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Does Risk of Death Increase With Insulin Dosage?


December 07, 2016

A recent retrospective, observational cohort study from Canada that examined the link between increasing insulin dosage and death and cardiovascular events demonstrated the safety of insulin use in the treatment of type 2 diabetes.

Previous research on insulin therapy safety in individuals with type 2 diabetes has shown conflicting results. Some observational studies, for example, have reported dose-dependent increased risks of all-cause mortality and cardiovascular events, while other randomized, clinical trials have reported no such increased risks.

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“Our findings provide additional evidence regarding the overall and cardiovascular safety of insulin treatment in type 2 diabetes,” lead author John-Michael Gamble, BScPharm, PhD, School of Pharmacy, Memorial University of Newfoundland, St John's, NL, Canada, told the Pharmacy Learning Network. “However, our study does not provide complete reassurance, as no single study can, but suggests that confounding may be partially responsible for the observed dose-dependent association between insulin and mortality.”

Dr. Gamble and colleagues examined the healthcare records of patients with type 2 diabetes from the Clinical Practice Research Datalink database; participants started metformin monotherapy between 2001 and 2012. They included 6072 individuals who were new add-on insulin users in the study cohort and 3599 individuals who were new add-on insulin users in the subcohort that was linked to hospital admission and death certificate records.

“Our study used a clinically relevant study population of people who started insulin some point after metformin monotherapy,” explained Dr. Gamble. “We used multiple approaches to adjust for potential confounders that may be responsible for the observed association between insulin dosage and death. Notably, the strength of association decreased as we further adjusted for time-related confounders.”

More specifically, the authors used marginal structural models to “reduce bias introduced by the time-dependent confounders affected by previous treatment,” they wrote. Further, differences in mortality and major adverse cardiovascular events between individuals who received varying insulin doses were analyzed.

After adjusting for potential confounders, including HbA1c, weight, hypoglycemic events, and cardiovascular events, the authors found that higher insulin doses were not linked with an increased risk of mortality or major adverse cardiovascular events.

“For all-cause mortality, it was not until after we used a marginal structural model to account for potential time-dependent confounders within the putative causal pathways that an insulin dose-response relationship was no longer observed,” the authors wrote. “These findings could partly explain, and help to reconcile, the opposing conclusions reached by previous observational studies and randomised trials with respect to the safety of insulin.”

Some limitations of the study are the possibilities of residual confounding, despite the fact that the researchers adjusted for several socioeconomic, physiologic, clinical, and treatment covariates, and imprecise insulin dose measurements.

The study findings may provide patients and physicians with reassurance of the overall safety of insulin therapy for individuals with type 2 diabetes and help to explain some of the aforementioned discrepancies in study results regarding insulin safety.

“Our findings should not alter the current approach to using insulin in the management of type 2 diabetes, but rather provide further evidence supporting current clinical practice guidelines,” Dr. Gamble cautioned. “Of course, it is still important to not overtreat with insulin given the known risks, such as hypoglycemia.”

This research was published online in The Lancet Diabetes & Endocrinology and was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the Newfoundland and Labrador Research and Development Corporation.--Meredith Edwards White

Reference

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)30316-3/abstract

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