Characteristics Associated With Decreased or Increased Mortality Risk From Glycemic Therapy Among Patients With Type 2 Diabetes and High Cardiovascular Risk: Machine Learning Analysis of the ACCORD Trial

OBJECTIVE: Identifying patients who may experience decreased or increased mortality risk from intensive glycemic therapy for type 2 diabetes remains an important clinical challenge. We sought to identify characteristics of patients at high cardiovascular risk with decreased or increased mortality risk from glycemic therapy for type 2 diabetes using new methods to identify complex combinations of treatment effect modifiers. RESEARCH DESIGN AND METHODS: The machine learning method of gradient forest analysis was applied to understand the variation in all-cause mortality within the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 10,251), whose participants were 40–79 years old with type 2 diabetes, hemoglobin A(1c) (HbA(1c)) ≥7.5% (58 mmol/mol), cardiovascular disease (CVD) or multiple CVD risk factors, and randomized to target HbA(1c) <6.0% (42 mmol/mol; intensive) or 7.0–7.9% (53–63 mmol/mol; standard). Covariates included demographics, BMI, hemoglobin glycosylation index (HGI; observed minus expected HbA(1c) derived from prerandomization fasting plasma glucose), other biomarkers, history, and medications. RESULTS: The analysis identified four groups defined by age, BMI, and HGI with varied risk for mortality under intensive glycemic therapy. The lowest risk group (HGI <0.44, BMI <30 kg/m(2), age <61 years) had an absolute mortality risk decrease of 2.3% attributable to intensive therapy (95% CI 0.2 to 4.5, P = 0.038; number needed to treat: 43), whereas the highest risk group (HGI ≥0.44) had an absolute mortality risk increase of 3.7% attributable to intensive therapy (95% CI 1.5 to 6.0; P < 0.001; number needed to harm: 27). CONCLUSIONS: Age, BMI, and HGI may help individualize prediction of the benefit and harm from intensive glycemic therapy.