Dual receptor agonist showed promising glycemic control and weight reduction in the phase 3 SURPASS-1 study

Incretin hormones are secreted in response to food ingestion and are directly correlated to the postprandial secretion of insulin.1 The malfunction and malsecretion of two incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are known to have a role in the pathogenesis of type 2 diabetes mellitus (T2DM).1 In a previous phase 2 study, tirzepatide, a dual GLP-1 and GIP receptor agonist (RA), has demonstrated a significantly greater glucose control and weight loss when compared to the selective GLP-1 RA dulaglutide.2 Recently, the efficacy estimand of the phase 3 SURPASS-1 study has further supported tirzepatide as a promising glucose-lowering agent for T2DM patients in glycated hemoglobin (HbA1c) and body weight reductions when compared to placebo.3

GLP-1 RAs can improve glucose-dependent insulin secretion, reduce glucagon secretion, decrease the rate of gastric emptying and are commonly used in treating T2DM patients for better glycemic control.4 In addition, GLP-1 RAs are also associated with a reduction in appetite and consequently a reduction in weight.4 However, not all patients treated with GLP-1 RAs can reach their glycemic target and would often require further glucoselowering treatment.4 On the other hand, GIP regulates glucose uptake, lipolysis and lipoprotein lipase activity, and its agonism can be additive to the glucose-lowering benefits of GLP-1 RAs.4 As such, the co-agonism of GLP-1 and GIP receptors can support a broader therapeutic window for T2DM patients than the selective GLP-1 RAs.4

Tirzepatide is a dual GLP-1 and GIP RA which showed a dose-dependent reduction effect in HbA1c of up to 2.4% and a weight loss of up to 11.3kg in a phase 2 study.4 When compared to the selective GLP-1 RA dulaglutide, tirzepatide has demonstrated superior HbA1c and weight control without a significant increase in gastrointestinal adverse events (AE).4 To further evaluate the efficacy and safety of tirzepatide monotherapy, a phase 3, multi-center, randomized, double-blind, parallel, placebo-controlled SURPASS-1 trial was conducted in adult T2DM patients who were naïve to injectable therapy and were inadequately controlled with diet and exercise alone.3 478 patients were randomized to receive either 5, 10 and 15mg of tirzepatide or placebo in a 1:1:1:1 ratio.3 All patients in the tirzepatide arms started at a dose of 2.5mg once-weekly which was stepwise increased at 4-week intervals to reach the final randomized maintenance dose of 5, 10 and 15mg.3

After 40 weeks of treatment, tirzepatide monotherapy has demonstrated statistically superior HbA1c and body weight reduction from baseline regardless of dose.3 Notably, 15mg tirzepatide reduced HbA1c by 2.11% and body weight by 8.8kg across efficacy estimand when compared to placebo.3 87.9% of patients in the 15mg arm also achieved a HbA1c level of <7%, the American Diabetes Association’s recommended target for diabetic patients.3,5 Moreover, over half (51.7%) of the patients in the 15mg tirzepatide arm achieved a HbA1c level of <5.7%, a HbA1c level that was comparable to those without diabetes.3,5

In terms of safety, tirzepatide was associated with mild to moderate gastrointestinal-related AEs, including nausea, diarrhea, vomiting and constipation that were commonly observed during the dose escalation period.3 No events of severe hypoglycemia or hypoglycemia of <54mg/dL were observed in the tirzepatide arms.3 The overall treatment discontinuation rates were 9.1%, 9.9% and 21.5% for 5, 10 and 15mg tirzepatide, respectively, when compared to 14.8% for the placebo group.3 While the treatment discontinuation rate for 15mg tirzepatide may appear greater than placebo, a majority of the patients discontinued treatment due to reasons other than AEs, including the coronavirus pandemic and family or work reasons.3 In fact, the actual treatment discontinuation rates due to AEs were <7% in each tirzepatide arm.3

With the phase 3 SURPASS-1 study demonstrating consistent efficacy and safety of tirzepatide when compared to previous phase 2 studies, Dr. Julio Rosenstock, Director of the Dallas Diabetes Research Center and Principal Investigator of SURPASS-1, concluded that, “Not only did nearly 90% of all participants taking tirzepatide meet the standard HbA1c goal of <7%, more than half taking the highest dose also achieved a HbA1c of <5.7%, the level seen in people without diabetes – an unprecedented finding and unique endpoint in trials evaluating glucose-lowering agents.” Notably, not all data from the SURPASS-1 study have been evaluated yet, and a complete analysis to be presented at the American Diabetes Association 81st Scientific Sessions later this year would shed more light on the efficacy and safety of tirzepatide.3

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