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Large Doses of Insulin Increase Risk of Mortality for Type 2 Patients?

Study offers at least partial explanation for opposing findings between previous observational studies.

The randomized clinical trials such as the UK Prospective Diabetes Study (UKPDS) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) suggested that insulin is not cardio-toxic. However, newer research indicates that higher insulin doses do not raise the risks for mortality or major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

Existing studies have shown conflicting evidence regarding the safety of exogenous insulin therapy in patients with type 2 diabetes. In particular, observational studies have reported an increased risk of death and cardiovascular disease among users of higher versus lower doses of insulin. The purpose of the study was to quantify the association between increasing dosage of insulin exposure and death and cardiovascular events, while taking into account time-dependent confounding and mediation that might have biased previous studies.

A cohort study was done using primary care records from patients in the UK. New users of metformin monotherapy were identified in the period between Jan 1, 2001, and Dec 31, 2012. Patients in this group were then identified within this group with a new prescription for insulin. Insulin exposure was categorized into groups according to the mean dose (units) per day within 180-day time segments throughout each patient’s follow-up. Relative differences in mortality and major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, cardiovascular-related mortality) were assessed using conventional multivariable Cox proportional hazards models. Marginal structural models were then applied to reduce bias introduced by the time-dependent confounders affected by previous treatment.

In the current study, both raw and adjusted data did suggest an increase in death and MACE with increasing insulin doses in type 2 diabetes patients. However, that association disappeared after they applied a statistical approach called “marginal structural models,” which adjusts for factors that change over time and that are affected by insulin dosage — such as number of hypoglycemic events, body weight, and glycemic control.

Those same factors also in turn influence insulin dosage and are related to the outcomes of interest — in this case, death — and therefore may be responsible for a spurious association between insulin dosage and death.

165,308 adults with type 2 diabetes in the CPRD database were identified. From the results it was concluded that, in conventional multivariable regression analysis, higher insulin doses are associated with increased mortality after adjustment for baseline covariates. However, this effect seems to be confounded by time-dependent factors such as insulin exposure, glycemic control, bodyweight gain, and the occurrence of cardiovascular and hypoglycemic events. This study provides reassurance of the overall safety of insulin use in the treatment of type 2 diabetes and contributes to our understanding of the contrasting conclusions from non-randomized and randomized studies regarding dose-dependent effects of insulin on cardiovascular events and mortality.

The findings provide additional evidence regarding the overall and cardiovascular safety of insulin treatment in type 2 diabetes. The study does not provide complete reassurance, as no single study can, but provides convincing evidence that confounding may be partially responsible for the observed dose-dependent association between insulin and mortality.

Practice Pearls:

  • For adults with type 2 diabetes initiating insulin therapy, there is no dose-response relationship between the amount of daily insulin and all-cause death or cardiovascular risk, according to a retrospective study.
  • Higher insulin doses were not associated with composite major adverse CV events, according to researchers.
  • The UK Prospective Diabetes Study (UKPDS) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) suggested that insulin is not cardiotoxic.

Lancet Diabetes Endocrinol. Published online November 16, 2016. Abstract, Editorial