Spotlight on tirzepatide

The first glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist was approved by the FDA and analyzed by a number of recent studies.

A new drug for type 2 diabetes, tirzepatide, received approval last month and was the focus of several studies.

On May 13, tirzepatide injection (Mounjaro) was approved by the FDA to improve blood glucose control in adults with type 2 diabetes, as an addition to diet and exercise. The drug is a first-in-class medicine that activates both the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptors. It is administered subcutaneously once weekly, with the dose adjusted as tolerated to meet blood glucose goals. Three different doses (5 mg, 10 mg, and 15 mg) were evaluated in trials. Side effects include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain. The drug is not indicated for use in patients with type 1 diabetes and has not been studied in patients with a history of pancreatitis. In addition, it causes thyroid C-cell tumors in rats; it is unknown whether it causes such tumors, including medullary thyroid cancer, in humans.

A systematic review of tirzepatide data was published by Diabetologia on May 17. It included seven randomized trials published before Oct. 27, 2021, with a total of 6,609 participants. The review found that tirzepatide had shown superiority in lowering HbA1c levels versus placebo, a GLP-1 receptor agonist, or basal insulin. It was also the most effective at reducing body weight. Odds of gastrointestinal events were similar overall between tirzepatide and GLP-1 receptor agonists, except diarrhea was more common with the 10-mg dose of the new drug. The 15-mg dose had a higher discontinuation rate than the comparators due to adverse events. The authors concluded that “tirzepatide could be a reasonable treatment option when glycaemic control and body weight loss are therapeutic priorities” but that some patients may experience gastrointestinal adverse events which could possibly lead to discontinuation of treatment.

A manufacturer-funded analysis of the drug, looking at its effects versus semaglutide, was published by Diabetes, Obesity and Metabolism on May 19. The adjusted indirect treatment comparison aggregated data from the SURPASS-2 and SUSTAIN FORTE trials. It found that in patients who had been taking only metformin, being randomized to tirzepatide at a 10- or 15-mg dose was associated with significantly reduced HbA1c level compared to receiving semaglutide, 2 mg. Body weight was also significantly reduced with either dose compared to semaglutide. There was no significant difference between tirzepatide, 5 mg, and semaglutide, 2 mg, on either outcome. The authors noted that their findings “cannot replace a direct head-to-head trial, and conducting a trial to compare tirzepatide and semaglutide 2 mg would validate these findings.”

Finally, a manufacturer-funded trial of tirzepatide for weight loss in patients without diabetes (SURMOUNT-1) was published by the New England Journal of Medicine on June 4. Patients in the trial had a mean body mass index of 38.0 kg/m2. Those randomized to a weekly subcutaneous dose of tirzepatide showed significantly greater change in weight at week 72: −15.0% with 5 mg, −19.5% with 10 mg, and −20.9% with 15 mg versus −3.1% with placebo (P<0.001 for all comparisons with placebo).

“It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass,” said an accompanying editorial. However, the editorial cautioned that there are a number of unanswered questions about the drug, including how it will affect risk of major cardiovascular events and whether the observed gastrointestinal side effects could lead to other health issues.