1. From baseline to 52 weeks, tirzepatide resulted in a greater reduction in mean HbA1c levels compared to insulin glargine.
2. The number of major adverse cardiovascular events in both groups was comparable.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Glucagon-like peptide 1 (GLP-1) receptor agonists have recently emerged as potential first-line therapy for patients with type 2 diabetes. Tirzepatide, a combined GIP and GLP-1 agonist, works through direct binding to pancreatic beta cells leading to insulin secretion and appetite suppression. However, there is limited research on the long-term efficacy of tirzepatide in patients with significant cardiovascular risk factors. This randomized controlled trial aimed to determine the efficacy and tolerability of tirzepatide versus insulin glargine in high-risk cardiovascular patients with type 2 diabetes. The primary outcome was non-inferiority of change in HbA1c from baseline to 52 weeks between tirzepatide and insulin glargine. Key secondary outcomes included proportion of patients with HbA1c <7.0% and major adverse cardiovascular events. According to study results, tirzepatide resulted in significantly reduced mean HbA1c levels compared to insulin glargine. Among patients not on sulfonylureas, fewer participants reported instances of hypoglycemia in the tirzepatide group. Furthermore, the rate of major adverse cardiovascular events was similar between tirzepatide and insulin glargine. This study was strengthened by a large sample size, with individuals from multiple countries.
In-depth [randomized controlled trial]: Between Nov 20, 2018, and Dec 30, 2019, 3045 patients were assessed for eligibility across 187 sites in 14 countries. Included were those ≥18 years with type 2 diabetes, glycated hemoglobin (HbA1c) of 7.5-10.5%, body-mass index (BMI) ≥25 kg/m2, and active or high-risk cardiovascular disease. Altogether, 2002 patients were randomly assigned to tirzepatide (n=329 for 5 mg, n=328 for 10 mg, and n=338 for 15 mg) or glargine (100 U/mL, titrated to reach fasting blood glucose <100 mg/dL; n=1000). The primary outcome of mean change in HbA1c level from baseline to 52 weeks was greatest with tirzepatide 15 mg (-2.58%, standard deviation [SD] 0.05), followed by tirzepatide 10 mg (-2.43%, SD 0.05) and glargine (-1.44%, SD 0.03). The non-inferiority margin of 0.3% was met for both doses of tirzepatide and the change in HbA1c was much greater than with glargine. Additional analyses also demonstrated superiority of tirzepatide 10 and 15 mg over insulin glargine (p<0.0001 for both). Fewer instances of hypoglycemia were noted with tirzepatide (6-9%) compared to glargine (19%). Finally, tirzepatide did not result in an increase in major adverse cardiovascular events, such as death, MI, stroke, or hospitalization for unstable angina, compared with glargine (hazard ratio [HR] 0.74, 95% CI 0.51-1.08). Overall, tirzepatide showed increased efficacy than glargine in high-risk cardiovascular patients with type 2 diabetes.
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