SURPASS-6: Tirzepatide add-on boosts type 2 diabetes control

medwireNews: The SURPASS-6 findings support the addition of tirzepatide to basal insulin for people with poorly controlled type 2 diabetes, demonstrating significant improvements in mean glycated hemoglobin (HbA1c) and other benefits compared with use of adjunct insulin lispro. The open-label phase 3b trial findings were presented at the 59th EASD Annual Meeting in Hamburg, Germany, by Juan Pablo Frías (Velocity Clinical Research, Los Angeles, California, USA) to coincide with their publication in JAMA. “The effects of tirzepatide on glycemic control, weight loss, and other cardiometabolic parameters were consistent with other SURPASS trials,” the authors say. The study recruited 1428 participants whose type 2 diabetes was inadequately controlled by basal insulin and up to two oral glucose-lowering medications, namely metformin ≥1500 mg/day, a sulfonylurea, or a dipeptidyl peptidase-4 inhibitor. Baseline criteria for the study were an HbA1c of 7.5–11.0% (58–97 mmol/mol) and a BMI of 23–45 kg/m2. Over half (58%) of participants were women, the average age was 59 years, the average diabetes duration was 14 years, the mean HbA1c was 8.8% (73 mmol/mol), and the average weight was 90.5 kg. Ten weeks before randomization, the participants switched therapy to a standard dose of insulin glargine 100 IU/ml and discontinued other medications except for metformin, allowing insulin stabilization and adjustment to a target fasting blood glucose of 100–125 mg/dL (5.6–6.9 mmol/L). The participants were then randomly assigned to receive once weekly subcutaneous tirzepatide at a dose of 5 mg (n=243), 10 mg (n=238), or 15 mg (n=236), or to receive prandial thrice-daily insulin lispro (n=708). The primary endpoint of statistical noninferiority (margin 0.3%) of tirzepatide to insulin lispro for the reduction of HbA1c from baseline over 52 weeks was met and statistical superiority was achieved with a mean difference of –0.98% between the regimens, the researchers say. Specifically, pooled data for the three tirzepatide treatment arms gave an estimated mean reduction in HbA1c of 2.1% versus 1.1% with insulin lispro, resulting in HbA1c levels of 6.7% (49.7 mmol/mol) and 7.7% (60.7 mmol/mol), respectively. Of note, this statistical superiority of tirzepatide over insulin lispro was achieved at the 5 mg, 10 mg, and 15 mg dosing levels, with estimated treatment differences of –0.79%, –1.01%, and –1.13%, respectively. Indeed, people given tirzepatide were 4.2 times more likely than those given insulin lispro to reduce their HbA1c level below 7.0% (53 mmol/mol), at 68% versus 36%, and also had a higher rate of achieving targets of 6.5% (47.5 mmol/mol; 56 vs 22%) and 5.7% (38.8 mmol/mol; 18 vs 3%). Use of tirzepatide also achieved significantly greater weight loss than insulin lispro at week 52, at an average of 9.0 and 3.2 kg, respectively. The 5 mg, 10 mg, and 15 mg tirzepatide doses were associated with weight reductions of 6.7, 9.2, and 11.0 kg, respectively, and were all statistically superior to the control treatment. Tirzepatide-treated participants were significantly more likely to achieve at least a 5% weight loss than those given insulin lispro (72 vs 10%) and a similar pattern was noted for a 10% or greater weight loss (46 vs 5%). In addition, Frías et al report that all three doses of tirzepatide were associated with greater reductions in fasting serum glucose at 52 weeks and greater reductions in mean daily 2-hour postprandial glucose than insulin lispro. Tirzepatide doses were also associated with significantly greater reductions in triglycerides, total cholesterol, low-density, very-low-density, and non-high-density lipoprotein than insulin lispro, as well as a significantly larger increase in high-density lipoprotein. “The safety profile of tirzepatide was consistent with that reported previously in other SURPASS trials,” the study investigators say. Treatment-emergent adverse events (AEs) were more common with tirzepatide than insulin lispro, affecting 71.8% and 55.6% of the groups, respectively. The most common AEs were gastrointestinal (42.3 vs 8.6%), namely nausea (19.9 vs 1.1%), diarrhea (12.7 vs 2.4%), decreased appetite (12.3 vs 0.1%), dyspepsia (9.6 vs 0.6%), and vomiting (8.6 vs 0.6%). However, serious AEs were less common with tirzepatide than insulin lispro (6.1 vs 10.9%) and there was a comparable rate of AEs leading to discontinuation (1.7 vs 2.1%). There were 18 (1.3%) deaths in the study but none were attributed to study treatment. Clinically significant hypoglycemia occurred in 12%, 9%, and 11% of participants given the 5, 10, and 15 mg doses of tirzepatide, respectively, versus 48% of those given insulin lispro, giving corresponding rates of 0.4 and 4.4 events per person–year. Severe hypoglycemia was also less common with tirzepatide, affecting three individuals given the 10 mg dose and 30 individuals given insulin lispro (17 and 89 events, respectively). medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group JAMA 2023; doi:10.1001/jama.2023.20294 EASD Annual Meeting; Hamburg, Germany: Oct 2–6, 2023

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SURPASS-6: Tirzepatide add-on boosts type 2 diabetes control

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