Peptides for Weight Loss: What You Need to Know

The landscape of obesity treatment has been transformed by peptide-based medications. These drugs work with your body’s natural hunger-regulation systems, offering substantial weight loss results that were previously only achievable through surgery. Here’s what the science tells us about how these medications work, what results you can expect, and what you should consider before starting treatment.

What Are Weight Loss Peptides

Peptide medications for weight loss primarily work by mimicking glucagon-like peptide-1 (GLP-1), a hormone your gut naturally releases after eating. This hormone signals to your brain that you’re full, slows stomach emptying, and helps regulate blood sugar. The synthetic versions of these hormones called GLP-1 receptor agonists amplify these effects, leading to reduced appetite and significant weight loss.

GLP-1 naturally has a half-life of only about two minutes because your body breaks it down quickly. Pharmaceutical versions are engineered to last much longer some working for an entire week from a single injection which makes them practical for ongoing treatment.

How Do These Medications Work

Weight loss peptides work through multiple pathways simultaneously:

Brain signaling: GLP-1 receptor agonists cross the blood-brain barrier and activate receptors in brain regions that control appetite and reward. A study published in Diabetes demonstrated that GLP-1 receptor activation modulates appetite-related brain areas including the insula and amygdala, reducing the neural reward response to food images (van Bloemendaal et al., “GLP-1 Receptor Activation Modulates Appetite- and Reward-Related Brain Areas in Humans,” 2014.

Delayed gastric emptying: These medications slow how quickly food leaves your stomach, helping you feel full longer after meals.

Insulin regulation: GLP-1 agonists enhance insulin secretion in response to food, helping regulate blood sugar levels which is why they were originally developed for diabetes treatment.

Reduced food noise: Many patients report a dramatic decrease in constant thoughts about food, making it easier to stick to healthier eating patterns.

Currently Approved Medications

Several peptide-based medications are now FDA-approved for weight management:

Semaglutide (Wegovy) A once-weekly injection that remains the most widely used GLP-1 medication for weight loss. In December 2025, the FDA approved an oral form of Wegovy, making it the first oral GLP-1 for weight management. The STEP 1 trial published in the New England Journal of Medicine demonstrated that participants taking semaglutide 2.4 mg lost an average of 14.9% of their body weight over 68 weeks, compared to 2.4% with placebo (Wilding et al., “Once-Weekly Semaglutide in Adults with Overweight or Obesity,” 2021.

Tirzepatide (Zepbound) A dual GIP/GLP-1 receptor agonist that targets two hormone pathways simultaneously. The SURMOUNT-1 trial showed participants achieved average weight reductions of 16.0% (5 mg), 21.4% (10 mg), and 22.5% (15 mg) over 72 weeks (Jastreboff et al., “Tirzepatide Once Weekly for the Treatment of Obesity,” New England Journal of Medicine, 2022.

Liraglutide (Saxenda) A once-daily injection that was the first GLP-1 receptor agonist approved specifically for weight management. Generic versions became available in August 2025.

How Much Weight Can You Expect to Lose

Clinical trial results demonstrate substantial weight loss potential:

The STEP clinical trial program consistently showed semaglutide 2.4 mg producing mean weight losses of 14.9% to 17.4% in participants without diabetes over 68 weeks. The newer STEP UP trial presented at the American Diabetes Association Scientific Sessions in 2025 demonstrated that a higher 7.2 mg dose of semaglutide achieved 20.7% weight loss in adherent participants over 72 weeks.

For tirzepatide, the SURMOUNT trials showed even more impressive results. At the 15 mg dose, 89% to 91% of participants lost at least 5% of their body weight a commonly used threshold for clinically meaningful weight loss. More remarkably, 50% to 57% lost 20% or more of their starting weight.

Weight loss with these medications continues gradually over time. In the SELECT trial, semaglutide produced weight loss that continued over 65 weeks and was sustained for up to four years, with a mean reduction of 10.2% at week 208 (Lincoff et al., “Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial,” Nature Medicine, 2024).

The Next Generation Triple Agonists

Retatrutide represents the next evolution in weight loss peptides. This investigational medication targets three receptors simultaneously: GLP-1, GIP, and glucagon. In a phase 2 trial published in the New England Journal of Medicine, the 12 mg dose produced a mean weight reduction of 24.2% after just 48 weeks approaching results typically seen only with bariatric surgery (Jastreboff et al., “Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial,” 2023).

The TRIUMPH-4 phase 3 trial announced in December 2025 showed participants on retatrutide 12 mg lost an average of 71.2 pounds (28.7% body weight) over 68 weeks, with substantial improvements in knee osteoarthritis pain.

Understanding the Side Effects

Gastrointestinal symptoms are the most common side effects, particularly during the dose-escalation period:

• Nausea affects approximately 20-40% of users
• Diarrhea occurs in roughly 15-25% of patients
• Constipation, vomiting, and abdominal discomfort are also frequently reported

A systematic review and network meta-analysis published in the International Journal of Obesity found that increasing doses of GLP-1 receptor agonists heighten the risk of gastrointestinal adverse events, but these risks typically peak early and diminish over time as the body adjusts (Younes et al., 2025).

Most side effects are mild to moderate and tend to improve after the initial weeks of treatment. Clinical guidelines recommend gradual dose escalation to minimize these symptoms. Eating smaller meals, avoiding high-fat foods, and staying hydrated can help manage digestive discomfort.

Rare but more serious side effects have been reported, including pancreatitis and gallbladder problems. These medications carry a boxed warning about potential thyroid C-cell tumor risk based on animal studies.

The Weight Regain Question

One crucial consideration is what happens when treatment stops. Studies consistently show that discontinuing GLP-1 medications leads to weight regain.

A systematic review and meta-analysis published in Obesity Reviews found that after stopping GLP-1 receptor agonist therapy, participants who had taken semaglutide or tirzepatide regained an average of 9.69 kg (Berg et al., “Discontinuing glucagon-like peptide-1 receptor agonists and body habitus,” 2025). The weight regain was proportional to the original weight loss those who lost more also regained more.

The SURMOUNT-4 trial demonstrated this pattern clearly: participants who switched from tirzepatide to placebo after 36 weeks of treatment experienced substantial weight regain. Among those in the placebo arm, 82% regained more than 25% of their lost weight within one year (Aronne et al., “Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity,” JAMA, 2024).

This highlights that obesity is a chronic condition requiring ongoing management similar to medications for blood pressure or diabetes. Stopping treatment typically means the underlying biology that drives weight gain reasserts itself.

Beyond Weight Loss Additional Health Benefits

These medications offer benefits beyond the number on the scale:

Cardiovascular protection: The SELECT trial, published in the New England Journal of Medicine, showed that semaglutide reduced major adverse cardiovascular events by 20% in patients with established cardiovascular disease and overweight or obesity (Lincoff et al., “Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes,” 2023).

Sleep apnea improvement: Tirzepatide became the first medication approved for moderate-to-severe obstructive sleep apnea in December 2024, based on the SURMOUNT-OSA trial results.

Liver health: Semaglutide received FDA approval in 2025 for metabolic dysfunction-associated steatohepatitis (MASH), a serious fatty liver condition.

Metabolic improvements: Clinical trials consistently show improvements in blood pressure, cholesterol levels, triglycerides, and blood sugar control alongside weight loss.

Who Should Consider These Medications

GLP-1 receptor agonists are generally indicated for adults with:

• A body mass index (BMI) of 30 or greater (obesity), OR
• A BMI of 27 or greater (overweight) with at least one weight-related condition such as high blood pressure, type 2 diabetes, or high cholesterol

These medications work best as part of a comprehensive approach that includes dietary changes and increased physical activity. They are not appropriate for everyone people with a history of medullary thyroid cancer, multiple endocrine neoplasia syndrome type 2, or pancreatitis may not be candidates.

Injectable vs. Oral Options

Until recently, most GLP-1 medications required injection. The December 2025 FDA approval of oral semaglutide (Wegovy pill) at 25 mg for weight management offers an alternative for those who prefer pills to needles.

The oral form must be taken on an empty stomach, at least 30 minutes before the first food, beverage, or other medication of the day, with no more than four ounces of plain water. This strict dosing protocol is necessary because the peptide is fragile and easily degraded by stomach acid.

Clinical trials showed the oral form produced weight loss comparable to the injectable version about 13.6% body weight reduction at 64 weeks in the OASIS 4 trial (Wharton et al., “Oral semaglutide at a dose of 25 mg in adults with overweight or obesity,” New England Journal of Medicine, 2025).

What to Discuss with Your Doctor

Before starting any weight loss medication, have an honest conversation with your healthcare provider about:

• Your weight history and previous weight loss attempts.
• Current medications and medical conditions.
• Realistic expectations for weight loss.
• The long-term nature of treatment.
• Costs and insurance coverage (these medications can be expensive without coverage).
• Lifestyle changes you’re prepared to make alongside medication.

The Bottom Line

Peptide-based weight loss medications represent a genuine breakthrough in obesity treatment. They can produce substantial, clinically meaningful weight loss for many people when combined with lifestyle modifications. However, they require ongoing use to maintain results, come with common (if usually manageable) side effects, and work best as one component of a comprehensive weight management strategy.

The field continues to advance rapidly, with newer medications in development promising even greater efficacy. Working closely with a healthcare provider is essential for determining whether these medications are appropriate for your individual situation and for monitoring your response to treatment over time.

References:

• Aronne LJ, et al. “Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.” JAMA. 2024.
• Berg N, et al. “Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis.” Obesity Reviews. 2025.
• Jastreboff AM, et al. “Tirzepatide Once Weekly for the Treatment of Obesity.” New England Journal of Medicine. 2022.
• Jastreboff AM, et al. “Triple–Hormone-Receptor Agonist Retatrutide for Obesity A Phase 2 Trial.” New England Journal of Medicine. 2023.
• Lincoff AM, et al. “Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.” Nature Medicine. 2024.
• Lincoff AM, et al. “Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.” New England Journal of Medicine. 2023.
• van Bloemendaal L, et al. “GLP-1 Receptor Activation Modulates Appetite- and Reward-Related Brain Areas in Humans.” Diabetes. 2014.
• Wharton S, et al. “Oral semaglutide at a dose of 25 mg in adults with overweight or obesity.” New England Journal of Medicine. 2025.
• Wilding JPH, et al. “Once-Weekly Semaglutide in Adults with Overweight or Obesity.” New England Journal of Medicine. 2021.
• Younes N, et al. “Gastrointestinal adverse events associated with GLP-1 RA in non-diabetic patients with overweight or obesity.” International Journal of Obesity. 2025.