medwireNews: Tirzepatide provides better glucose control than insulin glargine in people with type 2 diabetes taking multiple oral antidiabetes medications (OADs), report the SURPASS-4 investigators in The Lancet.
The 1995 participants of SURPASS-4 had lived with type 2 diabetes for a median of 10.5 years and had an average glycated hemoglobin (HbA1c) level of 8.52% (69.7 mmol/mol) despite use of multiple OADs. Almost all participants were using metformin, around half were taking a sulfonylurea and about a quarter a sodium-glucose cotransporter 2 inhibitor.
Stefano Del Prato discusses the advantages of tirzepatide over insulin glargine for people with type 2 diabetes, and how the SURPASS-4 findings fit with those of the rest of the clinical trial program.
The primary endpoint was change in HbA1c at 52 weeks, at which time people randomly assigned to take tirzepatide 5, 10, or 15 mg/week had achieved average reductions of 2.24, 2.43, and 2.58 percentage points (24.5, 26.6, 28.2 mmol/mol), respectively.
Those who were randomly assigned to take insulin glargine-100, titrated to a fasting blood glucose of less than 100 mg/dL, achieved a 1.44 percentage point (15.7 mmol/mol) reduction. All differences between tirzepatide and glargine were statistically significant.
Stefano Del Prato (University of Pisa, Italy) and team note that “the doses of glargine used and the fasting glucose achieved suggest that the glargine titration algorithm was followed appropriately.”
Tirzepatide also resulted in significant and dose-dependent reductions in bodyweight, versus an increase with glargine, and a markedly lower rate of hypoglycemia, so that 74–88% of people taking tirzepatide achieved HbA1c below 7.0% (53 mmol/mol) without weight gain or clinically significant or severe hypoglycemia, compared with just 13% of those given glargine.
Longer-term follow-up, at 78 weeks for 1166 participants and 104 weeks for 199 people, showed the glycemic and weight benefits with tirzepatide were sustained.
Blood pressure decreased with tirzepatide but increased with glargine, and tirzepatide treatment also reduced levels of atherogenic lipids, compared with “marginal changes” in people taking glargine.
For SURPASS-4, the researchers recruited people at high cardiovascular risk, with 87% having previous events. Over the full course of the trial, 5% of tirzepatide-treated participants and 6% of those taking glargine had a major adverse cardiovascular event – myocardial infarction, stroke, hospitalization for unstable angina, or cardiovascular death.
The authors of a linked commentary – Bernard Khoo (University College London, UK) and Tricia Tan (Imperial College London, UK) – note that glucagon-like peptide (GLP)-1 receptor agonists are already “beginning to supplant insulin glargine” as the favored option for people with poor control on maximal OADs.
They say SURPASS-4 “widens the indications for tirzepatide” to encompass this group, and add that the SURPASS-CVOT trial, due in 2024, will determine the cardioprotective ability of tirzepatide versus dulaglutide.
They conclude: “The prospect of a weekly injectable treatment with demonstrably better glycaemic control, clinically significant weight loss, and reduced hypoglycaemia risk makes tirzepatide a compelling alternative to the tried-and-trusted insulin glargine, and a worthy competitor to weekly GLP-1 analogues in this context.”
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Lancet 2021; doi:10.1016/S0140-6736(21)02188-7
Lancet 2021; doi:10.1016/S0140-6736(21)02279-0