Abstract
The comparative cardiovascular safety of analogue and human insulins in adults with type 2 diabetes who initiate insulin therapy in usual care settings has not been carefully evaluated using machine learning and other rigorous analytic methods. To examine the association of analogue vs human insulin use with mortality and major cardiovascular events. This retrospective cohort study included 127 600 adults aged 21 to 89 years with type 2 diabetes at 4 health care delivery systems who initiated insulin therapy from January 1, 2000, through December 31, 2013. Machine learning and rigorous inference methods with time-varying exposures were used to evaluate associations of continuous exposure to analogue vs human insulins with mortality and major cardiovascular events. Data were analyzed from September 1, 2017, through June 30, 2018. On the index date (first insulin dispensing), participants were classified as using analogue insulin with or without human insulin or human insulin only. Overall mortality, mortality due to cardiovascular disease (CVD), myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) were evaluated. Marginal structural modeling (MSM) with inverse probability weighting was used to compare event-free survival in separate per-protocol analyses. Adjusted and unadjusted hazard ratios and cumulative risk differences were based on logistic MSM parameterizations for counterfactual hazards. Propensity scores were estimated using a data-adaptive approach (machine learning) based on 3 nested covariate adjustment sets. Sensitivity analyses were conducted to address potential residual confounding from unmeasured differences in risk factors across delivery systems. The 127 600 participants (mean [SD] age, 59.4 [12.6] years; 68 588 men [53.8%]; mean [SD] body mass index, 32.3 [7.1]) had a median follow-up of 4 quarters (interquartile range, 3-9 quarters) and experienced 5464 deaths overall (4.3%), 1729 MIs (1.4%), 1301 CVAs (1.0%), and 3082 CHF hospitalizations (2.4%). There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), MI (1.11; 95% CI, 0.77-1.45), CVA (1.30; 95% CI, 0.81-1.78), or CHF hospitalization (0.93; 95% CI, 0.75-1.11). Insulin-naive adults with type 2 diabetes who initiate and continue treatment with human vs analogue insulins had similar observed rates of major cardiovascular events, CVD mortality, and overall mortality.
Highlights
Because major cardiovascular events and mortality due to cardiovascular disease (CVD) are the principal causes of excess mortality and health care costs in adults with type 2 diabetes, the selection of agents to lower glucose levels for those with type 2 diabetes is necessarily informed by the effects of various agents on major cardiovascular events and mortality, as well as by other factors such as rates of hypoglycemia, convenience of use, and medication costs.[1,2] The US Food and Drug Administration has required randomized cardiovascular outcome trials for all agents to lower glucose levels approved since 2008
There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), myocardial infarction (MI) (1.11; 95% CI, 0.77-1.45), cerebrovascular accident (CVA) (1.30; 95% CI, 0.81-1.78), or congestive heart failure (CHF) hospitalization (0.93; 95% CI, 0.75-1.11)
We report the results of a large, multisite, National Institutes of Health–funded retrospective cohort study designed to assess the occurrence of mortality, CVD mortality, acute myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) in adults with type 2 diabetes who initiated and adhered to a regimen of human vs analogue insulin
Summary
Because major cardiovascular events and mortality due to cardiovascular disease (CVD) are the principal causes of excess mortality and health care costs in adults with type 2 diabetes, the selection of agents to lower glucose levels for those with type 2 diabetes is necessarily informed by the effects of various agents on major cardiovascular events and mortality, as well as by other factors such as rates of hypoglycemia, convenience of use, and medication costs.[1,2] The US Food and Drug Administration has required randomized cardiovascular outcome trials for all agents to lower glucose levels approved since 2008 The results of these trials demonstrate that some agents confer substantive cardiovascular-related benefits among some individuals with type 2 diabetes, whereas other agents do not.[3,4,5,6,7,8,9]. More recent trials, such as ACCORD (Action to Control Cardiovascular Risk in Diabetes)[14] and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation),[15] included the use of analogue insulins, the study designs preclude inferences about the cardiovascular safety of specific agents to lower glucose levels and direct comparison of the cardiovascular effects of human and analogue insulins.[12,15,16,17,18]
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