Home / Resources / Articles / Tirzepatide Outperforms Insulin Glargine in HbA1c and Weight Loss

Tirzepatide Outperforms Insulin Glargine in HbA1c and Weight Loss

Jun 12, 2021
Editor: Steve Freed, R.PH., CDE

Author: Mary Gerges, PharmD Candidate 2022, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences

SURPASS-4 is a randomized controlled trial of tirzepatide once a week vs. insulin glargine once a day in type 2 diabetes patients with high cardiovascular risk.

Tirzepatide is a once-weekly insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that combines the effects of both incretins into a single molecule. GIP is a hormone that may help GLP-1 receptor agonists work better. GIP has been found in preclinical models to reduce food intake while increasing energy expenditure, resulting in weight loss. When paired with a GLP-1 receptor agonist, it may have even more significant effects on glucose and body weight. Tirzepatide is now in phase 3 testing for blood glucose management and chronic weight management in individuals with type 2 diabetes. It’s also being researched for nonalcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction. 


SURPASS-4 is a 52-week, randomized, parallel, open-label trial that compares the efficacy and safety of tirzepatide 5 mg, 10 mg, and 15 mg versus insulin glargine in adults with type 2 diabetes that is poorly controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas, or SGLT-2 inhibitors), and who have an increased cardiovascular risk. The trial randomly assigned 2,002 research participants to receive either tirzepatide 5 mg, 10 mg, or 15 mg or insulin glargine in a 1:1:1:3 ratio. The European Union, North America, Australia, Israel, Taiwan, and Latin America were among the participants. The inclusion criteria were that participants must have been diagnosed with type 2 diabetes, have increased risk of cardiovascular events, have an A1C of 7.5 to 10.5%, and a BMI of greater than or equal to 25 kg/m2. The exclusion criteria were participants with type 1 diabetes, who have had chronic or acute pancreatitis any time before study entry, or have had a heart attack, stroke, or hospitalization for congestive heart failure in the past two months. 

The study’s primary endpoint showed that tirzepatide (10 mg and 15 mg) is non-inferior to insulin glargine in terms of change from baseline A1C at 52 weeks in persons with type 2 diabetes and high CV risk. At 52 weeks, the primary and critical secondary endpoints were evaluated, with some patients receiving therapy for up to two years. All patients in the tirzepatide treatment arms began the study with a once-weekly dose of tirzepatide 2.5 mg, which was gradually raised at four-week intervals to their final randomized maintenance dose. The titrated insulin glargine treatment arm began with a baseline dose of 10 units per day and titrated to fasting blood glucose less than 100 mg/dL using a treat-to-target algorithm. 

In the treatment-regimen, the 5mg, 10mg, and 15mg dosages of tirzepatide were linked with the following HbA1c and body weight reductions compared to insulin glargine: HbA1c reduction: -2.11%, -2.30%, -2.41% vs -1.39% and weight reduction: -6.4kg, -8.9kg, -10.6kg vs +1.7kg. The most commonly reported adverse events across all treatment arms were gastrointestinal-related. Overall, compared to placebo, all three dosages of tirzepatide showed greater A1C and weight reductions from baseline. On tirzepatide, up to 97.4% of individuals achieved an A1C of less than 7% across the three doses. Finally, treatment discontinuation rates due to adverse events (nausea, diarrhea, vomiting, constipation) were 6.0% (tirzepatide 5 mg), 8.4% (tirzepatide 10 mg), and 10.8% (tirzepatide 15 mg), compared with 2.5% (placebo). 

This study has shown strong results that reinforce the potential tirzepatide has for treating people living with type 2 diabetes. Even though the side effects reported were higher in the tirzapatide groups, the benefit of the drug still outweighs those side effects. 

Practice Pearls: 

  • The new glucose-lowering combination therapy “dual GIP and GLP-1 receptor agonist” can help people with type 2 diabetes lose an average of 25 pounds and lower their A1c by nearly 2.5%. 
  • Type 2 diabetes is the most common type of diabetes worldwide, accounting for 90 to 95 % of all diabetes cases in the U.S. alone. 
  • According to the findings, the most common side effects for tirzepatide are comparable to those seen with GLP-1 receptor agonists, such as nausea, vomiting, and diarrhea. 


Ernst, D. Tirzepatide Bests Insulin Glargine in HbA1c, Weight Reduction. Endocrinology Advisor, May 24, 2021 

Tirzepatide achieves all primary and key secondary study outcomes against insulin glargine in adults with type 2 diabetes and increased cardiovascular risk in the SURPASS-4 trial. Eli and Company May 2021 


Mary Gerges, PharmD Candidate 2022, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences 



In addition to this coverage of SURPASS-4, see our other coverage of the tirzepatide SURPASS trials.