Dapagliflozin and Outcomes in Patients with Peripheral Artery Disease: Insights

from DECLARE-TIMI 58

Marc P. Bonaca MD MPHfor the DECLARE – TIMI 58 Investigators

American College of CardiologyMarch 2019

Background

Diabetes and peripheral artery disease (PAD) are frequently comorbid conditions

SGLT2 inhibitors:• Reduce heart failure and renal complications in patients with

diabetes• Have been associated with amputation risk with 1 available

agent but not the other 2; however, trials thus far have not been designed to evaluate amputation or limb ischemic events

• To date, a detailed examination of all limb ischemic events in high-risk subpopulations has not been performed

Trial Design

DAPAGLIFLOZIN10 mg DAILY PLACEBO

Median follow up4.2 years

RANDOMIZE 1:1DOUBLE BLIND

All other DM Rx per treating MD

Wiviott SD, Raz I…Sabatine MA, AHJ 2018

17,160 with Type 2 DM andEstablished CV Disease (6974 incl 1025 w/PAD) or MRF (10186)

PAD Inclusion Criteria:Current claudication + ABI < 0.90 or history of peripheral

revascularization or amputation for ischemia

Follow-up visits In Person Q 6 mo/ telephone Q 3 mo

Primary EPsSafety: MACE (CVD/MI/Ischemic Stroke)

Dual Efficacy: CVD/HHF, MACE

Primary Endpoints

MACE8.8% vs 9.4%HR 0.93 (0.84-1.03)P(Noninferiority) <0.001P(Superiority) 0.17

CVD/HHF4.9% vs 5.8%HR 0.83 (0.73-0.95)P(Superiority) 0.005

Wiviott SD, Raz I…Sabatine MA, NEJM 2019; 380:347-357

Methods

Cardiac Events:• MACE: composite of CV death, MI or ischemic stroke• HHF: Hospitalization for heart failure

Renal Events:• Renal primary: ≥ 40% decrease in eGFR to < 60 ml/minute/1.73 m2

of BSA, new ESRD or death from renal or CV causes

Limb outcomes:• Limb ischemic AEs with subset of:

• Acute limb ischemia (ALI)• Chronic critical limb ischemia (CLI)

• Amputations, primary etiology, contributing where multifactorial• Non-coronary revascularizations (urgent and elective)• Major adverse limb events (MALE) – defined as composite of ALI,

CLI, amputation for ischemia or urgent revascularization

Methods

1. To compare the risk of cardiac, renal and limb events in patients with vs. w/o known PAD (in placebo arm)

2. To evaluate the efficacy of dapagliflozin vs. placebo for cardiac and renal events in patients with and w/o PAD

3. To evaluate the safety of dapagliflozin vs. placebo for limb ischemic events and amputations in:• All patients

• High risk subgroups including known PAD

Baseline Characteristics

PADN=1,025

No PADN=16,135

Age, median (IQR) 62 (57, 68) 64 (60, 68)Female sex, % 32 38Body Mass Index, median (IQR) 31 (28, 35) 31 (28, 36)Caucasian, % 84 79History Hypertension, % 85 90Current Smoker, % 23 14Duration of Diabetes (yrs), median (IQR) 12 (7, 18) 10 (6, 16)Hemoglobin A1C, % (IQR) 8 (8, 9) 8 (7, 9)Insulin, % 52 40Estimated GFR (CKD-EPI) < 60, % 11 7History of Ischemic Heart Disease, % 46 32History of Myocardial Infarction, % 27 20History of Cerebrovascular Disease, % 15 7History of CHF, % 14 10

All p-values < 0.001 except BMI (p=0.0256)

PAD Characteristics

52.1%37.6%

10.3%

Claudication onlyPrior RevascularizationPrior Amputation

Fontaine Classification at Randomization, %

Stage I: Asymptomatic 25

Stage IIa: Mild claudication 49

Stage IIb: Moderate-severe claudication 21

Stage III or IV: Ischemia rest pain, ulceration or gangrene 6

Ankle Brachial Index Category, %< 0.5 5

0.5-<0.9 930.9-<1.4 2

Hierarchically Defined:Amputation = any history of amputation regardless of current symptomsRevascularization = any history of revascularization but no history of amputationClaudication = claudication with no history of amputation or revascularization

Epidemiology of cardiac, renal and limb outcomes in patients with vs. w/o PAD

randomized to placebo

Cardiovascular & Renal Risk by PAD in Placebo Patients

15.9%

12.1%10.9%

9.0%

5.4% 5.3%

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

MACE CVD/HF Renal Primary

PAD no PADAdj HR 1.23(0.97 – 1.56)

Adj HR 1.60(1.21 – 2.12)

Adj HR 1.51(1.13 – 2.03)

n/N

(%)

Adjusted for age, sex, race, BMI, hypertension, dyslipidemia, smoking, duration of DM, A1c, eGFR, hx CAD, and hx cerebrovascular disease

Limb Outcomes by PAD Status in Placebo Patients

20.3%

3.4%5.0% 5.6%

8.2%

2.1%0.1% 0.3% 1.1%

3.3%

0%

5%

10%

15%

20%

25%

Any LimbAdverse

Event

Acute LimbIschemia

Critical LimbIschemia

Amputation LimbInfection

PAD no PAD

Adj HR8.37

P<0.01

n/N

(%)

N=8075N=503

Adj HR12.99

P<0.01

Adj HR19.69

P<0.01

Adj HR2.13

P<0.01

Adj HR4.47

P<0.01

Adjusted for age, sex, race, BMI, hypertension, dyslipidemia, smoking, duration of DM, A1c, eGFR, hx CAD, and hx cerebrovascular disease

Limb Outcomes by PAD Status in Placebo Patients

20.3%

3.4%5.0% 5.6%

8.2%

2.1%0.1% 0.3% 1.1%

3.3%

0%

5%

10%

15%

20%

25%

Any LimbAdverse

Event

Acute LimbIschemia

Critical LimbIschemia

Amputation LimbInfection

PAD no PAD

Adj HR8.37

P<0.01

Adjusted for age, sex, race, BMI, hypertension, dyslipidemia, smoking, duration of DM, A1c, eGFR, hx CAD, and hx cerebrovascular disease

N=8075N=503

Adj HR12.99

P<0.01

Adj HR19.69

P<0.01

Adj HR2.13

P<0.01

Adj HR4.47

P<0.01

22, 51%

6, 14%

15, 35%

123, 85%

7, 5%14,

10%

Infection ALI CLI

PAD

No PAD

Distribution of Amputation by Primary Etiology*

*Investigator Reported

n/N

(%)

Efficacy of Dapagliflozin in Patients with and without PAD

CV Death orHosp. for Heart Failure

Renal Primary

Consistent Benefit of Dapagliflozin in Patients with and without PAD

CV Death, MI or Ischemic Stroke 0.92

1.05

0.93

0.82

0.86

0.83

0.76

0.78

0.76

Pbo DapaP-interaction

0.42

0.79

0.84

No PAD – N=16135PAD – N=1025Overall

10.9% 8.8%

5.3% 4.0%

ARR

2.1%

1.3%

12.1% 10.7%

5.4% 4.5%

1.4%

0.9%

15.9% 16.9%

9.0% 8.3%

--%

0.7%

0.75 1.00 1.5

Favors Dapagliflozin

Favors Placebo

n/N (%)

Safety of Dapagliflozin vs. Placebofor Limb Outcomes in All Patients

Dapagliflozin and Limb OutcomesAll Patients

3.37%

1.39%

0.33%

0.82%

0.52%

1.57%

3.16%

1.24%

0.33%0.58% 0.61%

1.48%

0%

1%

2%

3%

4%

Any limb ischemic AE MALE Acute Limb Ischemia Critical Limb Ischemia UrgentRevascularization

ElectiveRevascularization

DAPA Placebo

28 28

n/N

(%)

HR 1.12(0.86 – 1.46)

HR 1.00(0.59 – 1.69)

All p-values > 0.05

HR 1.40(0.97 – 2.01)

HR 0.86(0.58 – 1.28)

HR 1.06(0.83 – 1.35)

HR 1.07(0.90 – 1.26)

MALE Defined as ALI, CLI, amputation for ischemia or Urgent Revascularization for Ischemia

289 271 119 106 70 50 45 52 135 127

8574 8569

Dapagliflozin and AmputationsAll Patients

1.43%

0.12%

0.30%

1.12%

1.32%

0.12%0.26%

0.98%

0%

1%

2%

Amputation Amputation for ALI Amputation for CLI Amputation for Infection

DAPA Placebo

n/N

(%)

HR 1.09(0.84 – 1.40)

HR 0.99(0.41 – 2.39)

HR 1.18(0.67 – 2.08)

HR 1.14(0.85 – 1.53)

All p-values > 0.05

8574 8569

123 113 10 10 26 22 96 84

Safety of Dapagliflozin vs. Placebofor Amputation and Other Limb Events

in High Risk Subgroups

Dapagliflozin and Amputation in Key Subgroups

Diabetes Duration ≤ 5 yrs

Age < 65 years

No PAD

1.19

1.46

0.931.51

1.09

Pbon/N

Dapan/N

P-interaction

0.3895

0.5922

0.0926

0.50 1.00 1.5

Favors Dapagliflozin

Favors Placebo

3.00.75

Age ≥ 65 years

1.24

Diabetes Duration > 20 yrs

1.23

eGFR < 600.6920

0.80

1.06

PAD

Overall

0.95

0.92Diabetes Duration >5 - ≤ 10 yrsDiabetes Duration >10 - ≤ 15 yrsDiabetes Duration >15 - ≤ 20 yrs

eGFR 60-90eGFR ≥ 90

0.841.21

1.05

HgbA1C ≥ 9%

HgbA1C < 7%HgbA1C 7% - < 8%HgbA1C 8% - < 9%

1.201.37

0.88

0.5495

75/4626 62/461948/3948 51/395020/1883 14/194820/2373 22/235427/2014 21/193633/1246 25/118623/1058 31/114411/604 15/65855/3836 46/389057/4133 52/40214/771 4/772

35/3314 29/330630/2190 24/232454/2297 56/216379/8053 85/806744/521 28/502

Dapagliflozin and Limb OutcomesPAD Patients

19.4%

9.6%

2.9%

5.8%

4.0%

12.1%

8.4%

20.3%

10.2%

3.4%5.0% 5.0%

14.1%

5.6%

0%

5%

10%

15%

20%

25%

Any limb ischemicAE

MALE Acute LimbIschemia

Critical LimbIschemia

UrgentRevascularization

ElectiveRevascularization

Amputation

DAPA Placebo

n/N

(%)

HR 0.92(0.62 – 1.35)

HR 0.84(0.42 – 1.69)

All p-values > 0.05

HR 1.12(0.66 – 1.91)

HR 0.79(0.44 – 1.42)

HR 0.84(0.60 – 1.19)

HR 0.93(0.71 – 1.23)

MALE Defined as ALI, CLI, amputation for ischemia or Urgent Revascularization for Ischemia

N=1025

30 2515 1750 51 63 7121 25101 102 44 28

HR 1.51(0.94 – 2.42)

Summary

1. Patients with PAD were at heightened risk of cardiac, renal and limb complications vs. those without

2. The efficacy of dapagliflozin for CVD/HF and renal outcomes was consistent regardless of PAD status but with greater absolute benefits in PAD

3. There was no significant excess risk of amputations or limb ischemic events with dapagliflozin in the overall population

4. There was no consistent pattern of risk or benefit related to limb events in patients with PAD or other high-risk subgroups