Conference Coverage

Fasting glucose fluctuations, severe hypoglycemia up T2DM death risk


Key clinical point: Evenly maintained blood glucose levels may save lives in T2DM.

Major finding: Patients with greater fluctuations of fasting plasma glucose were more likely to die than were those with more episodes of severe hypoglycemia.

Data source: Further analysis of data from both DEVOTE 2 and DEVOTE 3, involving 7,637 patients with type 2 diabetes who were treated with either insulin degludec or insulin glargine.

Disclosures: The study was funded by Novo Nordisk. All presenters have received consulting fees from Novo Nordisk among other pharmaceutical companies. Two presenters (Dr. Zinman and Dr. Pieber) also disclosed receiving research support from the company.


AT EASD 2017

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.

Dr. Martin Rutter, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England. Susanne Wysocki/EASD 2017
Dr. Martin Rutter
“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. Neil Poulter, Imperial Clinical Trials Unit at Imperial College London (England) Sara Freeman/Frontline Medical News
Dr. Neil Poulter
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. Bernard Zinman, director of the Lunenfield-Tanerbaum Research Institute at Mount Sinai Hospital in Toronto Sara Freeman/Frontline Medical News
Dr. Bernard Zinman
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.

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