Abstract
Cardiovascular events and mortality are the principal causes of excess mortality and health care costs for people with type 2 diabetes. No large studies have specifically compared long-acting insulin alone with long-acting plus short-acting insulin with regard to cardiovascular outcomes. To compare cardiovascular events and mortality in adults with type 2 diabetes receiving long-acting insulin who do or do not add short-acting insulin. This retrospective cohort study emulated a randomized experiment in which adults with type 2 diabetes who experienced a qualifying glycated hemoglobin A1c (HbA1c) level of 6.8% to 8.5% with long-acting insulin were randomized to continuing treatment with long-acting insulin (LA group) or adding short-acting insulin within 1 year of the qualifying HbA1c level (LA plus SA group). Retrospective data in 4 integrated health care delivery systems from the Health Care Systems Research Network from January 1, 2005, to December 31, 2013, were used. Analysis used inverse probability weighting estimation with Super Learner for propensity score estimation. Analyses took place from April 1, 2018, to June 30, 2019. Long-acting insulin alone or with added short-acting insulin within 1 year from the qualifying HbA1c level. Mortality, cardiovascular mortality, acute myocardial infarction, stroke, and hospitalization for heart failure. Among 57 278 individuals (39 279 with data on cardiovascular mortality) with a mean (SD) age of 60.6 (11.5) years, 53.6% men, 43.5% non-Hispanic White individuals, and 4 years of follow-up (median follow-up of 11 [interquartile range, 5-20] calendar quarters), the LA plus SA group was associated with increased all-cause mortality compared with the LA group (hazard ratio, 1.27; 95% CI, 1.05-1.49) and a decreased risk of acute myocardial infarction (hazard ratio, 0.89; 95% CI, 0.81-0.97). Treatment with long-acting plus short-acting insulin was not associated with increased risks of congestive heart failure, stroke, or cardiovascular mortality. Findings of this retrospective cohort study suggested an increased risk of all-cause mortality and a decreased risk of acute myocardial infarction for the LA plus SA group compared with the LA group. Given the lack of an increase in major cardiovascular events or cardiovascular mortality, the increased all-cause mortality with long-acting plus short-acting insulin may be explained by noncardiovascular events or unmeasured confounding.
Highlights
Type 2 diabetes is often a progressive disease
Among 57 278 individuals (39 279 with data on cardiovascular mortality) with a mean (SD) age of 60.6 (11.5) years, 53.6% men, 43.5% non-Hispanic White individuals, and 4 years of follow-up, the LA plus long-acting plus short-acting (SA) group was associated with increased all-cause mortality compared with the LA group and a decreased risk of acute myocardial infarction
Treatment with long-acting plus short-acting insulin was not associated with increased risks of congestive heart failure, stroke, or cardiovascular mortality
Summary
Type 2 diabetes is often a progressive disease. Increasing insulin resistance with decreasing insulin production often necessitates intensification of pharmaceutical therapy over time to maintain control of glucose levels. For individuals who are already using medication regimens that include basal insulin, the step is often the addition of prandial, or short-acting, insulin.[2] Results from trials such as ACCORD (Action to Control Cardiovascular Risk in Diabetes) have raised concerns that, in some circumstances, treatment intensification may lead to increased cardiovascular disease (CVD) or increased overall mortality.[3,4]. This concern is especially important given that major cardiovascular events and cardiovascular mortality are the principal causes of excess mortality and health care costs in adults with type 2 diabetes.[5,6]. Results from trials such as ACCORD (Action to Control Cardiovascular Risk in Diabetes) have raised concerns that, in some circumstances, treatment intensification may lead to increased cardiovascular disease (CVD) or increased overall mortality.[3,4] This concern is especially important given that major cardiovascular events and cardiovascular mortality are the principal causes of excess mortality and health care costs in adults with type 2 diabetes.[5,6] ACCORD4 and similar large randomized trials of glycemic control[7,8] were not designed to assess the relative effectiveness and safety of specific medications to lower glucose levels
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