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Background Type 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 findings In 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. Conclusions Our 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., Author summary Why was this study done? There is marked heterogeneity in the rate of progression to insulin requirement in patients with type 2 diabetes (T2D). Whereas some patients can maintain optimal glycemic control with oral glucose-lowering drugs for prolonged periods, others experience rapid deterioration in glycemia, requiring early insulin treatment. It is important to gain insight into what factors are associated with glycemic progression. Previous studies identified baseline HbA1c, young age, and weight gain as independent clinical predictors for glycemic progression in White populations, but there is a paucity of data in Asians. Besides environmental and lifestyle factors including obesity, it is well known that genetic factors play a pivotal role in the onset of diabetes. However, it remains unclear whether genetic variants of body mass index (BMI) and T2D predicts glycemic progression once T2D develops. Moreover, genetic variants associated with response to oral glucose-lowering drugs might also predict glycemic progression. What did the researchers do and find? We investigated glycemic progression among 7,091 Chinese patients with T2D from the Hong Kong Diabetes Register enrolled between 1995 and 2007. We explored the associations of clinical variables and different polygenic risk scores (PRSs) of obesity, T2D, and response to oral glucose-lowering drugs with glycemic progression and validated the associations of PRSs in another multicenter prospective cohort of Hong Kong Diabetes Biobank (HKDB). We found that there was an approximately 1.3-year delay of insulin use after oral glucose-lowering drug failure in real-world practice. We observed a U-shape association between BMI and glycemic progression and found that young age of diagnosis, high HbA1c and triglyceride, use of tobacco, and presence of microvascular complications also predicted rapid glycemic progression. We found that the PRS derived from 123 known risk variants for T2D was associated with early age of diagnosis and rapid glycemic progression, with validation in the replication cohort of HKDB, whereas the PRS derived from 63 BMI-related variants was associated with BMI but not glycemic progression. What do these findings mean? This study highlighted the delay in insulin treatment after oral glucose-lowering drug failure, which represents an important treatment gap in clinical practice. This work emphasized the importance of both genetic and modifiable risk factors, notably lipo-glucotoxicity, obesity, and tobacco use on glycemic progression, which enables identification of high-risk patients for optimal control of risk factors to improve glycemic durability. This study provides novel insights toward the underlying pathophysiology underlining glycemic progression, highlighting some overlap with pathogenesis of T2D. Our work highlights the potential utility of incorporating PRSs for drug response to guide clinical management of T2D.

Background Polycystic ovary syndrome (PCOS) is associated with increased metabolic risk, though data on long-term follow-up of cardiometabolic traits are limited. We postulated that Chinese women with PCOS would have higher risk of incident diabetes and cardiometabolic abnormalities than those without PCOS during long-term follow-up. Methods and findings One hundred ninety-nine Chinese women with PCOS diagnosed by the Rotterdam criteria and with a mean age of 41.2 years (SD = 6.4) completed a follow-up evaluation after an average of 10.6 ± 1.3 years. Two hundred twenty-five women without PCOS (mean age: 54.1 ± 6.7 years) who underwent baseline and follow-up evaluation over the same period were used for comparison. Progression of glycaemic status of women both with and without PCOS was assessed by using 75-g oral glucose tolerance test (OGTT) screening with the adoption of 2009 American Diabetes Association diagnostic criteria. The frequency of impaired glucose regulation, hypertension, and hyperlipidaemia of women with PCOS at follow-up has increased from 31.7% (95% CI 25.2%–38.1%) to 47.2% (95% CI 40.3%–54.2%), 16.1% (95% CI 11.0%–21.2%) to 34.7% (95% CI 28.1%–41.3%), and 52.3% (95% CI 45.3%–59.2%) to 64.3% (95% CI 57.7%–71.0%), respectively. The cumulative incidence of diabetes mellitus (DM) in follow-up women with PCOS is 26.1% (95% CI 20.0%–32.2%), almost double that in the cohort of women without PCOS (p < 0.001). Age-standardised incidence of diabetes among women with PCOS was 22.12 per 1,000 person-years (95% CI 10.86–33.37) compared with the local female population incidence rate of 8.76 per 1,000 person-years (95% CI 8.72–8.80) and 10.09 per 1,000 person-years (95% CI 4.92–15.26, p < 0.001) for women without PCOS in our study. Incidence rate for women with PCOS aged 30–39 years was 20.56 per 1,000 person-years (95% CI 12.57–31.87), which is approximately 10-fold higher than that of the age-matched general female population in Hong Kong (1.88 per 1,000 person-years, [95% CI 1.85–1.92]). The incidence rate of type 2 DM (T2DM) of both normal-weight and overweight women with PCOS was around double that of corresponding control groups (normal weight: 8.96 [95% CI 3.92–17.72] versus 4.86 per 1,000 person-years [95% CI 2.13–9.62], p > 0.05; overweight/obese: 28.64 [95% CI 19.55–40.60] versus 14.1 per 1,000 person-years [95% CI 8.20–22.76], p < 0.05). Logistic regression analysis identified that baseline waist-to-hip ratio (odds ratio [OR] = 1.71 [95% CI 1.08–2.69], p < 0.05) and elevated triglyceride (OR = 6.63 [95% CI 1.23–35.69], p < 0.05) are associated with the progression to T2DM in PCOS. Limitations of this study include moderate sample size with limited number of incident diabetes during follow-up period and potential selection bias. Conclusions High risk of diabetes and increased cardiovascular disease risk factors among Chinese women with PCOS are highlighted in this long-term follow-up study. Diabetes onset was, on average, 10 years earlier among women with PCOS than in women without PCOS., Ronald Ching Wan Ma and colleagues reveal the higher incidence of diabetes and CVD in Chinese women with polycystic ovary syndrome., Author summary Why was this study done? Besides reproductive abnormality, it is known that women with polycystic ovary syndrome (PCOS) are at high risk of metabolic complications, such as insulin resistance (IR), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM). The majority of the accessible longitudinal studies regarding the progression of T2DM in women with PCOS are from the United States, Australia, and Europe. Previous studies have mainly relied on self-report of diabetes status or linkage through national patient registries, which might underestimate the prevalence and incident rate of T2DM in women with PCOS. What did the researchers do and find? During 2016–2017, we prospectively investigated the progression of glycaemic status among 199 Chinese women with PCOS and compared the data with those of 242 women without PCOS by using oral glucose tolerance test (OGTT) for comprehensive glycaemic status screening. We found that the age-standardised incidence rate of T2DM among women with PCOS was around 2.5-fold higher compared with the local female population incidence rate. We noted that the incidence rate of T2DM of both normal-weight and overweight women with PCOS was around double that of respective control groups. This is a key controversial area in international literature and differs from data on individuals of European descent. Diabetes onset was, on average, 10 years earlier among women with PCOS than in women without PCOS. Chinese women with PCOS were at 6-fold higher risk of developing T2DM compared with those without PCOS. High waist-to-hip ratio (WHR), elevated triglyceride, and presence of hyperandrogenism are associated with the progression to T2DM in PCOS. What do these findings mean? This study highlighted the risk of diabetes and metabolic abnormalities in women with PCOS. The study has shed some light on the potential burden of young-onset diabetes associated with PCOS. This work has already been considered in the recent international guidelines, suggesting the clinical relevance of this work. Our data provide useful insights that universal screening should be considered in all Chinese adult women with PCOS. Our data suggested WHR, elevated triglyceride, and hyperandrogenism are associated with the progression to T2DM in PCOS, although we were unable to explore relationships with IR. Therefore, further research is clearly warranted.