Retatrutide vs Tirzepatide vs Semaglutide (Ozempic): What's the difference?

By Dr Frank Yap, MD -

Introduction

The landscape of obesity treatment has evolved dramatically with the introduction of advanced medical therapeutics like retatrutide (RETA, LY3437943), tirzepatide, and semaglutide. These drugs, originally developed to manage type 2 diabetes, have shown remarkable efficacy in promoting weight loss, making them game-changers for obesity management. However, each drug has unique mechanisms, benefits, and potential applications, including emerging roles in cancer prevention. This article compares retatrutide, tirzepatide, and semaglutide, highlighting their differences in mechanism of action, weight loss efficacy, additional health benefits, and side effects to help patients and healthcare providers make informed decisions.

Mechanism of Action

  • Semaglutide: Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). It mimics the action of GLP-1, a hormone that enhances insulin secretion, suppresses glucagon release, slows gastric emptying, and reduces appetite. Marketed as Ozempic for diabetes and Wegovy for weight loss, semaglutide primarily targets the GLP-1 receptor to regulate blood sugar and promote satiety.
  • Tirzepatide: Tirzepatide, sold as Mounjaro, is a dual agonist that targets both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. GIP is another incretin hormone that enhances insulin secretion and may improve fat metabolism. This dual action amplifies tirzepatide’s effects on glucose control and weight loss compared to GLP-1-only therapies like semaglutide.
  • Retatrutide: Retatrutide takes it a step further as a triple agonist, targeting GLP-1, GIP, and glucagon receptors. The addition of glucagon receptor agonism increases energy expenditure by stimulating thermogenesis and fat oxidation, making retatrutide a potent candidate for weight loss. This unique mechanism also contributes to its emerging role in cancer prevention, as discussed in recent studies.
    • "Triple–hormone-receptor agonist retatrutide, showed unprecedented efficacy in treating obesity, with 24% weight loss over 48 weeks."(NEJM 2023)
    • "Triple G agonists (retatrutide) could provide a bridge to more permanent surgical weight loss or potentially augment surgical efficacy." (NEJM 2023)
    • "Beyond glycemic control and weight reduction, retatrutide shows promise in mitigating cardiovascular risk factors and addressing non-alcoholic fatty liver disease, expanding its potential impact on metabolic health." (European Journal of Pharmacology 2024)

Weight Loss Efficacy

  • Semaglutide: In clinical trials like the STEP program, semaglutide (Wegovy) achieved an average weight loss of 15-20% of body weight over 68 weeks at a 2.4 mg weekly dose. It’s highly effective for many patients but may plateau for some, particularly those with higher baseline weights.
  • Tirzepatide: Tirzepatide has shown superior weight loss compared to semaglutide in head-to-head trials like SURPASS. At its highest dose (15 mg weekly), tirzepatide resulted in 20-25% body weight reduction over 72 weeks, with some patients losing up to 50 pounds. The dual GIP/GLP-1 action likely contributes to its enhanced efficacy.
  • Retatrutide: Retatrutide is the newest contender and has demonstrated unprecedented weight loss in early-phase trials. In a phase 2 study, patients on the highest dose (12 mg weekly) achieved up to 24.2% weight loss over 48 weeks—outpacing both semaglutide and tirzepatide in shorter timeframes. Some participants lost nearly 30% of their body weight, approaching the efficacy of bariatric surgery. The triple-agonist mechanism, particularly glucagon’s role in boosting metabolism, sets retatrutide apart.
Source: eClinicalMedicine 2024

Additional Health Benefits

  • Semaglutide: Beyond weight loss, semaglutide reduces cardiovascular risk in patients with type 2 diabetes (as shown in the SUSTAIN trials) and improves glycemic control. Preclinical studies also suggest modest anti-tumor effects, with a 4-fold reduction in pancreatic tumor volume in mouse models.
  • Tirzepatide: Tirzepatide offers similar cardiovascular benefits and superior glycemic control compared to semaglutide, thanks to its GIP agonism. It also improves lipid profiles, reducing triglycerides and increasing HDL cholesterol. However, its effects on cancer are less studied.
  • Retatrutide: Retatrutide’s triple-agonist action provides unique benefits, including significant improvements in liver fat reduction (up to 90% in some patients), which is critical for non-alcoholic fatty liver disease (NAFLD). Most notably, retatrutide has shown profound anti-tumor effects in preclinical models, with a 14-fold reduction in pancreatic tumor volume, a 17-fold reduction in lung tumor volume, and enhanced chemotherapy efficacy in obese triple-negative breast cancer (TNBC) models. These effects are linked to immune reprogramming and inhibition of the hexosamine biosynthetic pathway (HBP) and EIF3H/YAP axis, suggesting a potential role in reducing obesity-associated cancer risk.
  • Additionally, Retatrutide could be repurposed as a potential cancer treatment as well:

Side Effects and Tolerability

  • Semaglutide: Common side effects include nausea, vomiting, diarrhea, and constipation, which typically subside over time. There’s a rare risk of pancreatitis and a potential association with thyroid C-cell tumors (based on rodent studies), though human data is inconclusive.
  • Tirzepatide: Tirzepatide shares a similar side effect profile to semaglutide, with gastrointestinal issues being the most common. However, its dual agonism may lead to slightly higher rates of nausea in some patients. Like semaglutide, it carries a warning for thyroid tumors.
  • Retatrutide: As a triple agonist, retatrutide also causes gastrointestinal side effects, but early data suggest a higher incidence of mild-to-moderate nausea and vomiting, likely due to its glucagon component. Some patients experience transient increases in heart rate, a known effect of glucagon receptor agonism. Long-term safety data, including cancer risk, is still under investigation, but its anti-tumor effects in preclinical models are promising.

Cost and Accessibility

  • Semaglutide: Widely available as Ozempic and Wegovy, semaglutide is expensive without insurance (around $1,300/month in the U.S.). Generic versions are not yet available, but its established market presence makes it more accessible than newer drugs.
  • Tirzepatide: Mounjaro is similarly priced (approximately $1,200/month), though insurance coverage varies. Its newer status means it may be harder to access in some regions, but Eli Lilly has expanded production to meet demand.
  • Retatrutide: Still in clinical development, retatrutide is not yet commercially available as of April 2025. Pricing is unknown, but given its advanced mechanism, it may be costlier than semaglutide and tirzepatide upon launch. Access will likely be limited until phase 3 trials conclude and regulatory approval is granted.

Which Drug Is Right for You?

  • Choose Semaglutide if you’re looking for a well-established option with proven weight loss and cardiovascular benefits, and you prefer a drug with a longer safety track record.
  • Choose Tirzepatide if you want greater weight loss potential and improved glycemic control, especially if you have type 2 diabetes or need better lipid management.
  • Choose Retatrutide (once available) if you’re seeking maximum weight loss and are at high risk for obesity-associated cancers, given its promising anti-tumor effects. However, you’ll need to weigh its side effect profile and await its market availability.

Conclusion

Retatrutide, tirzepatide, and semaglutide represent a new era in obesity management, each with distinct mechanisms and benefits. Semaglutide offers a reliable, well-studied option; tirzepatide provides enhanced weight loss and metabolic benefits; and retatrutide, though not yet available, promises unparalleled weight loss and potential cancer risk reduction. As research progresses, these drugs may redefine how we approach obesity and its associated comorbidities, offering hope to millions worldwide. Consult your healthcare provider to determine which option aligns best with your health goals.


References:

GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review (eClinicalMedicine 2024)

SELECT trial: Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design (American Heart Journal 2020)

SUSTAIN 10 trial: Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes. (Diabetes & Metabolism 2020)

SURMOUNT 4 trial: Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity (JAMA 2023)

SURMOUNT 2 trial: Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial (Lancet 2023)

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