Could SWITCHing to Insulin Degludec Thwart Hypoglycemia?

Marlene Busko

July 03, 2017

In two phase 3b crossover trials, adults with diabetes had fewer episodes of overall, nocturnal, and severe hypoglycemia when they were receiving daily injections of U-100 insulin degludec (Tresiba, Novo Nordisk) than when they were using daily injections of U-100 insulin glargine (Lantus, Sanofi).

The SWITCH 1 study by Wendy Lane, MD, from the Mountain Diabetes and Endocrine Center, in Asheville, North Carolina, and colleagues randomized 501 patients with type 1 diabetes to these two treatment options, and the SWITCH 2 study by Carol Wysham, MD, from the University of Washington, in Spokane, and colleagues, randomized 721 patients with type 2 diabetes to the same therapy options.  

The two studies are published in the July 4 issue of the Journal of the American Medical Association.

They provide "a rare head-to-head comparison of hypoglycemia rates between two commercially available insulin products," Elizabeth R Seaquist, MD, and Lisa S Chow, MD, from the University of Minnesota, Minneapolis, write in an accompanying editorial.

Both types of insulin are used as the basal component of insulin regimens, but insulin degludec has a longer half-life than insulin glargine U-100 (25.4 hours vs 12.1 hours), a flatter insulin action curve, and less variability, they observe.

But do their findings "justify the recommendation of insulin degludec over insulin glargine U-100 in patients with type 1 diabetes or type 2 diabetes at risk for hypoglycemia?" they ask rhetorically.

The trials have certain caveats, they note. Nevertheless, "despite these concerns, the SWITCH 1 and SWITCH 2 studies show that insulin degludec has lower rates of hypoglycemia than insulin glargine U-100."

Thus, "given the risks associated with hypoglycemia and the negative consequences that concern about hypoglycemia has for patients and their families, any basal insulin associated with a reduced rate of hypoglycemia would seem to represent an advance in therapy," they cautiously conclude.

SWITCH 1 and SWITCH 2 Summaries

As previously reported by Medscape Medical News, the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE), which was presented at the recent American Diabetes Association (ADA) 2017 Scientific Sessions and simultaneously published in the New England Journal of Medicine, demonstrated that insulin degludec has a safe cardiovascular profile.

The SWITCH trials aimed to determine whether insulin degludec was noninferior or superior to insulin glargine in reducing the rate of symptomatic hypoglycemic episodes (the primary outcome) and nocturnal and severe hypoglycemia (the two secondary outcomes).

A symptomatic hypoglycemic episode was defined as a severe hypoglycemic episode (that required assistance) or where blood-glucose was <56 mg/dL.

The patients received one type of insulin for 16 weeks of titration and 16 weeks of maintenance, followed by the other type of insulin for 16 weeks of titration and 16 weeks of maintenance.

In SWITCH 1, patients with type 1 diabetes who received insulin degludec had an 11% reduction in the rate of symptomatic hypoglycemia, a 36% reduction in the rate of nocturnal hypoglycemia, and a 35% drop in severe hypoglycemia during the maintenance phase, compared with patients who received insulin glargine.

In SWITCH 2, the benefits seemed to be somewhat greater in patients with type 2 diabetes who received insulin degludec — they had a 30% reduction in the rate of symptomatic hypoglycemia, a 42% fall in the rate of nocturnal hypoglycemia, and a 51% reduction in severe hypoglycemia during the maintenance phase, compared with patients who were receiving insulin glargine.

Strengths, Caveats, and Insurance Coverage Issues

These studies have several strengths, including the crossover, double-blind design, according to Drs Seaquist and Chow.

Adverse events, weight gain, and glycemic control were comparable with the two types of basal long-acting insulin, they note. "Yet several caveats need to be considered," they caution.

Trial limitations include the high dropout rate (roughly 20%), although the completers and noncompleters had similar characteristics.

In addition, because the SWITCH 1 and SWITCH 2 studies did not count asymptomatic episodes with glucose less than 56 mg/dL as hypoglycemia, it will be difficult to compare results with future trials, they observe.

Insulin was titrated using a set protocol that probably exceeds common clinical practice, "so cautious clinicians may want to see the results of a more pragmatic trial," Drs Seaquist and Chow add.

Also, the studies were funded by Novo Nordisk, the manufacturer of insulin degludec, although the design and implementation helped reduce the risk of bias.

And the results may not be generalizable to insulin glargine U-300 or other alternative basal insulins.

Last, "insurance coverage and affordability are a critical component in the choice of basal insulin," Drs Seaquist and Chow observe.

Indeed, the senior investigator of the DEVOTE trial, John B Buse, MD, PhD, of the University of North Carolina School of Medicine, Chapel Hill, made just that point to Medscape Medical News at the ADA meeting.

In the United States, there has been an uproar about the cost of insulin, and Dr Buse said that, as a clinician, he's in the dark.

"I don't know how the cost compares.…I really don't know. This unsophisticated conversation about price is a waste of time. At least in the US, there is no price. The decision making is all by pharmacy benefits managers. They decide if Tresiba is available, or Lantus is available, or Basaglar, or Toujeo — they tell you which one's available….Sometimes you've got one choice, sometimes you've got no choice."

The trial was sponsored by Novo Nordisk. Dr Lane has served on speaker and advisory panels for Novo Nordisk and Insulet; she has also served as an author for Novo Nordisk and received research funds from Novo Nordisk, Insulet, and Eli Lilly. Dr Wysham reported receiving research support from and serving on advisory panels or speaker's bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; receiving personal fees and nonfinancial support from Insulet; and serving as a consultant for Eli Lilly. Disclosures for the coauthors are listed in the papers. Dr Seaquist reported being the principal investigator on two projects funded by Eli Lilly; serving as a consultant for Eli Lilly, Locemia, Medtronic, Sanofi, and Zucera; serving as a member of the International Hypoglycemia Study Group; and serving on the examination committee for the American Board of Internal Medicine. Dr Chow reported being a coinvestigator on a project funded by Eli Lilly.

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JAMA. 2017;318:31-32, 33-44, 45-56. SWITCH 1 article, SWITCH 2 article, Editorial



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