• Guozhi Jiang, Andrea O Luk, Claudia H T Tam, Eric S Lau, Risa Ozaki, Elaine Y K Chow, KongAlice P SAPS0000-0001-8927-6764Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China., Cadmon K P Lim, Ka Fai Lee, Shing Chung Siu, Grace Hui, Chiu Chi Tsang, Kam Piu Lau, Jenny Y Y Leung, Man-Wo Tsang, Grace Kam, Ip Tim Lau, June K Li, Vincent T Yeung, Emmy Lau, Stanley Lo, Samuel K S Fung, Yuk Lun Cheng, Chun Chung Chow, Ewan R Pearson, Wing Yee So, ChanJuliana C NJCN0000-0003-1325-1194Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, Chin, MaRonald C WRCW0000-0002-1227-803XDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.L, Hong Kong Diabetes Register TRS Study Group, and Hong Kong Diabetes Biobank Study Group.
• Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
• PLoS Med. 2020 Jul 1; 17 (7): e1003209.

BackgroundType 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D.Methods And FindingsIn 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1-9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03-1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06-1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10-8) but not glycemic progression (HR: 1.01 [95% CI 0.96-1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort.ConclusionsOur results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.

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