Tirzepatide Versus Insulin Glargine in Type 2 Diabetes and Increased Cardiovascular Risk - SURPASS-4

Contribution To Literature:

The SURPASS-4 trial showed that tirzepatide demonstrated greater reductions in HbA1c and lower incidence of hypoglycemia as compared with glargine among patients with inadequately controlled type 2 diabetes and increased cardiovascular risk.


The goal of the trial was to assess the long-term efficacy and cardiovascular safety of tirzepatide, a dual GIP and GLP-1 agonist, as compared to insulin glargine among patients with inadequately controlled type 2 diabetes and increased cardiovascular risk.

Study Design

Patients were randomized in a 1:1:1:3 open-label fashion to either tirzepatide (5 mg, n = 329; 10 mg, n = 328; or 15 mg, n = 338), or insulin glargine (n = 1,000) titrated to fasting glucose <100 mg/dl. Tirzepatide was initiated at a dose of 2.5 mg once weekly, and the doses were increased by 2.5 mg every 4 weeks until the randomly assigned dose was reached.

  • Total screened: 3,045
  • Total number of enrollees: 1,995
  • Duration of follow-up: median 85 weeks
  • Mean patient age: 64 years
  • Percentage female: 38%

Inclusion criteria:

  • Age ≥18 years
  • Glycated hemoglobin (HbA1c) 7.5-10.5% (on any of: metformin, sulfonylurea, or
  • sodium-glucose co-transporter-2 [SGLT2] inhibitor)
  • Body mass index (BMI) of ≥25 kg/m2 with stable weight over the preceding 3 months
  • Elevated risk of cardiovascular events (known atherosclerotic disease; age ≥50 years with or without estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2; history of heart failure)

Exclusion criteria:

  • Type 1 diabetes
  • History of pancreatitis

Other salient features/characteristics:

  • Mean HbA1c: 8.5%
  • Mean BMI: 32.5%
  • History of cardiovascular disease: 87%
  • eGFR <60: 17%
  • SGLT2 inhibitor use: 25%

Principal Findings:

The primary outcome, change in HbA1c from baseline to 52 weeks for tirzepatide vs. glargine, was -2.2% at 5 mg (p = 0.053), -2.4% at 10 mg (p = 0.053), -2.6% at 15 mg (p = 0.053) vs. -1.4% (p = 0.03) with glargine. Estimated treatment difference in HbA1c vs. glargine was tirzepatide 5 mg: -0.8 (p < 0.001), tirzepatide 10 mg: -1.0 (p < 0.001), and tirzepatide 15 mg: -1.14 (p < 0.001).

Key secondary outcomes for tirzepatide vs. glargine:

  • Mean bodyweight changes: -7.1 kg at tirzepatide 5 mg, -9.5 kg at tirzepatide 10 mg, -11.7 kg at tirzepatide 15 mg, +1.9 kg with glargine
  • Major adverse cardiac events for tirzapetide vs. glargine: 5% vs. 6%, hazard ratio 0.74, 95% confidence interval 0.51-1.08
  • Diarrhea: 13-22% with tirzepatide, 4% with glargine
  • Nausea: 12-23% with tirzepatide, 2% with glargine
  • Hypoglycemia: 6-9% with tirzepatide, 19% with glargine


The results of this trial indicate that among patients with long-standing, inadequately controlled type 2 diabetes at high cardiovascular risk, once weekly tirzepatide met criteria for noninferiority and superiority for better glycemic control compared with daily glargine, both administered subcutaneously. Tirzepatide also reduced bodyweight; both of these benefits were sustained beyond 1 year of treatment. A greater proportion of patients met target HbA1c with tirzepatide as compared to insulin glargine. Additionally, favorable changes were seen in blood pressure, heart rate, and lipid concentrations with tirzepatide as compared to glargine.

The changes in glycemia and weight with tirzepatide at 52 weeks were similar to previous studies of tirzepatide (SURPASS-1 and -2) compared to placebo, semaglutide, and insulin degludec, with the present study having the longest follow-up period. Fewer patients had hypoglycemia with tirzepatide; however, gastrointestinal adverse effects were higher with tirzepatide. Cardiovascular outcomes trials for tirzepatide are currently ongoing.


Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomized, open-label, parallel-group, multicenter, phase 3 trial. Lancet 2021;Oct 18:[Epub ahead of print].

Editorial Comment: Khoo B, Tan TM. Surpassing insulin glargine in type 2 diabetes with tirzepatide. Lancet 2021;Oct 18:[Epub ahead of print].

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Blood Pressure, Body Mass Index, Diabetes Mellitus, Type 2, Diarrhea, Glomerular Filtration Rate, Glucagon-Like Peptide 1, Glucose, Glycemic Control, Heart Failure, Glycated Hemoglobin A, Hypoglycemia, Insulin Glargine, Metformin, Primary Prevention, Risk Factors, Sodium-Glucose Transporter 2 Inhibitors

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