Investigating the Impact of Weekly Incretin on Cardiovascular Events in Diabetes

Individuals with type 2 diabetes have an increased risk of cardiovascular events compared to those without the condition. Research indicates that certain GLP-1 receptor agonists have shown promising results in reducing cardiovascular events in diabetic patients with specific HbA1c levels. However, the effects of these medications in individuals with varying cardiovascular risks and different HbA1c levels remain unclear. Dulaglutide, a GLP-1 receptor agonist, has demonstrated potential in improving glucose control, blood pressure, and weight management, with potential cardiovascular benefits. Previous large-scale trials have tested different GLP-1 receptor agonists and provided insights into their efficacy and impact on cardiovascular outcomes.

• Diabetes
• Cardiovascular Events
• GLP-1 Receptor Agonists
• Dulaglutide
• Research

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1. Researching CV Events with a Weekly INcretin in Diabetes

2. Introduction People with type 2 diabetes (DM) 1.5 to 2-fold higher risk of CV (cardiovascular) outcomes or death than unaffected people The risk rises with # of risk factors (Rawshani et al. NEJM 2018;633) Myocardial Infarction Stroke 3 Risk Factors 80+ 65-70 55-64 <55 4 Risk Factors 80+ 65-70 55-64 <55 5 Risk Factors 80+ 65-70 55-64 <55 Hazard Ratio 1.78 2.11 2.16 3.02 Hazard Ratio 1.35 1.73 2.13 2.78 2.32 2.87 3.32 4.56 1.54 2.31 2.66 3.34 3.19 4.60 4.84 7.69 2.65 3.54 2.79 6.23

3. Introduction Large RCTs have reported that 3 GLP-1 RAs (glucagon-like peptide receptor 1 agonists) reduced CV events in people with type 2 DM whose mean HbA1c was 8.0% & whose annual risk of CV events was 4% The CV effects of GLP-1 RAs in people with type 2 DM with a broader range of CV risk & with HbA1c levels more reflective of those in the general population is not known Dulaglutide is a GLP-1 RA comprising 2 modified human GLP-1 molecules linked to an IgG4 heavy chain with t1/2 = 5 d Dosed weekly at 0.75 mg or 1.5 mg sc Reduces glucose, BP, weight May have CV benefits similar to other GLP1 RAs

4. Background: Previous GLP-1 RA Trials ELIXA LEADER SUSTAIN 6 EXSCEL HARMONY N 6068 9340 3297 14752 9463 Drug Tested Lixisenatide/d Liraglutide/d Semaglutide/wk Exenatide/wk Albiglutide/wk Prior CVD 100% 81% 83% 73% 100% Mean Age 60 y 64 y 54 y 62 y 64 y Women 30% 36% 39% 38% 31% Median F/U 2.1 y 3.8 y 2.1 y 3.2 y 1.6 y

5. Background: Previous GLP-1 RA Trials ELIXA LEADER SUSTAIN 6 EXSCEL HARMONY N 6068 9340 3297 14752 9463 Drug Tested Prior CVD Lixisenatide/d 100% Liraglutide/d Semaglutide/wk Exenatide/wk Albiglutide/wk 81% 83% 73% 100% Mean Age Women Median F/U 60 y 30% 2.1 y 64 y 36% 3.8 y 54 y 39% 2.1 y 62 y 38% 3.2 y 64 y 31% 1.6 y

6. Background: Previous GLP-1 RA Trials ELIXA LEADER SUSTAIN 6 EXSCEL HARMONY N 6068 9340 3297 14752 9463 Drug Tested Prior CVD Lixisenatide/d 100% Liraglutide/d Semaglutide/wk Exenatide/wk Albiglutide/wk 81% 83% 73% 100% Mean Age Women Median F/U 60 y 30% 2.1 y 64 y 36% 3.8 y 54 y 39% 2.1 y 62 y 38% 3.2 y 64 y 31% 1.6 y DM Duration 9.2 y 12.8 y 13.9 y 13.1 y 14.2 y Baseline A1c 7.7% 8.7% 8.7% 8.1% 8.8% Baseline eGFR 76 ~75 ~75 76 79 Insulin Use 39% 45% 58% 46% 59% Adherence ~75% 84% 88% 76% 86%

7. Background: Previous GLP-1 RA Trials ELIXA LEADER SUSTAIN 6 EXSCEL HARMONY N 6068 9340 3297 14752 9463 Drug Tested Prior CVD Lixisenatide/d 100% Liraglutide/d Semaglutide/wk Exenatide/wk Albiglutide/wk 81% 83% 73% 100% Mean Age Women Median F/U 60 y 30% 2.1 y 64 y 36% 3.8 y 54 y 39% 2.1 y 62 y 38% 3.2 y 64 y 31% 1.6 y DM Duration Baseline A1c 9.2 y 7.7% 12.8 y 8.7% 13.9 y 8.7% 13.1 y 8.1% 14.2 y 8.8% Baseline eGFR 76 ~75 ~75 76 79 Insulin Use 39% 45% 58% 46% 59% Adherence ~75% 84% 88% 76% 86%

8. Annual Placebo MACE Rates by Trial 7 6 6.3% 5.9% 5 N/100 py 4.4% 4 4.0% 3.9% 3 2 1 0 ELIXA LEADER SUSTAIN 6 EXSCEL HARMONY

9. Meta-analysis of MACE (GLP-1 RA CVOTs) Zelniker et al. Circulation 2019:2022 HR (95% CI) Trials Patients Events Treatment Placebo Weights 1.02 (0.89, 1.17) ELIXA 6068 805 406/3034 399/3034 16.7 0.87 (0.78, 0.97) LEADER 9340 1302 608/4668 694/4672 26.3 0.74 (0.58, 0.95) SUSTAIN 6 3297 254 108/1648 146/1649 5.1 0.91 (0.83, 1.00) EXSCEL 14752 1744 839/7356 905/7396 36.0 0.78 (0.68, 0.90) HARMONY 9463 766 338/4731 428/4732 15.9 Fixed Effects for MACE Outcome (P-value < 0.001) 0.88 (0.84, 0.94)

10. Meta-analysis of MACE (GLP-1 RA CVOTs) Zelniker et al. Circulation 2019:2022 Fixed Effects P-value < 0.001 0.87 (0.82, 0.92) Fixed Effects P-value = 0.71 1.03 (0.87, 1.23)

11. Meta-analysis of MACE (GLP-1 RA CVOTs) Zelniker et al. Circulation 2019:2022 Fixed Effects P-value < 0.001 0.87 (0.82, 0.92) Fixed Effects P-value = 0.71 1.03 (0.87, 1.23)

12. Research Question In men & women with established or newly detected type 2 diabetes who have additional CV risk factors dulaglutide (1.5 mg) to the medical regimen safely reduce serious CV outcomes more than adding a wkly sc. placebo injection? does adding a weekly sc. injection of the GLP-1 RA

13. Key Inclusion Criteria Type 2 DM - New or previously diagnosed (with stable glucose drugs X 3 mo) - On 0-2 oral glucose drugs +/- basal insulin or GLP-1 RA A1C 9.5% (81 mmol/mol) BMI > 23 kg/m2 Age 50 & vascular disease 55 & subclinical vascular disease 60 & 2 CV risk factors (prior MI, stroke, revascularization, or unstable angina + ECG changes or PCI or positive imaging) (positive stress test/image, >50% stenosis, ABI<0.9; eGFR <60; hypertension + LVH, or albuminuria) (tobacco, lipid drug, LDL-C 3.4 (130 mg/dl), HDL-C < 1.0 (40 mg/dl) for men & < 1.3 (50 mg/dl) for women or TG 2.3 (200 mg/dl), 1 BP drug or SBP 140 or DBP 95. waist:hip ratio >1.0 for men & > 0.8 for women)

14. Trial Outcomes Primary Composite: First Occurrence of a MACE Outcome Nonfatal MI (including silent), nonfatal stroke, or CV death Secondary Outcomes Microvascular composite outcome o Retinopathy: laser Rx/anti VEGF, vitrectomy o Nephropathy: clinical proteinuria, 30% eGFR fall, renal replacement Rx Hospitalization for unstable angina Hospitalization or urgent visit for heart failure Each component of the primary outcome Total mortality

15. Other Trial Outcomes HbA1c Weight & Waist/Hip Ratio Expanded Composite CV Outcome: MACE or Hosp for UA Revascularization (coronary, carotid, or peripheral) Any hospitalization Any fracture Cholelithiasis Erectile dysfunction in men (IIEF) Cognitive decline (DSST & MOCA)

16. Trial Leadership Academic: Population Health Research Institute (PHRI) & Global Network HC Gerstein, HM Colhoun, GR Dagenais R Diaz, P Pais, J Probstfield, MC Riddle, L Ryd n, D Xavier, A Avezum, J Basile, N Chung, I Conget, WC Cushman, E Franek, N Hancu, M Hanefeld, S Holt, P Jansky, M Keltai, F Lanas, LA Leiter, P Lopez-Jaramillo, EGC Munoz, V Pirags, N Pogosova, PJ Raubenheimer, JE Shaw, W Sheu, T Temelkova-Kurktschiev Sponsor: Eli Lilly & Company M Lakshmanan, JS Riesmeyer, C Atisso Data Collection & Site Management: ICON Statistical & Organizational: PHRI L Dyal, S Hall, P Rao-Melacini, G Wong Independent Data Monitoring Committee (IDMC) J Wittes, B Byington, S Griffin, C Hennekens, P Moayyedi 16

17. Recruitment at 371 sites from Aug 2011-Aug 2013 Randomly assigned to dulaglutide 1.5 mg sc/wk or identical placebo

18. Baseline Characteristics All Participants N=9901 66.2 46.4 75.7 14.2 31.5 20.6 93.2 8.6 Dulaglutide N=4949 66.2 46.6 75.9 14.0 31.5 20.8 93.0 8.5 Placebo N=4952 66.2 46.1 75.6 14.4 31.4 20.3 93.3 8.7 Age (years) Females (%) White (%) Current Tobacco (%) Prior CV Disease (%) Prior MI or Ischemic Stroke (%) Prior Hypertension (%) Prior Heart Failure (%) History of MI, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging or stress test, or revascularization (coronary, carotid or peripheral)

19. Diabetes-related Characteristics All Participants N=9901 7.3 10.5 9.0 22.2 35.0 81.2 46.0 23.9 5.7 1.7 0.3 Dulaglutide N=4949 7.3 10.5 9.1 21.8 34.5 81.3 45.9 24.0 5.4 2.0 0.3 Placebo N=4952 7.4 10.6 8.9 22.6 35.5 81.1 46.1 23.7 6.0 1.4 0.4 HbA1c (%) DM Duration (y) Retinopathy (%) eGFR <60 ml/min/1.73m2 (%) Albuminuria (%)* Metformin (%) Sulfonylurea (%) Insulin (%) DPP4i (%) Thiazolidinedione (%) Other incl. SGLT2i (%) * ACR > 3.39 mg/mmol or 30 mg/g

20. Baseline Measures SI Units All Participants N=9901 32.3 137.2 78.5 71.5 84.1 74.9 1.82 4.52 2.56 1.18 1.60 Dulaglutide N=4949 32.3 137.1 78.4 71.4 83.7 75.3 1.80 4.52 2.56 1.18 1.60 Placebo N=4952 32.3 137.3 78.5 71.6 84.5 74.7 1.88 4.52 2.56 1.18 1.60 BMI (kg/m2) Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart Rate (bpm) Serum Creat (umol/l) Median eGFR (ml/min/1.73m2) Median ACR (mg/mmol) Cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) Median Triglycerides (mmol/L)

21. Baseline Measures Conventional Units All Participants N=9901 32.3 137.2 78.5 71.5 0.95 74.9 16.1 174.5 98.8 45.6 141.6 Dulaglutide N=4949 32.3 137.1 78.4 71.4 0.95 75.3 15.9 174.5 98.8 45.6 141.6 Placebo N=4952 32.3 137.3 78.5 71.6 0.96 74.7 16.6 174.5 98.8 45.6 141.6 BMI (kg/m2) Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart Rate (bpm) Serum Creat (mg/dl) Median eGFR (ml/min/1.73m2) Median ACR (mg/g) Cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) Median Triglycerides (mg/dl)

22. Baseline use of CV Drugs All Participants N=9901 Dulaglutide N=4949 Placebo N=4952 ACE/ARB (%) 81.5 81.0 82.0 Beta Blocker (%) 45.6 45.2 45.9 Other Blood Pressure (%) 56.6 55.9 57.2 Statin (%) 66.1 66.3 66.0 Fibrate (%) 9.1 9.1 9.0 Antiplatelet (%) 54.0 53.8 54.1

23. Follow-up Time, Retention, Adherence Median follow-up period = 5.4 years (IQR 5.1, 5.9) Person years of follow-up = 51820

24. 12133 Screened 1216 Excluded 974 Ineligible 186 Withdrew Consent 49 Physician Decision 6 Sponsor Decision 1 Adverse Event 10917 Run-in 1016 Excluded 566 Ineligible 376 Withdrew Consent 54 Physician Decision 11 Sponsor Decision 9 Adverse Event 9901 Randomized 97.1% Retention Dulaglutide N=4949 i.e. primary Outcome, final visit without primary outcome, or non-CV death Placebo N=4952 4935 (99.7%) Final Status Known 17 Unknown Final Status 2 Physician Decision 10 Participant Decision 5 Sponsor Decision 4932 (99.7%) Final Status Known 17 Unknown Final Status 5 Lost to Follow-up 5 Participant Decision 7 Sponsor Decision 99.7% Vital Status 4817 (97.3%) Final Visit/Primary Outcome/non CV Death 132 No Final Visit & No Primary Outcome or Death 115 Vital Status Known 17 Vital Status Unknown 4793 (96.8%) Final Visit/Primary Outcome/non CV Death 159 No Final Visit & No Primary Outcome or Death 142 Vital Status Known 17 Vital Status Unknown Analyzed N=4949 Analyzed N=4952

25. Study Drug Adherence In 9901 Participants followed for a Median of 5.4 years Dulaglutide N = 4949 Placebo N =4952 % F/U Time on Study Drug 82.2% 83.1%

26. Study Drug Adherence In 9901 Participants followed for a Median of 5.4 years Dulaglutide N = 4949 Placebo N =4952 % F/U Time on Study Drug 82.2% 83.1% Study Drug @ Last Visit 73.2% 71.1%

27. Study Drug Adherence In 9901 Participants followed for a Median of 5.4 years Dulaglutide N = 4949 Placebo N =4952 % F/U Time on Study Drug 82.2% 83.1% Study Drug @ Last Visit 73.2% 71.1% Never Stopped at All 57.7% 56.2%

28. Study Drug Adherence In 9901 Participants followed for a Median of 5.4 years Dulaglutide N = 4949 Placebo N =4952 % F/U Time on Study Drug 82.2% 83.1% Study Drug @ Last Visit 73.2% 71.1% Never Stopped at All 57.7% 56.2% Stopped due to an AE 11.0% 7.5%

29. Dulaglutides Effect on HbA1c Overall LSM Difference: -0.61% (95% CI -0.65, -0.58) P < 0.0001

30. Dulaglutides Effect on Weight Overall LSM Difference: -1.5 kg (95% CI -1.7, -1.3) P < 0.0001

31. Dulaglutides Effect on SBP & Heart Rate Systolic Blood Pressure Heart Rate Overall LSM Difference: -1.7 mm (95% CI -2.1, -1.3) P < 0.0001 Overall LSM Difference: 1.9 bpm (95% CI 1.6, 2.1) P < 0.0001

32. Dulaglutides Effect on LDL Cholesterol LDL Cholesterol 3.0 Overall LSM Difference = -0.05; 95% CI (-0.08, -0.02) Overall LSM Difference = -0.05; 95% CI (-0.08; -0.02); P = 0.85 P = 0.001 Overall LSM Difference: -0.05 mmol/l (95% CI -0.08, -0.02) -1.9 mg/dl (95% CI -3.1, -0.8) P = 0.001 2.8 Mean LDL (mmol/L) Placebo 2.6 2.4 Dulaglutide 2.2 2.0 0 1 2 3 4 5 Years

33. Summary of Effect on Clinical Measures P Measurement HbA1c (%) Dulaglutide Placebo -0.46 Difference -0.61 0.16 <0.0001 LDL (mmol/l) -0.15 -0.09 -0.05 0.001 Weight (kg) Body Mass Index -2.95 -1.08 -1.49 -0.55 -1.46 -0.53 <0.0001 <0.0001 Waist:Hip (Men) Waist:Hip (Women) -0.007 -0.005 -0.004 0.0 -0.003 -0.005 0.04 0.009 Systolic BP (mm Hg) -3.15 -1.44 -1.70 <0.0001 Mean BP (mm) -2.34 -1.85 -0.49 <0.0001 Heart Rate (bpm) 2.95 1.09 1.87 <0.0001

34. Research Question In men & women with established or newly detected type 2 diabetes who have additional CV risk factors dulaglutide (1.5 mg) to the medical regimen safely reduce serious CV outcomes more than adding a wkly sc. placebo injection? does adding a wkly sc. injection of the GLP-1 RA

35. Dulaglutides Effect on the CV Composite Primary Outcome: 1st Occurrence of Nonfatal MI, Nonfatal Stroke, CV Death HR 0.88 (95% CI 0.79, 0.99) HR 0.88 (95% CI 0.77, 0.99) P = 0.026 P = 0.026

36. Dulaglutides Effect on Nonfatal MI HR 0.96 (95% CI 0.79, 1.16) P = 0.65

37. Dulaglutides Effect on Nonfatal Stroke HR 0.76 (95% CI 0.61, 0.95) P = 0.017

38. Dulaglutides Effect on CV Death HR 0.91 (95% CI 0.78, 1.06) P = 0.21

39. Dulagutides Effect on All-Cause Death HR 0.90 (95% CI 0.80, 1.01)

40. CV Composite in Prespecified Subgroups

41. CV Composite in Prespecified Subgroups

42. CV Composite in Other Subgroups Dulaglutide (N/100 py) 2.35 Placebo (N/100 py) 2.66 HR (95%CI) P Int Overall 0.88 (0.79, 0.99) White Black Asian Other 2.40 2.30 1.97 2.23 2.67 2.98 2.80 2.42 0.90 (0.79, 1.02) 0.77 (0.51, 1.17) 0.71 (0.40, 1.24) 0.92 (0.67, 1.28) 0.77

43. CV & Diabetes Medications at Last Visit Dulaglutide N = 4949 70 33 27 5 1 2 67 76 50 47 Placebo N = 4952 73 38 36 7 1 2 68 78 51 47 Metformin (%) Sulfonylurea (%) Insulin (%) SGLT2i (%) GLP-1 RA (%) Thiazolidinedione (%) Statin (%) ARB or ACEi (%) ASA (%) Beta Blocker (%)

44. Summary: Dulaglutide & Outcomes Dulaglutide (N=4949) N (%) 594 (12.0) Placebo (N=4952) N (%) 663 (13.4) HR (95%CI) N/100 py 2.35 N/100 py 2.66 Primary Composite 0.88 (0.79, 0.99) MI Nonfatal MI Fatal MI Stroke Nonfatal Stroke Fatal Stroke CV Death 223 (4.5) 205 (4.1) 26 (0.5) 158 (3.2) 135 (2.7) 26 (0.5) 317 (6.4) 0.87 0.80 0.10 0.61 0.52 0.10 1.22 231 (4.7) 212 (4.3) 20 (0.4) 205 (4.1) 175 (3.5) 33 (0.7) 346 (7.0) 0.91 0.84 0.08 0.81 0.69 0.13 1.34 0.96 (0.79, 1.15) 0.96 (0.79, 1.16) 1.29 (0.72, 2.30) 0.76 (0.62, 0.94) 0.76 (0.61, 0.95) 0.78 (0.47, 1.30) 0.91 (0.78, 1.06) Non-CV Death All Death Heart Failure Unstable Angina 219 (4.4) 536 (10.8) 213 (4.3) 88 (1.8) 0.84 2.06 0.83 0.34 246 (5.0) 592 (12.0) 226 (4.6) 77 (1.6) 0.95 2.29 0.89 0.30 0.88 (0.73, 1.06) 0.90 (0.80, 1.01) 0.93 (0.77, 1.12) 1.14 (0.84, 1.54) Composite Microvascular Eye Outcome Renal Outcome 910 (18.4) 95 (1.9) 848 (17.1) 3.76 0.40 3.47 1019 (20.6) 76 (1.5) 970 (19.6) 4.31 0.30 4.07 0.87 (0.79, 0.95) 1.24 (0.92, 1.68) 0.85 (0.77, 0.93) 0.5 1 2 HR Favors Dulaglutide Favors Placebo

45. Microvascular Composite Outcome Eye or Kidney laser, anti VEGF, vitrectomy new macroalbuminuria, or 30% fall in eGFR, or renal replacement Rx HR 0.87 (95% CI 0.79, 0.95) HR 0.90 (95% CI 0.80, 1.01)

46. Baseline Renal Characteristics All Participants N=9901 66.2 46.4 75.7 31.5 Dulaglutide N=4949 66.2 46.6 75.9 31.5 Placebo N=4952 66.2 46.1 75.6 31.4 Age (years) Females (%) White (%) Prior CV Disease (%) ACE/ARB (%) Mean HbA1c (%) Mean Blood Pressure (mm Hg) 81.5 7.3 137/79 81.0 7.3 137/78 82.0 7.4 137/79 Mean eGFR (ml/min/1.73m2) Median Urine ACR (mg/mmol) 77 1.82 77 1.80 77 1.88

47. Baseline Renal Characteristics All Participants N=9901 25.6 49.5 21.1 1.1 Dulaglutide N=4949 26.2 49.2 20.8 1.0 Placebo N=4952 25.0 49.9 21.5 1.1 eGFR 90 (%) eGFR 60-89 (%) eGFR 30-59 (%) eGFR < 30 (%) Albuminuriaa (%) Microalbuminuriab (%) Macroalbuminuriac (%) 35.0 27.0 8.0 34.5 26.8 7.7 35.5 27.3 8.3 eGFR < 60 & albuminuria (%) eGFR < 60 & no albuminuria (%) eGFR 60 & albuminuria (%) eGFR 60 & no albuminuria (%) 10.5 10.5 24.0 47.0 10.0 10.5 23.9 47.5 11.0 10.5 24.1 46.5 aACR 3.39 mg/mmol (30 mg/g); bACR 3.39 - 33.9 mg/mmol (30-300 mg/g); cACR > 33.9 mg/mmol (300 mg/g)

48. Effect on eGFR & Urine Alb/Creatinine Estimated GFR Urine Albumin/Creatinine Geometric mean ACR (mg/mmol) Overall LSM Proportional Difference: 0.82 (95% CI 0.78, 0.86); P < 0.0001 Overall LSM Difference: 0.4 (95% CI -0.1, 1.0) P = 0.12 Mean eGFR (ml/min/1.73m2) 18% lower ACR

49. Renal Composite Outcome New Macroalbuminuria, 30% fall in eGFR, or Renal Replacement Rx HR 0.85 (95% CI 0.77, 0.93) P = 0.0004

50. Development of New Macroalbuminuria New Urine Albumin/Creatinine > 33.9 mg/mmol (300 mg/g) HR 0.77 (95% CI 0.68, 0.87) P < 0.0001

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