SURPASS-5: Tirzepatide lowers HbA1c in adults with type 2 diabetes on insulin glargine
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Adults with type 2 diabetes on treatment with insulin glargine assigned tirzepatide had greater reductions in HbA1c and body weight compared with placebo, according to data from the SURPASS trial program.
In findings from the SURPASS-5 randomized clinical trial published in JAMA, participants assigned 5 mg, 10 mg or 15 mg tirzepatide (Eli Lilly), a glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, alongside once-daily insulin glargine had a greater decrease in HbA1c and body weight compared with placebo. Additionally, more than 85% of participants in all three tirzepatide groups had an HbA1c of less than 7% at 40 weeks.
“SURPASS-5 was the first study assessing the combination of a GIP/GLP-1 receptor agonist and a basal insulin,” Ángel Rodríguez, MD, PhD, a clinical research physician for Lilly Spain, told Healio. “In patients that needed to optimize their basal insulin regimen, the study showed that the addition of tirzepatide to titrated basal insulin glargine can provide meaningful improvements in glycemic control, together with significant weight loss and lower insulin doses when compared to placebo.”
In SURPASS-5, 475 adults with type 2 diabetes, a baseline HbA1c between 7% and 10.5% and a BMI of at least 23 kg/m2 receiving stable once-daily doses of insulin glargine with or without metformin were enrolled in a 40-week, randomized, double-blind, placebo-controlled trial (mean age, 61 years; mean BMI, 33.4 kg/m2; mean HbA1c, 8.31%; mean diabetes duration, 13.3 years). Enrollment took place from Aug. 30, 2019, to March 20, 2020, with follow-up until Jan. 13, 2021. Participants were randomly assigned to 5 mg, 10 mg or 15 mg tirzepatide or placebo. The trial began with a 4-week insulin stabilization period followed by insulin titration for 36 weeks. All participants followed a treat-to-target titration algorithm and measured fasting blood glucose daily. The trial concluded with a 4-week safety follow-up. The primary endpoint was the mean change in HbA1c at week 40 for the 10 mg and 15 mg tirzepatide groups compared with placebo.
Preliminary findings from the SURPASS-5 study were presented at the American Diabetes Association Scientific Sessions and the European Association for the Study of Diabetes annual meeting in 2021.
Most reach HbA1c target with tirzepatide
At 40 weeks, the 10 mg tirzepatide group had a 1.53% greater reduction in HbA1c compared with placebo (95% CI, –1.8 to –1.27; P < .001), and the 15 mg tirzepatide group had a 1.47% greater HbA1c reduction than placebo (95% CI, –1.75 to –1.2; P < .001). The 5 mg tirzepatide group also had a greater HbA1c decrease compared with placebo (mean difference, –1.24%; 95% CI, –1.48 to –1.01; P < .001).
The percentage of participants achieving an HbA1c of less than 7% at 40 weeks was at least 85% in all three tirzepatide groups compared with 34% for placebo (P < .001 for all). Half of the 15 mg tirzepatide group and 42% in 10 mg group achieved an HbA1c of less than 5.7% compared with 3% for placebo (P < .001 for both).
At 40 weeks, all three tirzepatide groups had decreases in mean body weight, with a reduction of 5.4 kg in the 5 mg group, 7.5 kg in the 10 mg group and 8.8 kg in the 15 mg group, compared with a 1.6 kg increase in body weight for placebo at 40 weeks (P < .001 for all). All three tirzepatide groups also had greater decreases in mean fasting serum glucose at 40 weeks compared with placebo (P < .001 for all).
“The proportion of patients that achieved their target values for HbA1c at week 40 were consistent with the rest of the SURPASS studies,” Rodriguez said. “Similarly, the self-measured glucose profiles showed a significant improvement throughout the day, with 2-hour post-meal daily mean values within normal range across all doses of tirzepatide. These results, along with previously published SURPASS trials, illustrate the potential of tirzepatide to significantly improve glycemic control irrespective of background therapy and duration of diabetes.”
Between 68.1% and 78.3% of participants in the tirzepatide treatment groups had at least one adverse event during the study compared with 67.5% in the placebo group. The most common adverse events were gastrointestinal, including diarrhea, nausea, vomiting and decreased appetite.
More research needed on dosing, comorbidities
In a related editorial, Stuart R. Chipkin, MD, a research professor at the University of Massachusetts Amherst School of Public Health and Health Sciences, said there are several questions the SURPASS-5 study did not answer.
“The study did not compare tirzepatide with other treatments that could have been used to target the postprandial glycemic pattern of the study population,” Chipkin wrote. “Although patients are likely to embrace a medication with weight-loss outcomes, the protocol also leaves unanswered questions about reducing insulin and evaluating the comparative risk of adverse effects.”
Chipkin wrote that the study did not evaluate the efficacy of tirzepatide for adults with comorbidities since participants with retinopathy, low estimated glomerular filtration rates, severe diabetic gastroparesis, hospitalization for cardiovascular event in the past 2 months and hypoglycemia awareness were excluded. Chipkin also noted the study did not permit dividing insulin glargine doses or adding therapies, which may differ from what providers may recommend in clinical care.
“Even though the results of this investigation are important for demonstrating the potential clinical benefit of this dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist and may help to advance the goal of achieving U.S. 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,” Chipkin wrote.
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Ángel Rodríguez, MD, PhD, can be reached at rodriguez_angel@lilly.com.
Perspective
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In this study, once-weekly administration of three different doses of the dual GIP/GLP-1 receptor analog tirzepatide in patients with poorly controlled diabetes on basal insulin was found to be associated with a significant reduction in HbA1c of up to 2.4% compared to 0.86% with ongoing titration of glargine insulin. Of those treated with tirzepatide, 85% to 90% reached an HbA1c target of less than 7%, compared to 34% with titrated glargine. Importantly, this was accomplished without an increased risk for hypoglycemia and with greater than 10 kg average weight loss in those on the highest dose. In the placebo group, glargine was titrated aggressively, with a mean dose of 58 units (0.62 U/kg) at the end of the trial. Although not studied head-to-head in this study, the magnitude of the effects of tirzepatide on HbA1c and weight appear to be greater than any of the GLP-1 receptor agonist and basal insulin studies to date.
Clinical guidelines from the American Diabetes Association and American Association of Clinical Endocrinology recommend GLP-1 receptor agonists as first injection for those with type 2 diabetes who fail to achieve target HbA1c on one or more oral agents. However, a substantial proportion of patients are still receiving basal insulin as their first injectable. Furthermore, in clinical practice, the initiation of basal insulin is often delayed. In recent real-world studies, mean HbA1c upon initiation of insulin is 9% to 9.5%, and fewer than 30% of those treated reach an HbA1c of less than 7%.
The intensification of basal insulin with GLP-1 receptor agonists has been shown to be as effective in lowering HbA1c as three injections of prandial insulin, with less hypoglycemia and a reduction in weight. In SUSTAIN-5, the addition of semaglutide 1 mg was associated with 79% of patients reaching an HbA1c of less than 7% and 26% achieving at least a 10% weight loss. In the current study, 90% of patients on highest dose of tirzepatide reached HbA1c of less than 7% and 40% achieved at least a 10% reduction in weight. It is this level of weight loss that is associated with a reduction in cardiovascular events, hepatic steatosis and even the remission of diabetes.
If approved by the FDA, it is likely that tirzepatide would be used in patients with type 2 diabetes who would benefit from greater reduction in HbA1c and weight, perhaps in place of a GLP-1 receptor agonist. The significant reduction in cardiometabolic risk factors with tirzepatide is intriguing, but without CV outcomes studies, I would not recommend these agents in place of those agents with improved CV outcomes.
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