Review Details Efficacy, Safety of Tirzepatide in T2D from Clinical Trials

Thomas Kariagiannis, PhD, MSc

Data from a systematic review and meta-analysis of randomized clinical trials with tirzepatide describe the safety and efficacy of the novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist in the management of type 2 diabetes.

Leveraging data from 7 clinical trials with more than 6500 participants, results of the study provide an overview of the HbA1c lowering, incidence of hypoglycemia, and risk of discontinuation seen with various doses of tirzepatide compared against placebo therapy, basal insulins, and GLP-1 receptor agonists.

“Our meta-analysis findings can help clinicians and other diabetes stakeholders to determine the optimal place of tirzepatide among existing medications for type 2 diabetes,” wrote investigators. “We found that tirzepatide is superior in reducing HbA1c compared with other injectable therapies, in particular basal insulin and once-weekly GLP-1 RAs. In addition, tirzepatide, even at the lowest maintenance dose of 5 mg, can reduce body weight to a greater extent compared with GLP-1 RAs including subcutaneous semaglutide which, in turn, has been shown to be superior to other glucose-lowering agents.”

Approved by the US Food and Drug Administration on May 13 for improving glycemic control in patients with type 2 diabetes, tirzepatide (Mounjaro) is being welcomed as monumental moment in the landscape of diabetes care. A first-in-class agent approved based on the SURPASS trials, with additional data backing use in obesity, endocrinologists, diabetologists, and primary care providers alike have been captivated by the agent’s potential in multiple disease states.

Spurred by Eli Lilly and Company’s announcement of their new drug application to the FDA in fall of 2021, the current systematic review and meta-analysis was designed by a team of investigators from the Aristotle University of Thessaloniki in Greece, led by Thomas Karagiannis, PhD, MSc, with the intent of providing clinicians with synthesized data from available randomized controlled trials of tirzepatide. From a search of the PubMed, Embase, Cochrane and ClinicalTrials.gov from inception through October 27, 2021 for randomized controlled trials with a duration of at least 12 weeks, investigators identified 7 trials for inclusion in their study.

The 7 trials identified for inclusion were SURPASS 1-5, a double-blind phase 2 trial comparing tirzepatide in 5, 10, and 15 mg doses to placebo or dulaglutide 1.5 mg in patients with type 2 diabetes who were drug-naive or on metformin monotherapy, and a double-blind phase 2 trial comparing tirzepatide 15 mg against placebo in patients with type 2 diabetes who were drug-naive or on metformin monotherapy. Investigator noted all studies had a parallel-group design and 3 were open-label. The duration of interventions in the trials ranged from 12-52 weeks.

From these trials, investigators obtained data related to a cohort of 6609 participants for inclusion in their analyses. At baseline, the mean age of this cohort was 58 years, the mean body weight was 91.5 kg, and the mean HbA1c was 8.2%. The primary outcome of interest for the investigators’ current analyses were the change in HbA2c from baseline. Secondary outcomes of interest included change in body weight and safety outcomes.

Results demonstrated a dose-dependent superiority for lowing HbA1c was observed with the 5, 10, and 15 mg doses of tirzepatide against all comparators, with mean differences ranging from -1.62% to -2.06% against placebo, -0.29% to -0.92% against GLP-1 receptor agonists, and -0.70% to -1.09% against basal insulin regimens. Similarly, superior reductions in bodyweight were observed with tirzepatide against all comparators, with investigators highlighting reductions versus GLP-1 receptor agonists ranging from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg.

When assessing the safety of tirzepatide, results indicated the incidence of hypoglycemia observed with tirzepatide was similar to the incidence rate observed with placebo therapy and lower than rates observed with basal insulin. Investigators pointed out nausea was more frequent with tirzepatide than placebo therapy, especially with tirzepatide 15 mg (OR, 5.60 [95% CI, 3.12 to 10.06]). Tirzepatide 15 mg was also associated with increased incidence of vomiting (OR, 5.50 [95% CI, 2.40 to 12.59]) and diarrhea (OR, 3.31 [95% CI, 1.40 to 7.85]). Investigators also pointed out tirzepatide 15 mg was associated with a higher discontinuation rate due to adverse events regardless of comparator, but all tirzepatide doses were considered safe in terms of serious adverse events and mortality.

“The findings of this meta-analysis of seven RCTs suggest a dose-dependent superiority of all three tirzepatide maintenance doses on glycemic control, not only vs placebo but also vs long-acting GLP-1 RAs and basal insulin regimens. All tirzepatide doses were superior to all comparators in terms of reducing body weight,” wrote investigators.

This study, “Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis,” was published in Diabetologia.