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Tirzepatide in Treating Obesity in Type 2 Diabetes: SURMOUNT-2 Trial Findings

Robust weight reduction is observed in people with obesity but without T2D, unlike individuals with obesity and T2D who respond less to anti-obesity medications (AOMs). The SURMOUNT-2 trial was designed to evaluate the safety and efficacy of tirzepatide in treating obesity in individuals with T2D. Results show that tirzepatide at 10mg and 15mg once-weekly significantly outperformed placebo in achieving weight loss, with secondary outcomes including HbA1c reduction and improvements in metabolic parameters. The trial demonstrated the potential of tirzepatide in managing both weight and glycemic control in T2D patients.

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Tirzepatide in Treating Obesity in Type 2 Diabetes: SURMOUNT-2 Trial Findings

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  1. Welcome to the 83 Scientific Sessions RD

  2. The Need for Separate Studies in People with T2D • Robust body weight reduction was observed in the SURMOUNT-1 trial in people with obesity without T2D. • However, people with obesity and T2D often have less weight reduction in response to treatment with AOMs compared to those without diabetes. • Therefore, dedicated studies in people with T2D and obesity are warranted.

  3. The Rationale for SURMOUNT-2 • Tirzepatide demonstrated HbA1c lowering and body weight reduction in the SURPASS trials. • However, these trials were primarily designed to assess glycemic control, rather than weight management, in people with T2D. Studies designed for glycemic control in T2D Studies designed for weight management in T2D Also include lower BMIs (as low as 22 kg/m2) BMI >27 kg/m2(AOM-eligible population) Less prescriptive lifestyle intervention Dietitian-guided diet and exercise counseling Generally shorter duration (primary outcome at ~40-52 weeks) 72 weeks and at least 52 weeks after dose escalation (per regulatory guidance) HbA1c primary outcome Weight loss primary outcome • SURMOUNT-2 was therefore designed to assess the safety and efficacy of tirzepatide for treatment of obesity in T2D.

  4. SURMOUNT-2 Study Design1 A Randomized, Double-Blind, Multicenter, Placebo-Controlled Trial Key Inclusion Criteria • T2D • ≥18 years old • BMI ≥27 kg/m2 • HbA1c ≥7% to ≤10% • Stable weight and T2D treatment. • On any oral agent (except DPP-4i or GLP-1 RA) Randomization stratified by country, sex, and weight effect of baseline antihyperglycemic medications One study drug dose reduction permitted to help manage intolerable gastrointestinal symptoms. 1. Le Roux C, et al. Obesity (Silver Spring). 2023;31(1):96-110

  5. Objectives of the SURMOUNT 2 Trial To demonstrate that tirzepatide 10 mg and/or 15 mg a once-weekly is superior to placebo at 72 weeks for: Primary Objectives  percent change in body weight, AND ≥5% body weight reduction Key Secondary Objectives body weight reduction thresholds of: 10% or more, 15% or more, and 20% or more ♦ change in HbA1c achieving HbA1c <7%, HbA1c ≤6.5%, and HbA1c <5.7%; change in fasting glucose ♦ change in waist circumference ♦ ♦ change in fasting triglycerides, HDL-cholesterol, non-HDL-cholesterol; systolic blood pressure

  6. Baseline Characteristics Age 58.8 years Female 57.9 % Note: Well balanced across treatment groups: placebo, tirzepatide 10 mg, and tirzepatide 15 mg Race / Ethnicity • Black • White • Hispanic/Latino 17.5 % 77.8 % 40.9 % 36.1 kg/m2 BMI Waist 114.9 cm Systolic BP 130.5 mmHg HbA1c 8.02 % Diabetes Duration 8.5 years

  7. Weight Reduction Over 72 Weeks Percent Change Overall mean baseline weight = 100.8 kg 0 Weight change from baseline (%) -3.2% -3.3% -5 placebo tirzepatide 10mg tirzepatide 15mg -10 -12.8% -13.4% -14.7% -15 -15.7% -20 0 4 8 12 16 20 TRE 24 36 48 60 72 Weeks since randomization Tirzepatide vs. placebo at 72 weeks: p<0.001. Garvey WT, et al. The Lancet. In Press.

  8. Proportion of Participants Achieving Weight-Reduction Thresholds at 72 Weeks On Treatment Efficacy Estimand In Trial 100 placebo tirzepatide 10mg tirzepatide 15mg Treatment-Regimen Estimand 100 *** *** 86.4 82.8 *** *** 79.2 81.6 80 Percentage of Participants 80 *** *** 69.6 64.8 *** *** 63.4 60.5 60 60 *** 51.8 *** 48.0 *** *** 41.4 39.7 40 40 *** 34.0 *** 30.8 32.5 30.6 *** 23.0 21.5 *** 20 *** 20 17.2 *** 15.5 *** 9.0 10.0 *** 9.5 8.7 2.6 2.7 1.0 1.0 0.3 0.3 0 0 ≥5 % ≥10 % Body Weight-Reduction Threshold (%) ≥15 % ≥20 % ≥25% ≥5 % ≥10 % ≥15 % ≥20 % ≥25% Body Weight-Reduction Threshold (%) Tirzepatide vs. placebo at 72 weeks: ***p<0.001. Garvey WT, et al. The Lancet. In Press.

  9. Change in HbA1c Overall mean HbA1c at baseline = 8.02% 1 1 In Trial On Treatment Efficacy Estimand Treatment-Regimen Estimand placebo tirzepatide 10mg tirzepatide 15mg Change in HbA1c (%) Change in HbA1c (%) 0 0 -0.16 -0.51 -1 -1 -2 -2 -2.07*** -2.08*** -2.14*** -2.22*** -3 -3 Tirzepatide vs. placebo at 72 weeks: ***p<0.001. Garvey WT, et al. The Lancet. In Press.

  10. Proportion of Participants Achieving HbA1c Targets In Trial On Treatment Efficacy Estimand 100 100 Treatment-Regimen Estimand >80% achieved ADA’s recommended target <7% 90.7 90 86.9 86.7 84.2 84.1 79.7 79.4 80 80 >75% achieved AACE’s recommended target ≤6.5% Percentage of Participants Percentage of Participants 60 60 55.3 ~50% achieved normoglycemia (<5.7%) 48.6 50.2 46.0 40 36.2 40 29.3 placebo tirzepatide 10mg tirzepatide 15mg 20.0 20 20 15.5 3.9 2.8 0 0 <7% <5.7% ≤6.5% <7% <5.7% ≤6.5% HbA1c Target (%) HbA1c Target (%) Tirzepatide vs. placebo at 72 weeks: ***p<0.001. Garvey WT, et al. The Lancet. In Press.

  11. Incidence of Documented Hypoglycemia No cases of severe hypoglycemia were reported. mITT population (safety analysis set)

  12. Cardiometabolic Disease Risk Factors Tirzepatide 15 mg, on treatment Tirzepatide 15 mg -13.8 Placebo -3.4 Waist Circumference (in) BMI (kg/m2) -5.7 -1.2 Systolic BP mmHg -7.2 -1.0 Diastolic BP mmHg -2.6 -0.2 Triglycerides -28.6 -5.8 HDL-c +8.2 +1.1 Non-HDL-c Fasting Glucose -6.6 -51.7 +2.3 -2.4 Fasting Insulin (% of baseline) -41 -15 Garvey WT, et al. The Lancet. In Press.

  13. Overview of Adverse Events Note: Participants may be counted in more than 1 category. mITT population (safety analysis set) *Deaths are also included as SAEs and discontinuations due to AE. Similar percentages of participants in the tirzepatide and placebo groups reported serious adverse events.

  14. Treatment Emergent Adverse Events With >5% Frequency in Any Treatment Arm mITT population (safety analysis set); n (%)=number (percentage) of participants; TEAE=treatment emergent adverse event. The majority of TEAEs were gastrointestinal in nature.

  15. Conclusions ♦ Both tirzepatide 10 mg and 15 mg demonstrated superior and clinically meaningful body weight reduction versus placebo in participants with obesity/overweight and T2D with ~50% achieving weight loss of 15% ♦ HbA1c fell from 8% at baseline to 5.9%, and was normalized in ~ 50% of participants. This occurred without any episodes of severe hypoglycemia. ♦ Treatment with tirzepatide at both doses translated to clinically meaningful improvements in cardiometabolic risk factors. ♦ The safety profile of tirzepatide in people with obesity/overweight and T2D is consistent with the safety profile of safety profile of tirzepatide observed in the SURPASS studies and other incretin-based therapies for obesity.

  16. Weight Loss Therapies in T2D: Range of Efficacy 0% 5% 10% 15% 20% 25% 30% 35% 25-40% 2-7% 12-20% Gastric Bypass Lifestyle LapBand 2-6% 20-35% Gastric Sleeve T2D Meds 4% to up to ≥ 22 with second generation meds Current Obesity Meds without diabetes 4-10% Current Obesity Meds in T2D Sufficient to prevent and treat obesity complications and provide glycemic control. Weight loss becomes primary therapeutic modality in many patients 2ndGeneration Obesity Meds in T2D

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