Across 38 randomized controlled trials enrolling 25,816 adults with overweight or obesity but without diabetes, placebo-subtracted weight loss varied dramatically by agent: liraglutide achieved just -5.8%, subcutaneous semaglutide -14.8%, oral semaglutide -14.3%, orforglipron -12.4%, and tirzepatide -19.0%. Emerging multiagonists pushed further still — amycretin reached -23.9% and retatrutide -22.1%. Gastrointestinal side effects remained the dominant tolerability issue (76% vs. 40% on placebo), though discontinuation rates stayed relatively low at 10.7%, and serious adverse events were rare.
This review crystallizes what practitioners have observed clinically: the GLP-1 class is not monolithic. The jump from liraglutide to semaglutide to tirzepatide represents stepwise mechanistic escalation — from pure GLP-1 agonism to dual GIP/GLP-1 co-agonism — and the weight outcomes follow accordingly. The multiagonist pipeline (retatrutide adds glucagon receptor agonism; amycretin combines GLP-1 with amylin analogy) suggests a ceiling has not yet been reached. Practically, these magnitude differences matter enormously: a -19% vs. -5.8% body weight reduction separates metabolic disease modification from modest benefit.
Limitations are meaningful: heterogeneity prevented meta-analytic pooling, safety reporting was inconsistent across trials, and trial durations rarely exceed two years, leaving long-term cardiovascular and oncologic signals unclear. This review is confirmatory for established agents but genuinely signals a paradigm shift for pipeline compounds — oral options and triple agonists may soon redefine obesity pharmacotherapy benchmarks.