Re-examining insulin dose and cardiovascular death

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A NIH-sponsored double-blinded, randomised clinical trial entitled Action to Control Cardiovascular Risk in Diabetes (ACCORD) came to a halt seven years ago after patients receiving more intensive diabetes therapy were found to have a higher mortality rate, compared to the standard therapy. In 2008, the results were released, puzzling researchers. Subsequent investigations have not been able to clearly identify the exact reason for the increased mortality, although some previous epidemiologic and mechanistic studies did suggest that insulin may be associated with adverse cardiovascular outcomes.

It was with this knowledge that Dr Elias S Siraj, professor of medicine at the Lewis Katz School of Medicine at Temple University (LKSOM) and director of the diabetes programme at Temple University Hospital (TUH), and Dr Daniel J Rubin, assistant professor of medicine at LKSOM and chair of the Glycaemic Control Taskforce at TUH, joined others in the ACCORD study group to examine whether it was the dose of insulin that could be contributing to increased cardiovascular mortality.

“Insulin is a very important medication for patients with diabetes and everyone really wanted to know if insulin could be harmful at higher doses,” says Siraj, lead investigator of the post-hoc analysis. “Our initial un-adjusted analysis showed that an increase in insulin dose by 1 unit/ kg of body weight increased the risk of cardiovascular death by 83% to 236% (Hazards ratio of 1.83 to 3.36). But, we had to adjust the data for various medical conditions and other factors potentially associated with insulin use,” says Siraj.

After appropriate statistical adjustment, the dose of insulin was found not to be associated with increased cardiovascular death, and therefore Siraj and his team concluded that insulin is not an independent risk factor for cardiovascular death. “This is reassuring for many physicians and their patients. But, our findings won’t lay to rest the on-going discussion about insulin use and the potential for increased risk, especially at higher doses. There are still unanswered questions and more studies are needed to answer them definitively,” explains Siraj.

In the US, diabetes is the leading cause of blindness, kidney failure, non-traumatic amputations, and a major contributor to cardiovascular disease and death. In 2014, more than 29m Americans were diagnosed with diabetes, up from the previous estimate of 26m in 2010, according to the US Centres for Disease Control and Prevention. A substantial percentage of patients with diabetes are managed with insulin therapy.

The initial ACCORD study recruited and studied over 10,000 patients with type 2 diabetes in the US and Canada. It examined whether outcomes, including cardiovascular outcomes, were different when aiming for a lower, near normal blood sugar target (using an intensive therapy approach, which usually leads to more insulin use) compared to a higher (but acceptable) blood sugar target using a standard approach.

“Whether or not insulin has harmful cardiovascular effects is an important question. We were pleased with the opportunity to be the first group to test our hypothesis in a relatively large and well-characterised population. While this does not end the debate, our results are reassuring,” says Rubin.

OBJECTIVE: In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality.
RESEARCH DESIGN AND METHODS: We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment.
RESULTS: More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation.
CONCLUSIONS: These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.

Temple University material
Diabetes Care abstract

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