SURPASS-3: Tirzepatide superior to basal insulin for HbA1c, body weight reduction
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The dual incretin agonist tirzepatide was superior to titrated insulin degludec for adults with type 2 diabetes, with greater reductions in HbA1c and body weight at week 52 and lower risk for hypoglycemia, data published in The Lancet show.
The SURPASS-3 study, one of multiple trials assessing the safety and efficacy tirzepatide (Eli Lilly), is the first to compare an investigational glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist with a basal insulin in patients failing treatment with metformin plus or minus an SGLT2 inhibitor.
“In this study, up to 93% of participants on tirzepatide achieved the HbA1c target of less than 7% and 26% to 48% of participants treated with tirzepatide achieved an HbA1c level of less than 5.7%, indicating normoglycemia,” Juan Pablo Frias, MD, FACE, medical director and a principal investigator of the National Research Institute in Los Angeles, and colleagues wrote. “Moreover, 69% to 86% of participants treated with tirzepatide achieved HbA1c target values of 6.5% or lower without weight gain and clinically significant hypoglycemia, which indicates it is possible to achieve well-established, but stringent, HbA1c goals for type 2 diabetes in a safe manner.”
Tirzepatide vs. basal insulin
In an open-label, parallel-group study, researchers compared 5 mg, 10 mg or 15 mg tirzepatide doses with titrated, once-daily insulin degludec (Tresiba, Novo Nordisk) on glycemic response in participants with type 2 diabetes as an add-on to metformin therapy, with or without SGLT2 inhibitors (mean age, 57 years; 44.2% women; mean diabetes duration, 8.4 years; mean HbA1c, 8.17%; mean BMI, 33.5 kg/m²; 32% prescribed SGLT2 inhibitors). A cohort of 1,444 participants from 13 countries were assigned tirzepatide 5 mg (n = 359), 10 mg (n = 361) or 15 mg (n = 359), or insulin degludec (n = 365) for 52 weeks. The primary efficacy endpoint was noninferiority of tirzepatide 10 mg or 15 mg, or both, vs. insulin degludec in mean change from baseline in HbA1c at week 52.
Key secondary efficacy endpoints were noninferiority of tirzepatide 5 mg vs. insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide vs. insulin degludec in mean change from baseline in HbA1c and body weight, and the proportion of participants achieving an HbA1c of less than 7% at week 52.
Frias noted that for the active comparator arm of SURPASS-3, insulin degludec was well titrated, making it a more fair comparison.
“The target fasting glucose was 90 mg/dL and the insulin dose was titrated from a starting dose of 10 U daily to a mean dose of 48.8 U daily, or 0.5 U/kg per day,” Frias told Healio. “These doses are similar to those achieved in previous studies of insulin degludec using a treat-to-target algorithm in a similar patient population.”
The modified intention-to-treat population included 1,437 participants from the tirzepatide 5 mg (n = 358), tirzepatide 10 mg (n = 360), tirzepatide 15 mg (n = 359) and insulin degludec (n = 360) groups.
At week 52, reductions from baseline in HbA1c were 1.93%, 2.2% and 2.37% for the tirzepatide 5 mg, 10 mg and 15 mg groups, respectively, and 1.34% for the insulin degludec group; the noninferiority margin of 0.3% was met. The estimated treatment difference vs. insulin degludec ranged from –0.59% to –1.04% for tirzepatide (P < .0001 for all tirzepatide doses).
The proportion of participants achieving a HbA1c of less than 7% at week 52 was greater in all three tirzepatide groups (82% to 93%) vs. insulin degludec (61%; P < .0001).
At week 52, body weight decreased by –7.5 kg, –10.7 kg and –12.9 kg across the three dose groups, respectively, whereas participants in the insulin degludec group gained a mean 2.3 kg. The estimated treatment difference vs. insulin degludec ranged from –9.8 kg to –15.2 kg for tirzepatide (P < .0001 for all tirzepatide doses).
The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time, including nausea (12%-24%) diarrhea (15%-17%), decreased appetite (6%-12%) and vomiting (6%-10%).
Clinically significant hypoglycemia (level 2), defined as a glucose level less than 54 mg/dL, was reported in five (1%), four (1%) and eight (2%) participants in the tirzepatide 5 mg, 10 mg and 15 mg groups, respectively, vs. 26 participants (7%) in the insulin degludec group.
Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment.
“Tirzepatide-treated participants had clinically meaningful and superior improvements in glycemic control and body weight, with lower risk of hypoglycemia, than did participants treated with titrated insulin degludec, in a population with type 2 diabetes inadequately controlled by metformin with or without an SGLT2 inhibitor,” the researchers wrote. “These results support the use of tirzepatide for the treatment of type 2 diabetes and provide further evidence for the potential role of this dual GIP and GLP-1 receptor agonist as the next step in the treatment continuum when injectable therapy is considered.”
Important questions remain
In a related editorial, Christopher K. Rayner, MBBS, PhD, FRACP, the Gwendolyn Michell professor at the University of Adelaide Medical School and a consultant gastroenterologist at the Royal Adelaide Hospital, South Australia, and Michael Horowitz, PhD, professor of medicine and director of the endocrine and metabolic unit at the Royal Adelaide Hospital, wrote that there are important questions that must be answered by continued research, such as how much does GIP receptor stimulation contribute to the effects of tirzepatide.
“The positioning of tirzepatide in the therapeutic algorithm will be influenced by emerging information on cardiovascular outcomes, fatty liver disease, renal protection and durability of effects, which is awaited with interest,” Rayner and Horowitz wrote.
Reference:
Rayner CK, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)01597.
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