From the Journals

Do latest SURPASS findings with twincretin in diabetes impress?


 

Adding the investigational twincretin tirzepatide (Eli Lilly) to insulin glargine significantly improves blood glucose control after 40 weeks, compared with placebo among patients with type 2 diabetes, new research shows.

The novel once-weekly injectable agent is nicknamed a twincretin because it combines two different gut-hormone activities. It works both as a glucagonlike peptide-1 (GLP-1) receptor agonist and as an agent that mimics the glucose-dependent insulinotropic polypeptide (GIP).

Findings from the randomized phase 3 SURPASS-5 clinical trial were published online Feb. 8 in JAMA.

This is the latest in a series of SURPASS trials of tirzepatide in individuals with type 2 diabetes for which results have been presented at various conferences, announced by the company, and/or published since late 2020.

SURPASS-5 specifically investigated the effect on glycemic control of adding three different doses of once-weekly subcutaneous tirzepatide compared with placebo in 475 adults who hadn’t achieved target A1c levels using insulin glargine with or without metformin. Statistically significant reductions in A1c were found at 40 weeks for all three doses.

Moreover, authors Dominik Dahl, MD, group practice for internal medicine and diabetology, Hamburg, Germany, and colleagues note that the improvements in the tirzepatide groups “were associated with significantly lower insulin glargine use and significant bodyweight reduction compared with placebo.”

“Despite the differences in glycemic control between the tirzepatide and placebo groups, the rate of clinically significant or severe hypoglycemia was below one event per patient-year in all treatment groups,” they add.

However, concerns about the study protocol and generalizability were raised in an accompanying editorial by Stuart R. Chipkin, MD, of the School of Public Health & Health Sciences, University of Massachusetts Amherst.

“Importantly, the study did not compare tirzepatide with other treatments that could have been used to target the postprandial glycemic pattern of the study population,” he writes.

And ultimately, he says: “Even though the results of this investigation are important for demonstrating the potential clinical benefit of [tirzepatide], and may help to advance the goal of achieving U.S. Food and Drug Administration approval, the study may leave clinicians uncertain about when and how to best use tirzepatide to improve clinical outcomes for patients with type 2 diabetes.”

Significant A1c, weight reductions when added to insulin glargine

The randomized, phase 3 SURPASS-5 trial was conducted at 45 centers in eight countries between August 2019 and January 2021. The 475 adult participants had type 2 diabetes inadequately controlled (baseline A1c, 7.0%-10.5%) with once-daily insulin glargine, with or without metformin. They were randomized to receive once-weekly subcutaneous injections of tirzepatide in doses of 5 mg, 10 mg, or 15 mg, or volume-matched placebo injections over 40 weeks.

The mean changes from baseline in A1c at week 40, the primary study endpoint, were –2.11, –2.40, and –2.34 percentage points for the 5 mg, 10 mg, and 15 mg doses of tirzepatide, respectively (P < .001), versus a nonsignificant change of –0.86 percentage points with placebo. The differences from placebo at week 40 were also significant for the 10-mg and 15-mg doses (both P < .001).

Significantly higher proportions of patients receiving 5 mg, 10 mg, and 15 mg tirzepatide met the A1c target of less than 7% at week 40, compared with placebo (85%-90% vs. 34%; P < .001). Significantly higher proportions of patients in the 10-mg and 15-mg dose groups also achieved A1c less than 5.7% (42% and 50%, respectively, vs. 3%).

Mean fasting glucose was also reduced significantly with all doses of tirzepatide by 58.2 mg/dL, 64.0 mg/dL, and 62.6 mg/dL, respectively, versus 39.2 mg/dL with placebo (all P <0.001 vs. placebo).

At week 40, mean body weight reductions from baseline were 5.4 kg (11.9 lbs), 7.5 kg, and 8.8 kg versus just 1.6 kg with placebo (all P <0.001 vs. placebo).

All three tirzepatide doses were also associated with significant improvements from baseline in total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and triglycerides.

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