The Swedish Obese Subjects (SOS) study demonstrated that bariatric surgery is associated with a 29% reduction in adjusted all-cause mortality compared with conventional obesity treatment over an average 10.9 years of follow-up, with reductions in both cardiovascular and cancer deaths, providing the first prospective controlled evidence for the long-term survival benefit of surgical weight loss.
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The Look AHEAD trial demonstrated that intensive lifestyle intervention targeting weight loss in overweight or obese adults with type 2 diabetes did not reduce cardiovascular events over 9.6 years despite clear differences in weight, fitness, and glycaemic control, establishing a critical negative result that informed the rationale for pharmacological obesity treatment with greater weight loss efficacy.
The SCALE trial established liraglutide 3.0 mg as the first GLP-1 receptor agonist approved for chronic weight management, demonstrating a mean weight reduction of 8.0% versus 2.6% with placebo and a 79% reduction in progression from prediabetes to type 2 diabetes in a 160-week extension analysis, setting the clinical and regulatory template for GLP-1 receptor agonist obesity pharmacotherapy.
The SELECT trial demonstrated that semaglutide 2.4 mg reduces 3-point MACE by 20% in overweight or obese adults with pre-existing cardiovascular disease and no diabetes, becoming the first obesity pharmacotherapy trial to demonstrate a hard cardiovascular endpoint benefit and establishing GLP-1 receptor agonism as a cardiovascular intervention in non-diabetic obesity.
SURMOUNT-1 demonstrated that tirzepatide, a dual GIP/GLP-1 receptor agonist, produces dose-dependent mean weight reductions of 15.0–20.9% in adults with obesity without type 2 diabetes, with 57% of participants at the 15 mg dose losing 20% or more of body weight, setting a new pharmacological efficacy benchmark comparable in magnitude to bariatric surgery outcomes.
STEP 1 demonstrated that once-weekly semaglutide 2.4 mg produced a mean weight reduction of 14.9% compared with 2.4% with placebo in adults with obesity without type 2 diabetes, with a third of participants losing more than 20% of body weight, setting a new benchmark for pharmacological weight management and preceding the cardiovascular outcomes evidence from SELECT.
The REWIND trial demonstrated that dulaglutide reduces 3-point MACE in a broad type 2 diabetes population of which 69% had no established cardiovascular disease, with a significant 24% reduction in nonfatal stroke and consistent renal benefit, extending GLP-1 receptor agonist cardiovascular protection into a primary prevention context.
The SUSTAIN-6 trial demonstrated that once-weekly semaglutide reduced 3-point MACE by 26% in high-cardiovascular-risk type 2 diabetes, driven primarily by a significant 39% reduction in nonfatal stroke, while identifying a retinopathy complication signal attributable to rapid glucose lowering in patients with pre-existing retinopathy.
The LEADER trial demonstrated that liraglutide significantly reduced 3-point MACE and cardiovascular mortality in patients with type 2 diabetes and high cardiovascular risk, becoming the first GLP-1 receptor agonist CVOT to demonstrate superiority and characterising an atherosclerotic rather than heart failure protection profile distinct from SGLT2 inhibitors.
DAPA-CKD demonstrated that dapagliflozin reduced the composite of a sustained 50% or greater eGFR decline, end-stage kidney disease, or renal or cardiovascular death by 39% in patients with albuminuric CKD with or without type 2 diabetes, extending nephroprotective SGLT2 inhibition beyond diabetic nephropathy to a broad CKD population for the first time.