'Most Powerful' Combo for Type 2 Diabetes Fulfills Promise

September 12, 2014

New research published in the Lancet suggests that a combination of an injectable glucagonlike peptide-1 (GLP-1) agonist with basal insulin may be an excellent treatment option in patients with type 2 diabetes, resulting in robust blood glucose control with no increased hypoglycemia or weight gain.

The combination offers great potential due to the complementary effects of the 2 agents, explain Conrad Eng, MSc, of the Leadership Sinai Centre for Diabetes, Toronto, Ontario, and colleagues in their paper published online September 12.

Senior author Ravi Retnakaran, MD, also of the Leadership Sinai Centre for Diabetes, explained that there has been a "flurry of recent trials that have come out suddenly" studying combinations of these 2 therapies. He and his colleagues therefore decided to perform a meta-analysis. Of the 15 trials they included, the first few were conducted in 2011, but "9 or 10 are from 2014, and the majority from the past 3 months," he noted.

In their analysis, they found the combination resulted in a reduction in HbA1c, improved likelihood of achieving the target HbA1c of 7.0% or lower, no increased relative risk for hypoglycemia, and a reduction in weight compared with other antidiabetic therapies.

"We found the combination of GLP-1 agonist and basal insulin has fulfilled the promise ascribed to it," Dr. Retnakaran told Medscape Medical News.

Coauthor of an accompanying comment, John B. Buse, MD, of the University of North Carolina School of Medicine, Chapel Hill, told Medscape Medical News that the 2 agents, GLP-1 agonists and basal insulin, "individually are arguably the 2 most powerful agents we have for type 2 diabetes.

The net-net-net of all this is that you have, run away, the most effective treatment ever marketed in diabetes....It's a pretty remarkable combination. Dr. John B. Buse

"When you combine them, you pretty much eliminate the adverse effects of each; whether that is because the dose is advanced very slowly, or you use less of one, or they really do counteract each other in a number of important places is unclear," he added."But the net-net-net of all this is that you have, run away, the most effective treatment ever marketed in diabetes, with really minimal risk of hypoglycemia, no weight gain, and minimal gastrointestinal adverse effects. It's a pretty remarkable combination."

However, a major barrier to widespread adoption of this treatment combination is likely to be cost, notes Dr. Buse. "Both GLP-1 agonists and insulin analogs are among the most expensive [agents] in diabetes care," he writes in the comment, along with coauthor Laura A. Young, MD, also of the University of North Carolina School of Medicine.

As well as the option of giving the 2 therapies separately, fixed-dose combination products are in development. The closest to market is Novo Nordisk's Xultophy (formerly known as IDegLira), a fixed-dose combination of the basal insulin analog degludec (100 U/mL) and GLP-1 agonist liraglutide (3.6 mg/mL), which was recommended for approval in the European Union in July. It's not yet clear how the product will be priced.

Dr. Retnakaran agreed that the expense of these agents is a concern but noted that GLP-1 agonists are a new class, and "so cost should improve over time."

Combo Patients Almost Twice as Likely to Reach Target HbA1c

Dr. Retnakaran explained that patients with type 2 diabetes typically start treatment with metformin and progress to other oral antidiabetic agents or injectable GLP-1 agonists before basal insulin is eventually added if glycemic control is not achieved.

Following this come more complex regimens, with the addition of prandial or bolus insulin. Finally, basal–bolus regimens, whereby patients take basal insulin once or twice daily and bolus insulin before each meal, are typically last in the therapeutic progression of type 2 diabetes.

For some years there has been interest in combining GLP-1 agonists — typically used as second- or third-line agents after the failure of 1 or more oral antidiabetic drugs — with basal insulin, he noted; hence, the flurry of recent trials.

In their meta-analysis, 15 studies that compared a GLP-1 agonist and basal insulin combination treatment with other antidiabetic therapies involving 4348 participants were included. The main end points were glycemic control, hypoglycemia, and weight change.

Compared with the other antidiabetic treatments, GLP-1 agonist/basal insulin combination treatment yielded a mean reduction in HbA1c of 0.44%, an improved likelihood of achieving the target HbA1c of 7.0% or lower (relative risk [RR], 1.92), no increased relative risk of hypoglycemia (RR 0.99), and a mean reduction in weight of 3.22 kg.

Furthermore, compared with basal–bolus insulin regimens, the combination treatment yielded a mean reduction in HbA1c of 0.1%, with a lower relative risk of hypoglycemia (RR, 0.67), and reduction in weight (5.66 kg).

Can the Combo Alter the Natural History of Diabetes?

The Canadian physicians recognize the limitations of their work, which include the short-term nature of the studies (maximum 24 weeks) and the fact that there were differences in the GLP-1 agonists used across the trials (some were short-acting, twice-daily formulations; others were intermediate, once-daily ones; and others were longer-acting, once-weekly agents).

In addition, the ideal timing for beginning this combination treatment in the course of type 2 diabetes remains unknown, they add.

Dr. Retnakaran explained that the patients included in the meta-analysis had an average duration of diabetes of 12 years. "In all these trials, intervention was late, but this is a very impressive therapeutic effect." Curious to know what will happen with earlier intervention, Dr. Retnakaran and his colleagues are planning such a trial, called PREVAIL.

In the meantime, although further studies are needed "to establish the optimal approach to the application of this treatment in practice, our findings clearly lend support to the use of GLP-1 agonists in combination with basal insulin in the clinical management of patients with type 2 diabetes," they conclude.

Will Fixed-Dose Combos Supersede Other Approaches?

In their editorial, Drs. Young and Buse say several questions remain.

"Do shorter-acting GLP-1 agonists with their unparalleled efficacy on postprandial glucose provide unique advantages over long-acting GLP-1 agonists combined with basal insulin? There are no adequate trials to answer this question, but it seems that the differences are probably small."

A second issue tangential to this meta-analysis is "whether there is a role for long-acting GLP-1 agonists combined with prandial insulin (injected or inhaled)," they note.

"Perhaps the most practical and immediate issue is whether the fixed-dose combinations of a GLP-1 agonist and basal insulin in development will supersede other approaches," they observe.

"This is an unsettled question, but it seems likely that fixed-dose combinations will be welcomed in view of their convenience and efficacy." And although expense is still a bugbear, "One can hope that some incremental cost savings will come with combined products," they comment.

As well as the liraglutide/insulin degludec product Xultophy (Novo Nordisk), a lixisenatide/insulin glargine fixed-dose combination, LixiLan, is being developed by Sanofi. Both of these products, however, are unlikely to make it to the US market any time soon because insulin degludec and lixisenatide are not yet approved in the United States.

Drs. Young and Buse conclude: "It has been a 20-year journey, but the combination of GLP-1 agonist and basal insulin has finally arrived as a more powerful and safer alternative to insulin in the management of type 2 diabetes."

Dr. Retnakaran reports receiving grants and personal fees from Novo Nordisk and Merck, all outside the submitted work. Disclosures for other authors are listed in the paper. Dr. Buse is an investigator or consultant without direct financial benefit under contracts between his employer and the following companies: Amylin, Andromeda, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dance Biopharm, Elcelyx Therapeutics, Eli Lilly, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, Hoffmann-La Roche, Intarcia Therapeutics, Johnson & Johnson, Lexicon, LipoScience, Medtronic, Merck, Metavention, Novo Nordisk, Orexigen Therapeutics, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Quest Diagnostics, Sanofi, Santarus, Scion NeuroStim, Takeda, Tolerx, and TransTech Pharma. He is also a consultant to PhaseBio Pharmaceuticals and receives stock options and payments.

Lancet Diabetes Endocrinol. Published online September 12, 2014. Abstract, Comment


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