medwireNews: A high rate of nonsevere hypoglycemic episodes is associated with risk for severe hypoglycemia, major adverse cardiovascular events (MACE), and mortality in people with type 2 diabetes, shows an analysis of LEADER data.
“We would argue strongly that, whatever the underlying driver of the link between [cardiovascular disease] and hypoglycaemia, it is important that healthcare professionals and patients take steps to reduce this common complication of treatment,” say Simon Heller (University of Sheffield, UK) and study co-authors in Diabetologia.
In LEADER, the cardiovascular outcomes trial for liraglutide, more than 80% of the 9340 participants had pre-existing cardiovascular disease.
“The current findings therefore mainly apply to a secondary prevention population, who are at high risk of recurrent cardiovascular events,” caution the researchers.
During the trial, three-quarters of participants had fewer than two nonsevere hypoglycemic episodes per year. But 20.5% had between two and 11 episodes and 4.2% had 12 or more. People in the latter group had a longer duration of diabetes than other participants and were more frequently using insulin.
Relative to people with fewer than two nonsevere hypoglycemic events, the risk for severe hypoglycemic events was elevated a significant 1.61-fold in those with two to 11 events and 3.59-fold in those with 12 or more events. These associations were independent of baseline variables including renal function.
The risk for MACE (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) cardiovascular mortality, and all-cause mortality were not increased in people with two to 11 nonsevere hypoglycemic events, but were significantly elevated in those with 12 or more events. This was independent of baseline variables with the exception of renal function, at respective 1.51-, 2.00- and 1.76-fold increases.
All these associations lost statistical significance after further adjustment for renal function, which the researchers say “could be due to shared vulnerabilities in people with chronic kidney disease for hypoglycaemia and adverse cardiovascular events.”
Removing people who experienced a severe hypoglycemic event from the analysis abolished the association between nonsevere events and MACE, indicating this association was partly mediated through severe hypoglycemic events.
Yet the association with cardiovascular death remained, and the team notes that some elements of the hypoglycemia response, such as pro-thrombotic and inflammatory effects, could be causally linked to cardiovascular outcomes.
In the absence of a randomized trial that could settle the issue – “neither possible nor ethical” – the researchers conclude that existing “evidence supports the hypothesis that hypoglycaemia is both a risk marker and risk factor for cardiovascular events.”
They add: “Furthermore, independent of causality, reducing the risk of any hypoglycaemia by lifestyle intervention or pharmacological solutions will benefit individuals using insulin, including those at high cardiovascular risk.”
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Diabetologia 2021; doi:10.1007/s00125-021-05556-7