SURPASS-2: Tirzepatide bests semaglutide in HbA1c reduction, weight loss
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The investigational glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist tirzepatide led to significant and superior HbA1c and body weight reductions for adults with type 2 diabetes vs. semaglutide, SURPASS-2 study data show.
Additionally, a prespecified exploratory analysis showed 60% of participants on the highest, 15-mg dose of tirzepatide (Eli Lilly) achieved a composite endpoint of an HbA1c of 6.5% or lower and weight loss of 10% or greater with no reports of severe hypoglycemia, compared with 22% of participants assigned 1 mg semaglutide (Ozempic, Novo Nordisk).
“The results of the trial demonstrate that tirzepatide provided a degree of efficacy with respect to HbA1c lowering and reduction in body weight that has not previously been seen in clinical trials assessing antihyperglycemic agents,” Juan Pablo Frias, MD, FACE, medical director and a principal investigator of the National Research Institute in Los Angeles, told Healio. “Importantly, these efficacy results were seen with very low rates of clinically significant hypoglycemia and a safety and tolerability profile consistent with the GLP-1 receptor agonist class.”
Study design
For the phase 3 trial, Frias and colleagues analyzed data from 1,879 adults with type 2 diabetes inadequately controlled with metformin therapy of at least 1,500 mg daily (mean age, 57 years; mean baseline HbA1c, 8.28%; mean baseline weight, 93.7 kg). Researchers randomly assigned participants a once-weekly subcutaneous injection of 5 mg, 10 mg or 15 mg tirzepatide or 1 mg semaglutide for 40 weeks, followed by a 4-week safety follow-up period. Primary endpoint was change in HbA1c from baseline to 40 weeks.
The findings were presented as a late-breaking poster presentation and simultaneously published in The New England Journal of Medicine.
Researchers found the estimated mean change from baseline in the HbA1c level was –2.01 percentage points, –2.24 percentage points and –2.3 percentage points with the 5 mg, 10 mg and 15 mg doses of tirzepatide, respectively, and –1.86 percentage points with semaglutide. The estimated differences between the 5 mg, 10 mg and 15 mg tirzepatide groups and the semaglutide group were –0.15 percentage points (95% CI, –0.28 to –0.03), –0.39 percentage points (95% CI, –0.51 to –0.26) and –0.45 percentage points (95% CI, –0.57 to –0.32), respectively.
At all doses, tirzepatide was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide vs. semaglutide, with least-squares mean estimated treatment differences of 1.9 kg, 3.6 kg and 5.5 kg for the 5 mg, 10 mg and 15 mg doses, respectively (P < .001 for all).
The most common adverse events were gastrointestinal and primarily mild to moderate in severity in the tirzepatide and semaglutide groups.
Severe hypoglycemia, defined as blood glucose level less than 54 mg/dL, was observed in 0.6%, 0.2% and 1.7% of participants in the 5 mg, 10 mg and 15 mg tirzepatide groups, respectively, and in 0.4% of participants in the semaglutide group.
Serious adverse events were reported in 5% to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide.
“What is surprising is the proportion of patients who achieved excellent and even normal glycemic control, with 92% and 51% achieving an HbA1c of less than 6.5% and less than 5.7%, respectively, with the 15 mg tirzepatide dose, as well as the unprecedented proportion achieving at least 15% relative reduction in body weight — 40% with the 15 mg tirzepatide dose,” Frias told Healio. “And, in all arms of the study, it appeared that weight reduction had not plateaued at the end of the 40-week treatment period. If approved, this would likely make tirzepatide the most potent antihyperglycemic agent for type 2 diabetes, when considering glucose and body weight effects.”
A ‘new level’ of therapy
In a related editorial, Katherine R. Tuttle, MD, FASN, FACP, FNKF, executive director for research at Providence Health Care and professor of medicine in the nephrology division at the Institute of Translational Health Sciences at the University of Washington, wrote that the novel concept of combining a glucose-dependent insulinotropic polypeptide with a GLP-1 receptor agonist “takes incretin therapeutic agents to a new level.”
“In principle, treatment with a glucose-dependent insulinotropic polypeptide and a GLP-1 receptor agonist together would augment glucose lowering while providing defense against hypoglycemia,” Tuttle wrote. “Thus, in patients with type 2 diabetes, combination incretin therapy is poised to provide better glycemic efficacy than treatment with a GLP-1 receptor agonist alone while maintaining a good side-effect profile with respect to avoiding hypoglycemia.”
As Healio previously reported, top-line data from SURPASS-4, the largest and longest trial of the program to date, also demonstrated that tirzepatide significantly reduced HbA1c and body weight compared with insulin glargine (Lantus, Sanofi) for adults with type 2 diabetes at high cardiovascular risk. For the efficacy estimand, the highest dose of tirzepatide led to an HbA1c reduction of 2.58% and reduced body weight by –11.7 kg compared with insulin glargine (mean HbA1c reduction of 1.44% and mean weight gain of 1.9 kg) at 52 weeks. The full results from SURPASS-4 will be presented at the European Association for the Study of Diabetes annual meeting and published in a peer-reviewed journal, according to Eli Lilly.
References:
- Frias JP, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2107519.
- Tuttle KR. N Engl J Med. 2021;doi:10.1056/NEJMe2109957.
Perspective
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Jens Juul Holst, MD, DrMedSci
This is wonderful news for patients. I am not sure which dose the company will finally select for the various patient groups — the dropout rates and the adverse effect frequency are not negligeable. That said, this study represents a major advance. The mechanism of action is a matter that we have worked with quite a bit, and as far as I can see, tirzepatide is mainly a very good GLP-1 receptor agonist, but that does not change the fact that it is super effective. Congratulations to us all.
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Frias JP, et al. 84-LB. Presented at: American Diabetes Association Scientific Sessions; June 25-29, 2021 (virtual meeting).
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