November 20, 2020
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No causal link between severe hypoglycemia, increased mortality in type 2 diabetes

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Severe hypoglycemic episodes are a marker of, rather than causally related to, an increased risk for death among adults with type 2 diabetes, according to data published in Diabetologia.

“In light of the rising prevalence of severe hypoglycemia in multimorbid people with type 2 diabetes, clarifying whether hypoglycemia is causally related to an increased risk of cardiovascular disease remains important from both a patient and a public health perspective,” Francesco Zaccardi, PhD, MD, clinical epidemiologist and deputy director at the Leicester Real-World Evidence Unit in the Diabetes Research Centre at the University of Leicester, and colleagues wrote. “Most of the available evidence from epidemiological studies, in different geographical regions and from heterogeneous groups of patients with type 2 diabetes, has shown a positive association between severe or nonsevere hypoglycemia and risk of CVD events or death; these observations, however, have been inconsistent.”

Researchers analyzed data from adults with type 2 diabetes (n = 74,610) in the U.K.’s Clinical Practice Research Datalink who were linked to the Hospital Episode Statistics database and Office for National Statistics database. All participants were diagnosed with diabetes from 1998 to 2010.

Data from the Hospital Episode Statistics database were used to identify severe hypoglycemic episodes. Date and cause of death information were obtained through the Office for National Statistics, with deaths categorized as CV, cancer or other causes.

Of the total cohort, 388 had been admitted to the hospital for hypoglycemia. After a median follow-up of 7.1 years, 60.8% of those with severe hypoglycemia died, for a mean mortality rate of 132 per 1,000 person-years (95% CI, 117-150). Of those who did not have a severe hypoglycemic episode, 25% died, for a mean mortality rate of 40 per 1,000 person-years (95% CI, 39-41). Non-CV and noncancer deaths made up 44.5% of all deaths, whereas CV causes accounted for 29.1% of deaths and cancer accounted for 26.4%.

In a model adjusted for age, sex, ethnicity, health information, smoking status, alcohol consumption and deprivation, adults who were aged 50, 60, 70 and 80 years in the severe hypoglycemia group all had a greater likelihood of CV death than someone without a severe hypoglycemic episode, whereas the likelihood for cancer mortality among adults aged 50, 60 and 80 years with severe hypoglycemia were lower than for someone without severe hypoglycemia. Individuals in all four age groups with severe hypoglycemia had an elevated morality risk in the other causes category.

After adjustment for medications and comorbidities, use of sulfonylureas and insulin were both associated with increased CV, cancer and other cause mortality rates.

“As most of the causes of death in our study were not related to CVD, for which several pathophysiological mechanisms have been proposed, and a large set of potential confounders were accounted for, our results are highly suggestive for a noncausal relationship between severe hypoglycemia and long-term CVD complications. Severe hypoglycemia is very likely a marker of frailty, which is causally associated with a higher risk of death,” researchers wrote.

“Along with the clinical principle of reducing glucose without causing hypoglycemia to avoid short-term complications and preserve the quality of life in patients with diabetes, we underline that hospitalization for hypoglycemia identifies clinically complex phenotypes of type 2 diabetes,” researchers concluded. “In these patients, further research should be conducted to identify the optimal strategies to reduce the risk of death.”