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DEVOTE: Hypoglycemia, glycemic variability increase mortality risk in type 2 diabetes
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In adults with type 2 diabetes, higher day-to-day fasting glycemic variability and severe hypoglycemia are independently associated with all-cause mortality, according to two secondary analyses from the DEVOTE trial presented at the European Association for the Study of Diabetes Annual Meeting and published simultaneously in Diabetologia.
“The results from the new analyses reported here demonstrate an association between severe hypoglycemic events and a higher risk for all-cause mortality in the overall DEVOTE population,” Thomas R. Pieber, MD, of the division of endocrinology and metabolism at the University of Graz in Austria, and colleagues wrote. “In addition, the DEVOTE data suggest that an elevated risk of a fatal event might persist for many weeks and months after a severe hypoglycemic event, although the highest risk appears to be in the shorter time periods.”
The DEVOTE study, a randomized, double-blind, treat-to-target, event-driven, cardiovascular outcomes trial, included 7,637 patients with type 2 diabetes enrolled at 436 sites in 20 countries between October 2013 and November 2014. Researchers randomly assigned 3,818 patients to insulin degludec 100 U/mL (Tresiba, Novo Nordisk), a new-generation, ultra-long-acting basal insulin, and 3,819 to insulin glargine 100 U/mL (Lantus, Sanofi), a first-generation insulin, once per day between dinner and bedtime.
Patients enrolled were at high risk for CV events. At the beginning of the study, 85% had established CVD, chronic kidney disease or both. The mean age at baseline was 65 years, mean diabetes duration was 16 years and mean HbA1c was 8.4%.
The primary composite outcome was first occurrence of a major CV event, including death from CV causes, nonfatal myocardial infarction or nonfatal stroke. The secondary outcome was severe hypoglycemia. Patients were followed for approximately 2 years.
Glycemic variability and hypoglycemia
In DEVOTE 2, researchers assessed the associations between day-to-day glycemic variability (determined by pre-breakfast self-monitoring blood glucose) and severe hypoglycemia and CV outcomes. Each month, three pre-breakfast SMBG measurements were used to determine a day-to-day glycemic variability measure for each patient. Associations for the pooled trial population were analyzed with Cox proportional hazard models, with adjustments for baseline characteristics and most recent HbA1c.
In unadjusted analyses, researchers found that day-to-day fasting glycemic variability was associated with severe hypoglycemia (HR = 4.11; 95% CI, 3.15-5.35), major adverse cardiac events (HR = 1.36; 95% CI, 1.12-1.65) and all-cause mortality (HR = 1.58; 95% CI, 1.23-2.03). The relationships between day-to-day variability, severe hypoglycemia and all-cause mortality persisted after adjustment for baseline characteristics and most-recent HbA1c value, but the association with major adverse cardiac events was no longer significant, according to researchers.
“The findings from the current study provide further support for the concept that patients requiring insulin might benefit from treatment with a basal insulin that has low day-to-day variability and hence provides consistent fasting blood glucose levels,” the researchers wrote.
Hypoglycemia and mortality
In DEVOTE 3, researchers assessed the association between severe hypoglycemia and major adverse cardiac events and all-cause mortality in the pooled trial population using time-to-event analyses, with severe hypoglycemia as a time-dependent variable and randomized treatment as a fixed factor.
In the pooled population, researchers found participants who experienced a severe hypoglycemic event at any time were more than twice as likely to die of any cause vs. those who did not experience a severe hypoglycemic event (HR = 2.51; 95% CI, 1.79-3.5). When dividing the time after a severe hypoglycemic event, researchers observed a higher risk for all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycemia compared with not experiencing severe hypoglycemia in the same time interval.
“The risk appeared to be highest in the shorter-term windows and decreased with the longer-term windows, but remained significant for all,” the researchers wrote.The relationship persisted after adjustment for baseline characteristics.
Pieber said the findings from DEVOTE 3 support a “temporal relationship” between severe hypoglycemia and all-cause mortality.
“Severe hypoglycemia in patients with type 2 diabetes is more common and more dangerous than often anticipated,” Pieber told Endocrine Today. “Severe hypoglycemia is associated with adverse outcomes, thus, therapeutic measures to reduce that risk become increasingly important.”
Most fatal events were ascribed to non-CV causes (n = 17), and the remainder to CV causes (n = 14) or other causes (n = 7).
In commentary accompanying the two studies, Martin K. Rutter, MD, FRCP, senior lecturer and honorary consultant physician at the University of Manchester, U.K., said the findings of DEVOTE 2 and DEVOTE 3 raise awareness of the mortality risks associated with glucose variability and severe hypoglycemia in high-risk insulin-treated patients with type 2 diabetes, but they do not clarify casual relationships.
“Only the results of further clinical trials can genuinely guide physicians on whether to target glucose variability and risk for severe hypoglycemia to reduce the risk for CVD events and mortality in these individuals,” Rutter wrote. – by Regina Schaffer
Reference:
Insulin degludec vs. glargine: cardiovascular safety in type 2 diabetes: the DEVOTE study. Presented at: European Association for the Study of Diabetes Annual Meeting, Sept. 11-15, Lisbon, Portugal.
Pieber TR, et al. Diabetologia. 2017;doi:10.1007/s00125-017-4422-0.
Rutter MK. Diabetologia. 2017;doi: 10.1007/s00125-017-4421-1.
Zinman B, et al. Diabetologia. 2017;doi:10.1007/s00125-017-4423-z.
Disclosures: Novo Nordisk sponsored and funded the DEVOTE trial. Zinman reports he has received grant support from AstraZeneca, Boehringer Ingelheim and Novo Nordisk, and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. Pieber reports he has received research support from AstraZeneca and Novo Nordisk, and consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novo Nordisk and Roche Diabetes Care. Rutter reports he received honoraria and funding to attend educational meetings from Ascensia, Cell Catapult, Novo Nordisk and Roche Diabetes Care. Please see the studies for all other authors’ relevant financial disclosures.