What are the recommended medications, such as dulaglutide (GLP-1 receptor agonist) or oral semaglutide (GLP-1 receptor agonist), for weight loss?

Semaglutide is Superior to Dulaglutide for Weight Loss

For weight loss, semaglutide is the preferred GLP-1 receptor agonist over dulaglutide due to its superior efficacy, with clinical trials showing semaglutide achieves 14.9% weight loss compared to dulaglutide's more modest results. 1

Comparative Efficacy of GLP-1 Receptor Agonists for Weight Loss

Semaglutide

• Semaglutide acts on the hypothalamus to suppress appetite, delay gastric emptying, increase glucose-dependent insulin release, and decrease glucagon secretion 1
• In the STEP 1 trial, subcutaneous semaglutide 2.4mg weekly demonstrated mean weight loss of 14.9% at 68 weeks (vs 2.4% with placebo) 1, 2
• Oral semaglutide has also shown significant efficacy with 15.1% weight loss vs 2.4% for placebo in a 68-week trial 1
• Semaglutide has been FDA approved for obesity treatment since 2021 1, 2

Dulaglutide

• Dulaglutide is a GLP-1 receptor agonist approved for type 2 diabetes but not specifically FDA-approved for weight loss 3
• In head-to-head trials, dulaglutide showed significantly less weight reduction compared to semaglutide 4
• In the SUSTAIN 7 trial, semaglutide 0.5mg reduced weight by 4.6kg compared to 2.3kg with dulaglutide 0.75mg, while semaglutide 1.0mg reduced weight by 6.5kg compared to 3.0kg with dulaglutide 1.5mg 4

Tirzepatide (Newest Option)

• Tirzepatide, a dual GLP-1/GIP receptor agonist, has shown even greater weight loss efficacy than semaglutide 1, 2
• Tirzepatide achieves approximately 20.9% weight loss compared to semaglutide's 14.9% 2
• FDA approved for obesity treatment in November 2023 2

Mechanism of Action

• GLP-1 receptor agonists mimic the effects of GLP-1, acting on the hypothalamus to suppress appetite, delay gastric emptying, increase glucose-dependent insulin release, and decrease glucagon secretion 1, 5
• Semaglutide has 94% sequence homology to human GLP-1 and selectively binds to and activates the GLP-1 receptor 5
• The long half-life of semaglutide (approximately 1 week) is due to albumin binding, which decreases renal clearance and protects from metabolic degradation 5

Important Clinical Considerations

Weight Maintenance

• After cessation of semaglutide, significant weight regain occurs (11.6% of lost weight regained after 52 weeks), highlighting the need for long-term use 1, 2
• Antiobesity medications must be used in conjunction with lifestyle changes and may need to be used lifelong 1

Dosing and Administration

• Semaglutide for weight loss is administered subcutaneously once weekly at 2.4mg (different from the diabetes dosing of 0.5-1.0mg) 2
• Dulaglutide is administered subcutaneously once weekly 6
• Dose escalation is recommended for both medications to minimize gastrointestinal side effects 6

Side Effects

• Gastrointestinal disorders are the most frequently reported adverse events with both medications 4
• In comparative trials, gastrointestinal side effects were reported in 43-44% of patients on semaglutide and 33-48% of patients on dulaglutide 4
• Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 2

Additional Benefits Beyond Weight Loss

• Both medications improve glycemic control in patients with type 2 diabetes 6
• Semaglutide has demonstrated cardiovascular benefits, reducing the composite incidence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke 2
• Both medications have been shown to reduce epicardial adipose tissue thickness, a cardiovascular risk factor 7

Practical Considerations

• Insurance coverage for weight management medications remains limited, with many insurers requiring prior authorization proving FDA-approved diagnosis of type 2 diabetes 3
• Semaglutide is FDA-approved specifically for weight management, while dulaglutide is not 3
• For patients with both obesity and type 2 diabetes, these medications offer dual benefits of weight loss and improved glycemic control 1

Common Pitfalls and Caveats

• Weight regain is common after discontinuation, emphasizing the need for long-term therapy 1
• Weight loss appears to be lower in individuals with type 2 diabetes compared to those without diabetes 2
• Tirzepatide significantly reduces the bioavailability of oral hormonal contraceptives, unlike other GLP-1 receptor agonists, requiring additional contraceptive measures 1
• These medications should be used in conjunction with lifestyle modifications including reduced calorie diet and increased physical activity 1