Tirzepatide SURMOUNT and SURPASS Trials: Clinical Evidence Summary
Overview of Tirzepatide Development Programs
Tirzepatide is a first-in-class dual GIP/GLP-1 receptor agonist evaluated through two major clinical trial programs: SURPASS (for type 2 diabetes) and SURMOUNT (for obesity management), demonstrating unprecedented efficacy in both glycemic control and weight reduction. 1, 2
The SURPASS program consisted of 6 phase 3 trials (SURPASS 1-5 plus a Japan-specific trial) evaluating tirzepatide 5,10, and 15 mg weekly as monotherapy and combination therapy across diverse populations with type 2 diabetes over treatment periods up to 104 weeks. 1, 2, 3
SURPASS Program: Type 2 Diabetes Trials
Glycemic Control Efficacy
Tirzepatide achieved HbA1c reductions ranging from -1.87% to -3.02% (-20 to -28 mmol/mol) across the SURPASS trials, representing the most potent glucose-lowering effect of any currently available diabetes medication. 4, 1, 2
In SURPASS-2, tirzepatide demonstrated superior HbA1c reduction compared to semaglutide 1 mg, with a treatment difference of -1.5% (95% CI -1.71 to -1.4, p<0.0001). 5, 1
Between 23.0-62.4% of patients achieved HbA1c <5.7% (normal range) across the tirzepatide dose range, an unprecedented rate of near-normalization of glycemia. 5
Weight Loss in Diabetes Population
Tirzepatide produced weight reductions of -6.2 to -12.9 kg across the SURPASS trials in patients with type 2 diabetes, substantially exceeding weight loss achieved with traditional GLP-1 receptor agonists. 1, 2
The weight loss was dose-dependent, with the 15 mg dose achieving the greatest reductions. 1, 2
Compared to semaglutide 1 mg in SURPASS-2, tirzepatide demonstrated superior weight reduction across all dose levels. 1
Cardiometabolic Benefits
Tirzepatide reduced multiple cardiovascular risk parameters including blood pressure, visceral adiposity, circulating triglycerides, and liver fat content. 1, 2
The medication reduced new-onset macroalbuminuria and improved lipid profiles across the SURPASS program. 2
Tirzepatide showed favorable trends with MACE-4 events having hazard ratios <1.0 and upper confidence bounds <1.3, meeting cardiovascular safety criteria, though it did not reduce all-cause mortality compared to usual care. 4, 5
SURMOUNT Program: Obesity Trials
Weight Loss in Non-Diabetic Population
In SURMOUNT-1, tirzepatide 5 to 15 mg once weekly produced body weight reductions of 16.5% to 22.4% over 72 weeks in people with obesity but without diabetes—weight loss previously only achievable with bariatric surgery. 6, 2
The highest dose (15 mg) achieved mean weight loss of 20.9% at 72 weeks, representing a 6% absolute advantage over semaglutide 2.4 mg (14.9% weight loss). 5, 6
Nearly 40% of patients achieved ≥25% total body weight loss at 72 weeks with tirzepatide 15 mg. 6
Weight loss was consistently greater in non-diabetic individuals (15-20.9%) compared to those with diabetes (4-6.2%), suggesting metabolic factors influence treatment response. 5, 6
Comparison to Semaglutide
Tirzepatide demonstrated superior weight loss compared to semaglutide 2.4 mg, with a mean difference of 4.23 kg (95% CI: 3.22-5.25). 5
The weight loss efficacy of tirzepatide is comparable to what has previously only been reported with bariatric surgery. 6
Safety Profile Across Both Programs
Common Adverse Events
Gastrointestinal effects were the most frequently reported adverse events, including nausea (17-22%), diarrhea (13-16%), vomiting (6-10%), and constipation, which were predominantly mild-to-moderate, dose-dependent, and decreased over time. 4, 5, 6
The adverse event profile was generally similar to the GLP-1 receptor agonist class. 1, 2
Slow titration with gradual dose escalation every 4 weeks helped minimize gastrointestinal side effects and improve tolerability. 4, 5
Hypoglycemia Risk
Tirzepatide demonstrated a low risk of hypoglycemia when used without insulin or insulin secretagogues, due to its glucose-dependent mechanism of action. 5, 1, 2
When combined with insulin or sulfonylureas, dose reduction of these agents was necessary to prevent hypoglycemia. 5
Serious Adverse Events
Pancreatitis was reported in clinical trials, though causality has not been definitively established. 4, 5
Gallbladder disease (cholelithiasis and cholecystitis) occurred with tirzepatide, consistent with the GLP-1 receptor agonist class effect. 5
Tirzepatide is contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies. 4, 5
Comparative Efficacy Summary
Versus Other Diabetes Medications
Tirzepatide provided superior efficacy compared to placebo, semaglutide 1 mg, dulaglutide, insulin degludec, and insulin glargine across the SURPASS program. 2, 3
The medication represents the most potent glucose and body weight lowering agent currently available for type 2 diabetes management. 3
Versus Semaglutide Specifically
- In head-to-head comparison (SURPASS-2), tirzepatide achieved greater HbA1c reduction (treatment difference -1.5%), greater weight loss, and superior improvements in cardiometabolic parameters including waist circumference, triglycerides, and fasting glucose control. 5, 1
Ongoing Cardiovascular Outcomes Trials
Two large cardiovascular outcomes trials are currently ongoing: SURPASS-CVOT in patients with type 2 diabetes and SURMOUNT-MMO in patients with obesity, with results expected to provide definitive evidence on cardiovascular benefits. 7, 8, 3
A meta-analysis of phase 3 trials assessed tirzepatide cardiovascular safety, demonstrating favorable safety signals. 3
Results from SURPASS-CVOT are highly anticipated and expected in 2024. 3
Clinical Implications and Future Directions
The SURPASS and SURMOUNT programs collectively suggest that tirzepatide marks a new era in type 2 diabetes and obesity management through dual agonism of gut hormones. 2
Tirzepatide offers a new opportunity for effective lowering of HbA1c and body weight in adults with type 2 diabetes, with efficacy exceeding all previously available pharmacologic options. 1
Future large-scale trials are expected to verify long-term benefits in cardiovascular health management, providing stronger evidence for comprehensive treatment of diabetes and its complications. 7
Remaining Clinical Challenges
High treatment costs remain a barrier to widespread access, with average wholesale prices around $1,272 per 30-day supply. 5
The safety and efficacy of tirzepatide in special populations, such as patients with severe renal impairment, require further investigation. 7
Long-term continuous use is necessary to maintain weight loss benefits, as discontinuation leads to rapid weight regain of one-half to two-thirds of lost weight within 1 year. 5