GLP-1 Comparisons:
Retatrutide vs the Rest

Retatrutide is the most advanced obesity compound in clinical development. Its defining feature is the addition of glucagon receptor agonism to the GLP-1 and GIP dual action already seen in tirzepatide. This third receptor increases resting energy expenditure, meaning the body burns more calories even at rest — a mechanism absent in all other approved GLP-1 agents.

In the landmark Phase 2 trial published in the New England Journal of Medicine (2023), participants on the 12mg dose lost a mean of 24.2% of body weight over 48 weeks. Notably, 26% of participants lost more than 30% of body weight — a threshold previously unachievable with medication alone. The trial was shorter than most competitor trials, suggesting Phase 3 results at 72+ weeks could be significantly higher.

Beyond weight loss, retatrutide has demonstrated strong reductions in liver fat, making it a leading candidate for treating metabolic fatty liver disease (MASLD/MAFLD). Cardiovascular marker improvements — blood pressure, triglycerides, cholesterol — were consistent with the class. Phase 3 TRIUMPH trials are ongoing as of 2025, with approval likely 2027–2029 if results hold.

Tirzepatide was the first dual GLP-1/GIP agonist to reach market, approved in 2022 for type 2 diabetes (Mounjaro) and later for obesity (Zepbound). Its dual mechanism — combining GLP-1's appetite suppression with GIP's improvement in insulin sensitivity and fat storage — produces weight loss roughly 50% greater than semaglutide in head-to-head comparisons.

The SURMOUNT-1 Phase 3 trial demonstrated mean weight loss of 22.5% over 72 weeks at the 15mg dose, with some participants losing over 25% of body weight. Tolerability was generally good, with the GIP component thought to reduce GI side effects compared to GLP-1 agonism alone.

Tirzepatide has also shown strong cardiovascular benefits in the SURPASS-CVOT trial. It is currently the most effective approved obesity medication on the market and a close second to retatrutide in terms of absolute weight loss potential. For researchers, it represents the current benchmark against which newer compounds are measured.

Semaglutide brought GLP-1 therapy into mainstream awareness. Originally approved for type 2 diabetes as Ozempic (2017), its weight-loss potential led to approval as Wegovy for obesity in 2021. It works by selectively targeting the GLP-1 receptor, reducing appetite and slowing gastric emptying, leading to reduced food intake.

The STEP 1 Phase 3 trial demonstrated mean weight loss of 14.9% over 68 weeks at the 2.4mg weekly dose — groundbreaking at the time, though now surpassed by newer compounds. Semaglutide's cardiovascular credentials are strong: the SELECT trial showed a 20% reduction in major cardiovascular events in non-diabetic patients with obesity.

Semaglutide is also available in an oral formulation (Rybelsus), though the injection consistently outperforms it. As the most widely prescribed GLP-1 agent globally, it benefits from the largest real-world safety dataset of any compound in this class. It remains an excellent, well-understood option despite being outperformed by newer agents in weight loss magnitude.

Liraglutide was the first GLP-1 receptor agonist approved for chronic weight management (Saxenda, 2014), and the predecessor that demonstrated the class could produce clinically meaningful weight loss. Like semaglutide, it targets only the GLP-1 receptor — but requires daily rather than weekly injections due to its shorter half-life of approximately 13 hours.

The SCALE Obesity trial showed mean weight loss of approximately 8% over 56 weeks — substantially lower than later-generation compounds. Daily injection burden and lower efficacy have led most clinical guidelines to prefer semaglutide or tirzepatide over liraglutide where available.

Liraglutide has an established cardiovascular safety profile (LEADER trial showed cardiovascular benefit in high-risk diabetic patients). It remains relevant in contexts where newer compounds are unavailable or where its specific profile suits a patient, but it is broadly considered a first-generation compound superseded by weekly options.