Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals.ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality.We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio [HR] 0.34; P= 2.01 × 10-3) and microvascular outcomes (HR 0.86; P= 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in MAS1 reached suggestive significance in C4 (P= 4.34 × 10-7). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; P= 4.02 × 10-6), but not reduced risk of microvascular outcomes (P< 0.05). Mendelian randomization indicated causality between PS, on-trial HbA1c, and reduction in CVD outcomes (P< 0.05).We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation.
Arshiya Mariam, Galen Miller-Atkins, Kevin M Pantalone, Robert S Zimmerman, John Barnard, Michael W Kattan, Hetal Shah, Howard L McLeod, Alessandro Doria, Michael J Wagner, John B Buse, Alison A Motsinger-Reif, Daniel M Rotroff