Using Short and Long-Acting Insulin Together Does Not Increase Cardiovascular Events or Mortality

By Jessica Pyhtila, PharmD, BCGP, BCPS

A recent study in the Journal of the American Medical Association explored whether the combination of short and long-acting insulin, compared with long-acting insulin alone, increased cardiovascular events and mortality. The study was conducted to address a knowledge gap, as the FDA requires cardiovascular outcomes data for all antidiabetic medications except for insulin.

The study was a retrospective cohort designed to emulate a 4-year randomized experiment in diabetic adults with a qualifying HbA1c level of 6.8% to 8.5%. The study sites included 4 integrated health care systems in the United States. A qualifying HbA1c level was defined as the first HbA1c level between 6.8% and 8.5% after the person had been using long-acting insulin for at least 28 days.

Inclusion criteria included those aged 21 to 89 years with type 2 diabetes. Exclusion criteria included less than 12 months of health plan enrollment and pharmacy coverage prior to the index date, pregnancy, bariatric surgery within 2 years prior to the index date, end-stage kidney disease, evidence of known limited life expectancy, or no HbA1c level measurement in the 2 years before the index date.

Of the 1,084,052 patients with diabetes in the health systems, 57,278 met eligibility criteria and were enrolled in the study. Of these, only 39,279 were able to be evaluated in the CVD mortality analyses due to lags in vital statistics mortality data.

A total of 3,612 deaths, 1,457 myocardial infarctions, 2,040 hospitalizations due to heart failure, 1006 hospitalization from stroke, and 843 deaths due to cardiovascular disease occurred. For or overall mortality among participants on short and long-acting insulin, the adjusted mortality hazard ratio was 1.27 (95% CI, 1.05–1.49). For myocardial infarction, the hazard ratio was 0.89 (95% CI, 0.81–0.97). The CHF, stroke, and CVD mortality results were largely nonsignificant.

Due to the lack of an effect on major cardiovascular events and cardiovascular mortality, the researchers concluded that the observed increase in all-cause mortality may be explained by other etiologies or unmeasured confounding.

References:

Schroeder, Emily B.; Neugebauer, Romain; Reynolds, Kristi; et al. “Association of Cardiovascular Outcomes and Mortality With Sustained Long-Acting Insulin Only vs Long-Acting Plus Short-Acting Insulin Treatment,” Journal of the American Medical Association, September 24, 2021.