Adding Tirzepatide to Basal Insulin Cuts HbA1c in Poorly Controlled T2D

Derick Alison
Derick Alison
6 Min Read

HAMBURG, Germany — Adding weekly tirzepatide (Mounjaro) to basal insulin reduced HbA1c in patients with poorly controlled type 2 diabetes compared with adding three-times-daily insulin lispro, the phase IIIb SURPASS-6 trial showed.

In patients on an insulin glargine regimen, the estimated mean change from baseline in HbA1c at week 52 was -2.1% for those assigned to one of three different doses of the dual GIP/GLP-1 receptor agonist, as compared with -1.1% for those randomized to insulin lispro, resulting in mean HbA1c levels of 6.7% versus 7.7% (P<0.001), reported Juan P. Frías, MD, of Velocity Clinical Research in Los Angeles, during the European Association for the Study of Diabetes (EASD) annual meeting.

These results met noninferiority criteria, and statistical superiority was achieved, the authors wrote in JAMA, where the findings were also published.

Those who added tirzepatide had a more than four times higher chance of achieving an HbA1c under 7% (68% vs 36% in the insulin lispro group; OR 4.2, 95% CI 3.2-5.5) — meeting a key secondary endpoint.

In addition, patients taking tirzepatide had a mean weight loss of 9 kg (19.9 lb) over 52 weeks, while those who added insulin lispro gained 3.2 kg (7.1 lb).

“Tirzepatide demonstrated clinically meaningful and superior glycemic and body weight control versus insulin lispro and was associated with substantially less clinically significant hypoglycemia and less insulin use,” Frías said during his presentation.

The FDA approved tirzepatide in May 2022 as a first-in-class treatment for type 2 diabetes. It has since shot to popularity for its off-label weight-loss capabilities, demonstrating as much as a 15.7% (34.4 lb) body weight loss in a trial of patients with obesity or overweight and type 2 diabetes.

This trial marks the sixth installment of the SURPASS clinical program. Previously, the SURPASS-5 trial compared tirzepatide or placebo plus insulin glargine. Similarly, all three doses of tirzepatide — 5, 10, or 15 mg — yielded significantly greater HbA1c reductions by week 40 versus the placebo group.

In SURPASS-6, 1,428 participants were enrolled from 135 sites across 15 countries from 2020 to 2022. Mean age was 58.8, 57.7% were women, and mean HbA1c was 8.8%

To be included, all participants had to have their type 2 diabetes inadequately controlled with once- or twice-daily basal insulin, including insulin NPH, insulin glargine, insulin detemir, or insulin degludec, with a maximum combination of two oral antidiabetics including metformin, sulfonylurea, or a DPP-4 inhibitor. Oral agents except for metformin were discontinued at baseline.

Patients with type 1 diabetes, an eGFR under 30 mL/min/ 1.73 m2 or under 45 mL/min/1.73 m2 for those on metformin, and proliferative diabetic retinopathy, diabetic macular edema, or nonproliferative diabetic retinopathy requiring immediate treatment were excluded.

“Clinically, in those patients that have active retinopathy or maculopathy, I would be very careful about lowering the A1c … That said, in this study, there were really very few patients who had any worsening of retinopathy and it was equal between the two arms and it was minimal,” Frías said in response to a question about retinopathy risk with rapidly lowered HbA1c.

After randomization, 708 patients received prandial thrice-daily insulin lispro and 243, 238, and 236 patients received 5, 10, and 15 mg once-weekly tirzepatide injection, respectively. There was a target fasting glucose of 100-125 mg/dL during the trial.

After starting on an average of 46 IU/day of background insulin glargine at baseline, patients randomized to added insulin lispro ended up on a daily average of 62 IU/day of lispro and 42 IU/day of glargine by week 52. “So these patients were on over 100 units of insulin a day,” noted Frías. Patients also taking tirzepatide ended the trial on a daily average of 13 IU/day. “Although this was not one of the objectives of the trial, up to 20% of the patients [on tirzepatide] actually were able to come off basal insulin altogether,” he added.

As expected with a GLP-1 receptor agonist, the most common adverse events were mild to moderate gastrointestinal symptoms, including nausea, diarrhea, and vomiting. In contrast, only 1.1% of insulin lispro patients experienced nausea. However, hypoglycemia/severe hypoglycemia was more common in the insulin lispro group, occurring at a rate of 4.4 events per patient-year. Across all tirzepatide doses, there was an event rate of 0.4 events per patient-year.

  • author['full_name']

    Kristen Monaco is a senior staff writer, focusing on endocrinology, psychiatry, and nephrology news. Based out of the New York City office, she’s worked at the company since 2015.


The study was sponsored by Eli Lilly and Company.

Frías reported relationships with Eli Lilly and Company, Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Sanofi, and Novo Nordisk.

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Source Reference: Rosenstock J, et al “Tirzepatide vs insulin lispro added to basal insulin in type 2 diabetes” JAMA 2023; DOI: 10.1001/jama.2023.20294.

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