Significant weight loss and BP reduction also achieved

Tirzepatide—a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist—was noninferior and superior to semaglutide in effecting mean changes in glycated hemoglobin levels in patients with type 2 diabetes who were overweight or obese, according to results from the SURPASS-2 trial published in The New England Journal of Medicine.

The findings were also presented at the American Diabetes Association meeting.

Juan P. Frías, MD, of the National Research Institute in Los Angeles, and colleagues conducted this open-label, 40-week, phase III study to assess the efficacy and safety of treatment with once-weekly tirzepatide compared with semaglutide in patients with type 2 diabetes. They randomized 1,879 patients to tirzepatide given as a once-weekly injection at doses of 5, 10, or 15 mg, or semaglutide (1 mg) for 40 weeks, followed by a 4-week safety follow-up period.

Mean age of these patients was 56.6 years, 53.0% were women, 82.6% White, and 4.2% Black. Mean patient weight was 93.7 kg, and mean glycated hemoglobin was 8.28%.

Tirzepatide effected greater reductions in glycated hemoglobin levels, with an estimated mean change of −2.01 percentage points in patients treated with 5-mg tirzepatide, −2.24 percentage points in those taking the 10-mg dose, and −2.30 percentage points in those taking the 15-mg dose. In comparison, in patients treated with semaglutide, the estimated mean change was −1.86 percentage points. Thus, the differences between the 5-, 10-, and 15-mg tirzepatide and semaglutide treatment groups were −0.15 percentage points, −0.39 percentage points, and −0.45 percentage points, respectively, leading researchers to conclude that “Tirzepatide at all doses was noninferior and superior to semaglutide.”

In addition, according to Frias et al: “A total of 82 to 86% of the patients who received tirzepatide and 79% of those who received semaglutide reached the glycated hemoglobin level target of less than 7.0% that is recommended by the American Diabetes Association and the European Association for the Study of Diabetes. The glycated hemoglobin level target of less than 5.7% (normoglycemia) was met in 27 to 46% of the patients who received tirzepatide and in 19% of those who received semaglutide.”

They also found that treatment with tirzepatide also brought about greater body weight reductions compared with semaglutide for all doses and were dose dependent: −7.6 kg with the 5-mg, −9.3 kg with 10-mg, and −11.2 kg with the 15-mg doses, compared with −5.7 kg with semaglutide (least-squares mean estimated treatment difference compared with semaglutide: −1.9 kg, −3.6 kg, and −5.5 k; P˂0.001 for all).

“Notably, the change in body weight with tirzepatide was impressive (mean, −13.1% [or −12.4 kg] at the highest dose) and did not plateau at 40 weeks of treatment. Given the driving force of obesity in the epidemic of diabetes, as well as in the risks of cardiovascular and chronic kidney disease, this observation may lead to consideration of the use of tirzepatide for weight loss,” commented Katherine R. Tuttle, MD, of the Providence Medical Research Center, Providence Health Care, Spokane, and the University of Washington, Seattle, in an accompanying editorial.

Frías and colleagues also assessed changes in blood pressure.

“Systolic and diastolic blood pressure decreased with tirzepatide at a dose of 5 mg (−4.8 mmHg and −1.9 mmHg, respectively), at a dose of 10 mg (−5.3 mmHg and −2.5 mmHg, respectively), and at a dose of 15 mg (−6.5 mmHg and −2.9 mmHg, respectively) as compared with semaglutide (−3.6 mmHg and −1.0 mmHg, respectively),” they found.

Finally, tirzepatide had more positive effects on lipid profiles compared with semaglutide. After 40 weeks, patients treated with tirzepatide had lower triglyceride and serum very-low-density lipoprotein levels, and higher high-density lipoprotein levels compared with patients treated with semaglutide. No significant between-group differences were seen, however, in total cholesterol and low-density lipoprotein cholesterol levels.

The most common adverse events seen with both treatments were gastrointestinal, primarily mild-to-moderate in severity, and included nausea (17%-22% vs 18%, respectively), diarrhea (13%-16% vs 12%), and vomiting (6%-10% vs 8%). Serious adverse events occurred in 5% to 7% of patients treated with tirzepatide, versus 3% of those treated with semaglutide.

Frías and colleagues found a low incidence of hypoglycemia in all treatment groups: 0.6% of patients treated with 5-mg tirzepatide, 0.2% of the 10-mg group, and 1.7% of the 15-mg group, compared with 0.4% in those treated with semaglutide.

“The number of persons with diabetes is projected to grow from 463 million to 700 million worldwide between 2019 and 2045, with the greatest effect occurring in low- and middle-income countries. Given the growing number of cases of diabetes (90% of which are type 2), an increased incidence of complications of diabetes, particularly cardiovascular disease and chronic kidney disease, is anticipated. The need is urgent to develop and deploy effective therapies for diabetes — especially those that reduce the risks of serious complications — across populations,” commented Tuttle.

“At doses of 5 mg, 10 mg, or 15 mg weekly, tirzepatide provided more effective and dose-dependent reductions in the glycated hemoglobin level than standard treatment with the GLP-1 receptor agonist semaglutide (at a dose of 1 mg weekly),” she concluded.

Limitations of the study included unblinded treatment, short 40-week duration, and the inclusion of few Black patients.

  1. In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide in mean change in the glycated hemoglobin level from baseline to 40 weeks.

  2. Tirzepatide also brought about more significant reductions in body weight and blood pressure.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by Eli Lilly.

Frías has received support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Global Services, LLC, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi US Services Inc.

Tuttle reported personal fees and non-financial support from AstraZeneca, grants and personal fees from Bayer, personal fees and non-financial support from Kyokawa Hakko Kirin, personal fees from Janssen, grants from Goldfinch Bio, personal fees and non-financial support from Gilead, grants, personal fees and non-financial support from Eli Lilly, personal fees, non-financial support and other from Boehringer Ingelheim, personal fees and other from Novo Nordisk, outside the submitted work.

Cat ID: 12

Topic ID: 76,12,730,446,447,12,13,182,187,192,669,918,925,181