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Results from the SURPASS-4 clinical trial evaluating the effects of tirzepatide in patients with type 2 diabetes and increased cardiovascular risk showed that the investigational treatment led to superior hemoglobin A1c (HbA1c) and body weight reductions when compared with insulin glargine.
The 52-week SURPASS-4 trial (ClinicalTrials.gov: NCT03730662) is part of a phase 3 global clinical development program for tirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single molecule. The randomized, parallel, open-label study compared the safety and efficacy of tirzepatide to insulin glargine in adults with type 2 diabetes inadequately controlled with at least 1 and up to 3 oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors) and who have increased cardiovascular risk (N=2002; mean duration of diabetes, 11.8 years).
Patients were randomly assigned 1:1:1:3 to receive either tirzepatide 5mg, 10mg or 15mg or insulin glargine. The primary endpoint of the study was the change from baseline to week 52 in HbA1c. The study was meant to demonstrate that the 2 higher doses of tirzepatide (10mg and 15mg) were noninferior to insulin glargine.
Efficacy estimand results (representing efficacy prior to discontinuation of study drug or initiation of rescue therapy for persistent severe hyperglycemia) for tirzepatide 5mg, 10mg, and 15mg vs insulin glargine, respectively, included the following:
- HbA1c reduction: -2.11%, -2.30%, -2.41% vs -1.39%
- Weight reduction: -6.4kg, -8.9kg, -10.6kg vs +1.7kg
- Percentage of patients achieving HbA1c less than 7%: 75.1%, 82.9%, 84.9% vs 48.8%
In the treatment-regimen estimand (representing efficacy irrespective of adherence to the investigational drug or introduction of rescue therapy for persistent severe hyperglycemia), tirzepatide was associated with the following HbA1c and body weight reductions for the 5mg, 10mg, and 15mg doses vs insulin glargine, respectively:
- HbA1c reduction: -2.11%, -2.30%, -2.41% vs -1.39%
- Weight reduction: -6.4kg, -8.9kg, -10.6kg vs +1.7kg
- Percentage of patients achieving HbA1c less than 7%: 75.1%, 82.9%, 84.9% vs 48.8%
The most commonly reported adverse events across all treatment arms were gastrointestinal-related (ie, nausea, diarrhea, vomiting). Hypoglycemia less than 54mg/dL was reported in 6.7%, 5.5% and 6.5% of patients treated with tirzepatide 5mg, 10mg, and 15mg, respectively, and in 15% of those who received insulin glargine.
“These strong results reinforce our belief that tirzepatide has the potential to be an exciting treatment for people living with type 2 diabetes,” said Mike Mason, president, Lilly Diabetes. “We look forward to meeting our goal of bringing an important new therapy to people living with this condition, including sharing more detailed results at scientific congresses and submitting to regulatory authorities later this year.”
The Company also reported findings from a cardiovascular safety meta-analysis conducted across the tirzepatide clinical program. The meta-analysis included 116 patients with adjudicated MACE-4 (a composite endpoint of death from cardiovascular or undetermined causes, myocardial infarction, stroke and hospitalization for unstable angina); the SURPASS-4 trial contributed to the majority of MACE events in the analysis. Hazard ratios were observed to be 0.81 (97.85% confidence interval [CI], 0.52-1.26) when comparing pooled data for tirzepatide vs comparators and 0.74 (95% CI, 0.51-1.08) in the SURPASS-4 trial alone.
Reference
Lilly’s tirzepatide achieves all primary and key secondary study outcomes against insulin glargine in adults with type 2 diabetes and increased cardiovascular risk in SURPASS-4 trial. [press release]. Indianapolis, IN: Lilly Eli; May 20, 2021.
