SAN DIEGO – in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.
Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.
Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.
“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
Tirzepatide ‘fills the gap’
Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial.
Mitchel L. Zoler/MDedge News
Dr. W. Timothy Garvey
Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.
“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)
“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.
This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
Tirzepatide the ‘most effective agent’
Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.
Dr. Ildiko Lingvay
Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.
“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.
But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive.
Affordability and access will remain a ‘big problem’
Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.
“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”
“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.
SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
In-trial weight loss of 12.8%-14.7%
The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.
The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.
A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.
The results were simulatenously published online in The Lancet.
Glucose control without severe hypoglycemia
The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.
Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.
The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.
The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.
Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.