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Expectations High for Insulin GLP-1 Combinations in Diabetes Care

Andrew Smith
Two competing insulin / GLP-1 combinations, one from Sanofi and the other from Novo Nordisk, are under review at FDA.
Pills that combine metformin with some other class of medication for type 2 diabetes (T2D) have been around for more than a decade. There are now more than a dozen on the market, but their total impact on outcomes has been as modest as the difference between swallowing 1 pill or 2.

Expectations are higher for 2 injectable combinations that currently await approval from the FDA. Analysts expect annual sales of more than $1 billion from Sanofi’s iGlarLixi (formerly called LixiLan) and IDegLira, to be marketed by Novo Nordisk as Xultophy, which both mix a basal insulin with a glucagon-like peptide 1 (GLP-1) receptor agonist in a way that would be hard for patients to do on their own.

“The results of the IDegLira trials I’ve participated in have been very impressive. The percentage of patients who get A1C levels into the target range is high, while the risk of hypoglycemia or weight gain is low,” said John Buse, MD, PhD, a professor at the University of North Carolina School of Medicine and director of the university’s diabetes care center. “I’m not yet sure that the combination is always superior to a GLP-1 alone, but I am convinced it is superior in all cases to basal insulin alone,” Buse said in an interview with Evidence-Based Diabetes Management. “In a world where price was not an issue, it would quickly and entirely supplant insulin in the treatment of type 2 diabetes.”

The race to be first has been fierce—and costly. Sanofi announced in late August that FDA approval of iGlarLixi would be delayed until November while regulators reviewed additional information, not on the therapy itself, but on the pen delivery system. At first, it seemed Sanofi had essentially wasted a $245 million priority review voucher it had redeemed to jump ahead of Novo Nordisk.But over Labor Day weekend came word that FDA had extended the review period for IDegLira from September to December.2

IDegLira combines 2 medications with distinct advantages over some of the competition—insulin degludec, sold as Tresiba, and liraglutide, which is formulated for diabetes as Victoza. Insulin degludec lasts nearly 2 days, so patients can take their daily dose at different times.3 It also keeps blood sugar significantly more stable than older insulins, and there’s some evidence that it reduces the risk of hypoglycemia.4,5 As for liraglutide, it is only the second diabetes medication (after empagliflozin) to demonstrate cardiovascular (CV) benefit.6

Together, the 2 medications have shown themselves generally superior to insulin or GLP-1 monotherapy. 

In one phase 3 trial,7 investigators randomized 1663 metformin-using adults with glycated hemoglobin (A1C) levels of 7% to 10% to 26 weeks of IDegLira, insulin degludec, or liraglutide. Mean A1C levels fell by 1.9 percentage points (to 6.4%) in the IDegLira group, 1.4 percentage points (to 6.9%) in the insulin group, and 1.3 percentage points (to 7.0%) in the liraglutide group. Subsequent analysis found IDegLira noninferior to insulin degludec (estimated treatment difference, –0.47%; 95% confidence interval [CI], –0.58 to –0.36; P <.0001) and superior to liraglutide (estimated treatment difference, –0.64%; 95% CI, –0.75 to –0.53; P <.0001).

As for adverse events, IDegLira essentially averaged out the performance of its component parts. The number of confirmed hypoglycemic events per patient year were 2.6 for insulin degludec, 1.8 for IDegLira, and 0.2 for liraglutide. The percentage of users reporting nausea was 19.7 for liraglutide, 8.8 for IDegLira, and 3.6 for insulin degludec. “IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycemic control compared with its components given alone,” the investigators wrote.

Results from a 26-week extension of that original trial further supported the conclusion.8 Some 1311 of the original patients kept taking whatever medication they had started, and IDegLira maintained its advantage over its component parts. At the end of a full year of treatment, mean A1C levels were down 1.84 percentage points in the IDegLira group, 1.40 percentage points in the insulin group, and 1.21 percentage points in the liraglutide group. Some 78% of IDegLira users—but only 63% of insulin users and 57% of liraglutide users—got A1C levels below 7%. When investigators compared IDegLira users to insulin degludec users, they found that IDegLira users, on average, took less daily insulin (39 units vs 62 units), lost an additional 2.8 kg body weight, and suffered 37% less hypoglycemia.

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