DEVOTE: Tresiba as Safe as Glargine With Less Severe Hypoglycemia

June 12, 2017

SAN DIEGO — For the treatment of type 2 diabetes, the ultra-long–acting, once-daily basal insulin degludec (Tresiba, Novo Nordisk) is as safe in cardiovascular terms as insulin glargine and is associated with much lower rates of severe hypoglycemia, new data confirm.

Full results from the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) were reported by a number of investigators here at the American Diabetes Association (ADA) 2017 Scientific Sessions and were simultaneously published in the New England Journal of Medicine, with lead author Steven P Marso, MD, of the Research Medical Center, Kansas City, Missouri.

The top-line results of DEVOTE had already been reported by the company in November last year, and it recently applied to the Food and Drug Administration (FDA) to update the Tresiba label with these data.

Dr John B Buse

"For me, this is a robust demonstration of the cardiovascular safety of degludec — and a dramatic and unimpeachable demonstration of the relatively lower rate of severe hypoglycemia" with degludec compared with glargine, senior investigator of DEVOTE, John B Buse, MD, PhD, of University of North Carolina School of Medicine, Chapel Hill, told Medscape Medical News.

"The former is of regulatory significance and the latter is of meaningful clinical significance," he added.

The number of patients who would need to be treated with degludec rather than glargine to avert one severe hypoglycemic event was 40, the DEVOTE paper indicates.

Hypoglycemia: What's the Significance?

"There's always been this theory, demonstrated over and over again, that severe hypoglycemia is a big risk for subsequent cardiovascular events," Dr Buse explained to Medscape Medical News. "Whether it's related to the fact that the people who have severe hypoglycemia are also people who have cardiovascular events — because they are frail and have lots of comorbidities — or whether there is a causal relationship is still uncertain."

Asked by Medscape Medical News why — if there is a relationship between hypoglycemia and CVD — would he not have expected the rate of CVD to be significantly lower with degludec than with glargine in DEVOTE, Dr Marso said: "The short answer is no. There may well be a causal relationship between hypoglycemia and CV mortality, but in my opinion, if true, it's a small part of what drives cardiovascular events in people with diabetes.

"As cardiologists, we tend to be focused on the [atherosclerotic] plaque, I think too much focused, and I think in the diabetes world they tend to be too much focused on the hypoglycemia, and I think it's going to be much more complicated than just one or the other."

Meanwhile, discussant of the trial at ADA, Elizabeth R Seaquist, MD, from the University of Minnesota, Minneapolis, said there remain some unanswered questions in DEVOTE.

For instance, "data on moderate hypoglycemia were not collected, so the impact on the most common type of hypoglycemia experienced by patients cannot be addressed," she observed. And data were not collated on events when blood glucose was 54 mg/dL (3mmol/L) or lower, "so impact on the development of impaired awareness of hypoglycemia" again could not be assessed, she noted.

And finally, because investigators in DEVOTE could modify the titration process based on clinical judgment, "it isn't clear if this modification process was applied equally in both arms." Any differential application of this process could have affected the hypoglycemia outcomes.

DEVOTE Details

The US FDA insisted that Novo Nordisk conduct the DEVOTE trial before it would approve insulin degludec, despite the fact that the product was already approved in the European Union. In the end, the US agency approved insulin degludec in November 2015 on the basis of interim results from DEVOTE.

In the trial, 7637 patients with type 2 diabetes were randomized to receive either insulin degludec (n = 3818) or insulin glargine U100 (n = 3819) once daily between dinner and bedtime in a double-blind, treat-to-target fashion.

Dr Buse explained that insulin glargine was chosen as the comparator insulin because of the ORIGIN trial, which indicated no increased risk of cardiovascular events with glargine, "so that's why we picked it as a comparator."

Of the patients in DEVOTE, 85.2% had established cardiovascular disease, chronic kidney disease, or both. Mean age was 65 years, the mean duration of diabetes was 16.4 years, and mean HbA1c was 8.4%

The primary composite outcome was the first occurrence of an adjudicated major cardiovascular event (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke). Severe hypoglycemia, as defined by the ADA, was the prespecified secondary outcome.

The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% CI, 0.78 — 1.06; < .001 for noninferiority).

At 2 years, the mean HbA1c was 7.5% in each group, but the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128 vs 136 mg/dL; < .001).

Severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; < .001 for superiority).

Rates of adverse events did not differ between the two groups.

Is Insulin the Right Treatment for Type 2 Diabetes?

It is almost impossible to assess how the cost of different insulins compare with each other, both within one country and from country to country.

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 and you get to pick. Sometimes you've got one choice, sometimes you've got no choice," he told Medscape Medical News.

"NPH [human insulin] at Walmart is $25 a bottle without a prescription," he added. "It's a hell of a lot better than nothing. It's actually pretty good. I do not think these new insulins are 10 times better — they are probably twice as good."

He also questions whether insulin is even "the ideal drug" for the treatment of type 2 diabetes. "It's probably not. It is an acceptable drug, its cardiovascular safety is well established, but it's not empagliflozin, it's not liraglutide."

Follow Lisa Nainggolan on Twitter: @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

N Engl J Med. Published online June 12, 2017. Article

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