First-in-Class Tirzepatide Wins FDA Approval for Treatment of Type 2 Diabetes

Approval comes after tirzepatide received FDA priority review designation late in 2021.

Tirzepatide, the first-in-class dual incretin receptor agonist, was granted US Food and Drug Administration (FDA) approval on May 13, 2022, as an adjunct to diet and exercise to reduce hyperglycemia in adults with type 2 diabetes (T2D).

The injectable once-weekly agent mimics gut hormones GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1), binding to the receptors and stimulating glucose-dependent insulin release. Tirzepatide is manufactured by Eli Lilly and Company and will be marketed under the brand name Mounjaro, according to the FDA announcement.

“Given the challenges many patients experience in achieving their target blood sugar goals, today’s approval of Mounjaro is an important advance in the treatment of type 2 diabetes,” said Patrick Archdeacon, MD, associate director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research, in the FDA’s announcement.

The FDA’s approval is based on Lilly’s phase 3 SURPASS clinical trial program, a series of 5 studies comparing the glucose-lowering efficacy of tirzepatide against placebo and against 3 active comparators—the injectable GLP-1 receptor agonist semaglutide 1 mg and long-acting insulin analogs glargine and degludec. The 3 investigational doses of tirzepatide, 5 mg, 10 mg, and 15 mg, were evaluated as monotherapy and in combination with commonly prescribed antihyperglycemic agents including metformin, sodium glucose contransporter-2 inhibitors, sulfonlyureas, and insulin glargine.

Across the SURPASS program, patients who received once-weekly tirzepatide 15 mg (the maximum recommended dose) achieved mean reduction in HbA1c 1.6% greater than patients taking placebo when the dual incretin agonist was used as monotherapy and 1.5% greater vs placebo when added to treatment with a long-acting insulin analog.

In the studies that compared tirzepatide 15 mg against other common T2D medications, investigators reported that HbA1c reductions among tirzepatide-treated patients were 0.5% greater vs semaglutide, 0.9% greater vs insulin degludec, and 1.0% greater vs insulin glargine.

Tirzepatide impact on obesity, overweight

The FDA in its announcement also highlighted the impact of tirzepatide on overweight and obesity, both common among participants in the SURPASS clinical trials (mean BMI at enrollment 32-24 kg/m2).

Among the findings, average weight loss for patients randomized to tirzepatide 15 mg was 15 lbs more than among those treated with placebo when neither agent was taken with insulin. On a background of insulin therapy, the average reduction in weight for tirzepatide-treated patients was 23 lbs greater than for those treated with placebo.

In trials comparing the maximum tirzepatide dose to other antihyperglycemics, tirzepatide 15 mg was associated with weight loss of 12 lbs more than with semaglutide, 29 lbs more than with insulin degludec, and 27 lbs more than with insulin glargine. SURPASS participants who received insulin without the addition of tirzepatide had a net weight gain during the study.

"Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro's efficacy and safety in a broad range of adults with type 2 diabetes” who might be seen in routine clinical practice, said Juan Pablo Frías, MD, medical director of the National Research Institute and Investigator in the SURPASS program, in an Eli Lilly statement.

Frías adds that given the results seen across the SURPASS phase 3 trials, the current approval is “an exciting step forward for people living with type 2 diabetes.”

Adverse events, warnings

Common side effects with tirzepatide seen in the clinical trials are characteristic of the incretin class, including nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain, according to the FDA.

Also like other agents in the class, tirzepatide in animal studies has caused thyroid C-cell tumors but it is not known currently whether it causes such tumors in humans. FDA cautions that tirzepatide should not be used in any patient with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2.

Further, the agent has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes.