Tirzepatide may improve glycemic control when added to insulin glargine in type 2 diabetes
An industry-sponsored phase 3 trial found statistically significant improvements in HbA1c level among patients with type 2 diabetes who had inadequate glycemic control on insulin glargine and were randomly assigned to subcutaneous tirzepatide once weekly versus placebo.
Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, and it appeared to improve glycemic control in patients with type 2 diabetes when added to insulin glargine versus placebo, a new industry-funded trial found. In healthy individuals, glucose-dependent insulinotropic polypeptide is the primary incretin hormone responsible for meal-stimulated insulin secretion. It also suppresses glucagon secretion during hyperglycemia, signals glucagon secretion during hypoglycemia, facilitates postprandial lipid clearance, and promotes satiety.
Researchers performed a randomized phase 3 clinical trial at 45 medical research centers in eight countries to assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes who had inadequate glycemic control. Adult patients were eligible for the study if they had type 2 diabetes, a baseline HbA1c level of 7.0% to 10.5%, and a body mass index (BMI) of at least 23 kg/m2 while receiving stable doses of once-daily insulin glargine (>20 IU/d or >0.25 IU/kg/d) with or without metformin (≥1,500 mg/d).
From Aug. 30, 2019, to March 20, 2020, enrolled patients were randomly assigned to receive once-weekly subcutaneous injections of tirzepatide, 5 mg (n=116), 10 mg (n=119), or 15 mg (n=120), or volume-matched placebo (n=120) over 40 weeks. All patients receiving tirzepatide began at a dosage of 2.5 mg/wk, which was increased by 2.5 mg every four weeks until the assigned dosage was achieved. Follow-up was completed on Jan. 13, 2021. The trial's primary end point was mean change from baseline in HbA1c level at week 40. Key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels. The results of the trial, which was funded by Eli Lilly and Company, were published online Feb. 8 by JAMA.
Overall, 475 patients were randomly assigned to a treatment group. Forty-four percent were women, the mean age was 60.6 years, the mean body mass index was 33 kg/m2, and the mean HbA1c level was 8.31%. Four hundred fifty-one patients (94.5%) completed the trial, and 424 (89.3%) completed the study treatment. Ten percent of the 5-mg tirzepatide group, 12% of the 10-mg tirzepatide group, 18% of the 15-mg tirzepatide group, and 3% of the placebo group discontinued the trial early.
The mean change in HbA1c level from baseline was −2.11% in the 5-mg tirzepatide group, −2.40% in the 10-mg tirzepatide group, and −2.34% in the 15-mg tirzepatide group versus −0.86% with placebo (difference vs. placebo, −1.24% [95% CI, −1.48% to −1.01%], −1.53% [97.5% CI, −1.80% to −1.27%], and −1.47% [97.5% CI, −1.75% to −1.20%], respectively; P<0.001 for all comparisons). Mean change in body weight was −5.4 kg in the 5-mg group, −7.5 kg in the 10-mg group, −8.8 kg in the 15-mg group, and 1.6 kg in the placebo group (difference vs. placebo, −7.1 kg [95% CI, −8.7 to −5.4 kg], −9.1 kg [95% CI, −10.7 to −7.5 kg], and −10.5 kg [95% CI, −12.1 to −8.8 kg]; P<0.001 for all comparisons).
Patients treated with tirzepatide were more likely than those treated with placebo to have an HbA1c level below 7% (85% to 90% vs. 34%; P<0.001 for all comparisons). Diarrhea (12% to 21% vs. 10%) and nausea (13% to 18% vs. 3%) were the most common adverse events related to treatment.
The researchers noted that the study patients were receiving insulin glargine with or without metformin and that the results may not be generalizable to those taking other oral antihyperglycemic medications, among other limitations. They concluded that in patients with type 2 diabetes and poor glycemic control with insulin glargine, subcutaneous tirzepatide once weekly yielded statistically significant improvements in glycemic control after 40 weeks versus placebo.
An accompanying editorial noted that there was little difference in change from baseline in HbA1c or weight loss with 10 mg versus 15 mg of tirzepatide and called for future studies to clarify the existence of a dose-response effect. The editorial also pointed out that only 1.3% of the study participants self-identified as Black or African American. The author noted that the current trial addressed tirzepatide's efficacy as an add-on to insulin glargine but did not answer questions about its generalizability and effectiveness in different groups of patients, notably those with complications or comorbid chronic diseases. In addition, he wrote, it did not compare tirzepatide with other treatments and did not examine reductions in insulin or comparative risks of adverse effects.
“Thus, even though the results of this investigation are important for demonstrating the potential clinical benefit of this dual glucose-dependent insulinotropic polypeptide and [glucagon-like peptide]-1 receptor agonist, and may help to advance the goal of achieving US Food and Drug Administration approval, the study may leave clinicians uncertain about when and how to best use tirzepatide to improve clinical outcomes for patients with type 2 diabetes,” the editorial concluded.