Tirzepatide improves glycemic control and weight loss in patients with type 2 diabetes

1. Tirzepatide was superior to placebo with regard to changes in HbA_1c, serum glucose, body weight loss, and proportion of patients achieving HbA_1c targets of less than 7.0%.

2. Compared to placebo, the proportion of adverse events with tirzepatide were mildly elevated.

Evidence Rating Level: 1 (Excellent)

Study Rundown: In many patients with type 2 diabetes, management with diet and exercise may be inadequate to achieve treatment goals. Agonism of GLP-1 and glucose-dependent insulinotropic polypeptides (GIPs) receptors have shown efficacy for glycemic control and weight loss. However, the effects of dual-agonism have only been minimally studied. This randomized controlled trial aimed to assess the efficacy, safety, and tolerability of tirzepatide, a dual GIP and GLP-1 receptor agonist, versus placebo, in patients with inadequately controlled type 2 diabetes. Primary outcome for this study was mean difference in HbA_1c from baseline to 40 weeks of randomization, while secondary outcomes included change in serum glucose and body weight, and proportion of patients with HbA_1c <5.7% and <7.0%. According to study results, all doses of tirzepatide were superior to placebo with regard to the aforementioned primary and secondary outcomes at 40 weeks. Majority of the medication-induced side effects were mild to moderate in nature, with no treatment-delated deaths. Although this study was well constructed, it could benefit from a longer follow-up given the chronic and relapsing nature of type 2 diabetes and bodyweight changes.

Click to read the study in The Lancet

Relevant Reading: Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes

In-depth [randomized controlled trial]: Between Jun 3, 2019, and Oct 28, 2020, 705 individuals were assessed for eligibility across 52 clinical centers in India, Japan, Mexico, and the USA. Included patients were ≥18 years of age with inadequately controlled type 2 diabetes on exercise and diet. Altogether, 478 patients were randomized (121 to tirzepatide 5 mg, 121 to tirzepatide 10 mg, 121 to tirzepatide 15 mg, and 115 to placebo) and 428 completed the study. Mean age among enrolled patients was 54.1 years (standard deviation [SD] 11.9), while mean HbA_1c was 7.9%. The average BMI was 31.9 kg/m².

The primary outcome of mean treatment difference in HbA_1c, compared to placebo, was dose-dependent: -1.91% for tirzepatide 5 mg, -1.93% for tirzepatide 10 mg, and -2.11% for tirzepatide 15 mg (p<0.0001 for all doses vs. placebo). All three doses of tirzepatide were superior to placebo, from baseline to week 40, with regard to mean change in HbA_1c (1.87% decrease for tirzepatide 5 mg, 1.89% decrease for tirzepatide 10 mg, 2.07% decrease for tirzepatide 15 mg, 0.04% increase for placebo), serum glucose, body weight, as well as proportion of patients with HbA_1c <5.7% (31-52% with tirzepatide vs. 1% with placebo) and HbA_1c <7.0% (87-92% with tirzepatide vs. 20% with placebo). Compared to placebo, the proportion of adverse events with tirzepatide were slightly elevated (nausea: 6% vs. 12-18%, diarrhea: 8% vs. 12-14%, and vomiting: 2% vs. 2-6%). However, there were no medication-related deaths; only one death occurred in the placebo group. Overall, findings from this study demonstrate rigid evidence for tirzepatide use to achieve glycemic control in patients with lifestyle-resistant type 2 diabetes. 

Image: PD

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