The “Twincretin” era for treating patients with type 2 diabetes has begun as the US Food and Drug Administration’s (FDA) approved the use of tirzepatide for this indication on May 13, making it the first approved agent that works as a dual agonist for the two principal human incretins.
According to FDA’s Patrick Archdeacon, MD, associate director of the Division of Diabetes, Lipid Disorders, and Obesity, in a statement released by the agency, Tirzepatide represents “an important advance in the treatment of type 2 diabetes.”
That advance is based on tirzepatide’s engineering, giving it agonist properties for both glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP). Several agents are already approved for use which were based on single-agonist activity on the GLP-1 receptor, including semaglutide (Ozempic for treating patients with type 2 diabetes; Wegovy for weight loss).
The FDA’s approved label includes all three dosages of tirzepatide (5 mg, 10 mg, and 15 mg,) tested during the pivotal trials. Each of these doses were delivered by a subcutaneous injection once a week. The FDA also approved the 2.5 mg/week dose used when starting a patient on the agent. Gradual up-titration appears to minimize possible gastrointestinal adverse effects during initial tirzepatide use.
Tirzepatide, which will be marketed by Lilly as Mounjaro, will hit the US market with much anticipation. Results from five pivotal trials, (all reported during the past year or so) establishes the drug’s unprecedented efficacy for reducing A1c levels and enabling weight loss in most patients with a generally benign safety profile.
The effects from tirzepatide on A1c and weight seen in these studies was “impressive, and will likely drive use of this agent,” commented Carol H. Wysham, MD, an endocrinologist at the MultiCare Rockwood Clinic in Spokane, Washington.
Tirzepatide received good notices in several editorials that accompanied the published reports of the pivotal trials. The first of these, a commentary from two UK-based endocrinologists, said that “tirzepatide appears to represent an advantage over current GLP-1 analogues by providing enhanced glycemic and weight benefits without an added penalty in terms of gastrointestinal adverse effects.”
The pivotal trials included head-to-head comparisons between tirzepatide and a 1.0-mg/week dose of semaglutide, along with two other long-acting insulin analogs, insulin glargine (Lantus) and insulin degludec (Tresiba).
“These are the most important comparators,” Wysham said. “Tirzepatide was appropriately compared with the best-in-class and most effective glucose-lowering agents currently available,” said Ildiko Lingvay, MD, an endocrinologist and professor at the UT Southwestern Medical Center in Dallas. “Given its outstanding efficacy at both lowering glucose and weight, I expect tirzepatide to have quick uptake among patients with diabetes,” Lingvay said. “The only limiting factor will be cost,” she added in an interview, highlighting the major stumbling block that could limit tirzepatide’s uptake.
The timing of the comparison with Semaglutide leaves some unanswered questions. The SURPASS-2 trial compared the three primary tirzepatide regimens (5 mg, 10 mg, and 15 mg/week) with a 1.0 mg/week dose of semaglutide, which was at the time the only approved dosage of semaglutide for patients with type 2 diabetes. Since then, a 2.0 mg/week dosage of semaglutide (Ozempic) received US approval for treating patients with type 2 diabetes, and a 2.4 mg/week dosage (Wegovy) received an FDA nod for treating people with obesity.
The lack of head-to-head data for tirzepatide against the 2.0 mg/week dose of semaglutide “leaves a clinical gap,” said Alice Y.Y. Cheng, MD, an endocrinologist at the University of Toronto. Tirzepatide “represents an advance over semaglutide at the 1 mg/week dose, but we do not know for sure compared to the higher dose.”
Another important limitation for tirzepatide right now is that the agent’s obligatory cardiovascular outcome trial, SURPASS CVOT, with about 12,500 enrolled patients, will not have findings out until about 2025, leaving uncertainty until then about the drug’s cardiovascular effects.