Association of Sodium-Glucose Cotransporter 2 Inhibitor vs Dipeptidyl Peptidase-4 Inhibitor Use With Risk of Incident Obstructive Airway Disease and Exacerbation Events Among Patients With Type 2 Diabetes in Hong Kong.

Importance: Patients with diabetes are at higher risk for obstructive airway disease (OAD). In recent meta-analyses of post hoc analyses of cardiorenal trials, sodium-glucose cotransporter 2 inhibitors (SGLT2Is) were suggested to reduce the risk of OAD adverse events. However, a clinical investigation of this association is warranted. Objective: This study aimed to investigate the association of SGLT2I use vs dipeptidyl peptidase-4 inhibitor (DPP4I) use with OAD incidence and exacerbation events in patients with type 2 diabetes. Design, Setting, and Participants: This retrospective population-based cohort study used electronic health data from a territory-wide electronic medical database in Hong Kong. Data were collected for patients with type 2 diabetes who were prescribed SGLT2Is or DPP4Is between January 1, 2015, and December 31, 2018. Patients were followed for a median of 2.2 years between January 1, 2015, and December 31, 2020. A prevalent new-user design was adopted to match patients based on previous exposure to the study drugs. Propensity score matching was used to balance baseline characteristics. Exposures: Patients with type 2 diabetes using SGLT2Is (exposure of interest) or DPP4Is (active comparator). Main Outcomes and Measures: The main outcomes were the first incidence of OAD and the count of OAD exacerbations. The risk of incident OAD was estimated using a Cox proportional hazards regression model. The rate of exacerbations was estimated using zero-inflated Poisson regression. Statistical analysis was performed on November 13, 2022. Results: This study included 30 385 patients. The propensity score-matched non-OAD cohort (incidence analysis) consisted of 5696 SGLT2I users and 22 784 DPP4I users, while the matched OAD cohort (exacerbations analysis) comprised 381 SGLT2I users and 1524 DPP4I users. At baseline, 56% of patients in the non-OAD cohort were men and the mean (SD) age was 61.2 (9.9) years; 51% of patients in the OAD cohort were men and the mean age was 62.2 (10.8) years. Compared with DPP4I use, SGLT2I use was associated with a lower risk of incident OAD (hazard ratio, 0.65 [95% CI, 0.54-0.79]; P < .001) and a lower rate of exacerbations (rate ratio, 0.54 [95% CI, 0.36-0.83]; P = .01). The associations were consistent in sex subgroup analysis. Conclusions and Relevance: The findings of this retrospective cohort study of patients with type 2 diabetes in Hong Kong suggest that SGLT2I use was associated with a reduced risk of incident OAD and a lower rate of exacerbations in a clinical setting compared with DPP4I use. These findings further suggest that SGLT2Is may provide additional protective effects against OAD for patients with type 2 diabetes and that further investigation is warranted.

Association Between SGLT2 Inhibitors vs DPP4 Inhibitors and Renal Outcomes Among Patients With Type 2 Diabetes.

CONTEXT: Diabetic kidney disease is a major burden among diabetic patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were shown to reduce renal outcomes in clinical trials and real-world studies. However, head-to-head comparisons with individual classes of glucose-lowering agents warranted further investigation. OBJECTIVE: This work aimed to investigate the associations between SGLT2is use vs dipeptidyl peptidase-4 inhibitors (DPP4is) use and 4 renal outcomes: end-stage renal disease (ESRD), albuminuria, acute renal failure (ARF), and the rate of estimated glomerular filtration rate (eGFR) change using a territory-wide electronic medical database in Hong Kong. METHODS: For this retrospective cohort study, the "prevalent new-user" design was adopted to account for previous exposure to study drugs. Propensity score matching was used to balance baseline characteristics. Electronic health data of type 2 diabetes patients using SGLT2is and DPP4is between 2015 and 2018 were collected. RESULTS: The matched cohort consisted of 6333 SGLT2is users and 25 332 DPP4is users, with a median follow-up of 3.8 years. Compared to DPP4is, SGLT2is use was associated with lower risks of ESRD (hazard ratio [HR]: 0.51; 95% CI, 0.42-0.62; P < .001) and ARF (HR: 0.59; 95% CI, 0.48-0.73; P < .001), and a slower decline in eGFR. The associations remained statistically significant among patients with or without rapid eGFR decline and patients who added or switched to SGLT2is from DPP4is. The association with albuminuria was inconsistent across analyses. CONCLUSION: Compared to DPP4is, SGLT2is use was associated with reduced risks of ESRD and ARF, and a slower eGFR decline in a real-world setting. The associations remained statistically significant in patients with or without preindex rapid eGFR decline.

Association Between SGLT2 Inhibitors vs DPP-4 Inhibitors and Risk of Pneumonia Among Patients With Type 2 Diabetes.

CONTEXT: Patients with diabetes are at a higher risk of pneumonia and pneumonia mortality. Sodium glucose co-transporter 2 inhibitors (SGLT2is), the latest class of glucose-lowering agents, were shown to reduce the risk of pneumonia in clinical trials. However, the real-world effectiveness of SGLT2is on the risk of pneumonia is largely unknown. OBJECTIVE: To investigate the associations between SGLT2is use and the risk of pneumonia and pneumonia mortality compared with dipeptidyl peptidase-4 inhibitors (DPP4is) using an electronic medical database in Hong Kong. DESIGN: A retrospective cohort study. The "prevalent new-user" design was adopted to account for the previous exposure to the study drugs being compared. Propensity score (PS) matching (1:4) was used to balance the baseline characteristics of the 2 groups. SETTING AND PARTICIPANTS: Electronic health data of type 2 diabetes patients using SGLT2is and DPP4is between 2015 and 2018 was collected from the Clinical Data Analysis and Reporting System. MAIN OUTCOME MEASURES: Pneumonia incidence and mortality. RESULTS: The PS-matched cohort consisted of 6664 users of SGLT2is and 26 656 users of DPP4is, with a mean follow-up of 3.8 years. Poisson regression showed that SGLT2is use was associated with lower risk of pneumonia compared with DPP4is with an absolute rate difference of 4.05 per 1000 person-years (95% CI, 2.61-5.51). The corresponding incidence rate ratio was 0.71 (95% CI, 0.62-0.81). Similar reduction in risk of pneumonia death was observed (hazard ratio 0.57; 95% CI, 0.42-0.77). CONCLUSION: Compared with DPP4is, SGLT2is use was associated with a reduced risk of pneumonia and pneumonia mortality in a real-world setting.

Serum Metabolome of Coffee Consumption and its Association With Bone Mineral Density: The Hong Kong Osteoporosis Study.

BACKGROUND: Inconsistent associations between coffee consumption and bone mineral density (BMD) have been observed in epidemiological studies. Moreover, the relationship of bioactive components in coffee with BMD has not been studied. The aim of the current study is to identify coffee-associated metabolites and evaluate their association with BMD. METHODS: Two independent cohorts totaling 564 healthy community-dwelling adults from the Hong Kong Osteoporosis Study (HKOS) who visited in 2001-2010 (N = 329) and 2015-2016 (N = 235) were included. Coffee consumption was self-reported in an food frequency questionnaire. Untargeted metabolomic profiling on fasting serum samples was performed using liquid chromatography-mass spectrometry platforms. BMD at lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable linear regression and robust regression were used for the association analyses. RESULTS: 12 serum metabolites were positively correlated with coffee consumption after Bonferroni correction for multiple testing (P < 4.87 × 10-5), with quinate, 3-hydroxypyridine sulfate, and trigonelline (N'-methylnicotinate) showing the strongest association. Among these metabolites, 11 known metabolites were previously identified to be associated with coffee intake and 6 of them were related to caffeine metabolism. Habitual coffee intake was positively and significantly associated with BMD at the lumbar spine and femoral neck. The metabolite 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (ß = 0.012, SE = 0.005; P = 0.013) was significantly associated with BMD at the lumbar spine, whereas 3-hydroxyhippurate (ß = 0.007, SE = 0.003, P = 0.027) and trigonelline (ß = 0.007, SE = 0.004; P = 0.043) were significantly associated with BMD at the femoral neck. CONCLUSIONS: 12 metabolites were significantly associated with coffee intake, including 6 caffeine metabolites. Three of them (AFMU, 3-hydroxyhippurate, and trigonelline) were further associated with BMD. These metabolites could be potential biomarkers of coffee consumption and affect bone health.

Evaluation of GDF15 as a therapeutic target of cardiometabolic diseases in human: A Mendelian randomization study.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a key regulator of body weight in animals by regulating food intake. Its receptor, glial cell-derived neurotrophic factor receptor alpha-like (GFRAL), was identified recently. Pre-clinical studies showed that it is a promising therapeutic target for cardiometabolic diseases and anorexia/cachexia. Although many pharmaceutical companies are developing drugs targeting GFRAL, whether the findings from animal studies can be extrapolated to man is unknown. Mendelian randomization (MR) is useful in investigating the relationship between risk factors and disease outcomes. We aimed to use a two-sample MR approach to evaluate the clinical usefulness of targeting GDF15 for cardiometabolic diseases. METHODS: Genetic instruments and summary statistics for MR analyses were obtained from a large genome-wide association study (GWAS) of GDF15 and cardiometabolic outcomes (n = 27,394 to 644,875), including body mass index, waist-hip ratio, waist circumference, whole-body lean mass, fat percentage, Type 2 Diabetes, fasting glucose, glycated haemoglobin, fasting insulin, LDL-cholesterol, HDL-cholesterol, total cholesterol, triglycerides, coronary artery disease, and estimated BMD (eBMD). Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of GDF-15 with different outcomes; weighted median and MR-egger were used for sensitivity analyses. FINDINGS: There was null association between GDF15 levels and anthropometric outcomes. One SD increase in genetically-determined GDF15 was significantly associated with reduced HDL-C (beta: -0.048SD; SE: 0.014; P = .001) but the result was not significant in sensitivity analyses. A consistent significant causal association was observed between GDF15 and eBMD in IVW (beta: 0.026 SD; SE: 0.005; P < .001) and subsequent sensitivity analyses. INTERPRETATION: This study sheds lights on the potential of drugs targeting the GDF15/GFRAL axis. It suggested that the effect of targeting GDF15/GFRAL axis for weight control in human may be different from the effects observed in animal studies. GDF15 treatment may improve BMD in humans. FUND: No specific funding was received for this study.