Miriam E. Tucker

May 27, 2014

LAS VEGAS — The injectable glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) could benefit patients with type 1 diabetes when used in conjunction with insulin, according to the results of a 12-week randomized trial.

"With liraglutide, a significant percentage of type 1 diabetes patients would be able to achieve a goal HbA1c of 7% or below without too much additional hypoglycemia, along with weight loss and blood-pressure benefits," said Nitesh D. Kuhadiya, MD, assistant professor of medicine, section of endocrinology, diabetes, and metabolism, at the University of Buffalo (NY).

Dr. Kuhadiya presented the late-breaking data here at the American Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific and Clinical Congress.

"This is important, as approximately 40% of patients with type 1 diabetes in the United States now have metabolic syndrome, and liraglutide targets 3 out of the 5 key features: high blood pressure, diabetes, and obesity," Dr. Kuhadiya told Medscape Medical News.

This is the first randomized, placebo-controlled trial of liraglutide in type 1 diabetes, he added.

There are pluses and minuses to using the GLP-1 agonist in addition to insulin in type 1 diabetes patients, AACE president-elect George Grunberger, MD, founder of the Grunberger Diabetes Institute, Bloomfield Hills, Michigan, told Medscape Medical News. "People love it, but then you have to think of the logistics. It's adding another injection, and the cost of that, and then, because it's not approved for use in type 1, who's going to pay for it?"

On the other hand, "less hypoglycemia, 25% less insulin use, a drop in BP, a drop in weight, reducing glycemic variation....I think it's an incredibly attractive way to do it," said Dr. Grunberger.

Add-on Therapy

A total of 72 patients with type 1 diabetes were randomized to liraglutide in 1 of 3 daily doses (0.6, 1.2, 1.8 mg) or to placebo. The patients had a mean age of 44 years, diabetes duration of 24 years, weight 83 kg, body mass index of 29 kg/m2, and a mean HbA1c of 7.5%. All wore insulin pumps and continuous glucose monitors.

Insulin doses were left unchanged for the patients with baseline HbA1c levels above 7.5%, adjusted down by 10% for those with HbA1c between 7.0% and 7.5%, and reduced by 25% for those with baseline HbA1c below 7.0%. Insulin doses were titrated based on continuous glucose monitor and finger-stick readings.

A total of 63 patients (88%) completed the study. At week 12, mean blood glucose levels had fallen by about 10 mg/dL in both the 1.2- and 1.8-mg-liraglutide groups, both significant (P < .05) compared with placebo. HbA1c dropped by 0.8 percentage points in the 1.2-mg group, by 0.4 in the 1.8-mg group, by 0.2% with 0.6 mg, and 0.3% with placebo. The drop in the 1.2-mg group was significant (P < .05) vs placebo.

The researchers suggest that the reason HbA1c dropped more with 1.2 mg vs 1.8 mg is that the 1.2-mg group started out with a higher HbA1c, of about 7.8%, compared with 7.4% for the 1.8-mg group.

"The change in HbA1c was clearly related to baseline HbA1c when we did the correlation analysis. In other words, the higher the HbA1c, the greater the fall," Dr. Kuhadiya explained to Medscape Medical News.

The 1.2- and 1.8-mg-dose groups both spent 3% to 5% more time in the target glucose range of 70 to 160 mg/dL (P < .05 for 1.8 mg) and 2% to 4% less time in the ranges of 160 to 240 mg/dL and >240 mg (both P < .05 compared with placebo), he reported.

Both the 1.2- and 1.8-mg-liraglutide groups spent about 1% more time in the hypoglycemia ranges of 55 to 70 mg/dL and <55 mg/dL, whereas there was no additional hypoglycemia in the 0.6-mg or placebo groups (P < .05). There were no severe hypoglycemic episodes.

Insulin doses dropped by about 12 units in the 1.2-mg group and close to 10 units with 1.8 mg (P < .05).

Body weight dropped significantly in all 3 liraglutide dose groups, by about 5 kg with the 1.2- and 1.8-mg doses and about 3 kg with 0.6 mg (all P < .05 vs placebo).

"These people had a remarkable weight loss," said Dr. Kuhadiya.

Although the majority of the study participants were overweight or obese, liraglutide appeared to benefit those of normal weight as well. In the 1 patient in the 1.2-mg group with a BMI of just 25, HbA1c fell from 7.7% to 6.6%. In the 6 normal-weight patients in the 1.8-mg group, HbA1c fell from an average of 7.5% to 7.1%, with a 10% reduced insulin requirement.

For the entire study group at 12 weeks, systolic blood pressure had dropped by about 9 mm Hg in the 1.8-mg group, and by 5 mm Hg in the 0.6-mg group. The fact that the 0.6-mg group had a trend toward significance in blood-pressure reduction without an effect on glycemia "emphasizes the message that the effect of liraglutide on glycemia, weight, and blood pressure are independent of each other," said Dr. Kuhadiya.

Patients also reported significant quality-of-life improvements with both the 1.2- and 1.8-mg doses, including feeling less burden of type 1 diabetes and less fear of hypoglycemia and of diabetes in general. They also reported fewer hassles in managing diabetes, following their diets more closely, worrying less about the future, and improved leisure time and social lives.

Other companies are conducting similar trials for other GLP-1 agonists, as well as dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors, to see if they can extend their label indications to include type 1 diabetes patients, Dr. Grunberger told Medscape Medical News. "Every company in that space is doing a type 1 trial," he said.

This study was funded by Novo Nordisk. Dr. Kuhadiya received an endocrine fellow foundation grant award to conduct the trial. Dr. Grunberger has received speaker honoraria from Amarin, Janssen, Merck, Sanofi, Santarus, Takeda, and Valeritas. He has received research support from Bristol-Myers Squibb, Eli Lilly, and Novo Nordisk.

American Association of Clinical Endocrinologists 23rd Annual Scientific and Clinical Congress. Presented May 16, 2014.

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