Leigh Perreault, MD; Ania Jastreboff, MD, PhD; Sean Wharton, MD, FRCPC, PharmD; et al.
ObesityWeek 2024 – Oral presentation
Key messages
- SURMOUNT-1: Phase 3 clinical trial, with a prespecified analysis for prediabetes.
- Weight reduction was sustained over the 3 years of the trial, with up to 43% losing ≥25%.
- Nearly 99% of people with prediabetes at baseline remained T2D-free after 3 years on tirzepatide.
- These long-term and off-drug data suggest that treatment controls but does not cure obesity.
Background
What do we already know about this topic?
- In 2021, 537 million people globally were living with diabetes; this is projected to increase 45% by 2045.1
- Prediabetes affects 38% of the adult population in the United States.2
- The best way to prevent progression of prediabetes to type 2 diabetes (T2D) is with lifestyle modification, including weight loss.
- Tirzepatide is a dual GIP/GLP-1RA that is approved for weight loss.
- In clinical trials, weight loss of 22.5% was achieved at 72 weeks with the 15 mg dose.3
How was this study conducted?
- SURMOUNT-1: Phase 3 clinical trial, with a prespecified analysis for prediabetes.
- 2,539 participants with obesity or overweight but without T2D.
- Included adults with BMI ≥30 kg/m2 – or ≥27 kg/m2 with ≥1 weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).
- Randomized to placebo or tirzepatide 5, 10, or 15 mg – as an adjunct to a reduced-calorie diet and increased physical activity.
- Glycemic status was assessed at randomization with HbA1c, fasting serum glucose (FSG), and a 2-hour oral glucose tolerance test (OGTT).
- Participants with normoglycemia at baseline completed the study after 72 weeks of treatment.
- Approximately 40% of the initial population1 presented with prediabetes; these participants continued until Week 176, followed by a 17-week off-treatment period.
- Participants continued on their original randomized dose.
- The objective of this prespecified analysis was to demonstrate superiority in pooled tirzepatide groups for time to onset of T2D in the subgroup with prediabetes at baseline at Week 193, and superiority for weight loss at Week 176.
- Additional endpoints included reversion to normoglycemia and changes in cardiometabolic risk factors.
Findings
What does this study add?
- Baseline demographics and clinical characteristics were well balanced across treatment groups.
- The most common reason for discontinuation was ‘withdrawal by subject’, which occurred in more placebo than tirzepatide patients.
- At Week 176, the placebo group lost 2.1% body weight, compared with 15.4%, 19.9%, and 22.9% with 5, 10, and 15 mg tirzepatide (data are on-treatment efficacy estimands).
- Weight reduction was sustained over the 3 years of the trial.
- Up to 95% of tirzepatide-treated patients lost at least 5% of their starting body weight, with up to 43% losing at least 25%.
- In comparison, only 25% of placebo-treated patients were able to lose at least 5% of their body weight.
- Over 176 weeks, 12.6% of placebo participants were diagnosed with T2D, compared to only 1.2% with tirzepatide (on-treatment efficacy estimands).
- At Week 176, 27% of placebo patients still had prediabetes, and 60.4% had reverted to normoglycemia.
- In comparison, reversion to normoglycemia was demonstrated in nearly 95% of tirzepatide patients.
- With the 15 mg dose, no participant developed T2D, and less than 3% still had prediabetes.
- There were also improvements in systolic blood pressure, which did not appear dose-dependent.
- Participants who received tirzepatide reported greater improvements in all health-related quality of life domains compared to those on placebo.
- From Week 176 to Week 193 off-drug, there was an average weight regain of 7%.
- After 17 weeks off-drug, 8 additional participants in the tirzepatide group developed T2D.
- HbA1c and blood pressure also increased back towards baseline during the off-drug follow-up.
- There were no new safety signals in the 3-year SURMOUNT-1 study.
- The most common adverse events were gastrointestinal, generally mild to moderate, and occurring mainly during dose escalation.
- Gallbladder events were reported more often in the 10 and 15 mg groups compared to placebo, mainly due to increased incidence of cholelithiasis.
Perspectives
How does this study impact clinical practice?
- In SURMOUNT-1, there was a 94% reduction in the risk of progression from prediabetes to T2D.
- Nearly 99% of people who received tirzepatide remained free of T2D after 3 years.
- Tirzepatide delivers significant and sustained weight reduction compared to placebo over 3 years, alongside improvements in cardiometabolic measures and quality of life.
- Off-drug, weight regain was observed, accompanied by worsening glycemia and T2D progression.
- Tolerability and safety were generally consistent with incretin-based therapies in people with obesity.
- These long-term maintenance and off-drug data suggest that treatment controls but does not cure obesity, and this may impact prescribing decisions and patterns in clinical practice.
Source: Perreault L, Jastreboff A, Wharton S, et al. SURMOUNT Clinical Trials Orals Session. Presented at ObesityWeek® 2024.
The information and data provided are for informational purposes only. The author(s) of the original presentation had no involvement in the creation of this content.
Resources
- IDF Diabetes Atlas 2021, 10th edition. https://diabetesatlas.org/atlas/tenth-edition/
- CDC. National Diabetes Statistics Report, 2024. https://www.cdc.gov/diabetes/php/data-research/index.html
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022;387(3):205–16. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038
