Efficacy and safety of a novel GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a randomized, double-blind phase 3 trial


Background

Despite advances in care, many people with type 2 diabetes do not meet treatment goals; thus, the development of new therapies is necessary. Our objective was to assess the efficacy, safety and tolerability of a novel insulinotropic glucose-dependent polypeptide and GLP-1 receptor agonist monotherapy compared to placebo in people with type 2 diabetes. insufficiently controlled by diet and exercise alone.

Methods

We conducted a 40-week, double-blind, randomized, placebo-controlled, phase 3 trial (SURPASS-1) at 52 medical research centers and hospitals in India, Japan, Mexico and the United States. Adult participants (≥ 18 years of age) were included if they had type 2 diabetes insufficiently controlled by diet and exercise alone and if they were naïve to injectable diabetes therapy. Participants were randomly assigned (1: 1: 1: 1) via a computer-generated random sequence to once weekly tirzepatide (5, 10 or 15 mg) or placebo. All participants, investigators and the sponsor were masked for treatment assignment. The primary endpoint was the mean change in glycated hemoglobin (HbA1 C) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834.

Results

From June 3, 2019 to October 28, 2020, out of 705 people assessed for eligibility, 478 (average baseline HbA1 C 7.9% [63 mmol/mol], age 54 1 years old [SD 11·9], 231 [48%] women, duration of diabetes 4.7 years and body mass index 31.9 kg / m2) were randomized to receive 5 mg tirzepatide (n = 121 [25%]), tirzepatide 10 mg (n = 121
[25%]), tirzepatide 15 mg (n = 121 [25%]), or placebo (n = 115 [24%]). 66 (14%) participants discontinued study medication and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo in changes from baseline in HbA1 C, fasting blood sugar, body weight and HbA1 C targets less than 7.0% (1 C decreased by 1.87% (20 mmol / mol) with tirzepatide 5 mg, 1.89% (21 mmol / mol) with tirzepatide 10 mg and 2.07% (23 mmol / mol) with tirzepatide 15 mg versus + 0.04% with placebo (+ 0.4 mmol / mol), resulting in estimated treatment differences compared to placebo of -1.91% (-21 mmol / mol) with tirzepatide 5 mg, -1, 93% (-21 mmol / mol) with tirzepatide 10 mg, and -2 11% (-23 mmol / mol) with tirzepatide 15 mg (all p 1 C targets less than 7.0% (vs 20%) and 6.5% or less (≤ 48 mmol / mol; 81 to 86% vs 10%) and 31 to 52% of patients on tirzepatide versus 1% on placebo achieved HbA1 C less than 5.7% (vs 6%), diarrhea (12 to 14% vs 8%) and vomiting (2 to 6% vs 2%). No clinical significance (

Interpretation

Tirzepatide has shown strong improvements in blood sugar control and body weight, with no increased risk of hypoglycemia. The safety profile was consistent with that of GLP-1 receptor agonists, indicating potential monotherapy use of tirzepatide for the treatment of type 2 diabetes.

Funding

Eli Lilly and company.


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