Glycemic variability, hypoglycemia linked to poor outcomes in type 2 diabetes patients
medwireNews: Two secondary analyses of the DEVOTE trial suggest that type 2 diabetes patients with high day-to-day fasting glycemic variability and those who experience severe hypoglycemia are at increased risk for adverse outcomes.
The phase III DEVOTE trial, which found that insulin degludec has equivalent cardiovascular safety to that of insulin glargine and reduces hypoglycemia risk in patients with type 2 diabetes, “provides a valuable opportunity” to investigate associations between glycemic control and outcomes such as cardiovascular events and mortality, say the investigators.
The secondary analyses were presented at the EASD annual conference in Lisbon, Portugal, and published simultaneously in Diabetologia.
In the first study, DEVOTE 2, Bernard Zinman (University of Toronto, Ontario, Canada) and colleagues categorized the trial participants by their degree of glycemic variability, based on the standard deviation of pre-breakfast blood glucose measurements, and found that the risk for severe hypoglycemia and mortality increased with increasing glycemic variability.
In all, 3.28% of 2528 participants with low glycemic variability experienced severe hypoglycemia over a median follow-up of 1.99 years, compared with 4.58% of 2530 patients with medium variability and 9.38% of 2528 with high variability, giving corresponding rates of 1.69, 2.38, and 5.00 per 100 person–years.
Similarly, 4.55%, 5.18%, and 6.76% of patients in the low, medium, and high glycemic variability groups died from any cause over the follow-up period, translating into rates of 2.30, 2.61, and 3.40 per 100 person–years, respectively.
When a patient’s day-to-day fasting glycemic variability doubled, they had a 2.7-fold increased risk for severe hypoglycemia and a 1.4-fold increased risk for mortality, and these relationships remained significant after adjustment for HbA1c levels and baseline characteristics, report Zinman and co-authors.
The team also identified an elevated risk for major adverse cardiovascular events with increasing glycemic variability, but this association was not significant in the fully adjusted analysis.
These findings “raise the possibility that there are some patients who are more susceptible to severe hypoglycaemia because they are unable or unwilling, for a variety of reasons, to appropriately modify their insulin dose to reduce their fasting glycaemic variability,” say the researchers.
“On this basis, 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,” they conclude.
The second study, DEVOTE 3, found that participants with severe hypoglycemia had a greater risk for death than those who did not experience severe hypoglycemia, particularly in the short term.
Of the 423 patients who died from any cause, 8.98% died after experiencing a severe hypoglycemic event. Those who experienced severe hypoglycemia at any time during the study period were 2.51 times as likely to die as those who did not have hypoglycemia, rising to a 3.66-fold increased risk within the first 30 days of having a hypoglycemic episode, and to a 4.20-fold increased risk in the first 15 days.
“The results from these analyses add to the evidence for an association between severe hypoglycaemia and mortality,” say Thomas Pieber (Medical University of Graz, Austria) and fellow researchers.
However, study co-author Neil Poulter (Imperial College London, UK) pointed out in his presentation at the EASD meeting that “there may be confounding by frailty” for the observed associations in the DEVOTE study, in which approximately 10% of the participants were aged 75 years or older. Frailty is associated with hypoglycemia, glycemic variability, and adverse outcomes, he explained.
Furthermore, he noted that “the direction of the interrelationships cannot be proven from the data shown.”
And the author of an accompanying commentary in Diabetologia, Martin Rutter (University of Manchester, UK), concludes that taken together, the results of the DEVOTE 2 and DEVOTE 3 studies “raise awareness of the mortality risks associated with glucose variability and severe hypoglycaemia in high-risk insulin-treated patients with type 2 diabetes but they do not clarify causal relationships.”
He adds: “Only the results of further clinical trials can genuinely guide physicians on whether to target glucose variability and risk for severe hypoglycaemia to reduce the risks for CVD events and mortality in these individuals.
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