Heterogeneous treatment effects of intensive glycemic control on major adverse cardiovascular events in the ACCORD and VADT trials: a machine-learning analysis

Abstract

Background Evidence to guide type 2 diabetes treatment individualization is limited. We evaluated heterogeneous treatment effects (HTE) of intensive glycemic control in type 2 diabetes patients on major adverse cardiovascular events (MACE) in the Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) and the Veterans Affairs Diabetes Trial (VADT). Methods Causal forests machine learning analysis was performed using pooled individual data from two randomized trials (n = 12,042) to identify HTE of intensive versus standard glycemic control on MACE in patients with type 2 diabetes. We used variable prioritization from causal forests to build a summary decision tree and examined the risk difference of MACE between treatment arms in the resulting subgroups. Results A summary decision tree used five variables (hemoglobin glycation index, estimated glomerular filtration rate, fasting glucose, age, and body mass index) to define eight subgroups in which risk differences of MACE ranged from − 5.1% (95% CI − 8.7, − 1.5) to 3.1% (95% CI 0.2, 6.0) (negative values represent lower MACE associated with intensive glycemic control). Intensive glycemic control was associated with lower MACE in pooled study data in subgroups with low (− 4.2% [95% CI − 8.1, − 1.0]), intermediate (− 5.1% [95% CI − 8.7, − 1.5]), and high (− 4.3% [95% CI − 7.7, − 1.0]) MACE rates with consistent directions of effect in ACCORD and VADT alone. Conclusions This data-driven analysis provides evidence supporting the diabetes treatment guideline recommendation of intensive glucose lowering in diabetes patients with low cardiovascular risk and additionally suggests potential benefits of intensive glycemic control in some individuals at higher cardiovascular risk.

Sex‐specific associations between haemoglobin glycation index and the risk of cardiovascular and all‐cause mortality in individuals with pre‐diabetes and diabetes: A large prospective cohort study

“…In addition, the use of hypoglycaemic drugs may have an impact on the level of HGI. 22 We performed sensitivity analyses in a population of diabetics who had received treatment, and similar results were obtained. Therefore, the determination of HGI thresholds is of clinical relevance.…”

“…Our study observed sex differences between HGI and mortality, particularly CVD mortality. In addition, the use of hypoglycaemic drugs may have an impact on the level of HGI 22 . We performed sensitivity analyses in a population of diabetics who had received treatment, and similar results were obtained.…”

Some patients with type 2 diabetes may benefit from intensive glycaemic and blood pressure control: A post‐hoc machine learning analysis of ACCORD trial data

“…Setting a glycaemic goal to a specific subpopulation for optimal health outcomes has been a decade‐long debate with mixed evidence because of the variation of patient populations, achieved HbA1c levels and statistical approaches in the study. Post‐hoc studies 23,24 of the ACCORD trial indicated that among (a) younger participants with lower BMI and haemoglobin glycosylation index, or (b) impaired renal function and lower haemoglobin glycosylation index, intensive glucose control was associated with lower risk of mortality or MACE. A post‐hoc analysis of the ADVANCE trial 25 showed that baseline HbA1c was not an effect modifier for intensive glucose control in preventing MACE.…”

Glycemic control and clinical outcomes in diabetic patients with heart failure and reduced ejection fraction: insight from ventricular remodeling using cardiac MRI

“…It has long been recognized that hyperglycemia has adverse effects on the vasculature, and diabetes treatment guideline recommendations for intensive glucose lowering for T2DM patients have therefore been implemented for decades [ 13 ]. Data from recent studies seemingly showed that intensive glycemic control to achieve normal or near-normal HbA1c levels was potentially beneficial to delay the progression of microvascular or macrovascular complications and improve prognosis [ 14 – 17 ]. However, regarding T2DM patients with HFrEF, we found an unexpected risk with intensive glycemic control, which conveyed a more than 2-fold risk of adverse outcomes compared with modest glycemic control.…”