect this.2,3,5

Heart Failure For hospitalised heart failure all three CVOTs suggest that SGLT2i exposure leads to a reduction in this outcome.

empagliflozin, HR 0.65 (95% CI 0.50, 0.85)

dapagliflozin, HR 0.73 (95% CI 0.61, 0.88)

canagliflozin, HR 0.67 (95% CI 0.52, 0.87).2,3,5.

The Dapa-HF trial, in patients with and without T2D with baseline HF, showed a reduction for first worsening of HF, CVD mortality and ACM.4

Mortality The CVOT trials returned the following results for mortality outcomes.

54


Empagliflozin, CVD mortality: HR 0.62 (95% CI 0.49, 0.77); ACM: HR 0.68 (95% CI 0.57, 0.82).

Canagliflozin, CVD mortality: HR 0.87 (95% CI 0.72, 1.06); ACM: HR 0.87 (95% CI 0.74, 1.01).

Dapagliflozin, CVD mortality: HR 0.98 (95% CI 0.82, 1.17); ACM: HR 0.93 (95% CI 0.82, 1.04). 2,3,5

Renal outcomes Post-marketing reports to the FDA have suggested that both canagliflozin and dapagliflozin are associated with AKI, particularly after

immediate treatment initiation. This is multi-factorial, due to: volume depletion, hypotension or on concomitant nephrotoxic drugs.74 However,

both CVOTs and RCTs designed to test the effect on SGLT2is in diabetic nephropathy suggest that empagliflozin, canagliflozin and dapagliflozin

are associated with a reduced incidence of worsening nephropathy (although the benefit may be reduced in those with more severe renal

disease at baseline, possibly via a direct renovascular effect)87.

Empagliflozin showed a reduction in the composite of progression of microalbuminuria, doubling of serum creatinine, initiation of RRT or death

from renal causes, HR 0.61 (95% CI 0.53, 0.70).88

For canagliflozin, there was a reduction of the composite of ESRD, doubling of serum creatinine or death from cardiovascular and renal causes,

HR 0.70 (95% CI 0.59, 0.82).6

In the case of dapagliflozin, exposure was associated with a reduction of the composite of a ≥40% reduction or more in eGFR, new ESRD or death from cardiovascular or renal causes, HR 0.76 (95% CI 0.67, 0.87).3

Amputation SGLT2is, and particularly canagliflozin, have been associated with increased risk of amputation. Two RCTs investigating canagliflozin demonstrated a two-fold increase in the risk of (mainly toe and foot) amputation with those with PVD, neuropathy and prior amputation at the most elevated risk (IRR per 1000py, 5.9 vs. 2.8 (CANVAS) and 7.5 vs. 4.2 (CANVAS-R)5). Pharmacovigilance studies have also demonstrated an increased risk of amputation. Absolute numbers were low and the proportionality reporting ratio of adverse event descriptions may have been biased by knowledge of concern around SGLT2i exposure and amputation risk, making such events more likely to be reported in those taking SGLT2i.15

Diabetic ketoacidosis DKA, often euglycaemic, has been reported in people taking SGLT2i agents, particularly canagliflozin. In all three CVOTs the number of DKA

events were numerically higher in those exposed to SGLT2is but the absolute numbers were low.

Empagliflozin: n = 4 vs. 1,

Canagliflozin: IRR 0.6 per 1000py vs. 0.3

Dapagliflozin: HR 2.18 (95% CI 1.1, 4.3).2,3,5

Case series have also described associating SGLT2i exposure with an increased risk of DKA.23

Bone fracture SGLT2i exposure, especially canagliflozin, has been associated with an increased fracture risk. Putative mechanisms include trauma following

postural hypotension brought about by the volume depleting effect of SGLT2is (increased risk soon after therapy initiation) or a reduction of

55


bone mineral density (which would lead to a slower increase in risk of fracture as bone mineral depletion necessarily takes time).

In RCTs involving canagliflozin some, but not all, demonstrated a higher risk of fracture in those exposed to canagliflozin.6,25 For instance, a dose

response-effect was demonstrated in patients taking 100mg and 300mg of canagliflozin (IRR 1.4 and 1.5 fracture per 100py) and was elevated

compared to placebo (IRR 1.1 per 100 py).25 In a BMD trial, canagliflozin, when compared to placebo, was associated with a progressive decline

in BMD at the hip, with larger daily doses associated with a greater decline in BMD.7,10

Trials of dapagliflozin on BMD did not show an effect 18 and neither did pooled trial analysis of fracture risk for empagliflozin16.

Meta-analysis of safety outcomes did not find an increased fracture risk for empagliflozin and dapagliflozin, and the elevated odds ratio for canagliflozin was not statistically significant, OR 1.15 (95% CI 0.71, 1.88), although the source studies were not powered to detect fracture as an outcome.24

Genitourinary infection RCTs of SGLT2is show a two- to four-fold increase in the incidence of genitourinary candidiasis, with vulvovaginal candida infection occurring

in 10-15% of women exposed, compared to placebo.8,22 Meta-analyses have also found that exposure to SGLT2is is associated with an increased

risk of female genital candida infection.12,19,89

Also, there have been descriptions of SGLT2is being associated with urological sepsis and pyelonephritis, as well as necrotising fasciitis of the perineal tissues.9,14,17

Hypoglycaemia SGLT2i are insulin-independent agents and are not associated with an elevated risk of hypoglycaemia when not co-prescribed with treatment that cause hypoglycaemia. They reduce the risk of hypoglycaemia compared to SUs and insulin, and hence may be indicated in people at high-risk of hypoglycaemia (and weight gain), however there may increase the risk of hypoglycaemia when co-prescribed with these other drugs.11,20,26

Pancreatitis SGLT2is have not been reported, in the literature, to cause an increased risk of pancreatitis. However T2D, in and of itself, is associated with an increased risk of pancreatitis compared to those without the condition.13,21

Venous thromboembolism SGLT2is have been putatively suggested to increase the risk of venous thromboembolism, due to the haemoconcentration occurring through the osmotic diuresis which they bring about. There is no literature identified from RCTs to suggest an elevated risk of VTE.

56

Figures

Figure 1: PRISMA diagram

57

58

Figure 2: Renal outcomes

59

Figure 3: Amputation

60

Figure 4: DKA

61

Figure 5: Bone fracture

62

Figure 6: Urinary tract infection

63

Figure 7: Genital mycotic infection

64

Figure 8: Hypoglycaemia

65

Supplementary Tables

Table S1: Search Strategy (final search 30th December 2019)

Database StringWeb of Science (TS=((”observational” OR “clinical*practice” OR “real*” OR “cohort” OR “case*control”

OR “effectiveness”) AND "sodium*glucose*transport*protein*2*inhibitor*" OR ("sodium*glucose*transport*protein*ii*inhibitor*" OR "SGLT*2*inhibitor*” OR "SGLT*ii* inhibitor*” OR “canagliflozin” OR “dapagliflozin” OR “empagliflozin”)))

Medline on Ovid

EMBASE on Ovid

EMCARE on Ovid

CINAHL on EBSCO

1 "sodium glucose transport protein 2 inhibitor*".mp. (2)

2 "sodium glucose transport protein ii inhibitor".mp. (0)

3 *Sodium-Glucose Transporter 2 Inhibitors/ (1101)

4 "SGLT 2 inhibitor*".mp. (306)

5 "SGLT ii inhibitor*".mp. (0)

6 canagliflozin.mp. or *Canagliflozin/ (612)

7 dapagliflozin.mp. (549)

8 empagliflozin.mp. (665)

9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 (2038)

10 "observational".ab,ti. (112699)

11 "clinical practice".ab,ti. (119398)

12 real.ab,ti. (274130)

13 cohort.ab,ti. (344387)

14 "case control".ab,ti. (81498)

15 10 or 11 or 12 or 13 or 14 (870974)

16 "effect*".ab,ti. (3558014)

17 9 and 15 and 16 (118)

18 from 17 keep 1,3-4,8,10-16,18,20,22,25,29,33,35,41,44,47,51-52,56,59,61-

63,68,80,84,96,102-103,105-106,114 (37)

66

Table S2: Study inclusion/exclusion criteriaInclusion Criteria Exclusion Criteria

Observational study (all study designs)

SGLT2i (as class or individual agent)

Effectiveness/safety study of drug in question (or

study with focus on another therapeutic agent, but

with clear treatment effect estimates for drug in

question)

Drugs licensed in EU

English language publications

Type 2 Diabetes Mellitus

Electronic database study

RCT

Non-effectiveness or non-safety study (e.g. cost-

effectiveness study)

Systematic reviews/Meta-analysis

Case studies/case reports/case

series/letters/opinion/audit

Protocol/methodology

Adherence/persistence studies

Non-human studies/Pre-clinical studies

Studies published prior to the licensing of the drug

by EMA (11 Nov 2012)

Prevalence/descriptive studies

Conference abstracts

Adverse event disproportionality studies

Non-English language studies

67

Table S3: Data extraction templateStudy name Data source Baseline Characteristics

(after matching, if used)Exposed Control Outcome (include

negative control)Subgroups HR/RR/OR or other LCI UCI

PMID Country Age, years, mean (SD)

Exposure Year Female/Male delete as reported, n (%)

Exposed n EHR/Claims White, n (%)

Comparator Filled/Issued Rx

Asian, n (%)

Comparitor n Type (case-control, cohort, self-controlled case, nested case-control)

Black or African American, n (%)

Outcomes Statistical method

Current smoker, n (%)

References checked

Initiators/Switchers

Any atherosclerotic vascular disease history, n (%)

Nephropathy or eGFR (SD)Here nephropathy n (%)

History of hypertension, n (%)

LDL/HDL cholesterol ratio, mean ORLDL & HDLOR Hyprelipidaemia

Duration of diabetes

Glycated hemoglobin, %, mean (SD)

Systolic BP, mmHg, mean (SD)

Body mass index, kg/m2, mean (SD)

Number of antidiabetic drugsOR Proportion on background

68

metformin

69

70

Table S4: Total agreed quality scores (‡ nb. Since none of the studies were randomised, the maximum achievable score was 29)

Study Title and Reference Total Agreed Score (/31)‡

Risk of immortal time bias

Empagliflozin and the risk of heart failure hospitalization in routine clinical care63 18 N

Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE TIMI ‐58 trial: A nationwide observational study60

20 N

The effect of dapagliflozin on glycaemic control and other cardiovascular disease risk factors in type 2 diabetes mellitus: a real-world observational study59

20 N

Fracture risk after initiation of use of canagliflozin: a cohort study38 19 N

Acute renal outcomes with sodium glucose co transporter 2 inhibitors: Real world data analysis‐ ‐ ‐ ‐ 34 19 N

Increased risk of mycotic infections associated with sodium–glucose co transporter 2 inhibitors: a prescription sequence symmetry ‐analysis32

10 N

Cardiovascular outcomes of sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes‐ 37 14 N

Risk of amputations associated with SGLT2 inhibitors compared to DPP 4 inhibitors: a propensity matched cohort study‐ ‐ 33 17 N

Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register-based cohort study50 20 N

71

Comparative-effectiveness of canagliflozin, SGLT2 inhibitors and non SGLT2 inhibitors on the risk of hospitalization for heart failure and ‐amputation in patients with type 2 diabetes mellitus: A real world meta analysis of 4 observational databases (OBSERVE 4D)‐ ‐ ‐ 65

18 N

Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes35 16 N

Sodium-glucose co-transporter-2 inhibitors and the risk of ketoacidosis in patients with type 2 diabetes mellitus: A nationwide population-based cohort study41

18 N

Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2inhibitors versus other glucose-lowering agents in real-world clinical practice: Results from the CVD-REAL study.57

15 N

Association between sodium glucose co-transporter 2 inhibitors and a reduced risk of heart failure in patients with type 2 diabetes mellitus: a real-world nationwide population-based cohort study40

17 N

Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor results from the EASEL population-based cohort study (evidence for cardiovascular outcomes with sodium glucose cotransporter 2 inhibitors in the real world)66

18 N

Initiation of dapagliflozin and treatment emergent fractures‐ 48 16 N

Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study.68

18 N

Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin anti-diabetic drugs: population-based cohort study45 17 N

Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: a multinational observational study64

20 N

Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis54

21 N

72

Use of SGLT2 inhibitors for diabetes and risk of infection: analysis using general practice records from the NPS MedicineWise MedicineInsight program.39

16 N

Heart failure hospitalization risk associated with use of two classes of oral anti-diabetic medications: an observational, real-world analysis.55

17 N

Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs

The CVD-REAL study (comparative-effectiveness of cardiovascular outcomes in new-users of sodium-glucose cotransporter-2 inhibitors) 58

22 N

Incidence of diabetic ketoacidosis among patients with type 2 diabetes mellitus treated with SGLT2 inhibitors and other anti-hyperglycemic agents67

14 N

All-cause mortality in patients with diabetes under treatment with dapagliflozin: a population-based, open-cohort study in the health improvement network database.49

18 N

Healthcare costs of urinary tract infections and genital mycotic infections among patients with type 2 diabetes mellitus initiated on canagliflozin: a retrospective cohort study.53

14 N

Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study.47

19 N

Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register-based cohort study44

22 N

Sodium-glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections a population-based cohort study36 15 N

Loop-diuretic-use among patients with heart failure and type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors51 14 N

73

Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: A population-based study of older women and men with diabetes42

19 N

Cardiovascular events associated with sglt-2 inhibitors versus other glucose-lowering drugs56 17 N

Sodium-glucose co-transporter-2 inhibitors and the risk of fractures of the upper or lower-limbs in patients with type 2 diabetes: A nested case-control study.46

15 N

Association of second-line anti-diabetic medications with cardiovascular events among insured adults with type 2 diabetes62 14 N

Sodium glucose co transporter 2 inhibitor-use and risk of lower extremity amputation: evolving questions, evolving answers‐ ‐ ‐ ‐ 52 16 N

Risk of diabetic ketoacidosis after initiation of an sglt2 inhibitor83 14 N

Novel oral glucose-lowering drugs are associated with lower risk of all-cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes61

19 N

74

Table S5: CVD-REAL programmes’ description

CVD-REAL Collaboration between investigators using data sources in the United States, the United

Kingdom, Germany, Sweden, Denmark and Norway.54,57,58,64 The main analysis 58 involves all

data sources; because not all outcomes of interest or covariates were available in all the data

sources, subsequent analyses were conducted in restricted versions of the same cohort but

were published separately.54,57,64

CVD-REAL 2 Similar collaboration using data sources from South Korea, Japan, Singapore, Israel, Australia,

and Canada but formed a single study report.56

75

Table S6: Non-3P-MACE cardiovascular compositesLegend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Adjustments Database Exposure Comparison Composite outcome Subgroup/ Composite Component

Hazard Ratio (unless otherwise specified)

LCI UCI

S6.1 Cardiovascular outcomes of sodium glucose cotransporter 2 inhibitors in patients with type 2 ‐diabetes37

[USA, CDS]PS-Matched, Cox PHn = 62 767 (SU); 66 633 (DPP4i)Female = 47.7%Follow-up = 12moDuration of diabetes = NRMean HbA1c = NRBackground metformin = 57.8% (SU); 59.8 (DPP4i)IHD = 11.9% (SU); 12.6% (DPP4i)Hypertension = 67.3% (SU); 68.5% (DPP4i)Hyperlipidaemia = 66.5%; 66.4%Smoking = NR

baseline demographics, comorbidities and use of other medications

Truven Health MarketScan

SGLT2i SU CVD composite*‡

(MI and Stroke)

0.5 0.45 0.55

SGLT2i SU MI† 0.7 0.61 0.81SGLT2i SU Stroke† 0.69 0.61 0.78SGLT2i DPP4i CVD composite*‡

0.57 0.52 0.62

SGLT2i DPP4i MI† 0.72 0.63 0.82

SGLT2i DPP4i Stroke† 0.61 0.5 0.73

S6.2 Association of Second-line Anti-diabetic Medications With Cardiovascular Events Among Insured Adults With Type 2 Diabetes62

[USA, CDS]Unmatched, Cox PHn = 5677 (SGLT2i); 28 898 (DDP-4i)Female = 45.6%; 44.4%Follow-up = 169 384 person-years (2yrs)Duration of diabetes = NRMean HbA1c = reportedMetformin-use = 69.7%; 59.8%Primary prevention, n = 95.7%; 94.5%Secondary prevention, n = 4.3%; 5.5%Hypertension = 76.3%; 70.1%Dyslipidaemia = 69.9%; 70.1%Tobacco-use = 10.1%; 8.1%

patient baseline sociodemographic characteristics, haemoglobin A1c, cardiovascular risk factors, diabetes complications including prior cardiovascular events, as well as prior use of metformin and cardiovascular medications

Medicare Advantage + other unspecified health plans

SGLT2i DPP4i CVD Composite*‡ 0.81 0.57 1.53

HHF† 0.54 0.24 1.22IHD† 1.18 0.74 1.87Stroke† 0.56 0.26 1.12PAD†

(NOTE: not amputation)

1.11 0.33 3.65

SGLT2i DPP4i CVD - primary prevention*¶

0.91 0.63 1.31

CVD - secondary prevention*¶

0.36 0.09 1.45

S6.3 Lower risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs58

[USA, Norway, Denmark, Sweden, Germany, UK; mixed EHR/CDS]PS-Matched, Cox PHn = 154 528 (Cana 53%; Dapa 42%; Empa 5%)Female = 44.3%

(model-adjusted for history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, hypertension,

CVD-REALUnited States: Truven Health MarketScan Claims and Encounters Germany: the Diabetes

SGLT2i OAD CVD Composite*¶ 0.57 0.51 0.63

ACM†¶ 0.52 0.42 0.64

76



LCI UCI

Follow-up = 190 164 person-yearsDuration of diabetes = NRMean HbA1c = NRMetformin-use = 78.6% (SGLT2i); 79.9% (OAD)Anti-hypertensive therapy = 80.0%Statin-use = 67.3%Established CVD = ~13.0% (SGLT2i); 13.1% (OAD)Prior MI = 2.5%Heart failure at baseline = 3.1%Prior stroke = 4.1%Smoking = NR

obesity/body mass index, duration of diabetes mellitus, ACE inhibitor or ARB-use, -blockerβ or -blocker-use, αCa2+ channel blocker-use, loop-diuretic-use, thiazide diuretic-use).

Prospective Follow-Up initiative Sweden, Norway, and Denmark: mandatory full-population registries United Kingdom: CPRD + THIN

HHF‡† 0.61 0.53 0.69

S6.4 Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs56

[South Korea, Japan, Singapore, Israel, Australia, and Canada; mixed HER/CDS]PS Matching; Cox PHn = 235 064 (dapagliflozin: 75%, empagliflozin: 9, other SGLT2i: 1%-8%)Female = 45.0% (SGLT2i); 45.5% (OGLD)Follow-up = 374d; 392dDuration of diabetes = NRMean HbA1c = NRBackground metformin-use = 73.9%; 74.%CV history = 26.8%; 25.6%;Prior MI = 3.4%Heart failure at baseline = 6.8%; 6.7%Hypertension = NRHyperlipidaemia = NRSmoking = NR

age; sex; frailty; history of heart failure, MI, and atrial fibrillation; hypertension (if available); obesity/body mass index (if available); duration of diabetes (if available); and use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), -blockers,β Ca+-channel blockers, statins, loop-diuretics, and thiazide diuretics

CVD-REAL2Korea: National Health Insurance ServiceJapan: Medical Data Vision CoSingapore: SingHealth Diabetes RegistryIsrael: Maccabi Health Management OrganizationAustralia: National Diabetes Services SchemeCanada: Manitoba Centre for Health Policy’s Population Health Research Data Repository

SGLT2i OGLD CVD Composite‡*

(ITT) 0.6 0.47 0.76

ACM†‡ 0.51 0.37 0.7

HHF†‡ 0.64 0.5 0.82

S6.5 Cardiovascular Outcomes and risks After Initiation of a Sodium Glucose Cotransporter 2 InhibitorResults From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World)66

[USA, EHR]1:1 PS Matching, Cox PHn = 12629 (58.1% Cana, 26.4% Empa, 15.5% Dapa)Female = 43.3%

No adjustment after PS Matching

US Department of Defense Military Health System

SGLT2i Non-SGLT2i initiators

CVD Composite¶* (MACE + HHF)

0.66 0.6 0.74

CVD Composite‡*

(ACM + HHF) 0.57 0.5 0.65

77



LCI UCI

Follow-up = 1.6yrsDuration of diabetes = 5.6yrsMean HbA1c = NRBackground Metformin-use = 78.5%; 83.0%HTN = 86.5%; 85.8%Hyperlipidaemia = 75.8; 75.6%Cerebrovascular disease = 14.5%; 14.9%Congestive heart failure = 10.6%; 1.6%Prior MI = 5.8%; 5.7%

MACE¶*

(ACM, non-fatal MI, and non-fatal stroke)

0.67 0.6 0.75

ACM‡† 0.57 0.49 0.66

HHF‡† 0.57 0.45 0.73

S6.6 Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin anti-diabetic drugs: population-based cohort study45

[USA, EHR]1:1 PS matching (1:1); multivariable logistic regression

n = 17 667 (vs. DPP4i); 20 539 (vs. GLP-1); 17 354 (vs. SU)Female = 44.9%; 47.3%; 45.0%Follow-up = 0.6yrsDuration of diabetes = NRMean HbA1c = 8.8%; 8.8%; 8.7%Background metformin-use = 15.7%; 16.9%; 16.3%IHD = 11.4%; 11.8%; 10.9%Congestive cardiac failure at baseline = 3.2%; 3.4%; 3.0%Hypertension = 51.9%; 53.1%; 50.8%Hyperlipidaemia = 48.7%; 49.9%; 49.2%Smoker = 7.4%; 7.4%; 7.5% table S11 for further baseline characteristics

baseline haemoglobin A1c levels-only

Clinformatics Datamart Optum Insight

Canagliflozin DPP4i CVD composite*‡ 0.89 0.68 1.17

Acute MI‡† 0.91 0.64 1.29Stroke‡† 0.81 0.54 1.22

Canagliflozin GLP1RA CVD composite*‡ 1.03 0.79 1.35

Acute MI‡† 1.03 0.73 1.44Stroke‡† 1.07 0.69 1.66

Canagliflozin SU CVD composite*‡ 0.86 0.65 1.13

Acute MI‡† 0.85 0.59 1.23 Stroke‡† 0.87 0.57 1.31

Canagliflozin DPP4i Expanded composite*¶

(myocardial infarction, stroke, unstable angina, or coronary revascularization)

0.97 0.78 1.22

GLP1RA

0.95 0.77 1.17SU 0.9 0.72 1.13

Canagliflozin DPP4i Secondary prevention - admission to hospital for MI or stroke¶

0.9 0.59 1.38GLP1RA

0.89 0.59 1.35

SU 0.7 0.46 1.06

78



LCI UCI

S6.7 Novel Oral Glucose-Lowering Drugs Are Associated With Lower risk of All-Cause Mortality, Cardiovascular Events and Severe Hypoglycaemia Compared With Insulin in Patients With Type 2 Diabetes61

[Sweden, EHR]PS Matching (2:1), Cox PH, Kaplan Meiern = 10879Female = 41%Follow-up = 16 304 patient-years (1.51yrs)Duration of diabetes (as time since first GLD) = 5.0 yrsMean HbA1c = NRBackground metformin-use = 82%Anti-hypertensives = 76% (SGLT2i); 74% (Insulin)Statin-use = 60% (SGLT2i); 61% (Insulin)Prior MI = 9%Heart failure at baseline = 8%Prior cerebrovascular event = 9%PAD = 5%Smoking = NR

age, sex, frailty, prior CVD , and use of statins, low dose‐ aspirin, and anti-hypertensives

Swedish National Register

Dapagliflozin Insulin Fatal and non-fatal CVD‡*

(myocardial infarction, ischaemic stroke, unstable angina pectoris, heart failure or cardiovascular death)

Composite HRs not provided

0.51 0.3 0.86

S6.8 All-Cause Mortality in Patients With Diabetes Under Treatment With Dapagliflozin: A Population-Based, Open-Cohort Study in The Health Improvement Network Database49

[UK, EHR]Poisson regression, unmatchedn = 444 (exposed) vs. 17680 (unexposed)Female = 41.4%Follow-up = 9.3mo; 8.9moDuration of diabetes = 9.8yrs; 8.5yrsMean HbA1c = 9.1%; 7.5%Background metformin-use = NRHypertension = 55.1%; 58.3%Hyperlipidaemia = NRIHD = 13.2%; 14.8%Stroke / TIA = 4.9%; 5.9%Heart failure / LVD = 2.1%; 3.3%Smoking = 13.5%; 13.4%

age, sex, BMI, smoking, glycated haemoglobin A1c level, duration of diabetes, systolic blood pressure level, lipid-lowering medication, insulin-use, estimated glomerular filtration rate, social deprivation index, presence of hypertension, and Charlson comorbidity index

THIN Dapagliflozin Unexposed controls

Incident CVD composite*¶

(proxy for primary prevention in subgroup analysis of those patients without prior CVD)myocardial infarction and ischemic heart disease, stroke or TIA, and heart failure or left ventricular dysfunction

[Individual composite component HRs not provided]

RR 0.89 0.61 1.30

79



LCI UCI

S6.9 The Effect of Dapagliflozin on Glycaemic Control and Other Cardiovascular Disease risk Factors in Type 2 Diabetes Mellitus: A Real-World Observational Study59

[Scotland, EHR]Cohort; Liner regressionn = 8566 (exposed); 230,310 (unexposed)Female = 44.3%Follow-up = 6674 person yearsDuration of diabetes = 11.36 yrs; 8.96 yrsMean HbA1c = 9.26%; 7.51%Background metformin = not reportedHypertension = 29.4%; 30.6%Hyperlipidaemia = NRHeart failure at baseline = 3.5%; 4.6%Prior MI = 6.7%; 7.2%Stroke/TIA = 3.5%; 5.1%Smoking = 69.9%; 70.1%

age, sex and diabetes duration

SCI Diabetes Dapagliflozin Non-users CVD composite*¶

(chronic ischaemic heart disease,cerebrovascular disease, heart failure, cardiac arrhythmia orcoronary revascularisation)

[Individual composite component HRs not provided]

0.7 0.95 1.3

S6.10

Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study47

[Taiwan, EHR]Cox PH, no PS-matchedn = 5812 (Dapa); 6869 (Empa)Female = 45,5%; 42.5%Follow-up = 10 422 patient years (Dapa); 12 096 patient years (Empa)Duration of diabetes = NRMean HbA1c = recordedBackground metformin-use = 92.3%; 89.2%Hypertension = 64.0%; 67.1%Hyperlipidaemia = 73.5%; 72.4%Coronary heart disease = 14.3%; 17.6%Smoking = NR

age, sex, laboratory data, co-morbidities, and concomitant medications

Chang Gung Research Database (CGRD)

Dapagliflozin Empagliflozin

CVD composite‡* 0.91 0.73 1.14

Cardiovascular mortality‡†

0.54 0.14 2.12

Myocardial infarction‡†

0.77 0.49 1.19

Ischemic stroke‡†

1.15 0.8 1.65

Heart failure‡† 0.68 0.49 0.95

80

Table S7: Major adverse cardiovascular Events (3P-MACE)Legend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

81

Study Characteristics Adjustment Database Exposure Comparison Outcome Composite component Hazard Ratio

LCI UCI

S7.1 Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register-based cohort study44

[Denmark, Sweden and Norway, EHR]1:1 PS matching, Cox PHn = 41966 (Dapa 83%, Empa 16%, Cana 1%)Female = 40%Follow-up = 27 416 person yearsDuration of diabetes (as time since first diabetic drug) = reportedMean HbA1c = NRBackground metformin = 79%ACS = 7%; 8%Other IHD = 17%Heart failure/cardiomyopathy at baseline = 6%Prior stroke = 4%Hypertension at baseline = NRLipid lowering drug = 67%Smoking = NR

glycated haemoglobin, blood pressure, estimated glomerular filtration rate, albuminuria, body mass index, and smoking status

Population registries SGLT2i DPP4i MACE*‡ 0.94 0.84 1.06

SGLT2i DPP4i Cardiovascular mortality¶† 0.84 0.65 1.08

SGLT2i DPP4i Myocardial infarction¶† 0.99 0.85 1.17

SGLT2i DPP4i Stroke¶† 0.94 0.77 1.15

SGLT2i DPP4i MACE Primary prevention 0.9 0.77 1.05

SGLT2i DPP4i MACE Secondary prevention 1.05 0.87 1.26

S7.2 Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis54

CVD-REAL Sub-analysis [Denmark, Sweden and Norway, EHR]PS Matching, Cox PH, Kaplan Meiern = 22830 (SGLT2i); 68490 (OGLD)Empagliflozin 5%, Canagliflozin 1%, Dapagliflozin 94%Female 40.6%; 39.5%Follow-up = 0.9yrs (80 669 patient years)Duration of diabetes (as time since first GLD) = 7.3yrs; 7.6yrs Mean HbA1c = NRMetformin-use = 74.2%; 77.4%Cardiovascular disease at baseline = 24.9%; 24.8%Prior MI = 7.6%; 7.7%Prior Stroke = 6.7%; 6.6%Heart failure at baseline = 5.0%; 5.0%Anti-hypertensive-use = 76.0%; 75.7%Statin-use = 67.4%; 68.3%

Adjustment made to analyses on sub-analyses-only

Diabetes Register in Sweden, Denmark and Norway

SGLT2i OGLD MACE‡* 0.78 0.69 0.87

SGLT2i OGLD Cardiovascular mortality‡† 0.53 0.4 0.71

SGLT2i OGLD Non-fatal myocardial‡† infarction 0.87 0.73 1.03

SGLT2i OGLD Non-fatal Stroke (ischaemic or haemorrhagic) ‡†

0.86 0.72 1.04


MACE¶* 0.67 0.6 0.75

S7.3 Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 InhibitorResults From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter

No adjustment after PS Matching US Department of Defense Military Health System


ACM† 0.57 0.49 0.66


Non-fatal myocardial infarction† 0.81 0.6 0.74

82


LCI UCI

2 Inhibitors in the Real World)66

[USA, EHR]

MACE‡*


Non-fatal Stroke† 0.85 0.66 1.1

Dapagliflozin DPP4i 0.79 0.67 0.94

S7.4 Dapagliflozin is associated with lower risk of cardiovascular events and all cause mortality ‐in people with type 2 diabetes (CVD REAL ‐Nordic) when compared with dipeptidyl peptidase 4 inhibitor therapy: A multinational‐ observational study64

CVD-REAL Sub-analysis [Denmark, Sweden and Norway, EHR]PS Matching, Cox PH, Kaplan Meiern = 10227 (Dapagliflozin); 30681 (DPP4i);Female = 41.0%Follow-up = 0.95yrs (38760 patient-years)Duration of diabetes (as time since first GLD) = 6.5yrsMean HbA1c = NRBackground metformin-use = 83.3%; 83.8%Cardiovascular disease at baseline = 23.0%; 22.7%;Prior MI = 7.1%Prior Stroke = 5.5%Heart failure = 4.7%Statin-use at baseline = 63.1%; 63.2%Anti-hypertensive-use at baseline = 73.2%; 72.5%Smoking = NR

No adjustment after PS Matching Diabetes Register in Sweden, Denmark and Norway

Dapagliflozin DPP4i CV mortality‡† 0.76 0.53 1.08

Dapagliflozin DPP4i Non fatal myocardial infarction‡†‐ 0.91 0.72 1.16

Dapagliflozin DPP4i Non fatal stroke‡†‐ 0.79 0.61 1.03

Dapagliflozin OAD MACE¶* Intention to treat analysis (ITT) 0.9 0.79 1.03

S7.5 Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE‐TIMI 58 trial: A nationwide observational study60

history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, duration of diabetes mellitus treatment, angiotensin‐

Swedish diabetes register, linked to other data sources

MACE (ITT)

0.90 0.79 1.03

83


LCI UCI

[Sweden, EHR]

PS Matching, Cox PHn = 7102 (Dapagliflozin); 21306 (Other GLDs)Female = 33.6%Follow-up = 1.6yrs (45434 patient-years)Duration of diabetes (as time since first GLD) = 7.4yrs; 7.5yrs;Mean HbA1c = NRBackground metformin-use = 79.4%; 81.5%Cardiovascular disease at baseline = 33.7%; 34.8%Prior MI = 12.9%; 13.0%Prior Stroke = 7.3%; 7.4%Heart failure at baseline = 8.6%; 8.8%Statin-use at baseline = 77.0%; 77.2%Anti-hypertensive-use at baseline = 91.0%; 90.7%Smoking = NR

converting enzyme inhibitor or angiotensin II receptor blocker-use,

blocker or blocker-use, calcium β‐ α‐channel blocker-use, loop-diuretic-use, and thiazide diuretic-use

Dapagliflozin OAD

Cardiovascular mortality‡† 0.75 0.57 0.97

Myocardial¶† infarction 0.91 0.74 1.11

Stroke¶† 1.06 0.87 1.3

84

Table S8: Myocardial InfarctionLegend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Adjustment Database Exposure Comparison Outcome Hazard Ratio LCI UCI


[USA, CDS]

Previously reported – Table S6.2



SGLT2i DPP4i IHD† 1.18 0.74 1.87


[Denmark, Sweden and Norway, EHR]



Population registries SGLT2i DPP4i MI¶† 0.99 0.85 1.17

S8.3 Cardiovascular outcomes of sodium glucose cotransporter 2 inhibitors in‐ patients with type 2 diabetes37

[USA, CDS]




SGLT2i DPP4i MI† 0.72 0.63 0.82

SGLT2i SU MI† 0.7 0.61 0.81


CVD-REAL2 [South Korea, Japan, Singapore, Israel, Australia, and Canada; mixed EHR/CDS]


age; sex; frailty; history of heart failure, MI, and atrial fibrillation; hypertension (if available); obesity/body mass index (if available); duration of diabetes (if available); and use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), -blockers, Ca+-βchannel blockers, statins, loop-diuretics, and thiazide diuretics

Korea: National Health Insurance ServiceJapan: Medical Data Vision CoSingapore: SingHealth Diabetes RegistryIsrael: Maccabi Health Management OrganizationAustralia: National Diabetes Services SchemeCanada: Manitoba Centre for Health Policy’s Population Health Research Data

SGLT2i OAD MI†‡ 0.81 0.74 0.88

85



CVD-REAL Sub-analysis [Denmark, Sweden and Norway, EHR]


Adjustment made to analyses on sub-analyses-only Diabetes Register in Sweden, Denmark and Norway

SGLT2i OGLD Non-fatal MI‡†

0.87 0.73 1.03

S8.6 Rates of Myocardial Infarction and Stroke in Patients Initiating Treatment with SGLT2inhibitors versus other glucose-lowering agents in Real-World Clinical Practice: Results from the CVD-REAL study57

[USA, Norway, Sweden and Denmark, EHR]

1:1 PS-matchedn = 102,580Female = 43%Follow-up = 136,524 py (SGLT2i; 254d); 136,626 py (OGLD; 232d)Duration of diabetes = NRMean HbA1c = NRBackground metformin-use = 12%Baseline CVD = 14%Statin-use at baseline = NRAnti-hypertensive-use at baseline = NRSmoking = NR

No adjustment United States: Truven Health MarketScan Claims and Encounters Sweden, Norway, and Denmark: mandatory full-population registries

SGLT2i OGLD MI‡ 0.85 0.72 1.00

S8.7 Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 InhibitorResults From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World)66

[USA, EHR]




Non-fatal MI‡†

0.74 0.6 0.81

S8.8 Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE TIMI 58 ‐trial: A nationwide observational study60

[Sweden, EHR]


history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, duration of diabetes mellitus treatment, angiotensin converting enzyme inhibitor‐ or angiotensin II receptor blocker-use, blocker or β‐ α‐blocker-use, calcium channel blocker-use, loop-diuretic-use, and thiazide diuretic-use


Dapagliflozin OAD MI† 0.91 0.74 1.11

S8.9 Dapagliflozin is associated with lower risk of cardiovascular events and all cause mortality in people with type 2 diabetes (CVD REAL Nordic) ‐ ‐when compared with dipeptidyl peptidase 4 inhibitor therapy: A ‐multinational observational study64



Dapagliflozin DPP4i Non fatal ‐myocardial infarction†‡

0.91 0.72 1.16

86


Previously reported – table S7.4


[USA, CDS]


baseline haemoglobin A1c levels-only Clinformatics Datamart Optum Insight

Canagliflozin DPP4i MI‡† 0.91 0.64 1.29

Canagliflozin GLP1RA MI‡† 1.03 0.73 1.44

Canagliflozin SU MI‡† 0.85 0.59 1.23

S8.11 Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study47

[Taiwan, EHR]




Dapagliflozin Empagliflozin MI‡† 0.77 0.49 1.19

87

Table S9: StrokeLegend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Maximal Adjustment Database Exposure Comparison

Outcome Hazard Ratio LCI UCI

S9.1 Cardiovascular outcomes of sodium glucose cotransporter 2 ‐inhibitors in patients with type 2 diabetes37

[USA, CDS]




SGLT2i SU Stroke† 0.69 0.61 0.78



[USA, CDS]









Population registries SGLT2i DPP4i Stroke¶† 0.94 0.77 1.15


CVD-REAL2

[South Korea, Japan, Singapore, Israel, Australia, and Canada; mixed HER/CDS]


age; sex; frailty; history of heart failure, MI, and atrial fibrillation; hypertension (if available); obesity/body mass index (if available); duration of diabetes (if available); and use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), -blockers, βCa+-channel blockers, statins, loop-diuretics, and thiazide diuretics

Korea: National Health Insurance ServiceJapan: Medical Data Vision CoSingapore: SingHealth Diabetes RegistryIsrael: Maccabi Health Management OrganizationAustralia: National Diabetes Services SchemeCanada: Manitoba Centre for Health Policy’s Population Health Research Data Repository

SGLT2i OAD Stroke†‡ 0.68 0.55 0.84

88





Adjustment made to analyses on sub-analyses-only Diabetes Register in Sweden, Denmark and Norway

SGLT2i OGLD Non-fatal stroke‡†

(ischaemic or haemorrhagic)

0·86 0·72 1·04

S9.6 Rates of Myocardial Infarction and Stroke in Patients Initiating Treatment with SGLT2inhibitors versus other glucose-lowering agents in Real-World Clinical Practice: Results from the CVD-REAL study57

[USA, Norway, Sweden and Denmark; mixed EHR/CDS]

Previously reported in Table S8.6

No adjustment United States: Truven Health MarketScan Claims and Encounters Sweden, Norway, and Denmark: mandatory full-population registries

SGLT2i OGLD Stroke‡ 0.83 0.71 0.97


[USA, EHR]




Non-fatal Stroke‡†

0.85 0.66 1.1

S9.8 Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE TIMI 58 trial: A nationwide observational study‐ 60

[Sweden. EHR]


history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, duration of diabetes mellitus treatment, angiotensin converting enzyme inhibitor or ‐angiotensin II receptor blocker-use, blocker or β‐ α‐blocker-use, calcium channel blocker-use, loop-diuretic-use, and thiazide diuretic-use


Dapagliflozin OAD Stroke† 1.06 0.87 1.3

89



S9.9 Dapagliflozin is associated with lower risk of cardiovascular events and all cause mortality in people with type 2 diabetes ‐(CVD REAL Nordic) when compared with dipeptidyl peptidase 4‐ ‐ inhibitor therapy: A multinational observational study64




Dapagliflozin DPP4i Non fatal ‐stroke‡†

0.79 0.61 1.03


[USA, CDS]



Canagliflozin DPP4i Stroke‡† 0.81 0.54 1.22

Canagliflozin GLP1RA Stroke‡† 1.07 0.69 1.66

Canagliflozin SU Stroke‡† 0.87 0.57 1.31


[Taiwan, EHR]





Ischemic stroke‡†

1.15 0.8 1.65

90

Table S10: Hospitalised Heart Failure Legend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Adjustment Database Exposure Comparison Outcome Hazard Ratio(unless labelled otherwise)

LCI UCI

S10.1 Cardiovascular outcomes of sodium glucose cotransporter 2 inhibitors in patients with type 2‐ diabetes37

[USA, CDS]




SGLT2i SU HHF¶ 0.48 0.4 0.57

SGLT2i DPP4i HHF¶ 0.54 0.48 0.6



Previously reported - table S7.1


Population registries SGLT2i DPP4i HHF‡ - Intention to Treat (ITT) analysis

0.66 0.53 0.81

SGLT2i DPP4i HHF¶ - primary HF prevention

0.68 0.51 0.91

SGLT2i DPP4i HHF¶ - secondary HF prevention

0.69 0.51 0.93


[USA, CDS]




SGLT2i DPP4i HHF† 0.54 0.24 1.22

91


LCI UCI

S10.4 Heart failure hospitalization risk associated with use of two classes of oral anti-diabetic medications: an observational, real-world analysis55

[USA, CDS]PS-Matched (2:1), IPTW, MSMn = 4899 (SGLT2i); 9798 (DPP4i)Female = 46.9%; 42.9%Follow-up = 23.0 mo; 23.8 moDuration of diabetes = NRMean HbA1c = NRBackground metformin-use = 62.3%; 63.0%Cardiovascular disease at baseline = 13.5%; 13.7%Cerebrovascular disease at baseline = 2.8%; 2.6%Congestive heart failure at baseline = 2.3%; 2.3%Hypertension = NRStatin-use at baseline = 54.2%; 55.0%Smoking = NR

Adjusted model utilised Cox PH HealthCore Integrated Research Environment

SGLT2i DPP4i HHF‡ - PSM 0.68 0.54 0.86

SGLT2i DPP4i HHF¶ - IPTW 0.66 0.5 0.88

SGLT2i DPP4i HHF¶ - MSM 0.6 0.5 0.71

S10.5 Association between sodium glucose co-transporter 2 inhibitors and a reduced risk of heart failure in patients with type 2 diabetes mellitus: a real-world nationwide population-based cohort study40

[South Korea, CDS]PS-Matched, Cox PH, Kaplan Meiern = 59479; dapagliflozin (90.2%), ipragliflozin (9.8%); Female = 45.2%Follow-up = 318.5 dDuration of diabetes = NRMean HbA1c = NR

Not reported Korean Health Insurance Review and Assessment Service (HIRA) database

SGLT2i DPP4i HHF‡ – 3 years after initiation

0.66 0.58 0.75

SGLT2i DPP4i HF¶ -Secondary HF Prevention - 3 years after initiation

0.66 0.58 0.78

SGLT2i DPP4i HF¶ – Primary HF Prevention - 3 years after initiation

0.76 0.63 0.95


[USA, EHR]


US Department of Defense Military Health System


HHF‡† 0.57 0.45 0.73

92


LCI UCI


CVD-REAL [USA, Norway, Denmark, Sweden, Germany, UK; mixed EHR/CDS]


(model-adjusted for history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, hypertension, obesity/body mass index, duration of diabetes mellitus, ACEi or ARB-use, -blocker or -blocker-use,β α Ca2+ channel blocker-use, loop-diuretic-use, thiazide diuretic-use).

United States: Truven Health MarketScan Claims and Encounters Germany: the Diabetes Prospective Follow-Up initiative Sweden, Norway, and Denmark: mandatory full-population registries United Kingdom: CPRD + THIN

SGLT2i OAD HHF‡ 0.61 0.53 0.69

S10.8 Loop-diuretic-use among patients with heart failure and type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors51

[USA, CDS]PSM, Mann Whitney U of loop-diuretic dose categories, Chi squared for dose changen = 750 (SGLT2i); 750 (OAD)Female = 37.3%Follow-up = 270 daysDuration of diabetes = NRMean HbA1c = NRHeart failure at baseline = NRPrior MI = NRPrior Stroke = NRHypertension = 10.3% (controlled); 75.1% (uncontrolled)Hyperlipidaemia/Statin-use at baseline = NRSmoking = NR

Not reported MarketScan database SGLT2i OAD New loop-diuretic-use (Proportion starting therapy)‡

22.70% 34.00%

SGLT2i OAD Increased mean loop-diuretic dose‡

9.50% 12.20%


CVD-REAL2 [South Korea, Japan, Singapore, Israel, Australia, and Canada; mixed HER/CDS]


age; sex; frailty; history of heart failure, MI, and atrial fibrillation; hypertension (if available); obesity/body mass index (if available); duration of diabetes (if available); and use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), -blockers, Ca+-channelβ blockers, statins, loop-diuretics, and thiazide diuretics


SGLT2i OAD HHF‡ 0.64 0.5 0.82

93


LCI UCI


CVD-REAL Sub-analysis [Denmark, Sweden and Norway; EHR]


Adjusted for multiple baseline covariates – but for subgroup analyses-only


SGLT2i OGLD HHF‡ 0.70 0.61 0.81

S10.11 Dapagliflozin is associated with lower risk of cardiovascular events and all cause mortality in ‐people with type 2 diabetes (CVD REAL Nordic) ‐when compared with dipeptidyl peptidase 4 ‐inhibitor therapy: A multinational observational study64

CVD-REAL Sub-analysis [Denmark, Sweden and Norway; EHR]




Dapagliflozin DPP4i HHF‡ 0.62 0.5 0.77


[USA, CDS]


baseline haemoglobin A1c levels-only

Clinformatics Datamart Optum Insight

Canagliflozin DPP4i HHF‡ 0.7 0.54 0.92

Canagliflozin GLP1RA HHF*¶ 0.61 0.47 0.78

Canagliflozin SU HHF*¶ 0.51 0.38 0.67

Canagliflozin DPP4i HF (diuretic-use)¶ 0.64 0.53 0.76

Canagliflozin GLP1RA HF (diuretic-use)¶ 0.68 0.58 0.81

Canagliflozin SU HF (diuretic-use)¶ 0.47 0.39 0.56

S10.13 Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE TIMI 58 ‐trial: A nationwide observational study60

[Sweden, EHR]


history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, duration of diabetes mellitus treatment, angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker-use, blocker or blocker-use,β‐ α‐ calcium channel blocker-use, loop-diuretic-use, and thiazide diuretic-use


Dapagliflozin OAD HHF‡ 0.79 0.67 0.93

94


LCI UCI


[Taiwan, EHR]





Heart failure‡† 0.68 0.49 0.95

S10,15 Empagliflozin and the risk of heart failure hospitalisation in routine clinical care63

[USA, EHR]PS matching (1:1), Cox PH n = 16,443Female = 46.4% (Empa); 46.6% (Sita)Follow-up = 5.3moDuration of diabetes = NRMean HbA1c = 8.46% ; 8.60%Background metformin-use = 61.4%; 60.9%Prior IHD = 18.1% ;18.3%Heart failure at baseline = 5.1%; 5.4%Hypertension = 76.1%; 76.4%LDL (mg/dL) = 88.07; 91.14Smoking history = NR

No adjustment Optum ClinformaticsIBM MarketScanMedicare Fee-for-Service

Empagliflozin

Sitagliptin HHF‡ 0.5 0.28 0.91

Empagliflozin

Sitagliptin HHF – secondary prevention (prior CV history)¶

0.55 0.27 1.1

Empagliflozin

Sitagliptin HHF – primary prevention (no prior CV history) ¶

0.41 0.1 1.68

S10.16 Comparative-effectiveness of canagliflozin, SGLT2 inhibitors and non SGLT2 inhibitors on ‐the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real world meta analysis of 4 ‐ ‐observational databases (OBSERVE 4D)‐ 65

[USA, CDS]PS-matched, Cox PHMeta-analysis of datasets (CCAE, MDCD, MDCR, Optum)Follow-up = 60-100 days on-treatment

Baseline characteristics reported in Supplementary Data (Table S13)


(1) Truven MarketScan® Commercial Claims and Encounters (CCAE) (2) Truven MarketScan® Multi‐state Medicaid (MDCD)(3) Truven MarketScan® Medicare Supplemental Beneficiaries (MDCR)(4) OptumInsight's Clinformatics® Datamart (Optum)

Canagliflozin all non-SGLT2i

HHF‡ 0.39 0.26 0.6

Canagliflozin select non-SGLT2i

HHF¶ 0.4 0.24 0.65

Canagliflozin other SGLT2i HHF¶ 0.85 0.41 1.71

Other SGLT2i all non-SGLT2i

HHF¶ 0.39 0.24 0.6

95

Table S11: Baseline characteristics of Patorno et al (2018)45

Baseline Characteristics(after matching, if used)

Exposed(n = 17,667)

Control – DPPIV-i(n = 17,667)

Exposed(n = 20,539)

Control - GLP1RA(n = 20,539)

Exposed (n = 17,354)

Control – SU(n = 17,354)

Age, years, mean (SD) 56.5 (10.6) 56.5 (10.7) 56.8 (10.9) 56.7 (10.8) 55.9 (10.5) 55.8 (10.5)

Female delete as reported, n (%)

7931 (44.9) 7954 (45.0) 9716 (47.3) 9702 (47.2) 7809 (45.0) 7835 (45.2)

White, n (%) NR NR NR NR NR NR

Asian, n (%) NR NR NR NR NR NR

Black or African American, n (%)

NR NR NR NR NR NR

Current smoker, n (%) 1333 (7.6) 1304 (7.4) 1553 (7.6) 1523 (7.4) 1321 (7.6) 1297 (7.5)

IHD, n (%) 2018 (11.4) 1975 (11.2) 2431 (11.8) 2454 (12.0) 1895 (10.9) 1906 (11.0)

Nephropathy or eGFR (SD) Here nephropathy n (%)

1217 (6.9) 1216 (6.9) 1530 (7.5) 1524 (7.4) 1103 (6.4) 1104 (6.4)

History of hypertension, n (%)

9170 (51.9) 9164 (51.9) 10 910 (53.1) 10 994 (53.5) 8821 (50.8) 8873 (51.1)

Hyperlipidaemia 8600 (48.7) 8556 (48.4) 10 246 (49.9) 10 342 (50.4) 8544 (49.2) 8532 (49.2)

Duration of diabetes NR NR NR NR NR NR

Glycated haemoglobin, %, mean (SD)

8.8 (1.9) 8.8 (1.9) 8.8 (1.8) 8.8 (1.9) 8.7 (1.9) 8.9 (2.0)

Systolic BP, mmHg, mean (SD)

NR NR NR NR NR NR

96


Exposed(n = 17,667)

Control – DPPIV-i(n = 17,667)

Exposed(n = 20,539)

Control - GLP1RA(n = 20,539)

Exposed (n = 17,354)

Control – SU(n = 17,354)

Body mass index, kg/m2, mean (SD)

NR NR NR NR NR NR

Proportion on background metformin

NR NR NR NR NR NR

97

Table S12: Complete Results of Patorno et al (2018)45

Canagliflozin as exposure

Outcome (include negative control) Comparison HR LCI UCIHHF vs. DPP4I 0.7 0.54 0.92

vs. GLP1RA 0.61 0.47 0.78vs. SU 0.51 0.38 0.67

Primary composite - hospitalisation for AMI, acute ischaemic stroke or haemorrhagic stroke

vs. DPP4I 0.89 0.68 1.17

vs. GLP1RA 1.03 0.79 1.35vs. SU 0.86 0.65 1.13

Secondary - HF (diuretic-use) vs. DPP4I 0.64 0.53 0.76vs. GLP1RA 0.68 0.58 0.81vs. SU 0.47 0.39 0.56

Secondary - Expanded composite vs. DPP4I 0.97 0.78 1.22vs. GLP1RA 0.95 0.77 1.17vs. SU 0.9 0.72 1.13

Composite component- MI vs. DPP4I 0.91 0.64 1.29vs. GLP1RA 1.03 0.73 1.44vs. SU 0.85 0.59 1.23

Composite component - Stroke vs. DPP4I 0.81 0.54 1.22vs. GLP1RA 1.07 0.69 1.66vs. SU 0.87 0.57 1.31

Composite component - Unstable angina vs. DPP4I 1.13 0.65 1.96vs. GLP1RA 0.73 0.46 1.17vs. SU 0.72 0.41 1.28

Composite component - Coronary revascularisation vs. DPP4I 1.07 0.79 1.45vs. GLP1RA 1.01 0.77 1.32vs. SU 1.05 0.77 1.43

Secondary - ACM vs. DPP4I 0.66 0.25 1.74vs. GLP1RA 0.77 0.32 1.85vs. SU 1.34 0.47 3.87

Secondary prevention vs. DPP4I 0.9 0.59 1.38vs. GLP1RA 0.89 0.59 1.35vs. SU 0.7 0.46 1.06

98

Table S13:Baseline Characteristics for Ryan et al, 201865


Exposed CCAE

ControlCCAE

ExposedMDCD

ControlMDCD

ExposedMDCR

ControlMDCR

ExposedOptum

ControlOptum

Age, years, mean (SD) NR NR NR NR NR NR NR NR

Female/Male (%) 45.4 45.3 64.7 65.0 42.7 42.9 44.1 43.7

White, n (%) NR NR NR NR NR NR NR NR

Asian, n (%) NR NR NR NR NR NR NR NR

Black or African American, n (%) NR NR NR NR NR NR NR NR

Current smoker, n (%) NR NR NR NR NR NR NR NR

Established IHD, n (%) 3.9 3.9 7.9 7.9 10.2 10.1 6.2 6.0

Nephropathy or eGFR (SD)Here nephropathy n (%)

3.5 3.5 6.8 6.7 11.2 11.0 8.8 8.6

History of hypertension, n (%) 71.4 71.3 77.4 77.7 81.6 82.7 77.3 77.0

Hyperlipidaemia 73.1 73.0 69.5 70.5 75.0 76.0 80.2 79.9

Duration of diabetes NR NR NR NR NR NR NR NR

Glycated haemoglobin, %, mean (SD) NR NR NR NR NR NR NR NR

Systolic BP, mmHg, mean (SD) NR NR NR NR NR NR NR NR

Body mass index, kg/m2, mean (SD) NR NR NR NR NR NR NR NR

99

Proportion on background metformin NR NR NR NR NR NR NR NR

CCAE: Truven MarketScan® Commercial Claims and Encounters

MDCD: Truven MarketScan® Multi‐state Medicaid

MDCR: Truven MarketScan® Medicare Supplemental Beneficiaries

Optum: OptumInsight's Clinformatics® Datamart

100

Table S14: MortalityLegend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Adjustment Database Exposure Comparison Outcome Hazard ratio (unless otherwise specified)

LCI UCI





Population registries SGLT2i DPP4i Cardiovascular mortality¶†

0.84 0.65 1.08

SGLT2i DPP4i ACM¶

(ITT Analysis)0.8 0.69 0.92

S14.2 Acute renal outcomes with sodium glucose co‐ ‐transporter 2 inhibitors: Real world data analysis‐ ‐ 34

[Israel, CDS]Case-control study, Logistic regressionn = 6418 (SGLT2i) vs. 5604 (DPP4i)Follow-up = 24wksMale = 61.7% vs. 57.0%HbA1c (at baseline) = 8.3% vs. 8.2%Duration of diabetes = 3.5% (2yrs), 31.0% (2-10yrs), 65.5% (10+ yrs)Background metformin = NReGFR (mean) = reportedHypertension = 70.3% vs. 67.1%

sex, age, CKD stage, BMI, diabetes duration, HbA1c, Urinary ACR, Insulin-use at baseline, and co-morbidities: CVD/IHD, HTN

Maccabi Healthcare Services SGLT2i DPP4i ACM¶ OR 0.43 0.20 0.95


[USA, Norway, Denmark, Sweden, Germany, UK; mixed EHR/CDS]


history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, hypertension, obesity/body mass index, duration of diabetes mellitus, ACEi or ARB-use, -βblocker or -blocker-use, Ca2+ channel αblocker-use, loop-diuretic-use, thiazide diuretic-use

United States: Truven Health MarketScan Claims and Encounters Germany: the Diabetes Prospective Follow-Up initiative Sweden, Norway, and Denmark: mandatory full-population registries United Kingdom: CPRD + THIN

SGLT2i OAD ACM†¶ 0.52 0.42 0.64




Adjustment made to analyses on sub-analyses-only


SGLT2i OGLD Cardiovascular mortality‡

0.53 0.4 0.71

SGLT2i OGLD ACM¶ 0.51 0.45 0.58

101


LCI UCI


[USA, EHR]



ACM†‡ 0.57 0.49 0.66


[South Korea, Japan, Singapore, Israel, Australia, and Canada, mixed EHR/CDS]


age; sex; frailty; history of heart failure, MI, and atrial fibrillation; hypertension (if available); obesity/body mass index (if available); duration of diabetes (if available); and use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs),

-blockers, Ca+-channel blockers, βstatins, loop-diuretics, and thiazide diuretics


SGLT2i OAD ACM‡ 0.51 0.37 0.7

SGLT2i OAD ACM - Primary prevention (no prior CVD history)¶

0.7 0.6 0.8

SGLT2i OAD ACM - Secondary prevention (prior CVD history) ¶

0.57 0.43 0.75

S14.7 Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE TIMI 58 trial: A ‐nationwide observational study60

[Sweden, EHR]


history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, duration of diabetes mellitus treatment, angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker-use, β‐blocker or blocker-use, calcium α‐channel blocker-use, loop-diuretic-use, and thiazide diuretic-use


Dapagliflozin OAD Cardiovascular mortality‡

(ITT analysis)

0.75 0.57 0.97

Dapagliflozin OAD ACM¶

(ITT analysis)0.63 0.54 0.74

S14.8 Dapagliflozin is associated with lower risk of cardiovascular events and all cause mortality in ‐people with type 2 diabetes (CVD REAL Nordic) when ‐compared with dipeptidyl peptidase 4 inhibitor ‐therapy: A multinational observational study64




Dapagliflozin DPP4i Cardiovascular mortality‡†

0.76 0.53 1.08

Dapagliflozin DPP4i ACM‡ 0.59 0.49 0.72


[USA, CDS]


Canagliflozin DPP4i ACM¶ 0.66 0.25 1.74

Canagliflozin GLP-1 ACM¶ 0.77 0.32 1.85

102


LCI UCI

Previously reported – Table S6.6Canagliflozin SU ACM¶ 1.34 0.47 3.87

S14.10

Novel Oral Glucose-Lowering Drugs Are Associated With Lower risk of All-Cause Mortality, Cardiovascular Events and Severe Hypoglycaemia Compared With Insulin in Patients With Type 2 Diabetes61

[Sweden, EHR]


age, sex, frailty, prior CVD , and use of statins, low dose aspirin, and anti-‐hypertensives

Swedish National Register Dapagliflozin Insulin ACM‡¶

Without pre-existing CVD

0.5 0.28 0.87

Dapagliflozin Insulin ACM‡¶

With pre-existing CVD

0.36 0.16 0.81

S14.11

All-Cause Mortality in Patients With Diabetes Under Treatment With Dapagliflozin: A Population-Based, Open-Cohort Study in The Health Improvement Network Database49

[UK, EHR]


age, sex, BMI, smoking, glycated haemoglobin A1c level, duration of diabetes, systolic blood pressure level, lipid-lowering medication, insulin-use, estimated glomerular filtration rate, social deprivation index, presence of hypertension, and Charlson comorbidity index

THIN Dapagliflozin Unexposed controls

ACM‡ - total population

0.5 0.33 0.75

Dapagliflozin Unexposed controls

ACM¶ - lowrisk CV population

0.44 0.25 0.78

S14.12

Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study47

[Taiwan, EHR]




Dapagliflozin Empagliflozin Cardiovascular mortality‡†

0.54 0.14 2.12

103

Table S15: Renal outcomes (acute kidney injury)Legend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component


Outcome Hazard Ratio (Unless otherwise specified)

LCI UCI

S15.1

Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register-based cohort study50

[Sweden/Denmark, EHR]]1:1 PS-Matched, Cox PHn = 17213 (Empa = 38%, Dapa = 61%, Cana = 1%)Follow-up = 6moMale = 61%HbA1c (at baseline) = recorded (in paper supplement)Duration of diabetes = recorded (as time since initiation of diabetes medication)Background metformin = 80%Nephropathy = 4% (baseline eGFR recorded in supplement)Urinary ACR = recorded (in supplement)Diabetic eye complications = 13%Neuropathy = not recorded

HbA1c, BP, albuminuria,eGFR, BMI, smoking status

Swedish National Diabetes Register

SGLT2i GLP-1 AKI¶ 0.72 0.44 1.118

No adjustment Multiple sources (inc Swedish National Diabetes Register)

SGLT2i GLP-1 AKI‡ 0.69 0.45 1.05

S15.2

Acute renal outcomes with sodium glucose co transporter 2 ‐ ‐ ‐inhibitors: Real world data analysis‐ 34

[Israel, CDS]


eGFR (mean) = reportedUrinary ACR = reportedHypertension = 70.3% vs. 67.1%Retinopathy = 11.7% vs. 6.5%Neuropathy = not reported

sex, age, CKD stage, BMI, diabetes duration, HbA1c, Urinary ACR, Insulin-use at baseline, and co-morbidities: CVD/IHD, HTN

Maccabi Healthcare Services

SGLT2i DPP4-i Hospitalisation with AKI / initiating dialysis / sustained eGFR < 15*‡

OR 0.47 0.27 0.8

S15.3

Acute Kidney Injury in Patients on SGLT2 Inhibitors: A Propensity-Matched Analysis43

[USA, EHR]Propensity-matched, Cox PHn = 372 (Mount Sinai); 1207 (Geisinger)MS: cana = 71.8%, dapa = 19.4%, empa 8.9%GHS: cana = 60.6%, dapa = 10.8%, empa 28.6%Follow-up = 14moHbA1c (at baseline) = 8.0% vs. 7.5%; 8.2% vs. 7.7%Diabetes duration = not reported Background Metformin = 89.3% vs. 83.3%; 85.2% vs. 85.4%eGFR (at baseline) = 63.7 vs. 60.6; 87.4 vs. 87.2Urinary ACR = reportedHypertension = 90.1% vs. 91.1%; 65.3% vs. 65.3%Retinopathy or Diabetic Eye Disease = not reportedNeuropathy = not reported

Metformin-use, thiazides, smoking status, HbA1c, and race

Mount Sinai chronic kidney disease registry

SGLT2i non-user AKI (KDIGO)‡ 0.40 0.02 0.70

SGLT2i non-user AKI (ICD)‡ 0.50 0.30 0.90

Canagliflozin non-user AKI¶ - Canagliflozin

0.2 0.1 0.5

Dapagliflozin non-user AKI¶ - Dapagliflozin

1 0.5 2.7

diastolic BP, total cholesterol, HbA1c, Hb, albuminuria, anti-hypertensive-use, loop-diuretic-use, thiazide diuretic-use, and metformin-use

Geisinger Health System cohort

SGLT2i non-user AKI (KDIGO) ‡ 0.6 0.4 1.1

SGLT2i non-user AKI (ICD) ‡ 0.56 0.27 1.16

Canagliflozin non-user AKI¶ - Canagliflozin

0.61 0.33 1.12

Dapagliflozin non-user AKI¶ - Dapagliflozin

0.32 0.02 5.18

Empagliflozin non-user AKI¶ - Empagliflozin

0.96 0.21 4.35

104

Table S16: AmputationLegend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study characteristics Maximal Adjustment Database Exposure Comparison Outcome Hazard Ratio)

LCI UCI

S16.1

Cardiovascular outcomes of sodium glucose cotransporter 2 ‐inhibitors in patients with type 2 diabetes37

[USA, CDS]

Previously described – Table S6.1

Baseline PVD = not reportedPrior amputations = not reported



SGLT2i SU LLA¶ 0.74 0.57 0.96

SGLT2i DPP4i LLA¶ 0.88 0.65 1.15

S16.2

Sodium glucose co transporter 2 inhibitor-use and risk of lower‐ ‐ ‐ ‐extremity amputation: Evolving questions, evolving answers52

[USA, CDS]PS-Matched, Cox PHn = 46878 (SU); 49324 (DPP4i)Male = 52.3% (SU); 52.8% (DPP4i)Follow-up = 1yrHbA1c = not reportedDuration of diabetes = not reportedBackground metformin = 77.7% (SU); 77.7% (DPP4i)Smoking = 4.8% (SU); 5.0% (DPP4i)Baseline PVD = 2.8% (SU); 2.8% (DPP4i)Prior amputations = 0.1% (SU); 0.2% (DPP4i)

age, sex, baseline neuropathy, peripheral vascular disease, congestive heart failure, chronic kidney disease, ischaemic heart disease, and metformin-use

MarketScan SGLT2i SU LLA‡ 1.02 0.67 1.55

SGLT2i DDP-4i LLA‡ 1.69 1.2 2.38

S16.3

Risk of amputations associated with SGLT2 inhibitors compared to DPP-4 inhibitors: A propensity-matched cohort study33

[USA, CDS]PSMatched, Cox PHn = 30216 (cana = 58.1%, empa = 26.4%, dapa = 15.5%)Female = 47.6%Follow-up = 0.6 yrsHbA1c = not reportedDuration of diabetes = not reportedBackground metformin = 70.3%Smoking = not reportedBaseline PVD = 4.6%Prior amputation = 0.1%

age, gender, calendar year of treatment initiation, adapted DCSI, OAD-use, presence of diabetic foot disease, PVD, history of amputations


SGLT2i DPP4i LLA‡ 1.38 0.83 2.31

S16.4




Baseline arterial disease (inc prior amputation) = 6%

HbA1c,BP, eGFR,albuminuria, BMI, and smoking status

Population registries

SGLT2i DPP4i LLA¶ 1.26 0.88 1.81

105


LCI UCI

S16.5

Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes35

[USA, CDS]PS-Matched, Cox PHn = 39869 (DPP4i); 39120 (GLP-1)Female = 47.3% (SGLT2i); 43.3% (DPP4i); 61.0% (GLP-1)Follow-up = not reportedHbA1c = not reportedDuration of diabetes = not reportedBackground metformin = 65.8% (DPP4i); 61.2% (GLP-1)Smoking = not reportedBaseline PVD = not reportedBaseline CVD = 5.8% (SGL); 6.7% (DPP4i); 5.4% (GLP-1)Prior amputation = not reported

Not reported Truven Health MarketScan

SGLT2i DPP4i LLA‡ 1.5 0.85 2.67

SGLT2i GLP-1 LLA‡ 1.47 0.64 3.36

S16.6


[Norway, Sweden, HER]


Baseline PVD = 6%Prior amputation = <1%Baseline CVD =


SGLT2i GLP-1 LLA‡ 2.32 1.37 3.91

HbA1c, BP, albuminuria,eGFR, BMI, and smoking status


SGLT2i GLP-1 LLA¶ 2.79 1.19 6.55

S16.7

Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 InhibitorResults From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World)66

[USA, EHR]


Baseline PVD = 16.3% (exposed); 15.4% (unexposed)Prior amputations = not reported

Not reported US Department of Defense Military Health System


LLA¶ 2.01 0.89 4.53

S16.8

Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium glucose co transporter 2 inhibitors ‐ ‐ ‐in the USA: A retrospective cohort study68

[USA, EHR]PS-Matched, Cox PHn = 63,845Female = 44.5%Follow-up = 1.27yrsDuration of diabetes = not reportedMean HbA1c = not reportedBackground metformin = 81.1%Smoking = not reportedBaseline PVD = 8.1%Prior amputation = not reported

Not reported Truven MarketScan CCAE database

Canagliflozin

Non-SGLT2i, non-metformin

LLA‡ 0.87 0.52 1.46

S16. The Effect of Dapagliflozin on Glycaemic Control and Other age, sex and diabetes duration SCI Diabetes Dapagliflozi Non-users LLA¶ 1.29 0.71 2.36

106


LCI UCI

9 Cardiovascular Disease risk Factors in Type 2 Diabetes Mellitus: A Real-World Observational Study59

[Scotland, EHR]


Baseline PVD = not reportedPrior amputation = not reported

n

107

Table S17: Diabetic ketoacidosisLegend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Maximally-adjusted: Database Exposure Comparison Outcome Hazard ratio

LCI UCI

S17.1


[Sweden/Denmark, EHR]PS-Matched, Cox PH


Background insulin = 16% (fast-acting); 29% (long-acting)Previous DKA = <1%


SGLT2i GLP-1 DKA‡ 2.14 1.01 4.52



SGLT2i GLP-1 DKA¶ 2.13 0.79 5.78

S17.2

Sodium glucose co transporter 2 inhibitors and the risk of ‐ ‐ ‐ketoacidosis in patients with type 2 diabetes mellitus: A nationwide population based cohort study‐ 41

[South Korea, CDS]PS-Matched, Cox PHn = 56,325Male = 55.3%Follow-up = 319.1 days (mean)Duration of diabetes = not reportedMean HbA1c = not reportedBackground metformin = 80.25%, Background insulin = 12.85%Previous DKA = not reported

age, sex, use of other medications (metformin, insulin, renin angiotensin ‐system inhibitors and diuretics), and the presence of diabetes related ‐macrovascular and microvascular complications

Korean Health Insurance Review and Assessment Service

SGLT2i DPP4i DKA‡ 0.96 0.58 1.57

S17.3




Background insulin = 32% Prior DKA = not reported

HbA1c,BP, eGFR, albuminuria, BMI, and smoking status

Population registries

SGLT2i DPP4i DKA¶ 2.14 1.17 4.09

S17.4

Incidence of diabetic ketoacidosis among patients with type 2 diabetes mellitus treated with SGLT2 inhibitors and other anti-hyperglycemic agents67

[USA, CDS]PS-Matched, Cox PHn = 30196Male/Female = not reportedFollow-up = not reportedDuration of diabetes = 5.4yrsMean HbA1c = not reportedBackground metformin = 90.5% (exposed); Background insulin = 10.3% (exposed); 7.8% (unexposed)Previous DKA = not reported

No adjustment (NOTE: refined definition for Type 2 DM)

Truven MarketScan SGLT2i OADs, non-metformin

DKA‡ 1.13 0.43 3

108

S17.5

The Effect of Dapagliflozin on Glycaemic Control and Other Cardiovascular Disease risk Factors in Type 2 Diabetes Mellitus: A Real-World Observational Study59

[Scotland, EHR]


Background insulin = 7.6% (exposed); 7.1% (unexposed)Previous DKA = not reported

age, sex and diabetes duration SCI Diabetes Dapagliflozin Non-exposure

DKA¶ 1.43 0.59 3.44

109

Table S18: Bone fracture Legend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Maximally-adjusted Database Exposure Comparison Outcome Result (HR unless otherwise specified)

LCI UCI

S18.1


[Sweden/Denmark, EHR]


Previous fracture = 2% (in preceding 12 mo)Background oral steroid = 7%Prior falls = not reportedOsteoporosis/Bisphosphonate use = not reported


SGLT2i GLP-1 Fracture‡ 1.11 0.93 1.33



SGLT2i GLP-1 Fracture¶ 1.09 0.86 1.39

S18.2 Sodium-glucose co-transporter-2 inhibitors and the risk of fractures of the upper or lower-limbs in patients with type2 diabetes: A nested case–control study46

[Germany, CDS]Conditional logistic regression, Nested, Matched, Case-Control (1:40)n = 7522 (exposed) vs. 296845 (unexposed)Female = 59.3%Follow-up = not reportedDuration of diabetes = not reportedMean HbA1c = not reportedBackground metformin = not reportedPrevious fracture = not reportedBackground oral steroid use = 38.4% (exposed); 34.5% (unexposed)Prior falls = not reportedOsteoporosis = 19.4% (exposed); 14.2% (unexposed)

risk of fractures, including indicators for type 2 diabetes severity and complications, co morbidities of type 2 ‐diabetes, and risk factors for fractures and falls

InGef database Metformin plus SGLT2i

Metformin plus any other AHA

Fracture‡ OR 0.99 0.71 1.37

S18.3

Fracture risk After Initiation of Use of Canagliflozin: A Cohort Study38

[USA, CDS]PS-Matched, Cox PHn = 79,964 (total) Male = 54.6% (Cana); 50.6% (GLP-1)Follow-up = 34wksDuration of diabetes = not reportedMean HbA1c = reportedBackground metformin = 56.9% (Cana); 56.9% (GLP-1)Previous fracture = not reportedBackground oral steroid-use = 9.0% (Cana); 8.9% (GLP-1)Prior falls = reportedOsteoporosis = 2.1% (Cana), 1.5% (GLP-1)

No further adjustment after propensity matching

Optum Clinformatics Data Mart (“Optum”) IBM MarketScan (“MarketScan”)

Canagliflozin

GLP-1 Fracture‡ 0.98 0.75 1.26

110

S18.4

Initiation of dapagliflozin and treatment emergent ‐fractures48

[UK, EHR]Cox regression, no matchingn = 4548 (exposed), 18070 (unexposed)Male = 43.3%Follow-up = 12.9mo (exposed); 11.9mo (unexposed)Duration of diabetes = 9.9yrs (exposed); 9.6 (unexposed)Mean HbA1c = 9.1% (exposed); 9.6% (unexposed)Background metformin = not reportedPrevious fracture = not reportedBackground oral steroid-use = 6.4% (exposed); 7.7% (unexposed)Prior falls = not reportedAnti-osteoporotic fracture = 2.0% (exposed); 2.6% (unexposed)

age, gender, BMI, smoking, HbA1c, duration of DM, insulin-use, eGFR, other co-morbidities

The Health Improvement Network

Dapagliflozin

Unexposed pt with T2DM

Fragility fracture‡

0.87 0.56 1.35

Dapagliflozin

Unexposed pt with T2DM

Any fracture¶ 0.89 0.66 1.2

111

Table S19: Genitourinary infection Legend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Adjustment Database Exposure Comparison Outcome Hazard ratio

LCI UCI

S19.1 Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register-based cohort study50

[Sweden/Denmark, EHR]PS-Matched, Cox PH


Oral steroid-use at baseline = 7%Prior UTI = 2%BPH = not reportedPrior infection = not reportedRecent anti-biotic-use = not reportedUrogenital surgery = not reportedUrinary incontinence = not reported


SGLT2i GLP-1 UTI‡ 0.89 0.67 1.19

HbA1c, BP, albuminuria, eGFR, BMI, and smoking


SGLT2i GLP-1 UTI¶ 0.81 0.55 1.2

S19.2 Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections A Population-Based Cohort Study36

[USA, CDS]PS Matching, Cox PH, followed bt PROC PREG procedureData source combined using Inverse Variance Fixed Effects meta-analysisn = 61876 (vs. DPP4-i); 55989 (vs. GLP-1)Male = 54.1% (DPP4-i); 49.4% (GLP-1)Follow-up = 204d (DPP4i); 221d (GLP-1)Duration of diabetes = not reportedMean HbA1c = 8.8% (DPP4i); 8.7% (GLP-1)Background metformin = 78.1% (DPP4-i); 76.1% (GLP-1)Steroid-use = 10.3% (DPP4-i); 10.4% (GLP-1)Recent anti-biotic-use = 23.3% (DPP4i); 24.4% (GLP-1)Prior mycotic infections = 5.5% (DPP4i); 6.2% (GLP-1)BPH = not reportedUrogenital surgery = not reportedUrinary incontinence = not reported

IBM MarketScan (“MarketScan”) and Optum Clinformatics Data Mart (“Optum”)

SGLT2i GLP-1 Severe UTI‡ 0.72 0.53 0.99

SGLT2i DPP4i Severe UTI‡ 0.98 0.68 1.41

S19.3 Use of SGLT2 inhibitors for diabetes and risk of infection: Analysis using general practice records from the NPS MedicineWise MedicineInsight program39

[Australia, CDS]Cox PHn = 1997 (SGLT2i) vs. 1964 (DPP4i)(92.7% on dapa; 3.0% cana; 4.3% empa)Female = 45% (SGLT2i); 41% (DPP4i)

age, gender, weight, geographical location, smoking status, prior infections and co-morbidity

MedicineInsight SGLT2i DPP4i UTI‡ 0.9 0.66 1.24

112


LCI UCI

Follow-up = 6 mo Duration of diabetes = not reportedMean HbA1c = 8.8% (SGLT2i); 8.4% (DPP4i)Prior UTI = 3% (SGLT2i); 4% (DPP4i)Prior GMI = 2% (SGLT2i); 1% (DPP4i)Oral steroid-use at baseline = not reportedRecent anti-biotic-use = not reportedBPH = not reportedUrogenital surgery = not reportedUrinary incontinence = not reported

SGLT2i DPP4i GMI‡ 3.5 1.95 5.89

S19.4 Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: A population-based study of older women and men with diabetes42

[Canada, CDS]Cohort, Cox PH, Duration response study (30d, 60d, 90d, 120d)n = 21444 vs. 22463 (DPP4i)(Cana = 69.7%, Empa 37.8%, Dapa = 8.3%)Female = 41.0% (SGLT2i); 46.1% (DPP4i)Follow-up = 120dDuration of diabetes = 14.3yrs (SGLT2i); 12.8yrs (DPP4i) Mean HbA1c = not reportedBackground metformin-use = 81% (SGLT2i); 79.5% (DPP4i)Anti-biotic prescription within 60d of index = 3.6% (SGLT2i); 5.5% (DPP4i) Prior GMI = 8.0% (SGLT2i); 6.8% (DPP4i)Prior UTI = 15.9% (SGLT2i); 18.% (DPP4i)BPH = 13.4% (SGLT2i); 14.0% (DPP4i)Urogenital surgery = 2.3% (SGLT2i); 2.6% (DPP4i)Urinary incontinence = 12.2% (SGLT2i); 14.3% (DPP4i)

age, sex, anti-biotic-use prior to 60 days of the index date and the propensity score

Ontario administrative database - analysed at Institute for Clinical Evaluative Sciences

SGLT2i DPP4i UTI (at 120d)¶ 0.99 0.92 1.06

SGLT2i DPP4i GMI (at 120d) ¶ 2.18 1.99 2.4

S19.5 Increased risk of mycotic infections associated with sodium–glucose co transporter 2 inhibitors: a prescription sequence ‐symmetry analysis32

[USA, CDS]Case-based prescription sequence symmetry analysisn = 23276 (exposed) vs. 17504 (exposed + remedy medication)Female = 49.5%(Cana = 68.9%, Dapa = 22.4%, Empa = 8.7%)Follow-up = 1yrDuration o+C17f diabetes = not reported Mean HbA1c = not reportedBackground metformin = not reportedOral steroid-use at baseline = not reportedRecent anti-biotic-use = not reportedBPH = not reportedPrior GMI/UTI = not reportedUrogenital surgery / urinary incontinence = not reported


SGLT2i No comparator Antifungal usage at 365 days‡

1.24 1.2 1.28

113


LCI UCI

S19.6 Healthcare costs of urinary tract infections and genital mycotic infections among patients with type 2 diabetes mellitus initiated on canagliflozin: a retrospective cohort study53

[USA, CDS]PS Matching, Chi-square or Fisher’s exact testsn = 31257Female = 44.3%Follow-up = 90dDuration of diabetes = not reportedMean HbA1c = not reportedBackground metformin-use = not reportedAnti-biotic prescription claim = 25.9%Prior UTI = 0%Steroid-use = 9.9%BPH = 2.2%Urogenital surgery = not reportedUrinary incontinence = not reported


Canagliflozin Non-SGLT2i AHA UTI‡ 0.98 0.89 1.08

Canagliflozin Non-SGLT2i AHA GMI‡ 2.08 1.75 2.48

114

Table S20: HypoglycaemiaLegend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Adjustment Database Exposure Comparison Outcome Result LCI UCI

S20.1

Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis54



Prior severe hypoglycaemia = not reportedCKD = 1.2% (exposed); 1.1% (unexposed)Insulin-use at baseline = 29.9% (exposed); 30.1% (unexposed)

Not reported Diabetes Register in Sweden, Denmark and Norway

SGLT2i OGLD Hypoglycaemia¶

0.76 0·65 0·90

S20.2

Dapagliflozin is associated with lower risk of cardiovascular events and all cause mortality in people with type 2 diabetes ‐(CVD REAL Nordic) when compared with dipeptidyl peptidase‐ ‐4 inhibitor therapy: A multinational observational study64



Prior severe hypoglycaemia = not reportedNephropathy = 2.1% (Dapa); 2.0% (DPP4i)Insulin-use at baseline = 30.4% (Dapa); 29.1% (DPP4i)

Not reported Diabetes Register in Sweden, Denmark and Norway

Dapagliflozin DPP4i Hypoglycaemia¶

0.94 0.74 1.19

S20.3

Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE TIMI 58 trial: A nationwide observational study‐ 60

[Sweden, EHR]


Prior Severe Hypoglycaemia = 0.5%CKD = 1.2%Insulin-use at baseline = 44.8%

history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, duration of diabetes mellitus treatment, angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker-use, β‐blocker or blocker-use, calcium channelα‐ blocker-use, loop-diuretic-use, and thiazide diuretic-use

Swedish diabetes resgister, linked to other data sources

Dapagliflozin OAD Hypoglycaemia¶

0.91 0.78 1.06

S20.4

Novel Oral Glucose-Lowering Drugs Are Associated With Lower risk of All-Cause Mortality, Cardiovascular Events and Severe Hypoglycaemia Compared With Insulin in Patients With Type 2 Diabetes61

[Sweden, EHR]


Prior severe hypoglycaemia = <1%Nephropathy = <1%Insulin-use at baseline = n/a

age and frailty Swedish National Regsiter

Dapagliflozin Insulin Hypoglycaemia‡

2.49 0.2 31.8

115

Table S21/S22: Pancreatitis and VTE Legend: ‡ = primary outcome, ¶ = secondary outcomes / subgroup analysis / sensitivity analysis, * = composite outcome, † = composite component

Study Characteristics Adjustment Database Comparison Group Outcome Hazard ratio LCI UCI

S21


[Sweden/Denmark, EHR]


Concurrent oral glucocorticoid-use = 7%Acute Pancreatitis = 1%


GLP-1 GLP-1 Pancreatitis‡ 1.16 0.64 2.12



GLP-1 GLP-1 Pancreatitis¶ 1.47 0.69 3.14

S22

Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register-based cohort study50 [Sweden/Denmark, EHR]


Previous VTE = 3%Cancer = 7%


GLP-1 GLP-1 VTE‡ 0.99 0.71 1.38



GLP-1 GLP-1 VTE¶ 1.11 0.72 1.71

Documents

· Web viewSodium-glucose co-transporter 2 inhibitors (SGLT2i) exposure and outcomes intype 2 diabetes: a systematic review of population-based observational studies . Thomas M