Dr W. Timothy Garvey
SAN DIEGO — Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to a US Food and Drug Administration (FDA) approval of a new indication for weight loss for tirzepatide.
Tirzepatide received in 2022 FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro. The agent — a "twincretin" that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor — had also previously scored a decisive win for weight loss in adults with overweight or obesity and no 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," said W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, during a press briefing here at the American Diabetes Association (ADA) 83rd Scientific Sessions.
Tirzepatide "Fills the Gap"
Tirzepatide "fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better," 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.
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 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," commented Marlon Pragnell, PhD, vice president, Research & 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," Pragnell said in an interview.
Affordability and Access Will Remain "A Big Problem"
Garvey cautioned, however, that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.
Janet Brown-Friday
"These medications are very expensive — more than $1000 a dose — and this cost limits access…[which is] a big problem," Garvey noted. US healthcare 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 & Education, ADA, who also 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 during March 2021-April 2023. The study had two primary outcomes: average percent change in body weight from baseline to week 72, and the percentage of participants who achieved a weight reduction from baseline of at least 5%, again 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 who achieved at least a 5% reduction in weight from baseline was 79% of those who received the 10-mg dose of tirzepatide, 83% of those on a 15-mg dose, and 32% of those on placebo, which also represented significant improvements 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," Garvey noted.
Simultaneously with the meeting report, the results were 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.
Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in hemoglobin A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and less than a 5% incidence of milder hypoglycemia.
The absence of any severe hypoglycemia was "amazing," Garvey said, especially given that 46%-49% of people on tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of the participants treated with placebo.
The results also showed the benefit of a "big reduction in fasting insulin levels" that averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Garvey said.
Lancet. Published online June 23, 2023. Full Text
ADA Scientific Sessions. Session CT-1.5-SY40. Presented June 23, 2023.
SURMOUNT-2 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Garvey has been a consultant to and received research funding from Eli Lilly, as well as a consultant or advisor to Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has also been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Pragnell and Brown-Friday disclosed no relevant financial relationships.
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