Tirzepatide With Insulin Glargine Improves Type 2 Diabetes

HAMBURG, Germany ― Once-weekly tirzepatide (Mounjaro, Lilly) added to insulin glargine resulted in greater reductions in A1c along with more weight loss and less hypoglycemia compared with prandial insulin lispro (Humalog, Sanofi) for patients with inadequately controlled type 2 diabetes, show data from the SURPASS-6 randomized clinical trial.

Tirzepatide led to a statistically and clinically significant reduction in mean A1c, at −2.1%, compared with insulin lispro, at −1.1%, by week 52. It also resulted in a higher percentage of participants meeting an A1c target of less than 7.0%, write the researchers, whose study was presented at the European Association for the Study of Diabetes (EASD) 2023 Annual Meeting and was published simultaneously in JAMA.

Also, daily insulin glargine use was substantially lower among participants who received tirzepatide compared with insulin lispro. Insulin glargine was administered at a dosage 13 IU/day; insulin lispro was administered at a dosage of 62 IU/day. “At the highest dose, some patients stopped their insulin [glargine] in the tirzepatide arm,” said Juan Pablo Frias, MD, medical director and principal investigator of Velocity Clinical Research, Los Angeles, California, who presented the findings in Hamburg. “We demonstrated clinically meaningful and superior glycemic and body weight control with tirzepatide compared with insulin lispro, while tirzepatide was also associated with less clinically significant hypoglycemia.”

Weight improved for participants who received tirzepatide compared with those who received insulin lispro, at -10 kg and +4 kg respectively. The rate of clinically significant hypoglycemia (blood glucose <54 mg/dL) or severe hypoglycemia was tenfold lower with tirzepatide compared with insulin lispro.

The session dedicated to tirzepatide was co-moderated by Apostolos Tsapas, MD, professor of medicine and diabetes, Aristotle University, Thessaloniki, Greece, and Konstantinos Toulis, MD, consultant in endocrinology and diabetes, General Military Hospital, Thessaloniki, Greece. Toulis remarked that in the chronic disease setting, management and treatment intensification are challenging to integrate, and there are barriers to adoption in routine practice. “This is particularly true when it adds complexity, as in the case of multiple prandial insulin injections on top of basal insulin in suboptimally treated individuals with type 2 diabetes.

“Demonstrating superiority over insulin lispro in terms of the so-called trio of A1c, weight loss, and hypoglycemic events, tirzepatide offers both a simpler to adhere to and a more efficacious treatment intensification option.” He noted that while long-term safety data are awaited, “this seems to be a definite step forward from any viewpoint, with the possible exception of the taxpayer’s perspective.”

Tsapas highlighted, “These data further support the very high dual glucose and weight efficacy of tirzepatide and the primary role of incretin-related therapies amongst the injectables for the treatment of type 2 diabetes.”

Tirzepatide 5, 10, 15 mg vs Insulin Lispro in Addition to Insulin Glargine

The researchers aimed to assess the efficacy and safety of adding once-weekly tirzepatide compared with thrice-daily prandial insulin lispro as an adjunctive therapy to insulin glargine for patients with type 2 diabetes that was inadequately controlled with basal insulin.

Tirzepatide activates the body’s receptors for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1). The study authors note that “recent guidelines support adding an injectable incretin-related therapy such as GLP-1 receptor agonist for glycemic control, rather than basal insulin, when oral medications are inadequate.”

The open-label, phase 3b clinical trial drew data from 135 sites across 15 countries and included 1428 adults with type 2 diabetes who were taking basal insulin. Participants were randomly assigned in a 1:1:1:3 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).

Both arms were well matched. The average age was 60 years, and 60% of participants were women. The average amount of time patients had type 2 diabetes was 14 years; 85% of participants continued taking metformin. The average A1c level was 8.8% at baseline. Patients were categorized as having obesity (average body mass index, 33 kg/m2). The average insulin glargine dose was 46 units, or 0.5 units/kg.

Outcomes included noninferiority of tirzepatide (pooled cohort) compared with insulin lispro, both in addition to insulin glargine; and A1c change from baseline to week 52 (noninferiority margin, 0.3%). Key secondary endpoints included change in body weight and percentage of participants who achieved an A1c target of <7.0%.

Ninety percent of participants who received the study drug completed the study, said Frias. “Only 0.5% of tirzepatide patients needed rescue therapy, while only 2% of the insulin lispro did.”

Prior to optimization, the average insulin glargine dose was 42 IU/kg; during optimization, it rose to an average of 46 IU/kg. “At 52 weeks, those on basal-bolus insulin found their insulin glargine dose stayed flat while insulin lispro was 62 units,” reported Frias. “The three tirzepatide doses show a reduction in insulin glargine, such that the pooled dose reached an average of 11 units, while 20% actually came off their basal insulin altogether [pooled tirzepatide].”

Tirzepatide (pooled) led to the recommended A1c target of <7.0% for 68% of patients, vs 36% of patients in the insulin lispro group.

Sixty-eight percent of the patients who received tirzepatide (pooled) achieved the recommended A1c target of <7.0%, v type 2 diabetes vs 36% of patients in the insulin lispro group.

“Individual tirzepatide doses and pooled doses showed significant reduction in A1c and up to a 2.5% reduction,” he added. “Normoglycemia was obtained by a greater proportion of patients on tirzepatide doses vs basal-bolus insulin ― one third in the 15-mg tirzepatide dose,” emphasized Frias.

Body Weight Reduction of 10% or More With Tirzepatide

Further, at week 52, weight loss of 5% or more was achieved by 75.4% of participants in the pooled tirzepatide group compared with 6.3% in the prandial lispro group. The weight loss was accompanied by clinically relevant improvements in cardiometabolic parameters.

In an exploratory analysis, weight loss of 10% or more was achieved by a mean of 48.9% of pooled tirzepatide-treated participants at week 52, compared with 2% of taking taking insulin lispro, said Frias.

“It is possible that the body weight loss induced by tirzepatide therapy and its reported effect in reducing liver fat content may have led to an improvement in insulin sensitivity and decreased insulin requirements,” write the researchers in their article.

Hypoglycemia risk and the weight gain observed with complex insulin regimens that include prandial insulin have been main limitations to optimally up-titrate insulin therapy in clinical practice, write the authors.

Frias noted that in this study, 48% of patients who received insulin lispro experienced clinically significant hypoglycemia, while only 10% of patients in the tirzepatide arms did. “This was 0.4 episodes per patient-year, vs 4.4 in tirzepatide and insulin lispro respectively.”

There were more reports of adverse events among the tirzepatide groups than the insulin lispro group. “Typically, with tirzepatide, the commonest adverse events were GI [gastrointestinal] in origin and were mild to moderate.” Rates were 14% to 26% for nausea, 11% to 15% for diarrhea, and 5% to 13% for vomiting.

The study was sponsored by Eli Lilly and Company. Frias has received grants from Eli Lilly and Company paid to his institution during the conduct of the study and grants, personal fees, or nonfinancial support from Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Eli Lilly, Sanofi, and Novo Nordisk outside the submitted work. Rosenstock has received grants from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Merck, Novartis, Novo Nordisk, Oramed, Pfizer, and Sanofi; personal fees from Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma, and Zealand (for which he served on scientific advisory boards and received honorarium or consulting fees); and personal fees from Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, and Sanofi (from which he received honoraria for lectures) during the conduct of the study. Toulis and Tsapas have declared no relevant disclosures.

European Association for the Study of Diabetes (EASD) 2023 Annual Meeting: Presented on October 3, 2023.

JAMA. Published October 3, 2023. Full text

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