American Diabetes Association
accord_int_dtw_draft_26Apr2021_SI_DMR.pdf (3.37 MB)

Type 2 Diabetes Subtype Responsive to ACCORD Intensive Glycemia Treatment

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Version 2 2021-04-26, 22:39
Version 1 2021-04-16, 21:06
posted on 2021-04-26, 22:39 authored by 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

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.

Research Design and Methods

ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D reduced 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 outcomes (HR=0.34, P=2.01x10-3) and microvascular outcomes (HR=0.86, P=.015) than standard treatment. A single nucleotide polymorphism, rs220721, in MAS1, reached suggestive significance with C4 (P=4.34x10-7). The PS predicted C4 with high accuracy (AUC=0.98), and predicted C4 displayed reduced CVD risk on intensive versus standard glycemia treatment (HR=0.53, P=4.02x10-6), but not for microvascular outcomes (P<.05). Mendelian randomization indicated causality between the PS, on-trial HbA1c, and reduction in CVD outcomes (P<.05).


We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership of this group can be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development for this landmark clinical trial warranting further investigation.


D.M.R., A.M., and G.M.A., were supported in part by the Clinical and Translational Science Collaborative of Cleveland, (KL2TR002547) from the National Center for Advancing Translational Sciences (NCATS) component of the NIH.