Comparing the newly FDA-approved tirzepatide with insulin glargine in T2DM patients at high CV risk: The SURPASS-4 trial

Tirzepatide was approved by the U.S. Food and Drug Administration (FDA) on May 13, 2022 as the first and only dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist for type 2 diabetes mellitus (T2DM), given its potent glucose-lowering effects.1 Treatment with tirzepatide achieved a superior reduction in glycated hemoglobin (HbA1c) vs. its comparators in the phase 3 SURPASS trials.2-6 Published by Del Prato et al. in the Lancet, the SURPASS-4 trial showed that tirzepatide demonstrated better efficacy and safety in comparison with insulin glargine in T2DM patients at high risk of cardiovascular (CV) events.2 The trial also provided first-time evidence of the sustained effects of tirzepatide as well as initial data on its CV safety.2,7

SURPASS-4 was an open-label, multicenter, parallel-group, randomized, phase 3 trial recruiting 3,045 participants from November 20, 2018 to December 30, 2019, of which 2,002 were randomly assigned 1:1:1:3 to tirzepatide or insulin glargine.2 The key criteria of participants included ≥18 years of age, being diagnosed with T2DM and treated with either metformin, sulfonylurea, or sodium-glucose cotransporter-2 inhibitor alone or any combination, having an HbA1c baseline of 7.5%-10.5% (58-91mmol/mol), body-mass index (BMI) ≥25kg/m2 and high risk of CV events, or diagnosed with CV diseases.2

The primary objective was to establish superiority of all 3 doses of tirzepatide (5mg, 10mg and 15mg) compared with insulin glargine, in terms of primary endpoint (change in HbA1c) from baseline to at least 52 weeks.2 The secondary endpoint was the change in body weight from baseline to 52 weeks, while the safety objective was to compare CV risk with tirzepatide and insulin glargine.2

Results showed that 1,995 participants received at least 1 subcutaneous injection, once per week of either tirzepatide 5mg (n=329, 17%), 10mg (n=328,16%), 15mg (n=338, 17%), or 100U/mL insulin glargine (n=1,000, 50%).2 Superior changes in the mean HbA1c were seen with tirzepatide vs. insulin glargine at 52 weeks; -2.24% (SE: 0.05) at 5mg, -2.43% (SE: 0.05) at 10mg and -2.58% (SE: 0.05) at 15mg vs. -1.44% (SE: 0.03) with insulin glargine, respectively.2 HbA1c reduction was sustained for up to 104 weeks.2 The estimated treatment differences of tirzepatide as compared with insulin glargine were -0.99% (multiplicity adjusted 97.5% CI: -1.13 to -0.86) for 10mg tirzepatide and -1.14 (-1.28 to -1.00) for 15mg tirzepatide, thus the 0.3% non-inferiority margin was achieved (p<0.0001 for both doses).2

Tirzepatide also reduced body weight in a dose-dependent manner.2 Alterations in the mean body weight at 52 weeks were -7.1kg (SE: 0.34), -8.1% (SE: 0.37) at 5mg; -9.5kg (SE: 0.34), -10.7% (SE: 0.37) at 10mg; and -11.7kg (SE: 0.33), -13.0% (SE: 0.36) at 15mg as compared with an increase with insulin glargine of 1.9kg (SE: 0.19), 2.2% (SE: 0.21).2 Body weight loss associated with tirzepatide was sustained for up to 104 weeks.2

Nausea (12%-23%), diarrhea (13%-22%), appetite loss (9%-11%), and vomiting (5%-9%) were observed more frequently in treatment with tirzepatide over insulin glargine.2 However, these side effects were mostly mild-to-moderate occurred in diminishing frequency after dose escalation.2 A smaller percentage of patients with hypoglycemia (glucose <54mg/dL) or severe hypoglycemia was observed when treated with tirzepatide (76 patients, 8%), as compared with insulin glargine (191 patients, 19%).2

Some 109 participants sustained at least 1 major adverse CV event (MACE-4) (CV death, myocardial infarction, hospitalization for unstable angina, stroke).2 No elevated risk of MACE-4 events for composite tirzepatide compared with insulin glargine (HR=0.74; 95% CI: 0.51-1.08) was observed.3 There were 60 reported deaths [n=25 (3%), tirzepatide; n=35 (4%), insulin glargine], but none appeared to be related to treatment medication.2

In conclusion, treatment with tirzepatide sustained superior glycemic control and body weight reduction compared with insulin glargine.2 There was no evidence that tirzepatide vs. insulin glargine increased CV risk in T2DM.2 Additional findings from the phase 3, randomized SURPASS-5 clinical trial also showed that adding tirzepatide to titrated insulin glargine resulted in significant improvement in glycemic control.6 Therefore, tirzepatide may be a more beneficial alternative therapy to insulin glargine in T2DM patients with or without high CV risk.2

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