The clinical trials that established the efficacy of GLP-1 receptor agonists for obesity and cardiovascular disease are, by any reasonable standard, impressive. The STEP and SURMOUNT trial programs recruited large numbers of patients, followed them for meaningful durations, and produced outcomes that are genuinely clinically significant. Understanding what those trials actually showed — and what they did not study — is the foundation for having informed conversations about these medications.
STEP 1: The Semaglutide Landmark
Population: 1,961 adults with BMI ≥30 (or ≥27 with weight-related comorbidity), without diabetes
Duration: 68 weeks
Intervention: Semaglutide 2.4 mg subcutaneous weekly vs. placebo, both with lifestyle intervention
Result: Mean weight reduction of 14.9% in the semaglutide group vs. 2.4% in placebo
What it did not study: Long-term maintenance (most weight is regained within 1 year of stopping), body composition change, or musculoskeletal outcomes
SURMOUNT-1: Tirzepatide Sets a New Bar
Population: 2,539 adults with BMI ≥30 (or ≥27 with comorbidity), without diabetes
Duration: 72 weeks
Intervention: Tirzepatide 5, 10, or 15 mg weekly vs. placebo
Result: Maximum dose group achieved mean weight reduction of 20.9% — unprecedented in pharmaceutical weight loss trials
Lean mass data: Approximately 33–40% of total weight loss was lean mass, consistent with STEP 1
The SELECT Trial: Cardiovascular Outcomes
Population: 17,604 adults with established cardiovascular disease, overweight or obesity, without diabetes
Duration: Mean 33.5 months
Result: 20% relative risk reduction in MACE (major adverse cardiovascular events) with semaglutide 2.4 mg vs. placebo
Significance: This is the cardiovascular outcomes data that moved GLP-1 agonists from weight-loss medications to cardiovascular medications in the eyes of most cardiologists — the effect appears to be partly independent of weight loss alone
The Discontinuation Problem
The detail most underemphasized in GLP-1 agonist discussions is what happens when the medication is stopped. A 2022 trial by Wilding and colleagues (the STEP 1 extension) followed patients after 20-week drug withdrawal and found that approximately two-thirds of weight lost during treatment was regained within 1 year of stopping, with partial regain of cardiometabolic risk markers. This has significant implications: these medications appear to require indefinite use to maintain their primary benefit. This is not inherently a reason not to use them, but it is a piece of information that changes the risk-benefit calculus — particularly regarding musculoskeletal effects — from "short-term intervention" to "lifelong medication."
What We Do Not Yet Know
The evidence base for GLP-1 agonists is better than for most medications at a comparable stage of adoption. It is also, by the standards of long-term pharmacotherapy, still early. The trials we have are largely 1–3 years in duration. We do not have 10-year data on bone density, tendon health, lean mass trajectories, or the downstream functional consequences of the body composition changes observed in the short-term trials. This is not a reason to avoid these medications when their cardiovascular and metabolic benefits are established — it is a reason to monitor the patients on them with the kind of musculoskeletal attention that has not yet been built into most prescribing protocols.
The practical recommendation: patients on long-term GLP-1 agonist therapy should be exercising regularly with an emphasis on resistance training, meeting protein targets deliberately, and — if over 45 — having bone density monitored. These are not extraordinary interventions. They are the standard of care for musculoskeletal health in any aging adult, and they are more important, not less, in the context of a medication that produces rapid and substantial weight loss.
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989–1002.
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205–216.
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221–2232.
- Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide. Diabetes Obes Metab. 2022;24(8):1553–1564.
- Bikou A, Konstantinou C, Paltoglou G, et al. GLP-1 receptor agonist effects on musculoskeletal outcomes in obesity: a systematic review. Obes Rev. 2024;25(4):e13679.