Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Patients receiving tirzepatide (5, 10, or 15 mg) reported significantly greater reductions in HbA1c compared to daily insulin degludec at 52 weeks post-randomization.

2. Tirzepatide (5, 10, or 15 mg) was superior to insulin degludec for the bodyweight reductions at 52 weeks post-randomization.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Current first-line injectable therapies for type 2 diabetes include basal insulin and glucagon-like peptide-1 (GLP-1) receptor agonists. Despite some efficacy, both therapies are associated with complications such as weight gain, hypoglycemia, and undesirable gastrointestinal side effects. A separate group of medications – glucose-dependent insulinotropic polypeptide (GIP) agonists – work by regulating insulin secretion and are said to be as effective as insulin and GLP-1 agonists, with fewer side effects. Tirzepatide is a novel dual GLP-1 and GIP receptor agonist currently being evaluated for treatment of patients with type 2 diabetes. This randomized controlled trial aimed to compare the safety and efficacy of once weekly tirzepatide 5 mg, 10 mg, and 15 mg, with daily insulin degludec in patients with type 2 diabetes inadequately controlled using metformin with or without SGLT2 inhibitors. The primary outcome for this study was noninferiority of tirzepatide 10 mg and 15 mg versus insulin degludec in mean change in HbA1c at week 52. Key secondary outcomes included noninferiority of tirzepatide 5 mg and superiority at all doses compared to insulin degludec for HbA1c and proportion of patients with HbA1c < 7.0% at 52 weeks post-randomization. According to study results, tirzepatide (5, 10, and 15 mg) resulted in significantly lower mean HbA1c levels and bodyweight at week 52 compared to titrated insulin degludec, with no increased risk of adverse events. This randomized controlled trial was strengthened by a large group of individuals from various countries, thus increasing the validity of results.

In-depth [randomized controlled trial]:

From Apr 1, 2019, to Nov 15, 2019, 1947 patients were assessed for eligibility from 122 centers across 13 countries. Included patients were ≥ 18 years old with a body-mass index ≥ 25 kg/m2 and baseline HbA1c between 7.0-10.5% who were not yet started on insulin. Altogether, 1437 patients received treatment (358 to tirzepatide 5 mg, 360 to tirzepatide 10 mg, 359 to tirzepatide 15 mg, and 360 to insulin degludec) and were included in the modified intention-to-treat and safety analyses.

Mean age among patients was 57.4 years (standard deviation [SD] 10.0) and the majority (56%) were men. At baseline, the mean HbA1c was 8.17% (SD 0.91) with the mean bodyweight being 94.3 kg (SD 20.1). The primary outcome of reduction in HbA1c levels from baseline to week 52 was greater for tirzepatide than insulin degludec, with a dose-dependent pattern in the treatment group (1.93% reduction for tirzepatide 5 mg, 2.20% reduction for tirzepatide 10 mg, 2.37% reduction for tirzepatide 15 mg, and 1.34% reduction for insulin degludec, standard error [SE] 0.05 for all). With regard to key secondary outcomes, superiority was displayed for all doses of tirzepatide (5, 10, and 15 mg) versus insulin degludec (p<0.0001), with the estimated treatment difference for HbA1c ranging from -0.59% to -1.04%. This was also the case for mean bodyweight at week 52 with all three groups of tirzepatide resulting in a decreased bodyweight (-7.5 kg to -12.9 kg) compared to insulin degludec (+2.3 kg). Significantly more individuals in the tirzepatide group achieved a target HbA1c < 7.0% compared to insulin degludec (82-93% vs. 61%, p<0.0001) at week 52. The most common treatment-related adverse events were mild to moderate, with a greater incidence of gastrointestinal symptoms in the tirzepatide group compared to insulin degludec. However, there were no treatment-related deaths.

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