MACE Risk With Insulin Dosage in Type 2 Diabetes

Insulin was not linked to MACE in type 2 diabetes.
Insulin was not linked to MACE in type 2 diabetes.
A cohort study of primary care records in the United Kingdom did not find an increased risk of major cardiovascular events in patients with type 2 diabetes treated with insulin.

Insulin dosage does not increase risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes, according to research published in The Lancet Diabetes & Endocrinology.

John-Michael Gamble, PhD, of the School of Pharmacy at Memorial University in St. John’s, Newfoundland, Canada, and colleagues conducted a retrospective cohort study in adults with type 2 diabetes (n=165,308) to determine the risk of cardiovascular disease (CVD) or death with increased insulin dosages.


The study cohort was identified using primary care records from the UK-based Clinical Practice Research Datalink (CPRD). The researchers identified new users of metformin between 2001 and 2012, and then further identified patients within the group who had a new prescription for insulin. Insulin exposure was grouped by the mean dosage in units per day. Primary outcomes were all-cause mortality and MACE.

Exclusion criteria were applied to isolate 6072 new add-on insulin users in the study cohort (mean age, 60±12.5 years; 54% men; mean glycated hemoglobin [HbA1c], 8.5%±1.75; median follow-up, 3.1 years [interquartile range (IQR)], 1.7-5.3). Nearly 3600 new add-on insulin users were included in the subcohort linked to hospital records and death certificate information.

Throughout the study, 691 deaths were reported. Crude mortality rates were as follows: 46 per 1000 person-years (95% CI, 39-55) for exposure to <25 units of insulin per day; 39 per 1000 person-years for exposure to 25 to <50 units of insulin per day; 27 per 1000 person-years for 50 to <75 units of insulin per day; 34 per 1000 person-years for 75 to <100 units of insulin per day; and 32 per 1000 person-years for ≥100 units of insulin per. Overall crude mortality rate was 31 deaths per 1000 person-years (95% CI, 29-33).

After adjustment for baseline covariates, the researchers found that higher daily insulin dosages were significantly associated with increased mortality (P value for trend: .006). When compared with patients receiving <25 units of insulin per day, adjusted hazard ratios (aHR) were higher in patients receiving 25 to <50, 50 to <75, 75 to <100, and ≥100 units of insulin per day (aHR: 1.41; 1.37; 1.85; and 2.16, respectively).

The researchers documented 548 instances of MACE within the study cohort, although higher insulin dosages were “not associated with the composite [MACE] outcome.” Adjusted HRs for 50 to 100 and >100 units of insulin per day were 1.17 and 1.06, respectively. The only significant association that researchers noted was the link between insulin dosage and cardiovascular related-death (aHR: 1.68; 95% CI, 1.17-2.42 and aHR: 2.65; 95% CI, 1.65-4.25 for 50 to 100 and >100 units of insulin per day, respectively; P >.1 for all).

“Our main analysis … is consistent with the findings of other observational studies that found a dose-response relation between insulin and all-cause mortality and cardiovascular morbidity,” the researchers noted. “[T]he result from this study reassures both patients and physicians of the overall safety and absence of major cardiovascular harms of insulin use in the treatment of type 2 diabetes.”

Study Limitations

  • There is the potential for residual confounding, despite adjustment for multiple socioeconomic, physiologic, and treatment covariates
  • A potentially imprecise measurement of insulin dose may have affected results
  • The reduced sample size used to assess MACE and cardiovascular-related mortality vs all-cause mortality resulted in an inability to conduct “data-intensive marginal structural models in this subgroup”
  • Information regarding insulin prescriptions may not have been fully captured

Disclosures: Dr Young reports receiving an unrestricted research grant from Sanofi-Aventis for work unrelated to diabetes. 

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Gamble J-M, Chibrikov E, Twells LK, et al. Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study. Lancet Diabetes Endocrinol. 2017;5:43-52. doi:10.1016/S2213-8587(16)303316-3