The Evolution of Weight Loss Medications: Semaglutide, Tirzepatide, and Retatrutide
In recent years, the landscape of obesity treatment has dramatically shifted with the introduction of novel medications that target the underlying physiology of appetite and energy balance. Semaglutide, tirzepatide, and retatrutide represent a progressive evolution from single to triple-action drugs—each iteration offering greater efficacy and a better side effect profile.
Good - Semaglutide: The Pioneer GLP-1 Agonist
Semaglutide (Ozempic, Wegovy) is a GLP-1 receptor agonist, mimicking the gut hormone glucagon-like peptide-1, which plays a critical role in glucose homeostasis and satiety. GLP-1 slows gastric emptying, enhances insulin secretion, suppresses glucagon, and directly signals satiety centers in the hypothalamus (Wilding et al., 2021).
In the STEP 1 trial, semaglutide 2.4 mg once weekly led to an average weight loss of 14.9% over 68 weeks in adults with obesity (Wilding et al., 2021). However, side effects were common—mainly nausea, vomiting, diarrhea, and constipation.
Better - Tirzepatide: Dual GIP/GLP-1 Receptor Agonist
Tirzepatide (Mounjaro) takes it further by acting as a dual agonist of both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors. GIP enhances insulin release and may also improve the tolerability of GLP-1 effects. This dual mechanism results in greater weight loss and glycemic control than GLP-1 alone (Jastreboff et al., 2022).
In the SURMOUNT-1 trial, tirzepatide at 15 mg weekly resulted in up to 22.5% body weight reduction over 72 weeks (Jastreboff et al., 2022). Side effects were similar to semaglutide but less severe, likely due to GIP's counteractive influence on nausea and gastric symptoms.
Best - Retatrutide: The Triple Agonist Breakthrough
Retatrutide is the newest and most promising agent, combining agonism at GLP-1, GIP, and glucagon receptors. While GLP-1 and GIP promote satiety and insulin secretion, glucagon receptor activation increases energy expenditure, providing a metabolic boost absent in earlier agents (Coskun et al., 2023).
According to the Phase 2 trial published in the New England Journal of Medicine, retatrutide achieved weight reductions up to 24.2% at 48 weeks, with projections nearing or exceeding 25% at full duration (Coskun et al., 2023). This level of efficacy rivals bariatric surgery.
Interestingly, retatrutide also had a favorable side effect profile, with mild to moderate gastrointestinal events and a lower discontinuation rate than earlier medications. The balanced receptor activity appears to reduce nausea and improve tolerability, likely by moderating the gastric-slowing effect of GLP-1 alone.
The Wrap Up
These medications represent a stepwise advancement in pharmacological weight loss, each improving on the limitations of its predecessor. Semaglutide is highly effective, tirzepatide is superior with dual agonism, and retatrutide, with its triple-action mechanism, currently offers the greatest weight loss and best tolerability seen in pharmacotherapy. As research continues, these drugs are not just reshaping waistlines but redefining obesity treatment at its biological roots.
References
Wilding, J. P. H., et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, 384(11), 989–1002. https://doi.org/10.1056/NEJMoa2032183
Jastreboff, A. M., et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine, 387(3), 205–216. https://doi.org/10.1056/NEJMoa2206038
Coskun, T., et al. (2023). Retatrutide, a Triple Hormone Receptor Agonist for Obesity — A Phase 2 Trial. New England Journal of Medicine, 389(6), 513–526. https://doi.org/10.1056/NEJMoa2301972
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