What are the risks of being overweight versus taking Glucagon-like peptide-1 (GLP-1) drugs?

Comparing the Risks of Being Overweight Versus Taking GLP-1 Drugs

The risks of being overweight significantly outweigh the risks of taking GLP-1 receptor agonists for most patients, as these medications not only provide effective weight loss but also offer additional cardiometabolic benefits that directly reduce morbidity and mortality. 1

Risks of Being Overweight

• Being overweight or obese is associated with increased risk of cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality 2
• Obesity is linked to nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH), which can lead to liver fibrosis and cirrhosis 1
• Excess weight contributes to insulin resistance and metabolic dysfunction, worsening glycemic control in patients with diabetes 3
• Obesity increases the risk of frailty and sarcopenic obesity, particularly with aging 1
• Simple calorie restriction often leads to rebound weight gain, making sustainable weight management difficult without additional interventions 2

Benefits of GLP-1 Receptor Agonists

• GLP-1 receptor agonists can reduce body weight by 15-25% on average after approximately one year of treatment 2
• These medications demonstrate significant cardiovascular benefits, including reduction in major adverse cardiovascular events in people with type 2 diabetes and established cardiovascular disease 1, 3
• Semaglutide 2.4 mg has shown reduction in cardiovascular events even in people with overweight or obesity without diabetes but with preexistent cardiovascular disease 1
• GLP-1 receptor agonists improve glycemic control in patients with diabetes 1
• These medications have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) 1

Risks of GLP-1 Receptor Agonists

• Common adverse effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea 4, 5
• Rare but serious potential adverse events include:
  • Pancreatitis (acute, hemorrhagic, and necrotizing) 4, 5
  • Gallbladder disease including cholelithiasis requiring cholecystectomy 5
  • Thyroid C-cell tumors in rodents (boxed warning, though human relevance is unknown) 4
• Contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 4
• Potential for significant weight regain upon discontinuation, necessitating long-term or indefinite use 6, 2
• May cause loss of lean body mass in addition to fat mass loss 1

Special Considerations

Diabetes Status

• Patients with type 2 diabetes typically experience less weight loss (4-6.2%) compared to non-diabetic patients (6.1-17.4%) when treated with GLP-1 receptor agonists 7
• For patients with diabetes and overweight/obesity, GLP-1 receptor agonists with greater weight loss efficacy (semaglutide or tirzepatide) are preferred due to their added glycemic and cardiometabolic benefits 1

Medication Selection

• Semaglutide 2.4 mg may be prioritized over other approved anti-obesity medications for most patients due to the magnitude of net benefit 1
• Tirzepatide (a dual GIP/GLP-1 receptor agonist) may provide greater weight loss compared to semaglutide for patients with insufficient response 6

Long-term Management

• Weight management pharmacotherapy should be continued beyond reaching weight loss goals to maintain health benefits 1
• Sudden discontinuation often results in weight regain and worsening of cardiometabolic risk factors 1, 6
• Regular physical activity, particularly muscle-strengthening activities, is recommended to reduce the loss of lean mass during treatment with GLP-1 receptor agonists 1

Algorithm for Decision-Making

1. Assess baseline risk factors:

   • BMI category (overweight: 25-29.9 kg/m², obesity: ≥30 kg/m²)
   • Presence of weight-related complications (diabetes, hypertension, dyslipidemia, NAFLD)
   • Cardiovascular disease status
   • Contraindications to GLP-1 receptor agonists

2. For patients with BMI ≥30 kg/m² or ≥27 kg/m² with weight-related complications:

   • Recommend GLP-1 receptor agonist therapy alongside lifestyle modifications 1
   • Prioritize semaglutide 2.4 mg or tirzepatide for maximum weight loss and cardiometabolic benefits 1, 6

3. For patients with diabetes and overweight/obesity:

   • Prioritize GLP-1 receptor agonists with proven cardiovascular benefits 1
   • Consider additional benefits for NAFLD/NASH if present 1

4. For patients with contraindications to GLP-1 receptor agonists:

   • Focus on intensive lifestyle interventions with structured support
   • Consider alternative weight management medications based on individual risk profile

5. Monitor for:

   • Weight loss response (expect 4% weight loss by 16 weeks) 6
   • Gastrointestinal side effects (manage with dose titration) 4
   • Nutritional status, especially with significant weight loss 1
   • Development of gallbladder disease or pancreatitis 5

In conclusion, while GLP-1 receptor agonists carry certain risks, the health consequences of remaining overweight or obese generally present a greater threat to morbidity, mortality, and quality of life for most eligible patients. The decision to use these medications should be made with full awareness of both the risks of the medication and the risks of untreated obesity.