“Tirzepatide versus Insulin Glargine in Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4): a Randomized, Open-Label, Parallel-Group, Multicentre, Phase 3 Trial”, 2021-11-13 (; backlinks):
Background: [SURPASS-4; next; previously, SURPASS-3] We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.
Method: This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on 5 continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7.5–10.5% (58–91 mmol/mol), body mass index of 25 kg⁄m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or insulin glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0.3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus insulin glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662.
Results: Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3,045 participants were screened, with 2,002 participants randomly assigned to tirzepatide or insulin glargine. 1,995 received at least one dose of tirzepatide 5 mg (n = 329, 17%), 10 mg (n = 328, 16%), or 15 mg (n = 338, 17%), or insulin glargine (n = 1,000, 50%), and were included in the modified intention-to-treat population.
At 52 weeks, mean HbA1c changes with tirzepatide were −2.43% (SD 0.05) with 10 mg and −2.58% (0.05) with 15 mg, versus −1.44% (0.03) with insulin glargine. The estimated treatment difference versus insulin glargine was −0.99% (multiplicity adjusted 97.5% CI −1.13 to −0.86) for tirzepatide 10 mg and −1.14% (−1.28 to −1.00) for 15 mg, and the non-inferiority margin of 0.3% was met for both doses.
The percentage of participants with hypoglycemia (glucose <54 mg/dL or severe) was lower with tirzepatide (6–9%) versus insulin glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs insulin glargine 16%).
Nausea (12–23%), diarrhea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than insulin glargine (nausea 2%, diarrhea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase…Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with insulin glargine (hazard ratio 0.74, 95% CI 0.51–1.08). 60 deaths (n = 25 [3%] tirzepatide; n = 35 [4%] insulin glargine) occurred during the study.
Interpretation: In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with insulin glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk.
Funding: Eli Lilly and Company.