CGM Metrics and HbA1c Are Differentially Associated with Complications and Plasma Metabolites in Long-Duration Type 1 Diabetes

Continuous glucose monitor (CGM)-derived metrics evaluate aspects of glycemic variability that are not assessed with HbA1c alone. However, the comparative contributions of these measures to chronic complications in long-duration Type 1 diabetes (T1D) have not been reported. From the Joslin Medalist Study composed of people with T1D≥50 years, a consecutive 14-day block of CGM data was obtained from a subset of CGM users (n=102) after performing usual activities. In linear regression models, mean historical HbA1c was associated with glucose management indicator (GMI), mean glucose, and time above range (TAR)>250 mg/dL; and inversely with time in range (TIR) 70-180 mg/dL and time below range (TBR)<70 mg/dL (all p<0.001). Medalists with GMI significantly greater (≥0.5%) than mean historical HbA1c also had greater coefficient of variability (p=0.04) and TAR (p=0.01). While retinopathy, nephropathy, and neuropathy were associated with GMI, mean glucose, and TAR (p<0.05), only neuropathy was associated with TBR (p=0.02). In contrast, HbA1c was associated only with self-reported cardiovascular disease in the overall Medalist cohort (n=952; p<0.05). Plasma global metabolomics studies (n=95) revealed that amino acid activation pathways, particularly asparagine and glutamine, were associated with lower TAR and higher TIR; while bile acid synthesis was associated with lower TBR (p<0.05). Meanwhile, amino acid metabolism pathways were associated with lower mean historical HbA1c (p<0.05). Our results suggest that while HbA1c and CGM metrics are closely related in long-duration T1D subjects, they provide differential contributions to the development of complications. Additionally, this is the first study to comprehensively characterize plasma metabolomics with both HbA1c and CGM metrics, which provided novel insights on potential therapeutic targets for glycemic control and variability in T1D, as well as potential protection from complications. Disclosure M.Yu: None. S.Jangolla: None. J.Gauthier: None. N.A.Ziemniak: None. H.Shah: None. G.L.King: Research Support; Janssen Research & Development, LLC. Funding American Diabetes Association (9-18-CVD1-005 to M.C.Y.); Mary K. Iacocca Family Foundation; Thomas J. Beatson, Jr. Foundation