The Evolving Universe of GLP-1 Medicines – What Does the Future Portend?

Daniel J. Drucker, MD
ObesityWeek 2024 – Oral presentation

Key messages

  • GLP-1RA have wider effects beyond simply inhibiting food intake.
  • There is an established evidence base in T2D, DKD, CVD, and obesity.
  • New data also show improvement in MASH.
  • Agents in development include new dual and triple agonists, as well as combinations and oral options.

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Background

What do we already know about this topic?

  • The insulin-stimulating effects of glucagon-like peptide-1 (GLP-1) were first described in the 1980s.1
  • Early animal models showed GLP-1 agonism inhibited food intake.2,3
  • The GLP-1 receptor is widely distributed in many organs.4
  • Today, there are several medications based on GLP-1 with an established evidence base in type 2 diabetes (T2D), diabetic kidney disease, cardiovascular disease, and obesity.5
New Data

Semaglutide:

  • ESSENCE: Phase 3 trial to evaluate the effect of once-weekly semaglutide 2.4 mg on liver tissue histology compared with placebo.6
  • Participants had metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced liver fibrosis.
  • Preliminary results show improvement in MASH with semaglutide.
  • Resolution of steatohepatitis was achieved in 62.9% on semaglutide versus 34.1% on placebo.

Tirzepatide:

  • SURMOUNT-4: Phase 3, randomized withdrawal clinical trial.7
  • 670 patients who had received tirzepatide for 36 weeks for weight loss were randomized to continue or stop for a further 1 year.
  • The mean weight change from Week 36 to 88 was a further –5.5% for those continuing on tirzepatide versus a gain of 14.0% for those switched to placebo.
  • Even after switching to placebo, participants ended the study with substantial weight reduction of –9.9% from the Week 0 baseline.
  • However, much of the initial improvement in cardiometabolic risk factors was reversed.

Ongoing trials and pipeline therapeutics:

  • Phase 1 data show rapid and substantial weight loss with durability of effect after once-monthly maridebart cafraglutide – a GIPR antagonist and GLP-1R agonist.8
  • New data are expected from SURPASS-CVOT in 12,500 patients with T2D and confirmed atherosclerotic disease.9
  • SURMOUNT-MMO is exploring the effect of tirzepatide on morbidity and mortality in adults living with obesity.10
  • Small-molecule oral GLP-1RA in development includes orforglipron, which shows weight loss of up to 14.7% over 36 weeks.11
  • Survodutide – a glucagon/GLP-1 co-agonist dose-dependently reduces weight by up to 18.7% over 46 weeks.12
  • Phase 2 data for retatrutide – a triple agonist – show weight reduction of up to 24.2%.13
  • Other avenues are exploring combinations, such as cagrilinitide-semaglutide.14
  • The future of GLP-1 medicines includes cell-based approaches and gene therapies.
Conclusions

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: Drucker D. The Evolving Universe of GLP-1 Medicines – What Does the Future Portend? 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
  1. Drucker DJ, Philippe J, Mojsov S, et al. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A. 1987;84:3434–8.
  2. Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996;379:69–72.
  3. Tang-Christensen M, Larsen PJ, Göke R, et al. Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. AJP 1996;271:R848–56.
  4. Drucker DJ, Holst JJ. The expanding incretin universe: from basic biology to clinical translation. Diabetalogia 2023;66(10):1765–79.
  5. Drucker DJ. Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity. Diabetes Care 2024;47(11):1873–88.
  6. https://www.prnewswire.com/news-releases/essence-phase-3-trial-results-demonstrating-statistically-significant-and-superior-improvements-with-semaglutide-2-4-mg-in-people-with-mash-presented-at-aasld-2024–the-liver-meeting-302310474.html
  7. Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA 2024;331(1):38–48.
  8. Véniant MM, Lu SC, Atangan L, et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab.2024;6(2):290–303.
  9. Nicholls SJ, Bhatt DL, Buse JB, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics. Am Heart J 2024;267:1-11.
  10. A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With Obesity (SURMOUNT-MMO). https://clinicaltrials.gov/study/NCT05556512
  11. Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med 2023;389:877–88.
  12. Le Roux C, Steen O, Lucas KJ, et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol 2024;12(3):162–73.
  13. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med 2023;389:514–26.
  14. Frías JP, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet 2023;402(10403):720–30.

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