IS IT TO BE OR NOT TO BE? - University Blog Servicesites.utexas.edu/pharmacotherapy-rounds/files/2020/02/Rosario-Phar… · ROSARIO | 1 Assessment Questions: 1. L.D. is a new patient

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The Wonder of GLP-1 RA and Kidneys: IS IT TO BE OR NOT TO BE?

Norbert Rosario, PharmD, BCPS PGY-2 Ambulatory Care Pharmacy Resident

Department of Pharmacotherapy and Pharmacy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, UT Health San Antonio

February 5th and 7th, 2020

At the end of this session, the participant(s) will be able to:

1. Review the pathophysiology of Diabetic Kidney Disease (DKD) and guideline recommended treatment ofdiabetes in patients with DKD.

2. Analyze the guidelines and evidence regarding Glucose-like-peptide-1 receptor agonists (GLP-1 RA) use inpatients with severe kidney disease.

3. Critique the pros and cons of utilizing GLP-1 RA in patients with severe kidney disease.

ROSARIO | 1

Assessment Questions:

1. L.D. is a new patient that comes into clinic with uncontrolled diabetes for 12 years and baseline labs indicate that she also has macroalbuminuria (312 mg/g). Is this patient at risk for developing diabetic kidney disease?

a. Yes b. No

2. Which of the following is the standard of care/first line option in the prevention of DKD in a patient with diabetes, hypertension, and proteinuria with regards to decreasing albuminuria, doubling serum creatinine, and incidence of ESRD/all-cause mortality?

a. Weight loss b. Blood pressure control c. Glycemic control d. RAAS blockade e. All the above

3. J.R. is a patient admitted to the medicine floor with a 2-week history of vomiting, fatigue, and dyspnea. Lab results return with SCr 3.2 mg/dL (baseline of 1.7 mg/dL) and an eGFR of 21 mL/min/1.73m2. Which of the following GLP-1 receptor agonists will most likely potentiate kidney injury or disease?

a. Exenatide b. Liraglutide c. Semaglutide d. Dulaglutide

4. D.J. presents to clinic with HFrEF, uncontrolled diabetes (HbA1c of 8.5%), history of hypoglycemia unawareness, eGFR of 20 mL/min/1.73m2 (stable), urine albumin-to-creatinine ratio (UACR) 550 mg/g (previously 330 mg/g), and BMI of 38. D.J.’s current diabetes medication regimen includes Lantus 30 units daily and Novolog 10 units three times per day with meals. D.J. has no cost restrictions. He expresses concern about the potential weight gain with increasing his total daily dose of insulin, because he has been working hard to lose weight. He has heard about the weight loss benefit with GLP-1 receptor agonists. Based on this information and the literature reviewed, which of the following GLP-1 receptor agonist(s) would be appropriate for D.J.?

a. Liraglutide b. Lixisenatide c. Dulaglutide d. A and C e. D.J. is not a candidate for a GLP-1 RA currently

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at [email protected].***

Faculty (Speaker) Disclosure: Norbert Rosario has indicated he has no relevant personal or financial relationships to disclose relative to the content of his presentation.

ROSARIO | 2

Backgrounds

I. Diabetic kidney disease (DKD) 1-6, 10, 11 a. Definition: characterized by reduced whole-kidney glomerular filtration rate (GFR) or urinary protein

leakage b. Increases the risk of

i. Cardiovascular events ii. Kidney failure requiring dialysis or a kidney transplant

iii. Hypoglycemia c. Chronic kidney disease (CKD): persistently elevated urine albumin excretion >30 mg/g creatinine,

persistently reduced estimated glomerular filtration (eGFR) <60 mL/min/1.73m2, or both for >3 months

d. End-stage renal disease (ESRD) or end-stage kidney disease (ESKD) – eGFR of <15 mL/min/1.73m2 and the need for kidney dialysis or transplant

i. In people with proteinuria; ESRD develops in approximately 1 in 12 people with uncontrolled diabetes mellitus (DM) after 10 years 4

II. Pathophysiology 1, 8-16 a. The exact mechanism of DKD unknown, but thought to be multifactorial with several pathogenic

contributing factors i. Chronic hyperglycemia – glomerular and tubular damage via inflammation (endothelial

damage caused by excessive and long duration of filtration and inability to filter all glucose) à leaky filters, buildup of waste products in the blood and loss of useful protein via urine

ii. Uncontrolled hypertension impairs glomerular structure and function 1. Glomerular hypertension also effects glomerular function due to imbalance in

regulation of afferent and efferent arteriolar pressure iii. Other factors that may have a role are:

1. Obesity 2. Insulin resistance 3. Dyslipidemia 4. High uric acid levels

III. Epidemiology 1-3, 5-11 a. Risk factors

Modifiable Non-modifiable Obesity Sedentary lifestyle Uncontrolled diabetes Uncontrolled hypertension Dyslipidemia Smoking

Age >40 yo Female sex Male sex has higher risk of progression to late-stage CKD or ESRD Family history of diabetes and kidney disease Ethnicity (African Americans, Latinos and Native Americans)

b. Prevalence of CKD has risen in proportion to the rise of persons with diabetes 3-6, 13, 14 i. DKD is the leading cause of CKD

ROSARIO | 3

1. Approximately 40-50% of diabetic patients will develop kidney disease in developed countries

a. Reported rates of 4% to 17% at 20 years and 16% at 30 years will progress to ESRD

ii. 2017 yielded 124,500 newly reported ESRD cases and continues to rise ~20,000 cases per year 1. Incidence rate of 370.2 per million/year in the US population

iii. Increased albuminuria and decreased glomerular filtration rate (GFR) independently and additively increased all-cause and cardiovascular disease (CVD) mortality

1. 8-fold higher risk compared to those without diabetes and CKD 2. Adjusted mortality rates for 2017 Medicare population (5% sample) with ESRD,

dialysis and transplant were: a. ESRD – 134 per 1,000 patient-years b. Dialysis – 165 per 1,000 patient-years c. Transplant – 29 per 1,000 patient-years

Table 1: Number and percentage of prevalent ESRD caused by diabetes, in the United States, 2017 6

Total HD PD Transplant N % N % N % Diabetes 287,181 218,282 76 20,255 7.1 48,644 16.9 Total 743,624 468,086 62.9 52,718 7.1 222,820 30 Data Source: Reference Table D.11 and special analyses, USRDS ESRD Database. The numbers in this table exclude “Uncertain Dialysis” and include "Unknown sex." Abbreviations: ESRD, end-stage renal disease; HD, hemodialysis; PD, peritoneal dialysis.

c. Economic Impact 3, 5-8 i. In 2011, DKD-related expenditures in the Medicare population cost ~$25 billion

1. Transition to ESRD costs per patient per year approximately $20,000 - $40,000 ii. In 2016, total Medicare (5% sample population) fee-for-service spending equaled $500.5

billion 1. $39.5 billion (13.75% of Medicare spending) was spent on patients with ESRD

a. 7.2% of the overall Medicare paid claims and has remained constant

Figure 1: Trends in total Medicare and ESRD fee-for-service spending ($, in billions), 2008-2017 6

ROSARIO | 4

Presentation and Diagnosis

I. Signs and Symptoms 1, 8, 10, 11 a. Early stages of diabetic nephropathy are usually asymptomatic b. Later stages, the following may occur:

i. Deteriorating blood pressure control ii. Proteinuria iii. Edema iv. Polyuria v. Reduced insulin or other diabetic

medication needs

vi. Confusion or difficulty concentrating vii. Dyspnea

viii. Loss of appetite ix. Nausea and vomiting x. Itching

xi. Fatigue II. Complications associated with DKD or diabetic nephropathy yield microvascular complications (i.e.

irreversible kidney damage) as well as macrovascular complications (i.e. vascular disease & strokes) 1, 10, 11 III. Laboratory Tests 3, 8, 10, 11

a. Provider prevalence of recognizing CKD amount all stages is approximately 14.5%, which does increase in stages 4 (53%) and 5 (59%)à goal is to prevent or prolong kidney disease

i. Serum Creatinine (SCr) ii. Urine albumin-to-creatinine ratio (UACR)

iii. Imaging to assess kidney structure, size and blood circulation.

iv. Kidney biopsy

Figure 2: Prognosis of CKD by GFR and albuminuria category 11

Kidney Disease Improving Global Outcomes (KDIGO) and American Diabetes Association (ADA) Guidelines

I. Prevention of DKD 1, 2, 9-11 a. Multifactorial diabetes management

i. Comprehensive care to reduce risk of kidney disease progression and cardiovascular disease

ROSARIO | 5

Glycemic control

RAAS blockade

Blood pressure control

Lipid management

Lifestyle/physical activity

Smoking cessation

Nutrition

Aspirin for prevalent cardiovascular disease

Figure 3: Diabetes with kidney disease; cardio-kidney treatment 11

b. Glycemic management 1, 10, 11 i. Lifestyle

1. Moderate-intensity activity for a cumulative duration of at least 150 minutes per week, or to a level compatible with cardiovascular and/or physical tolerance

a. Weight loss reduces kidney disease and CVD b. Reduce albumin excretion, improve blood pressure and blood glucose

ii. Nutrition 1, 5, 10, 11 1. Consume a diet in vegetables, fruits, whole grains, fiber, legumes, plant-based

proteins, unsaturated fats, and nuts and lower in processed meats, refined carbohydrates and sweetened beverages

a. Reduce proteinuria (cholesterol lowering medications also assist) 2. Sodium intake <2g per day (or <5g of sodium chloride per day)

a. To prevent CKD progression due to impaired urinary sodium excretion

c. Renin-angiotensin-aldosterone system (RAAS) blockade 5, 9-11 i. Reverses the RAAS effects of vasoconstriction on the post glomerular arterioles and reverse

the increasing glomerular hydraulic pressure and ultrafiltration of plasma proteins, which contribute to the onset and progression of chronic renal damage.

ii. ACEi or ARB to be initiated in patients with diabetes, hypertension, and albuminuria 1. Consider in patients with UACR 30-300 mg/dL 2. Recommended in patient with UACR >300 mg/dL 3. Two landmark trials, the IDNT and RENAAL were conducted in patients with diabetes

and CKD, having urinary protein excretion greater than 1g/day à ~33% decrease in doubling SCr, reduced incidence of ESRD and 16% decrease in death in combination with “conventional” therapy

ROSARIO | 6

II. Treatment of diabetes with kidney disease 1, 4, 5, 10-21

Figure 4: Glycemic treatment algorithm for patients with type-2 diabetes (T2D) and kidney disease 11

III. Guideline Recommendations for Monitoring of Diabetes with Kidney Disease 10-11 a. HbA1c is an advanced glycation end-product of hemoglobin b. Goal is to prevent diabetic complications and reduces risk of overall microvascular complications,

including nephropathy (e.g. progression of albuminuria and end-stage kidney disease), and retinopathy. 1, 5-11

i. Lower HbA1c target (e.g., <6.5% or <7.0%) might be preferred ii. Higher HbA1c target (e.g., <7.5% or <8.0%) for those with multiple co-morbidities or increased

burden of hypoglycemia might be preferred c. Glucose monitoring recommendations (Table 2) 10-11

Table 2: Recommendations in moderate to severe kidney disease10-11

Glucose Monitoring

Subjective blood glucose monitoring HbA1c Continuous glucose monitoring (CGM)

Moderate; Stage 3 (CrCl 30-50; eGFR 30-60) Reliable Reliable; recommended 2-4

times per year Useful

Severe or ESRD; Stage 4-5 (CrCl <30; eGFR <30 [ESRD <15 eGFR])

Fasting blood glucose (some reliability); other daily readings helpful

Not as reliable; recommended 2-4 times per year Commonly Useful

IV. Guideline drug therapy recommendations for patients with diabetes and CKD Table 3: Drug therapy options for T2D with kidney disease 1, 4, 10-11

Drug Class MOA HbA1c lowering Hypoglycemia risk *Biguanide âHepatic gluconeogenesis

áInsulin sensitivity 1-2% Lower

‡SGLT2i á Urinary glucose excretion 0.5-1% Lower

‡GLP-1 RA á Glucose-dependent insulin secretion, slows gastric emptying, stimulates satiety 1-1.5% Lower

‡DPP-4i á Glucose dependent insulin secretion 0.5-0.8% Lower ¥Insulins Insulin replacement to regulate metabolism no ceiling Higher *Sulfonylurea á Insulin secretion 1-2% Higher *TZD áInsulin sensitivity (PPAR-gamma agonist) 0.6-1.5% Lower Note: Cost categories based on AWP for a 30-day supply from Red Book | (*)Low = <$50; (†)Moderate = $51-150; (‡)High = >$150; (¥)Varies = >$25 | Abbreviations: sodium glucose co-transporter 2 inhibitor, SGLT2i; glucose-like peptide 1 receptor agonist, GLP-1 RA; dipeptidyl peptidase-4 inhibitor, DPP-4i; thiazolidinediones, TZD

ROSARIO | 7

a. Glucose-like peptide-1 (GLP-1) - is an incretin hormone secreted from the intestine after ingestion of glucose or other food nutrients and stimulates glucose-dependent release of insulin from the pancreatic islet cells. The incretin effect is reduced or absent in patients with T2D. 10-21

i. Incretin effect à improved blood glucose and HbA1c control, weight loss, blood pressure, reduce MACE with persistent HbA1c elevation >7% at high cardiovascular risk, and substantial reduction in albuminuria and likely preservation of eGFR. 10-15

Table 4: GLP-1 RA pharmacology review 1, 2, 10-40

Agent Dose Pharmacokinetics

Recommendations in patients with renal impairment Mild

(CrCl >50; eGFR 60-89)

Moderate (CrCl 30-50; eGFR 30-60)

Severe or ESRD (CrCl <30; eGFR <30

[ESRD <15 eGFR])

Exenatide 5-10 mcg BID Half-life: 2.4h Elimination: Renal

No adjustment Use is not recommended Not recommended

Lixisenatide 10-20 mcg daily Half-life: 3h Elimination: Renal No adjustment

No adjustment; monitor for GI effects which may lead to dehydration & worsening renal function

Not recommended; not studied

Exenatide LA 2mg weekly

Half-life: ~2 weeks Elimination: Renal No adjustment

>45 eGFR caution – monitor for hypovolemia

<45 eGFR not recommended

Not recommended

Liraglutide 0.6, 1.2, 1.8mg daily Half-life: ~13h Elimination: Peptidase and trace renal/feces

No adjustment No adjustment No adjustment

Dulaglutide 0.75-1.5mg weekly Half-life: ~5 days Elimination: Peptidase and trace renal

No adjustment No adjustment No adjustment (possibly)

Semaglutide 0.5-1mg weekly Half-life: ~1 week Elimination: Peptidase, trace renal (~3%) & feces

No adjustment Limited data Unknown

Rybelsus 3, 7, 14mg daily (oral)

Half-life: ~1 week Elimination: Peptidase; drug-related materials via urine & feces. ~3% trace renal

No adjustment Unknown Unknown

b. KDIGO GLP-1 RA recommendation for patients with T2D and CKD is for those that have not achieved glycemic targets despite use of metformin, SGLT2-I, or unable to use either of those medications (evidence level 1B) 11

i. Prioritize in patients with documented need for cardiovascular benefit ii. Start low and titrate slowly to minimize gastrointestinal side effects

iii. Doses of sulfonylureas and/or insulin may need to be reduced c. GLP-1 RA hypothesized pathophysiology for the mitigation of DKD 1, 8-16

i. The net effect of GLP-1RAs on renal hemodynamics is thus the result of a balance between stimulation of afferent vasodilation and inhibition of pathways that cause efferent vasoconstriction, leading to mostly neutral effects on renal hemodynamics13

i. Inhibition of glomerular hyperfiltration pathways include: 1. induce natriuresis via NHE3 inhibition – postprandial vasopressor response,

reduce glucagon, inhibition of sodium reabsorption, reduce renin-angiotensin system, nuclear factor-kB, and reduction of reactive oxygen species

ROSARIO | 8

Clinical Question: What is the role of GLP-1 RAs in severe kidney disease?

Exenatide Primary Literature Review

I. 78 reported cases of exenatide-induced renal disfunction from 2005 to 2008: 15, 22-23 a. Patients with mild renal impairment had a decrease in CrCl to 39 mL/min, which would be moderately-

severe impairment b. Hypothesis: Induced natriuresis and decreased renal perfusion à diuretic effect which can cause volume

contraction, ischemic glomeruli and tubular-interstitial injury

Table 5: Effect of renal Impairment on exenatide pharmacokinetics (PK) 24

Objective Baseline characteristics Interventions Results Take-away

Evaluate the PK, safety and tolerability of a single dose in patients with renal impairment

N = 31; 49% female 36-64 yo Normal (>80mL/min) = 8 [mean 111] Mild (51-80mL/min) = 8 [mean 68] Moderate (31-50mL/min) = 7 [mean 45] ESRD hemodialysis = 8

Exenatide 5 mcg or 10 mcg • 10mcg in

normal, mild and 2 of the moderate patients

• 5 mcg in moderate and ESRD

Normal AUC ~10,000 p mol Explore relationship of clearance (CLp/f) and CrCl • Mean half-life of

healthy vs. mild vs. moderate vs. ESRD = 1.5h vs. 2.1h vs. 3.2h vs. 6h

• CLp/f: 8.14 vs. 5.19 vs. 7.11 vs. 1.3 h-1

Results also added 4 single-dose crossover studies à 67 subjects (50 males and 17 females); 63 had normal renal function and 4 had mild impairment

Well tolerated in normal, mild and moderate impairment. à ok to use >30 mL/min

• Clearance reduced by 36% in moderate impairment; p = 0.008

• Clearance reduced by 84% in ESRD; p < 0.001

• AUC 1.63 times higher with moderate impairment

• AUC up to 6.24 times higher with ESRD

Increased nausea and vomiting in ESRD à poor tolerability at 5 mcg dose

Table 6: Primary and renal outcomes for exenatide 13, 15, 16, 25

Primary outcome Kidney outcomes Drug Trial Kidney-related

eligibility criteria Primary outcome

Effect on primary outcome

Effect on albuminuria

Effect on GFR loss*

Adverse effects

Exenatide EXSCEL eGFR >30 mL/min/1.73m2

MACE ND NA NA None noted

↓ = significant reduction in risk, with HR estimate >0.7 and 95% confidence interval not overlapping 1 ↓↓ = significant reduction in risk, with HR estimate ≤0.7 and 95% confidence interval not overlapping 1 * Variable composite outcomes that include loss of eGFR, ESKD, and related outcomes

ROSARIO | 9

Lixisenatide Primary Literature Review

Table 7: Renal baseline characteristics and outcomes for lixisenatide 13-14, 16, 26-27

Kidney outcomes Trial: ELIXA (N = 6068)

Albuminuria <30 mg/g 30-300 mg/g >300 mg/g

eGFR 60-89

eGFR 30-59

eGFR <30 ACEi or ARB Effect on

albuminuria Effect on GFR loss*

Adverse effects

Lixisenatide N = 2984

N=2250 N=552 N=182

57% (1280) 47% (259) 36% (65)

16% (367) 32% (175) 55% (101)

<1% (2) <1% (2) --

86.76% (1952) 86.78% (479) 89.1% (163)

↓ (-2%) (-16 to 22%) (-38 to 43%)

ND ND


Liraglutide Primary Literature Review

I. Case report of liraglutide induced kidney injury 15, 28-29 a. 53 yo female with sarcoidosis had severe and worsening gastrointestinal symptoms for weeks

i. Dehydration, acute kidney injury & lost 8.9 kg in the past month b. Liraglutide 1.8mg/day

i. Other medications included ciprofloxacin, quinapril, triamterene/hydrochlorothiazide, spironolactone, glipizide, pioglitazone, gemfibrozil, simvastatin, fish oil, fexofenadine, montelukast, fluticasone, Advair, ipratropium, aspirin, calcitriol, calcium with vitamin D, dicyclomine and promethazine.

c. Renal biopsy depicted acute tubular necrosis d. Discontinuation of liraglutide, quinapril volume repletion and hemodialysis e. Key points: liraglutide was started at highest dose without titration, multiple drug interactions (i.e.

spironolactone with triamterene, gemfibrozil with simvastatin), other medications that could cause nausea (i.e. fish oil and ciprofloxacin), missing lab information and possible pancreatitis.

Table 8: Safety and efficacy of liraglutide in patients with T2D and ESRD 30

Objective Baseline characteristics

Interventions (1 liraglutide:1 placebo)

Results Take-away

Safety and efficacy in dialysis dependent ESRD

(multicenter, placebo-controlled, double-blind, parallel-group, randomized trial) Denmark

Sept. 2011-Oct. 2013

N = 47 (24 ESRD; 23 normal renal function)

>18 yo, chronic hemodialysis or peritoneal dialysis, T2D

~80% men

10-16 + 3 years diabetes duration

90% on anti-hypertensives

HbA1c in ESRD 6.6%; control 7.8%

20 ESRD (14:10) 20 control (11:12) • Standard liraglutide

concentration in normal renal function is ~20,000 + 8,000 p mol/L

Primary: Change in dose corrected liraglutide trough • Concentration

increased 49% CI 6-109; p = 0.002

Secondary: adverse effects, glycemic control, change in baseline insulin, change weight, and hypoglycemic events • Increased nausea

and vomiting in ESRD; p<0.04

• No difference in hypoglycemia

Patients with ESRD titrated up on liraglutide more slowly; at comparable 1.2mg dose after 12 weeks.

No signs of progressive accumulation.

0.5% HbA1c lowering in ESRD

Weight loss benefit maintained ~3kg

Secondary endpoints not powered

ROSARIO | 10

Table 9: Effect of hemodialysis on plasma liraglutide levels in patients with T2D and ESRD 31

Objective Baseline characteristics

Interventions (stable dose for at least 2 weeks)

Results Take-away

Determine if hemodialysis (HD) affects the pharmacokinetic profile of liraglutide

(single-center, open-label, pilot study)

Japan; 90% male

N = 10 DM and ESRD – HD preformed on days 1 and 3 (~10h post dose)

>20 yo (65.8 + 9.3), body weight 57.9 + 9.8 kg, diabetes duration 20.1 + 9, baseline HbA1c 5.9 + 0.9%, eGFR 4.2 + 1.3 mL/min/1.73m2

Liraglutide 0.6mg (n = 1) or 0.9mg dose (n = 9)

Primary: efficacy of liraglutide in controlling blood glucose and evaluate the effect on hypoglycemia. • Max glucose 188 vs.

226; Min glucose 93 vs. 88; Time (minutes) <70mg/dL 2.5 + 5.4 vs. 6 + 17.3; AUC (mg/dL *min) 5 + 10.5 vs. 36.5 + 112

Secondary: evaluate the effect of off-HD vs. on-HD plasma levels of liraglutide • AUC pmol 415700

vs. 473100; Cmax 20940 vs. 22620; tmax 9.5 vs 10.5; CL/f 200 vs. 188

AUC and Cmax similar between patients with normal renal function. Unlike exenatide which was 3.37 and 1.38 times higher in non-diabetic ESRD patients than healthy control patients respectively.

No signs or symptoms of hypoglycemia observed.

No observed nausea or vomiting; likely due to patients being on stable doses.

Table 10: Primary and renal outcomes for liraglutide32





Effect on GFR loss*

Adverse effects

Liraglutide LEADER eGFR >15 mL/min/1.73m2

MACE ↓ ↓ ND GI


Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017; 377: 839-48.

Objectives Determine the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes.

Methods Multicenter (410 sites in 32 countries), double-blind, placebo-controlled trial, patients with T2D and a high risk of cardiovascular disease. Renal outcomes were ascertained every 12 months and at the end of the trial. 2010 to 2012; median follow-up 3.8 years (42 to 90-month follow-up)

Patient population Inclusion Criteria:

• T2DM and Hgb A1c ≥7.0% • If age ≥50 years, has ≥1 of the following:

o Cardiovascular, cerebrovascular, or peripheral vascular disease

o CKD with eGFR <60 mL/min/1.73m2, but not on HD

o HF with NYHA class II-III symptoms

Exclusion Criteria: • T1DM • Use of GLP-1 RA, DPP-4 inhibitor, or pramlintide <3

months prior to screening • Use of insulin except long-acting agents (including

NPH) in prior 3 months • Intensification of treatment to prevent acute

complications of diabetes in the last 3 months

ROSARIO | 11

• If age ≥60 years, has risk factors for vascular disease (microalbuminuria/proteinuria, HTN with LVH, systolic or diastolic LV dysfunction, or ABI <0.9)

• ACS or cerebrovascular event in < 14 days • ESRD, ESLD, or HF with NYHA class IV symptoms • Prior or anticipated organ transplantation • Family or personal history of multiple endocrine

neoplasia type 2 or familial medullary thyroid carcinoma

• History of non-familial medullary thyroid carcinoma • Malignant neoplasm in prior 5 years

Intervention N = 9340 participants [2158 with moderate to severe renal impairment] Drug:

• Liraglutide 1.8mg (n=4668) [1116] • Placebo (n=4672) [1042]

Outcomes Composite renal outcome(s): • new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level and an eGFR <45

mL/min/1.73 m2 of body surface area (hereafter referred to as persistent doubling of the serum creatinine level), the need for continuous renal-replacement therapy (end-stage renal disease) with no reversible cause of the renal disease, or death from renal disease.

Statistical analysis Post-hoc 85% power to detect a risk of the composite renal outcome Cox-proportional-hazards model 2-sided 95% confidence interval

Results

Liraglutide (n = 4668) Placebo (n = 4672) eGFR <60 (n = 2158) Female, N (%) 1657 (35.5) 1680 (36) 836 (38.7) Age, years 64.2 64.4 67.3 + 7.5 Diabetes duration, years 12.8 12.9 15.2 + 8.6 HbA1c, % 8.7 8.7 8.6 + 1.5 eGFR (mL/min/1.73m2) 80.2 80.6 -- Moderate impairment (eGFR 30-59) 999 (21.4) 935 (20) 1934 (89.6)

Severe impairment (eGFR <30) 117 (2.5) 107 (2.3) 224 (10.4) Microalbuminuria 1223 (26.2) 1233 (26.4) 625 (23.4) Macroalbuminuria 461 (9.9) 505 (10.8) 505 (23.4) ACEi or ARB 3905 (83.7) 3836 (82.1) 1862 (86.3) Insulin-naïve OAD only

2630 (56.3) 2436 (52.2)

2541 (54.4) 2375 (50.8)

1005 (46.6) 908 (42.1)

Insulin treated Insulin only Insulin + OAD

2038 (43.7) 361 (7.7) 1677 (35.9)

2131 (45.6) 377 (8.1) 1754 (37.5)

1153 (53.4) 373 (17.3) 780 (36.1)

ROSARIO | 12

Author’s conclusion

Lower rate of renal outcomes in the liraglutide group; driven mostly by the lower incidence of macroalbuminuria. There was also a non-significant lower risk of doubling serum creatinine and ESRD during the 5-year follow-up.

Reviewer’s critique Strengths: • Use of ACEi or ARB • Fairly large population size of moderate to severe

renal impairment

Limitations: • Not powered for renal analysis • Unable to extrapolate long-term outcomes • Generalizability (78% white)

Take-home points • Composite renal outcome that was 22% lower in liraglutide group (driven by new or worsening macroalbuminuria) • Prolonged time to decreasing eGFR in both moderate/moderately severe and severe kidney impairment • Less hypoglycemia events

Dulaglutide Primary Literature Review 34

Table 11: Primary and renal outcomes for dulaglutide 35

Primary outcome Kidney outcomes

Drug Trial Renal eligibility criteria

Primary outcome

Primary outcome effect


GFR loss effect*

Adverse effects

Dulaglutide REWIND eGFR >15 mL/min/1.73m2 MACE ↓ ↓ ↓ GI

Dulaglutide AWARD-7 eGFR >15 mL/min/1.73m2 Safety/Efficacy ↓ ↓ ↓ GI


Based on entire LEADER population: Microvascular event: 7.6% v. 8.9%; p=0.02; NNT 77 • Nephropathy: 5.7% vs. 7.2%; p=0.003; NNT 67

Severe hypoglycemia (<56 mg/dL): 2.4% vs. 3.3%; p=0.02; NNH 111

Nausea: 77 (1.6%) vs. 18 (0.4%); p <0.001

Vomiting: 31 (0.7%) vs. 2 (<0.1%); p <0.001

Diarrhea: 27 (0.6%) vs. 5 (0.1%); p <0.001

ROSARIO | 13

Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicenter, open-label, randomized trial. Lancet Diabetes Endocrinol. 2018; 6:605-17

Objectives Assess the efficacy and safety of dulaglutide in patients with T2D and moderate-to-severe CKD.

Methods

• 52-week, randomized, multicenter, open-label (masked dulaglutide dose), parallel-arm trial done at 99 clinical research sites in nine countries (Brazil, Hungary, Mexico, Poland, Romania, South Africa, Spain, Ukraine, and the USA).

• August 2012 to November 2015 • Kidney events defined as any increase in serum creatinine >30% above baseline.

Patient population

Inclusion Criteria:

• age > 18 years old (Japan: > 20 years old) • Diagnosed with type 2 diabetes and CKD stage

3-4 • HbA1c in the range 7·5–10·5% • treatment with insulin plus an oral

antihyperglycemic drug or only insulin treatment

• maximum tolerated dose of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker

Exclusion Criteria:

• type 1 diabetes; • treatment with oral antihyperglycemic drug without

insulin • treatment with GLP-1 receptor agonists or a DPP-4

inhibitor • chronic kidney disease stage 5, maintenance dialysis

treatment, likelihood of requiring dialysis or a kidney transplant during the study

• acute kidney injury within 2 months before randomization

Intervention N = 577 Drug: (target FBG <150 mg/dL – insulin titration allowed)

• Dulaglutide 1.5 mg weekly subcutaneous injections (N=193) • Dulaglutide 0.75 mg weekly subcutaneous injections (N=190) • Insulin glargine (N=194)

Outcomes

Primary outcome: • Change in HbA1c from baseline to week 26 Secondary outcome: (measured at baseline, 26 weeks & 52 weeks) • Change in eGFR creatinine, urine albumin-creatinine ratio (UACR), bodyweight, rate of hypoglycemia and allergic

reactions. Adverse events of interest: • Kidney events, acute pancreatitis, thyroid neoplasms, cardiovascular events and allergic reactions

Statistical analysis

N = 564 with 150 comparators per group at 26 weeks à 88% power for non-inferiority -- Accomplished Two-sided significance level of 0.05, with a margin of 0.4% and SD of 1.1%

ROSARIO | 14

Results Demographics Dulaglutide 1.5 mg

(n=192) Dulaglutide 0.75 mg (n=190)

Insulin glargine (n=194)

Age ~65 ~65 ~64 Female 88(46%) 86(45%) 101(52%) White 134(71%) 122(66%) 137(71%) Hispanic 78(41%) 75(39%) 79(41%) Diabetes duration (years) 17.6 (8.7) 18 (8.8) 18.7 (8.7) HbA1c; % 8.6 8.6 8.6 Duration of CKD (years) 4.2(5.6) 4(4.9) 3.5(4) eGFR ml/min/m2 38.1 (13.2) 38.3 (12.3) 38.5 (13) eGFR geometric mean; ml/min/m2 35.7 36.2 36.1 eGFR 60-89 ml/min/m2 9 (5%) 7 (4%) 14 (7%) eGFR 45-59 ml/min/m2 53 (28%) 53 (28%) 51 (26%) eGFR 30-44 ml/min/m2 73 (38%) 75 (39%) 67 (35%) eGFR 15-29 ml/min/m2 55 (29%) 55 (29%) 61 (31%) eGFR <15 ml/min/m2 2 (1%) 0 (0%) 1 (1%) UACR (mg/g, median [IQR]) 213.7 (45.8-868) 233.6 (36.7-946.5) 195.6 (30.1-1015.1) Normal albuminuria (<30 mg/g) 34 (18%) 44 (23%) 48 (25%) Microalbuminuria UACR 30-300 mg/g 74 (39%) 61 (32%) 56 (29%) Macroalbuminuria UACR >300 mg/g 84 (44%) 84 (44%) 90 (46%) ACEi or ARB 165 (90%) 170 (94%) 174 (94%)

Dulaglutide 1.5

mg (n=192) Dulaglutide 0.75 mg (n=190)

Insulin glargine (n=194)

p value • Column 1 v 3 • Column 2 v 3

Primary outcome

Change in HbA1c at 26 weeks -1.2 -1.1 -1.1 • <0.0001

= 0.0004 • 0.0001

Change in HbA1c at 52 weeks -1.1 -1.1 -1.0 • <0.0001

= 0.0005 • <0.0001

Secondary outcomes

Change in eGFR at 26 weeks -0.1 -0.4 -1.9 • 0.0111 • 0.0293

Change in eGFR at 52 weeks -1.1 -1.5 -2.9 Not significant Macroalbuminuria

% Change in UACR at 26 weeks -43.1 -25.3 -14.3 • 0.0076 • ND

% Change in UACR at 52 weeks -29 -12.3 0.1 • 0.0205 • ND

Adverse effects Serious adverse events (52 weeks) 38 (20%) 45 (24%) 52 (27%) • 0.113

• 0.516

Total Hypoglycemia, patients 95 (50%) 113 (60%) 145 (75%) • <0.0001 • <0.05

Documented symptomatic hypoglycemia, incidence 77 (41%) 91 (48%) 123 (64%) • <0.0001

• <0.05

ROSARIO | 15

Nocturnal hypoglycemia, proportion of patients 39 (21%) 45 (24%) 93 (48%) • <0.0001

• <0.0001 Severe hypoglycemia, proportion of patients 0 (0%) 5 (3%) 13 (7%) • <0.05

• ND

Diarrhea 33 (17%) 30 (16%) 14 (7%) • 0.003 • 0.011

Nausea 38 (20%) 27 (14%) 9 (5%) • <0.0001 • 0.001

Vomiting 26 (14%) 16 (8%) 9 (5%) • 0.002 • 0.108

Constipation 12 (6%) 10 (5%) 6 (3%) • 0.128 • 0.286

Kidney events 79 (41%) 73 (38%) 91 (47%) • 0.254 • 0.093

Pancreatitis 2 (1%) 0 (0%) 1 (1%) -- Transition to end-stage renal disease Transition to maintenance dialysis 0 (0%) 2 (1%) 2 (1%) Overall: 0.477

Kidney transplantation 0 (0%) 0 (0%) 0 (0%) -- Without reported dialysis or transplant 8 (4%) 12 (7%) 14 (7%) Overall: 0.430

Death due to kidney disease 0 (0%) 0 (0%) 0 (0%) -- All deaths 2 (1%) 7 (4%) 6 (3%) --

eGFR = estimated glomerular filtration rate; ND = no significant difference; v = versus; ACEi = Angiotensin-converting enzyme inhibitor(s); ARB = Angiotensin II-receptor blocker; GLP-1 RA = Glucagon-like peptide-1 receptor agonist(s); HbA1c = Hemoglobin A1c; UACR = urine albumin-creatinine ratio. Serious adverse events = hypoglycemia, AMI, AKI and increase in blood creatinine concentrations.

Author’s conclusion Patients with diabetes and moderate to severe chronic kidney disease had improved glycemic control, weight loss, lower rate of hypoglycemia, smaller eGFR decline and greater reduction in albuminuria compared to insulin glargine despite 90% of patients being on ACEi or ARB.

Reviewer’s critique Strengths:

• Randomized • Insulin titration allowed • Measured adherence • Appropriate labs • On appropriate preventative medications

Limitations: • Open label • Renal outcomes were secondary analysis • Secondary outcomes not powered for significance • Small population size

Take-home points • HbA1c lowering effect was maintained in dulaglutide groups at 26 and 52 weeks (~1% lowering) • Stage 3b through 5: dulaglutide 1.5mg = 130 (67.7%), dulaglutide 0.75mg = 130 (68.4%), and insulin glargine = 129

(66.5%) o Change in eGFR was significantly less in dulaglutide groups at 26 weeks, and while not significant at 52 weeks

it was > 50% less of a change than insulin glargine o ESRD occurred in 8 (4%) dulaglutide 1.5mg v. 14 (7%) dulaglutide 0.75mg v. 16 (8%) insulin glargine.

• Albuminuria between the groups were as follows: dulaglutide 1.5mg = 158 (82.3%), dulaglutide 0.75mg = 145 (76.3%), and insulin glargine = 146 (75.3%)

o UACR was reduced significantly in dulaglutide 1.5mg dose compared to insulin glargine, and while dulaglutide 0.75mg dose was not significant in reduction it did maintain reduction in albuminuria verses insulin glargine, which had in increase in UACR at 52 weeks.

• Significantly less hypoglycemic events in dulaglutide groups à 50% less events

ROSARIO | 16

DULAGLUTIDE IN SOLID ORGAN TRANSPLANT (SOT)

Singh P, Pesavento TE, Washburn K, Walsh D, and Meng S. Largest single-center experience of dulaglutide for management of diabetes mellitus in solid organ transplant recipients. Diabetes Obes Metab. 2019; 21:1061-1065.

Objectives Investigate whether the beneficial effects of GLP-1 RA hold true in solid organ transplant (SOT) recipients with T2D.

Methods Retrospective chart review from baseline to 24 months of SOT recipients October 2014-January 2018

Patient population Inclusion Criteria:

• >18 years old • History of any SOT • Follow-up of more than 6 months with

dulaglutide

Exclusion Criteria: • Personal or familial history of medullary or thyroid C-cell

carcinoma • Pancreatitis • Multiple endocrine neoplasia syndrome types-2 (MENS2) • Severe gastrointestinal disease

Intervention N = 80 (63 met inclusion criteria)

- 43 experienced T2D before transplantation - 20 post-transplant diabetes mellitus

Drug: • Dulaglutide, which was increased from 0.75mg to 1.5mg dose

Outcomes Primary endpoints: • Change in weight (kg), BMI (kg/m2), insulin requirements, cardiovascular morbidity, graft-survival and all-cause

mortality. Secondary endpoints:

• HbA1c, renal function (creatinine, mg/dL), estimated GFR (mL/min/1.73m2) and liver function tests (units/L) Safety-endpoints: • Severe and non-severe hypoglycemia, GI side effects (nausea, vomiting, diarrhea, abdominal pain, decrease appetite),

pancreatitis, gallstones and new diagnosis of malignancy. Statistical analysis

• Mean, median and percentage of data were calculated • Two-tailed paired t-test

Results Dulaglutide (n=63) Age (range), years 58 (30,74) Female 20 (32%) White 45 (71%) eGFR 60-89 ml/min/m2 16 (25.6%) eGFR 45-59 ml/min/m2 14 (22.2%) eGFR 30-44 ml/min/m2 19 (30.15%) eGFR 15-29 ml/min/m2 13 (20.6%) eGFR <15 ml/min/m2 0 (0%) Time since transplant, months 47.8 (7.8-330) Type of transplant

• Kidney • Liver • Liver-kidney • Heart

• 81% • 16% • 1.5% • 1.5%

ROSARIO | 17

Post-transplant diabetes mellitus onset since transplant • <1 month • 1-12 months • >12 months

20 (31.7%) • 86% • 9% • 5%

Immunosuppression classes • Calcineurin inhibitors • Cell cycle inhibitors • mTOR inhibitors • Maintenance steroid • Belatacept • Steroid used for rejection

• 81% • 57% • 54% • 21% • 3% • 22%

Insulin-glargine or detemir 45 (71.4%) Meal-time short acting (64%) Mean daily insulin requirements, units 22.9

Dulaglutide p-value Weight - 5.23 kg <0.03 BMI 2.01 <0.04 Insulin decrease; units -5.98 0.0002 Number of patients with decrease insulin requirement

47.3%

Number of patients with same insulin requirements

40% --

Discontinued all other antidiabetics 13% -- Reduction in combination insulin with oral anti-diabetics (OADs)

-9% --

HbA1c reduction at 6, 12 and 24 months -0.75, 0.41, 0.64% <0.001, 0.07, 0.23

Non-severe Hypoglycemia 6.3% -- GI side effects (nausea, vomiting, diarrhea or abdominal pain)

1.5-3% --

Mean paired eGFR difference -2.4, 0.14, -6.54 0.09, 0.93, 0.07 Kidney Graft failure 1 -- Percentage of graft survival at 6, 12 and 24 months 100, 98.2, 98.2% --

Mortalities 2 (3%) -- No significant interactions or dose adjustments made to immunosuppressive agents.

Author’s conclusion Study replicated beneficial effects of GLP-1RA in SOT recipients and maintained throughout the final follow-up periods.

Reviewer’s critique Strengths:

• SOT population • One of the first studies in this population • Appropriate laboratory monitoring

Limitations: • Generalizability • Small sample size • Single center • Retrospective

Take-home points • 72% were stage 3-4 of CKD and ~51% were stage 3b-4 (moderately severe to severe) of CKD. • Efficacy and safety were maintained and benefits of GLP-1RA remained in SOT population (i.e. 2-5kg weight reduction) • Decrease pill burden and reduction of insulin

ROSARIO | 18

Semaglutide Primary Literature Review

Table 12: Primary and renal outcomes for semaglutide 39-40





Effect on GFR loss*

Adverse effects

Semaglutide

SUSTAIN-6 Patients treated dialysis excluded

MACE ↓ ↓↓ NA GI

PIONEER-6 eGFR >30 mL/min/1.73m2

MACE ND NA NA GI


Future Studies: ClinicalTrials.gov Identifier: NCT03819153 A research study to see how semaglutide works compared to placebo in people with type-2 diabetes and chronic kidney disease (FLOW Trial) Objective: Determine if semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Start date: June 17, 2019 with an estimated completion date of August 19, 2024 Primary outcome: Time to first occurrence of a composite primary outcome event defined as persistent eGFR decline of greater than or equal to 50 percentage from trial start, reaching ESRD, death from kidney disease or death from cardiovascular disease [Time Frame: Week 0 to month 61] Measured in month(s).

Clinical Question: What is the role of GLP-1 RAs in severe kidney disease?

Conclusion and Final Recommendations

Table 13: Kidney outcomes from trials for GLP-1 RA11, 24-40

ELIXA LEADER SUSTAIN EXSCEL REWIND PIONEER 6 AWARD-7

Drug Lixisenatide Liraglutide Semaglutide Exenatide Dulaglutide Semaglutide (oral) Dulaglutide

Total number of participants 6068 9340 3297 14752 9901 3183 577

N (%) with CVD 100% 81.3% 83% 73% 31.5% 84.7% % with ACEi or

ARB -- 86.3% >83% >82% >83.5% >90%

eGFR criteria for enrollment

(mL/min/1.73m2) 76

>30, but did include 220

patients with eGFR 15-30

CKD Stage >3 (>30 eGFR) >30 eGFR eGFR >15

eGFR >30 (0.9% had eGFR < 30)

>15 eGFR

Mean eGFR at enrollment

(mL/min/1.73m2) -- 80 ~75 76 76.9 74 + 21 38

ROSARIO | 19

N (%) with eGFR <60

mL/min/1.73m2 1387 (22.9)

2158 (23.1)

[20.7% with eGFR 30 to <60]

663 (20.1) -- 2199 (22.2) 856 (26.9) 100% CKD G3a-G4

N (%) with eGFR <30

mL/min/1.73m2 8 (0.13) 224 (2.4) 49 (1.49) -- 105 (1.06) -- 174 (30.2)

N (%) with eGFR <15

mL/min/1.73m2 -- -- -- -- -- 16 (0.5) 3 (0.52)

Albuminuria, N 1537 (25.3%) 3422 (36.6%) -- --

3468 (35%)

7.9% with macroalbuminuria

---

449 (77.8%)

44.7% with macroalbuminuria

Follow-up time 25 months 3.8 years 2.1 years 3.2 years 5.4 years 15.9 months 52 weeks

Kidney outcome (secondary end

points)

Composite renal outcome

(reduced eGFR decline,

renal replacement

and albuminuria)

New-onset persistent

macroalbuminuria, persistent

doubling of SCr level, ESKD, or death due to

kidney disease

Persistent macroalbuminuria,

persistent doubling of SCr, a

CrCl of <45 mL/min, or need

for kidney replacement

therapy

Composite: reduce eGFR decline, renal

replacement & new

macroalbuminuria

New macroalbuminuria

ACR of >33.9 mg/mmol, a

sustained fall in eGFR of 30% from baseline, or use of

kidney replacement

therapy

New or worsening

nephropathy

Change in eGFR and albuminuria at 26 weeks and

52 weeks

Kidney outcome results

Reduction is new or worsening albuminuria up to 43% ND in eGFR or renal replacement

HR 0.78 (0.67, 0.92)

HR 0.64 (0.46, 0.88)

For 1mg dose:

UACR change of up to -4.9 vs. +5.4 (eGFR <60)

UACR change of up to -36 vs. -16 (eGFR <30)

eGFR decline -0.5 vs. -2.6

New/worsening nephropathy 23 (2.8%) vs. 45 (5.5%)

HR 0.88 (0.74, 1.05)

ND

HR 0.85 (0.73, 0.98)

Composite HR 0.85 (0.77, 0.93) Similar for eGFR >60 vs. <60

New macroalbuminuria HR 0.77 (0.68, 0.87)

eGFR decline >40% HR 0.70 (0.57, 0.85)

HR 0.64 (0.46, 0.88)

ND in eGFR decline (0.7 mL/min/1.73m2) with either dose whereas eGFR decreased by -3.3 with insulin glargine

Change in albuminuria -43 vs. -14.3

ACEi = angiotensin-converting enzyme inhibitor, ARB = angiotensin II receptor blockade, CrCl = creatinine clearance, CV = cardiovascular, CVD = cardiovascular disease, eGFR = estimated glomerular filtration rate, ESKD = end-stage kidney disease, GLP-1RA = glucagon-like peptide-1 receptor agonist, HR = hazard ratio, MI = myocardial infarction, NA = not available, ND = no significant difference, SCr = serum creatinine; ACR = albumin-creatinine ratio

I. Trials weren’t powered to show significance for secondary outcomes; yet the results on renal protective effects while on appropriate RAAS inhibitor therapy are promising a. Renal outcomes driven by new or worsening albuminuria

i. However, Increased albuminuria and decreased glomerular filtration rate (GFR) independently and additively increase all-cause and CVD mortality

1. Supporting GLP-1 RA benefit in patients with diabetes and CKD class 1-4 b. Based on the trials, case reports and pharmacokinetic studies for exenatide and lixisenatide

i. Use with caution in eGFR >30-59 and not recommended in eGFR <30 1. Renally cleared

ROSARIO | 20

2. Increased GI adverse effects and dehydration à worsening renal function 3. Numerous case reports for exenatide causing acute kidney injury and renal failure

a. Kinetic studies showed 36% reduced clearance in moderate renal impairment and 84% in ESRD

b. Half-life extended by 1.5 to 3 times normal kinetics 4. Limited studies on lixisenatide and its use in moderately severe to severe renal

dysfunction c. Based on the trials, case reports and pharmacokinetic studies for liraglutide and dulaglutide

i. Use in severe kidney disease including ESRD seem to be safe and effective 1. Metabolized and cleared via DPP-IV and neutral endopeptidase, like native GLP-1, but

at a slower rate à Not renally cleared 2. 2 case reports of AKI in patients using liraglutide, but those patients had many other

reasons: a. Drug-drug interactions b. Other medications that cause nausea and vomiting c. Inappropriate dose initiation

Table 14: Recommendation based off risk verses benefit of GLP-1 RA use in severe kidney disease

d. Evidence is lacking for injectable and oral semaglutide, but the FLOW trial is currently ongoing and hopefully that will provide more literature à unable to make a conclusion/recommendation

References 1. Mottl AK, Tuttle KR, Bakris GL, et al. Diabetic kidney disease. UpToDate. Post TW, ed. Waltham, MA: UpToDate Inc. http://www.uptodate.com

(Accessed on January 15, 2020.) 2. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic Kidney Disease: A Report From an ADA Consensus Conference. Diabetes Care 2014; 37(10):

2864-2883. 3. Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System—United States. website. http://www.cdc.gov/ckd

(Accessed on January 15th, 2020). 4. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes—2020. Diabetes Care

2020;43(Suppl. 1): S135–S151 5. Perkovic V, Agarwal R, Fioretto P, et al. Management of patients with diabetes and CKD: conclusions from a “Kidney Disease Improving Global

Outcomes” (KDIGO) Controversies Conference. Kidney Inter 2016; 90: 1175-1183. 6. United States Renal Data System. 2019 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of

Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2019. 7. Astor BC, Hallan SI, Miller ER 3rd, Yeung E, Coresh J. Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality

in the US population. Am J Epidemiol. 2008;167(10):1226-1234.

Use of liraglutide and dulaglutide in severe renal impairment Pros Cons • HbA1c lowering effect up to -1.2% • Cardiovascular benefit • Weight loss of up to 4kg • Prolong eGFR decline • Reduce new or worsening macroalbuminuria • Reduce hypoglycemic events • Reduce insulin need

• Decrease tolerability (limitation of studies, since maybe not properly educated on how to mitigate GI side effects)

• Injectable • Cost

ROSARIO | 21

8. Szczech LA, Stewart RC, Su HL, et al. Primary care detection of chronic kidney disease in adults with type-2 diabetes: the ADD-CKD Study (awareness, detection and drug therapy in type 2 diabetes and chronic kidney disease). PLoS One. 2014;9(11): e110535.

9. Remuzzi G, Perico N, Macia M and Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Inter. 2005; 68(supp 99): S57-S65.

10. American Diabetes Association’s Standards of Medical Care in Diabetes—2019. Diabetes Care 2019;42(Suppl. 1): S1–S204. 11. Kidney Disease: Improving Global Outcomes CKD Work Group. The 2019 Clinical Practice Guideline on the Management of Diabetes in CKD.

Kidney Inter. 2019; (Public Review Draft): 1-187. 12. Tanaka T, Higashijima Y, Wada T and Nangaku M. The potential for renoprotection with incretin-based drugs. Kidney Inter. 2014; 86: 701-711. 13. Van Baar MJB, van der Aart AB, Hoogenberg K, Joles JA, Heerspink HJL, and van Raalte DH. The incretin pathway as a therapeutic target in

diabetic kidney disease: a clinical focus on GLP-1 receptor agonists. Ther Adv Endocrinol Metab. 2019; 10: 1-11. 14. Scheen AJ. Pharmacokinetics and Clinical Use of Incretin-Based Therapies in Patients with Chronic Kidney Disease and Type 2 Diabetes. Clin

Pharmacokinet. 2015; 54: 1-24. 15. Filippatos TD and Elisaf MS. Effects of glucose-like peptide-1 receptor agonist on renal function. World J Diabetes. 2013; 4(5):190-201. 16. Giugliano D, De Nicola L, Maiorino MI, et al. Type 2 diabetes and the kidney: Insights from cardiovascular outcome trials. Diabetes Obes

Metab. 2019; 21: 1790-1800. 17. Exenatide. Lexi-Drugs. [updated 2020 Jan 1; cited 2020 Jan 15] In Lexicomp Online [Internet]. Wolters Kluwer Clinical Drug Information, Inc.

Hudson, Ohio. Available at: http://online.lexi.com/lco/action/home 18. Lixisenatide. Lexi-Drugs. [updated 2019 Nov 18; cited 2020 Jan 15] In Lexicomp Online [Internet]. Wolters Kluwer Clinical Drug Information,

Inc. Hudson, Ohio. Available at: http://online.lexi.com/lco/action/home 19. Liraglutide. Lexi-Drugs. [updated 2020 Jan 5; cited 2020 Jan 15] In Lexicomp Online [Internet]. Wolters Kluwer Clinical Drug Information, Inc.

Hudson, Ohio. Available at: http://online.lexi.com/lco/action/home 20. Dulaglutide. Lexi-Drugs. [updated 2019 Nov 18; cited 2020 Jan 15] In Lexicomp Online [Internet]. Wolters Kluwer Clinical Drug Information, Inc.

Hudson, Ohio. Available at: http://online.lexi.com/lco/action/home 21. Semaglutide. Lexi-Drugs. [updated 2019 Dec 18; cited 2020 Jan 15] In Lexicomp Online [Internet]. Wolters Kluwer Clinical Drug Information,

Inc. Hudson, Ohio. Available at: http://online.lexi.com/lco/action/home 22. Weise WJ, Sivanandy MS, Block CA, et al. Exenatide-Associated Ischemic Renal Failure. Diabetes Care. 2009; 32 (2): e22-23. 23. Ferrer-Garcia JC, Martinez-Chanza N, Tolosa-Torrens, et al. Exenatide and renal failure. Diabet Med. 2009; 1464-5491. 24. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. 2007; 64(3): 317-

327. 25. Holman RR, Bethel MA, Mentz RJ, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;

377: 1228-1239. 26. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015; 373:

2247-2257. 27. Muskiet MHA, Tonneijck L, Huang Y, et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an

exploratory analysis of the ELIXA randomized, placebo-controlled trial. Lancet Diabetes Endocrinol 2018; 6: 859–69 28. Kaakeh Y, Kanjee S, Boone K and Sutton J. Liraglutide-Induced Acute Kidney Injury. Pharmacotherapy 2012;32(1): e7–e11 29. Montanya E and Sesti G. A Review of Efficacy and Safety Data Regarding the Use of Liraglutide, a One-Daily Human Glucagon-Like Peptide 1

Analogue, in the Treatment of Type 2 Diabetes Mellitus. Clin Therapeutics. 2009; 31(11): 2472-2488. 30. Idorn T, Knop FK, Jorgensen MB, et al. Safety and Efficacy of Liraglutide in Patients with Type 2 Diabetes and End-Stage Renal Disease: An

Investigator-Initiated, Placebo-Controlled, Double-Blind, Parallel-Group, Randomized Trial. Diabetes Care. 2016; 39:206-213. 31. Osonoi T, Saito M, Tamasawa A, et al. Effect of Hemodialysis on Plasma Glucose Profile and Plasma Level of Liraglutide in Patients with Type 2

Diabetes Mellitus and End-Stage Renal Disease: A Pilot Study. PLoS ONE. 2014; 9(12): e113468. 32. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375: 311-322. 33. Mann JFE, Fonseca V, Mosenzon O, et al. Effects of Liraglutide Versus Placebo on Cardiovascular Events in Patients With Type 2 Diabetes

Mellitus and Chronic Kidney Disease. Circulation 2018; 138: 2908-2918. 34. Tuttle KR, McKinney TD, Davidson JA, et al. Effects of once weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II

and III clinical trials. Diabetes Obes Metab. 2017; 19(3):436-441. 35. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in T2DM (REWIND): a double-blind, randomized

placebo-controlled trial. Lancet 2019; 394: 121-30. 36. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in T2DM: an exploratory analysis of the REWIND randomized,

placebo-controlled trial. Lancet 2019; 394: 131-38. 37. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic

kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018; 6: 605-617. 38. Singh P, Pesavento TE, Washburn K, Walsh D, and Meng S. Largest single-center experience of dulaglutide for management of diabetes

mellitus in solid organ transplant recipients. Diabetes Obes Metab. 2019; 21:1061-1065. 39. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016; 375: 1834-

1844. 40. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med

2019; 381: 841-851.

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