GLP-1 Medications for Weight Loss: Semaglutide, Tirzepatide, and Retatrutide Compared
The landscape of obesity treatment has shifted dramatically over the past decade, thanks to a class of medications known as GLP-1 receptor agonists. Originally developed for type 2 diabetes, these drugs have now proven to be some of the most powerful tools for sustainable weight loss.
If you’ve been following the news around medications like semaglutide (Ozempic®, Wegovy®), tirzepatide (Mounjaro®, Zepbound®), and the newer retatrutide (still in clinical trials), you’ve probably heard about their impressive results. But how do these drugs compare, and which one might be best for you?
This article breaks down the science, clinical trial results, and real-world experiences with these medications to help you understand their role in weight loss.
What Are GLP-1 Medications?
GLP-1 stands for glucagon-like peptide-1, a hormone naturally produced in your gut after eating. GLP-1 medications mimic this hormone, leading to:
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Delayed gastric emptying (you feel full longer).
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Reduced appetite (your brain thinks you’ve eaten enough).
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Improved blood sugar control (slower glucose spikes).
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Enhanced satiety signals (better control over cravings).
Some of the newer drugs also mimic GIP (glucose-dependent insulinotropic polypeptide) or even glucagon receptors, offering an even broader metabolic impact.
The First Wave: Older GLP-1 Medications
Before semaglutide stole the spotlight, several other GLP-1 agonists were used primarily for diabetes management, with modest weight loss benefits. These include:
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Exenatide (Byetta®, Bydureon®) – One of the first GLP-1s, modest weight loss of 2–3%.
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Liraglutide (Victoza®, Saxenda®) – Approved for obesity at higher doses, typically results in 5–7% weight loss.
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Dulaglutide (Trulicity®) – Once-weekly injection, better tolerated but modest results (3–5% weight loss).
While these earlier drugs demonstrated the potential of GLP-1 therapy, the newer medications semaglutide, tirzepatide, and retatrutide have completely changed the game.
Semaglutide: The Breakthrough GLP-1
Semaglutide was the first GLP-1 drug to show double-digit percentage weight loss in large clinical trials.
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Brand names: Ozempic® (diabetes), Wegovy® (obesity).
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Mechanism: GLP-1 receptor agonist.
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Administration: Once-weekly injection.
Clinical Trial Results
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STEP trials (Semaglutide Treatment Effect in People with obesity):
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Average weight loss of ~15% of total body weight.
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Many patients lost 15–20% or more over 68 weeks.
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Strengths
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Proven, widely available, and FDA-approved for weight loss.
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Works well for many patients, especially those new to GLP-1 therapy.
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Improves blood sugar control and reduces cardiovascular risk.
Limitations
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Weight loss often plateaus after ~15%.
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Some patients experience nausea, constipation, or vomiting.
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Not as powerful as tirzepatide or retatrutide in head-to-head data.
Tirzepatide: The Dual Agonist
Tirzepatide is often referred to as the “next generation” GLP-1 because it targets two hormones:
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GLP-1 receptor
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GIP receptor (glucose-dependent insulinotropic polypeptide)
This dual mechanism seems to amplify its effects.
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Brand names: Mounjaro® (diabetes), Zepbound® (obesity).
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Administration: Once-weekly injection.
Clinical Trial Results
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SURMOUNT-1 trial:
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Average weight loss of ~20% of total body weight.
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Many participants lost more than 25% at higher doses.
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Strengths
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More effective than semaglutide in most patients.
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Improves insulin sensitivity and cardiovascular markers.
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Demonstrates greater fat mass reduction.
Limitations
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Side effects can be more pronounced initially (nausea, diarrhea).
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Still relatively new; long-term outcomes are being studied.
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Insurance coverage can be more challenging than semaglutide.
Retatrutide: The Triple Agonist
The newest GLP-1 medication in development, retatrutide, is showing jaw-dropping results in clinical trials.
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Mechanism: Targets GLP-1, GIP, and glucagon receptors.
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Status: Currently in phase-2 clinical trials.
Clinical Trial Results
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Phase 2 trial (published 2023):
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Patients lost an average of ~25% of their body weight at 48 weeks.
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Some patients achieved greater than 30% weight loss, rivaling bariatric surgery.
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Strengths
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The most powerful GLP-1 medication studied to date.
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Combines appetite suppression with increased metabolic rate from glucagon agonism.
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Could become the gold standard once approved.
Limitations
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Not yet FDA-approved (as of 2025).
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Long-term safety data still pending.
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May have higher risk of GI or metabolic side effects.
Comparing Semaglutide, Tirzepatide, and Retatrutide
| Medication | Avg. Weight Loss | Mechanism | Status |
|---|---|---|---|
| Semaglutide | ~15% | GLP-1 agonist | FDA-approved (Wegovy®) |
| Tirzepatide | ~20% | GLP-1 + GIP agonist | FDA-approved (Zepbound®) |
| Retatrutide | ~25% | GLP-1 + GIP + glucagon agonist | In clinical trials |
Why Semaglutide Still Works for Some Patients
Even though tirzepatide and retatrutide show greater average weight loss, not everyone needs (or tolerates) the most aggressive option.
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Individual response varies – some patients lose 20% on semaglutide.
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Side effect profiles differ – patients may tolerate semaglutide better.
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Insurance coverage – semaglutide often has broader approval.
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Metabolic goals – semaglutide still provides strong benefits for blood sugar and heart health.
Real-World Considerations
When choosing a GLP-1 medication, doctors and patients must weigh more than just the numbers.
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Cost and insurance coverage – newer drugs can be harder to access.
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Side effects – some patients do better with slower titration.
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Comorbidities – diabetes, heart disease, or fatty liver disease may influence drug choice.
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Long-term sustainability – weight loss is only helpful if it’s maintained.
The Future of GLP-1 Medications
GLP-1 therapy is no longer just about diabetes—it’s a cornerstone of obesity medicine. With retatrutide and other multi-agonists on the horizon, we may soon see drugs that approach the effectiveness of bariatric surgery without the invasiveness.
Combination therapies (GLP-1s with other peptides, metabolic drugs, or lifestyle protocols like the ProLon Fasting Mimicking Diet) are already being studied to push results even further.
Final Thoughts
GLP-1 medications have transformed how we treat obesity:
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Semaglutide broke ground with ~15% average weight loss.
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Tirzepatide raised the bar to ~20%.
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Retatrutide is setting new records at ~25% or more.
While semaglutide may not be as powerful as its successors, it remains a valuable and effective option for many patients. The future of obesity treatment is brighter than ever, and these medications are at the forefront.
Call to Action
If you’re struggling with weight loss and want to know whether semaglutide, tirzepatide, or retatrutide could be right for you, our team at Revolution Health is here to help. We specialize in integrative, physician-guided approaches that combine the latest medications with nutrition, lifestyle, and peptide support for long-term success.
Contact us today to schedule a consultation and take the first step toward a healthier future.
References
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Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." NEJM. 2021.
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Jastreboff AM, et al. "Tirzepatide Once Weekly for the Treatment of Obesity." NEJM. 2022.
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Rosenstock J, et al. "Efficacy and Safety of Retatrutide in Adults with Obesity." NEJM. 2023.
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Nauck MA, Meier JJ. "The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions." Lancet Diabetes Endocrinol. 2016.