What peptides are used for weight loss?

Peptides Used for Weight Loss

The primary peptides used for weight loss are GLP-1 receptor agonists (semaglutide and liraglutide) and the dual GIP/GLP-1 receptor agonist tirzepatide, with tirzepatide demonstrating superior efficacy (20.9% weight loss) compared to semaglutide (14.9%) and liraglutide (5-6%). 1

FDA-Approved Peptide Medications

First-Line: Tirzepatide (Zepbound)

• Tirzepatide is the most effective peptide for weight loss, achieving 20.9% mean weight loss at 72 weeks with the 15mg weekly dose. 1
• Acts as a dual agonist on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, providing enhanced metabolic benefits including delayed gastric emptying, appetite suppression, and improved insulin secretion. 1
• FDA-approved in November 2023 for chronic weight management in adults with BMI ≥30 or BMI ≥27 with weight-related comorbidities. 1
• Administered as once-weekly subcutaneous injection, starting at 5mg and titrating every 4 weeks to maximum 15mg weekly. 1

Second-Line: Semaglutide (Wegovy)

• Semaglutide 2.4mg weekly produces 14.9% mean weight loss at 68 weeks, significantly outperforming placebo (2.4%). 1, 2
• FDA-approved in 2021 for weight management at the 2.4mg weekly dose (higher than the diabetes dose of 1.0mg). 1, 2
• Acts on GLP-1 receptors in the hypothalamus to suppress appetite, delay gastric emptying, increase glucose-dependent insulin release, and decrease glucagon secretion. 1
• Has proven cardiovascular benefits, reducing composite cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80) in patients with cardiovascular disease and BMI ≥27. 1
• Titration schedule: start 0.25mg weekly for 4 weeks, then 0.5mg for 4 weeks, then 1.0mg for 4 weeks, then 1.7mg for 4 weeks, reaching maintenance 2.4mg at week 16. 1

Third-Line: Liraglutide (Saxenda)

• Liraglutide 3.0mg daily produces 5.24-6.1% mean weight loss, substantially less than semaglutide or tirzepatide. 2
• FDA-approved in 2014 for weight management, administered as once-daily subcutaneous injection. 2
• Discontinue if patient has not lost at least 4% body weight after 16 weeks of treatment. 2

Mechanism of Action

How These Peptides Promote Weight Loss

• GLP-1 receptor agonists activate receptors in the hypothalamus and brainstem to suppress appetite and increase satiety, working in concert with other satiety hormones like PYY and CCK. 2
• Delay gastric emptying, leading to prolonged feelings of fullness and reduced caloric intake. 2
• Reduce inappropriate glucagon secretion, helping prevent hepatic glucose production. 1
• Increase glucose-dependent insulin secretion from pancreatic β-cells while promoting β-cell proliferation and protecting against apoptosis. 1
• The glucose-dependent nature of insulin stimulation and glucagon suppression explains the low likelihood of hypoglycemia with these agents. 1

Clinical Decision Algorithm

Patient Selection Criteria

• Indicated for BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity (type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease). 3, 1
• Must be used as adjuncts to reduced-calorie diet and increased physical activity. 3

Choosing Between Peptides

1. For maximum weight loss: Start with tirzepatide 15mg weekly (20.9% weight loss). 1
2. For patients with established cardiovascular disease: Consider semaglutide 2.4mg weekly due to proven cardiovascular outcome benefits. 1
3. For patients who strongly prefer daily injections or have insurance limitations: Liraglutide 3.0mg daily, though expect less weight loss (5-6%). 2
4. For patients with type 2 diabetes and obesity: Prioritize tirzepatide or semaglutide 2.4mg over lower-dose formulations due to greater HbA1c reduction and cardiovascular risk reduction. 1

Safety Profile and Monitoring

Common Adverse Effects

• Gastrointestinal effects predominate: nausea (17-40%), diarrhea (12-16%), vomiting (6-16%), constipation, and abdominal pain. 1
• These effects are typically mild-to-moderate, occur primarily during dose escalation, and decrease over time. 1
• Slow titration is essential to minimize gastrointestinal side effects. 1

Serious but Rare Risks

• Pancreatitis has been reported in clinical trials, though causality not definitively established. 1
• Gallbladder disease including cholelithiasis and cholecystitis occurs with all agents. 1
• Risk of pulmonary aspiration under anesthesia due to delayed gastric emptying, even with extended fasting periods. 1

Absolute Contraindications

• Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (based on animal studies showing thyroid C-cell tumors). 3, 1

Monitoring Requirements

• Assess efficacy and safety at least monthly for first 3 months. 3
• Discontinue if weight loss <5% after 3 months or if significant safety/tolerability issues occur at any time. 3
• Monitor blood pressure as weight loss may necessitate antihypertensive medication adjustment. 1
• Monitor for signs of pancreatitis (persistent severe abdominal pain) and gallbladder disease symptoms. 1
• Monitor thyroid function, particularly in patients with hypothyroidism. 1
• Monitor nutritional status during treatment. 1

Critical Clinical Considerations

Long-Term Use Required

• Significant weight regain occurs after cessation (11.6% of lost weight regained after 52 weeks), highlighting the need for long-term or lifelong use. 1
• Patients must be counseled that these medications must be used in conjunction with lifestyle changes and may need to be used lifelong. 1

Treatment Discontinuation Rates

• Semaglutide: 34 more discontinuations per 1000 patients compared to placebo, primarily from gastrointestinal effects. 1
• Treatment discontinuation is higher with semaglutide compared to tirzepatide. 1

Special Populations

• Weight loss is lower in individuals with type 2 diabetes (4-6.2%) compared to those without diabetes (6.1-17.4%). 1
• For patients with BMI >35 kg/m², peptides may provide insufficient weight loss alone, and bariatric surgery may eventually be needed. 2
• Not recommended in older adults experiencing unexplained weight loss. 2

Cost Considerations

• Average wholesale prices approximately $1,300-$1,600 per month without insurance. 1
• Insurance authorization may be challenging, particularly for obesity management without diabetes. 1

Other Peptides (Not FDA-Approved for Weight Loss)

Tesamorelin

• A growth hormone-releasing factor (GRF) analog that stimulates growth hormone secretion. 4
• Not FDA-approved for general weight loss; specifically approved only for reducing excess abdominal fat in HIV-infected patients with lipodystrophy. 4
• Acts by binding to GRF receptors on pituitary somatotroph cells to stimulate endogenous growth hormone release, which has lipolytic effects. 4

Pramlintide (Amylin Analog)

• FDA-approved for use in combination with insulin in diabetes, can prevent weight gain or lead to weight loss by increasing satiety and decreasing food intake. 3
• Not specifically approved as a weight loss medication. 3

Common Pitfalls to Avoid

• Inadequate titration delays maximum effectiveness—follow the prescribed titration schedule strictly. 1
• Failing to combine medication with lifestyle modifications (reduced-calorie diet and increased physical activity) reduces efficacy. 1
• Not counseling patients about the need for long-term use leads to weight regain after discontinuation. 1
• Using lower doses than approved for weight loss (e.g., semaglutide 1.0mg instead of 2.4mg) results in suboptimal weight loss. 1
• Continuing treatment beyond 3 months without adequate response (<5% weight loss) wastes resources and exposes patients to unnecessary side effects. 3