AT EASD 2017

LISBON – Avoiding glycemic variability and severe hypoglycemia could be important in reducing the mortality risk in people with type 2 diabetes mellitus who are at high risk of cardiovascular disease and are being treated with insulin, new findings from a phase 3 study suggest.

A second wave of results from the DEVOTE study, which compared the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) versus insulin glargine, found that day-to-day variability in fasting plasma glucose (FPG) versus no FPG variability was significantly associated with both severe hypoglycemia (adjusted hazard ratio, 3.37; 95% confidence interval, 2.52-4.50; P less than .001), and all-cause mortality (aHR, 1.33; 95% CI, 1.01-1.75; P = .00432).

In addition, severe hypoglycemia was linked to all-cause mortality, with a temporal relationship seen such that the risk for death was higher the more recent the episode of severe hypoglycemia had been. Indeed, while the risk of death was 2.5 times higher at any time after an episode of severe hypoglycemia than if no prior severe hypoglycemia occurred (HR, 2.51; 95% CI, 1.35-13.09), it was four times higher 15 days after severe hypoglycemia than after no such event (HR, 4.20; 95% CI, 1.9-3.50).

These results of DEVOTE 2 and DEVOTE 3 were presented at the annual meeting of the European Association for the Study of Diabetes and published in Diabetologia on Sept. 15.

What do the results mean for current practice?

“There’s great interest in knowing whether glucose variability and severe hypoglycemia are associated with cardiovascular risk and mortality; these data are therefore important and timely,” said the invited commentator and editorialist for the study Martin Rutter, MD, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England.

“Taken together, DEVOTE 2 and DEVOTE 3 raise awareness of the mortality risk associated with glucose variability and severe hypoglycemia, but they can’t clarify a causal relationship,” Dr. Rutter observed. He suggested it was “premature” to target either on the basis of the current findings; these were observational data.

“Only further clinical trials can genuinely guide clinicians on whether to target glucose variability and risk for severe hypos to reduce the risk of cardiovascular events in people with type 2 diabetes. My hope is that these data will help to build a case for such trials,” Dr. Rutter said.

DEVOTE: main findings and secondary analyses

The main findings from the DEVOTE study were reported in June during the American Diabetes Association’s Annual Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017 Aug 24;377[8]:723-32). These showed that insulin degludec was noninferior to insulin glargine, with a similar rate of major cardiovascular events (MACE), which comprised nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (8.5% vs. 9.3%; HR, 0.91; 95% CI, 0.78-1.06; P less than .001). The rate of severe hypoglycemia was significantly (P less than .001) lower in the degludec than glargine arm, however, occurring in a respective 4.9% and 6.6% of patients in each group (odds ratio, 0.73).

“DEVOTE confirms the cardiovascular safety of insulin degludec, compared with glargine,” said DEVOTE study investigator, Neil Poulter, MD, FMedSci, of the Imperial Clinical Trials Unit at Imperial College London. “The rate of severe hypoglycemia was significantly reduced [with insulin degludec vs. glargine] in the DEVOTE trial.”

Dr. Poulter observed that “DEVOTE is consistent with data demonstrating an association between severe hypoglycemia and mortality” and that glycemic variability was significantly associated with severe hypoglycemia as well as all-cause death.

Role of glycemic variability

“It is well established that there is a relationship between glycemic variability and hypoglycemia,” said Bernard Zinman, MD, director of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, who presented the DEVOTE 2 findings. He commented that the “very dense data” collected during the main study had enabled a fuller analysis of glycemic variability. Dr. Zinman was keen to emphasize that it was the fasting variability that was studied.

Dr. Zinman noted that the day-to-day glycemic variability seen among the DEVOTE trial participants could be divided into three tertiles and that the baseline characteristics of each group varied. Participants with low glycemic variability tended to have shorter duration of diabetes versus those with medium to high variability (14 vs. 16 vs. 18 years, respectively). There were also increasing baseline levels of HbA1c, FPG, and reducing renal function.

Looking at outcomes, there was a dose relationship seen from low to high glycemic variability with increasing rates of severe hypoglycemia, MACE, and all-cause mortality the higher the variability, Dr. Zinman reported.

Although initially there was an increased risk for MACE with increasing glycemic variability, “the association was not maintained after adjusting for baseline characteristics and the most recent A1c,” Dr. Zinman said.

Timing of severe hypoglycemia could be vital

Severe hypoglycemia is under-reported and there is still concern over inducing hypoglycemia, which “conflicts with treatment success,” observed Thomas Pieber, MD, who presented the DEVOTE 3 findings on the relationship between severe hypoglycemia and outcomes.

Dr. Pieber, who is professor of medicine and chair of the departments of internal medicine and of endocrinology and diabetes at the Medical University of Graz (Austria), cited survey data showing people with diabetes, both type 1 and type 2, modifying their doses of insulin following a hypoglycemic episode, more so if the episode is severe.

“Up to 80% of us are concerned about the risk of hypoglycemia and we are not treating glycemic control as aggressively as we would do if there was not any worry about hypoglycemia,” Dr. Pieber said, referring to primary care physicians and diabetes specialists.

Talking about the DEVOTE 3 results, Dr. Pieber noted: “There was no significant association between severe hypoglycemia and MACE, but there was a significantly higher risk of cardiovascular death following a severe hypoglycemia event.” He reminded the audience that an episode of severe hypoglycemia was one which required the assistance of another person, as defined by International Hypoglycemia Study Group which has been acknowledged by both the ADA and EASD.

“These data we have analyzed support a temporal relationship between severe hypoglycemia and all-cause mortality,” Dr. Pieber, adding “the findings indicate that severe hypoglycemia is associated with higher subsequent mortality.”

Predicting severe hypos

“There are well-known factors that influence the risk of having a severe hypoglycemic event,” commented another of the DEVOTE study investigators, John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill. These include the insulin treatment regimen, the duration of diabetes, sex, and baseline HbA1c, to pick the more traditional ones. Additional ones that a post-hoc analysis of the DEVOTE data identified are baseline renal function, prior stroke, low-to-high-density lipoprotein ratio, diastolic blood pressure, hepatic impairment, and smoking status. Age, another traditional risk factor, was identified as well and all these went in to create the DEVOTE severe hypoglycemia risk prediction model.

“The DEVOTE severe hypoglycemia risk score was developed to identify patients at high risk of severe hypoglycemia,” Dr. Buse said. Such patients need extra attention and support from physicians, he proposed, and using the score can help identify those that are at risk and subsequent risk for MACE and all-cause mortality.

The DEVOTE hypoglycemia risk score is currently a work in progress; the app can be seen at http://www.hyporiskscore.com/. DEVOTE was funded by Novo Nordisk. Slides presented at the EASD meeting are available for download at https://tracs.unc.edu/DEVOTE.

Dr. Rutter disclosed receiving honoraria and funding to attend educational meetings from Novo Nordisk and honoraria and consulting fees from Ascensia, Cell Catapult, and Roche Diabetes Care.

Dr. Poulter has received speaker fees and consultancy fees from Novo Nordisk, Servier, Takeda, and AstraZeneca; and grants for his research group relating to type 2 diabetes mellitus from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, and the Julius Clinical and the British Heart Foundation.

Dr. Zinman has received grant support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. He disclosed receiving consulting fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Sharp & Dohme, and Sanofi.

Dr. Pieber disclosed receiving received research support from Novo Nordisk and AstraZeneca paid directly to his institution and personal honoraria from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Roche Diabetes Care. Dr. Pieber is the Chief Scientific Officer of the Center for Biomarker Research in Medicine, a publicly funded biomarker research company.

Dr. Buse reported receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly and Company, GI Dynamics, Elcelyx, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzhen High Tide, Fractyl, and Dexcom. He has also received consultancy fees and grant support from Eli Lilly and Company, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos, and Bayer. Dr. Buse has also received fees and holds stock options in PhaseBio and Insulin Algorithm, as well as serving on the board of the AstraZeneca Healthcare Foundation.

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Fasting glucose fluctuations, severe hypoglycemia up T2DM death risk