What are the outcomes of the Surmount trial for Tirzepatide (a dual GIP (Glucose-dependent Insulinotropic Polypeptide) and GLP-1 (Glucagon-like Peptide-1) receptor agonist) in patients with type 2 diabetes?

Tirzepatide SURMOUNT Trial Outcomes

Weight Loss Efficacy

Tirzepatide demonstrated unprecedented weight loss in the SURMOUNT trials, achieving 15.0% to 22.4% total body weight reduction at 72 weeks in adults with obesity but without diabetes, representing the most effective pharmacological obesity treatment currently available. 1, 2

• The 5 mg weekly dose resulted in 15.0% weight loss at 72 weeks 3
• The 10 mg weekly dose achieved 19.5% weight loss 3
• The 15 mg weekly dose produced maximum efficacy with 20.9-22.4% weight loss 1, 3, 2
• Placebo with lifestyle modifications resulted in only 3.1% weight loss 3

Proportion Achieving Clinically Significant Weight Loss

• Between 20.7-68.4% of patients achieved ≥10% total body weight loss across all doses 3, 4
• Nearly 40% of patients on the maximum 15 mg dose achieved ≥25% weight loss 3
• The weight loss outcomes were comparable to bariatric surgery results 3

Comparative Efficacy

• In head-to-head comparison, tirzepatide produced 5.5 kg more weight loss than semaglutide 1.0 mg at 40 weeks 3
• Tirzepatide's 20.9% weight loss substantially exceeded semaglutide 2.4 mg weekly (14.9% weight loss), representing a 6% absolute advantage 1
• Weight loss with tirzepatide was consistently greater in non-diabetic patients (6.1-17.4%) compared to those with diabetes (4-6.2%) 1

Cardiometabolic Benefits Beyond Weight Loss

• Tirzepatide improved multiple cardiometabolic risk factors including blood pressure reduction through multiple mechanisms 1, 3
• Significant improvements in lipid profiles were observed, with superior triglyceride reduction compared to semaglutide 1
• Liver fat reduction occurred with significant decreases in both hepatic steatosis and visceral adipose tissue 1
• Better fasting glucose control was achieved compared to semaglutide 2.4 mg 1

Safety Profile and Adverse Events

• The most common adverse events were gastrointestinal, including nausea (17-22%), diarrhea (13-16%), vomiting (6-10%), and constipation 1, 3
• Gastrointestinal effects were typically mild-to-moderate, transient, and decreased over time 1, 3
• The side effect profile was similar to GLP-1 receptor agonists, with comparable or slightly higher rates of diarrhea 5
• Serious but rare risks included pancreatitis and gallbladder disease (cholelithiasis, cholecystitis), though causality has not been definitively established 1, 3

Tolerability and Treatment Discontinuation

• Tirzepatide was well tolerated with good overall tolerability across all doses 6, 7
• Treatment discontinuation rates due to adverse events were primarily from gastrointestinal effects 1
• Management strategies for GI side effects include starting at low dose with slow upward titration, reducing meal size, limiting alcohol and carbonated drinks, and avoiding high-fat diets 3

Mechanism of Action Contributing to SURMOUNT Outcomes

• Tirzepatide's dual GIP/GLP-1 receptor activation provides enhanced metabolic benefits including delayed gastric emptying, suppressed appetite, and improved insulin secretion 1
• The anorexigenic effects are potentiated by dual GIP-GLP-1 activation, working through central appetite suppression, delayed gastric emptying, and increased energy expenditure 1
• The dual receptor mechanism produces synergistic effects on insulin response and glucagon suppression 1

Clinical Implications for Practice

• Long-term use of tirzepatide is necessary to maintain weight loss benefits, as sudden discontinuation results in regain of one-half to two-thirds of lost weight within 1 year 1, 3
• The medication must be used in conjunction with lifestyle modifications including reduced-calorie diet and increased physical activity for optimal results 1, 3
• Early responders who achieve ≥5% weight loss after 3 months should continue long-term therapy 1, 3