What is the role of semaglutide (glucagon-like peptide-1 receptor agonist) in weight loss for adults with obesity?

Semaglutide for Weight Loss in Adults with Obesity

Semaglutide 2.4 mg weekly produces substantial and sustained weight loss of approximately 14.9-16.0% over 68 weeks in adults with obesity or overweight with comorbidities, significantly outperforming placebo (2.4-5.7%), and should be used as an adjunct to lifestyle modifications including reduced-calorie diet and increased physical activity. 1, 2

Mechanism of Action

Semaglutide is a GLP-1 receptor agonist that acts on multiple pathways to promote weight loss 1:

• Appetite suppression through hypothalamic effects, reducing hunger and controlling eating behavior 1, 3
• Delayed gastric emptying in the early postprandial phase, slowing nutrient absorption 1, 4
• Glucose-dependent insulin release and decreased glucagon secretion, improving metabolic control 1, 4
• Decreased preference for fatty, energy-dense foods 3

The medication has a long half-life of approximately 1 week due to extensive albumin binding (>99%), allowing once-weekly dosing 4

Weight Loss Efficacy

Primary Outcomes

The STEP clinical trial program demonstrated robust weight loss results 1, 2, 5:

• Mean weight loss of 14.9-16.0% at 68 weeks with semaglutide 2.4 mg versus 2.4-5.7% with placebo 1, 2, 6
• 86.4% of patients achieved ≥5% weight loss compared to 31.5% with placebo 2
• 69.1% achieved ≥10% weight loss versus 12.0% with placebo 2
• 50.5% achieved ≥15% weight loss versus 4.9% with placebo 2

Long-Term Sustainability

Weight loss is sustained over 2 years with continued treatment 1, 7:

• At 104 weeks, mean weight loss was -15.2% with semaglutide versus -2.6% with placebo 7
• 77.1% maintained ≥5% weight loss at 2 years 7
• Weight regain of 11.6% occurs after cessation, emphasizing the need for lifelong use 1

Dosing and Administration

Standard Titration Protocol

Initiate at 0.25 mg weekly and titrate monthly over 16 weeks to the maintenance dose of 2.4 mg weekly 1, 8:

• Weeks 1-4: 0.25 mg once weekly 8
• Weeks 5-8: 0.5 mg once weekly 8
• Weeks 9-12: 1.0 mg once weekly 8
• Weeks 13-16: 1.7 mg once weekly 8
• Week 17 onward: 2.4 mg once weekly (maintenance) 8

Administration Details

• Subcutaneous injection in abdomen, thigh, or upper arm 8, 4
• Same day each week, any time of day, with or without meals 8
• Gradual titration minimizes gastrointestinal side effects 1, 8

Missed Dose Management

• If 1 dose missed: Resume at next scheduled dose 8
• If 2 consecutive doses missed: Use clinical judgment; may resume at same dose if previously well-tolerated 1, 8
• If ≥3 consecutive doses missed: Consider restarting titration schedule 1

Cardiovascular Benefits Beyond Weight Loss

Semaglutide provides significant cardiovascular risk reduction, particularly valuable in patients with established cardiovascular disease 1:

• 20% reduction in composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80,95% CI 0.74-0.95) in the SELECT trial 1
• 26% reduction in cardiovascular events in SUSTAIN-6 trial (HR 0.74,95% CI 0.58-0.95) 1
• Improvements in blood pressure, lipid profiles, and insulin sensitivity 1

Safety Profile and Adverse Effects

Common Gastrointestinal Effects

The most frequent adverse events are gastrointestinal, typically transient and mild-to-moderate 1, 2, 5:

• Nausea, vomiting, diarrhea, constipation, abdominal pain 1, 3
• Usually occur during dose escalation and subside with time 2, 5
• 4.5% discontinuation rate due to GI events versus 0.8% with placebo 2

Serious Adverse Events

Semaglutide carries a 38% higher risk of serious adverse events compared to placebo 1:

• Pancreatitis risk: Monitor for persistent severe abdominal pain 1
• Gallbladder disease: Increased risk of cholelithiasis and cholecystitis 1
• Perioperative aspiration risk: May increase pulmonary aspiration risk under anesthesia even with extended fasting 1

Absolute Contraindications

Do not use semaglutide in patients with 1, 4:

• Personal or family history of medullary thyroid cancer 1
• Multiple endocrine neoplasia syndrome type 2 1

Drug Interactions and Precautions

• Avoid concurrent use with other GLP-1 receptor agonists or DPP-4 inhibitors 8
• Use caution when combining with insulin or insulin secretagogues due to hypoglycemia risk 8
• No dose adjustment required for renal or hepatic impairment 8, 4

Clinical Implementation Algorithm

Patient Selection Criteria

Eligible patients include adults with 1:

• BMI ≥30 kg/m² (obesity), OR
• BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, cardiovascular disease, obstructive sleep apnea) 1

Pre-Treatment Screening

Before initiating semaglutide, assess for 1:

• Personal or family history of medullary thyroid cancer or MEN2 syndrome (absolute contraindication) 1
• History of pancreatitis (use with caution) 1
• Severe gastrointestinal motility disorders or gastroparesis 1

Monitoring Requirements

During treatment, monitor for 1:

• Blood pressure changes (may require antihypertensive adjustment as weight decreases) 1
• Signs of pancreatitis (persistent severe abdominal pain) 1
• Gallbladder disease symptoms 1
• Gastrointestinal tolerability during dose escalation 1

Lifestyle Modifications

Semaglutide must be combined with 1:

• Reduced-calorie diet 1, 2
• Increased physical activity 1, 2
• Behavioral interventions 1, 6
• Resistance training to preserve lean body mass 1

Special Populations

Patients with Type 2 Diabetes

• Semaglutide offers dual benefits of weight loss and improved glycemic control 1
• Weight loss appears lower in patients with diabetes (4-6.2%) compared to those without diabetes (6.1-17.4%) 1
• Provides cardiovascular protection in diabetic patients with established CVD 1

Patients with Cardiovascular Disease

Prioritize semaglutide in patients with both obesity and cardiovascular disease due to proven cardiovascular benefits 1:

• 20-26% reduction in major adverse cardiovascular events 1
• Improvements in multiple cardiovascular risk factors 1

Common Pitfalls and How to Avoid Them

• Pitfall: Rapid dose escalation leading to intolerable GI side effects

  • Solution: Strictly follow the 16-week titration schedule 1, 8

• Pitfall: Discontinuing treatment after achieving weight loss goal

  • Solution: Counsel patients that lifelong use is necessary to maintain weight loss; 11.6% weight regain occurs after cessation 1

• Pitfall: Using semaglutide as monotherapy without lifestyle modifications

  • Solution: Always combine with reduced-calorie diet, increased physical activity, and behavioral interventions 1, 2

• Pitfall: Failing to adjust antihypertensive medications as weight decreases

  • Solution: Monitor blood pressure closely and reduce antihypertensive doses as needed 1