Objective：We aimed to evaluate the important potential risks listed in the risk management plans of SGLT–2 inhibitors (SGLT–2i) using a real world database.Design: A cohort study of patients prescribed either SGLT–2i (exposure group) or DPP–4 inhibitors (DPP–4i, control group), using a large–scale health insurance database including claims and specific health checkup.Methods：The study population included the patients with type 2 diabetes between April 2014 and August 2021, and received either SGLT–2i or DPP–4i monotherapy, based on the claims in the database provided by DeSC Healthcare, Inc．The comparability between treatment groups was ensured by propensity score matching (PSM) and inverse probability treatment weighting (IPTW). The outcome events included liver disorder, malignant tumors, fractures, cardiovascular disease, acute pancreatitis, acute kidney injury, and lower limb amputation. Hazard ratios (HRs) were estimated using the Cox proportional hazards model, in addition to five types of bias analyses.Results：In the PSM population, the HRs (95% confidential interval [CI]) of the SGLT–2i group versus the DPP–4i group were 0.63 (0.28–1.44) for acute kidney injury, 0.75 (0.58–0.95) for fractures, 0.85 (0.67–1.07) for liver disorders, 0.87 (0.71–1.05) for cardiovascular diseases, 1.15 (0.88–1.51) for malignant tumors, 1.51 (0.71–3.19) for acute pancreatitis, and with no observation of lower limb amputation．In the IPTW population, the HRs (95% CI) of the SGLT–2i group versus the DPP–4i group were 0.72 (0.47–1.10) for acute kidney injury, 0.76 (0.67–0.86) for fractures, 0.91 (0.80–1.02) for liver disorders, 0.86 (0.78–0.94) for cardiovascular diseases, 1.04 (0.92–1.18) for malignant tumors, 1.81 (1.24–2.64) for acute pancreatitis, and 2.89 (0.69–12.1) for lower limb amputation. The ad hoc analysis of malignant tumors by type revealed several organ–specific statistically significant increases or decreases in HRs among the IPTW subjects; however, no significant overall HR for malignant tumors was observed. Some of the bias analysis revealed that there were significant decreases in HRs for acute kidney injury and liver disorders and a significant increase in HR for lower limb amputation.Conclusion：In comparison to DPP–4i, the use of SGLT–2i was not associated with overall risk of malignant tumors. Further confirmatory studies with fit–for–purpose design are warranted to verify the potential, increased or decreased organ–specific risks of malignant tumors by type and the results suggesting decreased risks of bone fracture and cardiovascular diseases, and an increased risk of acute pancreatitis.

BACKGROUND/OBJECTIVES: Recent studies have reported an association of the angiotensin II type 2 receptor (AT2R) 3123Cytosine/Adenine (3123C/A) polymorphism with essential hypertension and cardiovascular diseases. The purpose of the study was to investigate whether the AT2R 3123C/A polymorphism affects blood pressure for free-living hypertensive men during a 5-month intervention period. SUBJECTS/METHODS: The subjects were free-living hypertensive Japanese men aged 40 to 75 years who agreed to intervention in the period from 2004 to 2011. Detection of the AT2R 3123C/A polymorphism was determined by polymerase chain reaction. The dietary intervention was designed to decrease salt level and to increase potassium level through cooking instructions and self-monitoring of the diet. The exercise session consisted of activities such as stretching, resistance training, and walking. Blood pressure, urinary sodium and potassium excretion, dietary and lifestyle data, and non-fasting venous blood sample were collected at baseline and after the intervention period. RESULTS: Thirty nine subjects were eligible for participation and the follow-up rate was 97.4%. The C allele proportion was 57.9%. AT2R 3123C/A polymorphism was X-chromosome-linked, therefore we analyzed the C and A genotypes. At baseline, no significant differences were observed between the genotype groups. After the intervention, there were no significant differences in lifestyle habit between the groups. Nevertheless, the estimated salt excretion (g/day) was significantly decreased only in the C genotype (13.0-10.3, P = 0.031). No significant change was observed in systolic blood pressure (SBP) (mmHg) in the A genotype, but a significant decrease was observed in the C genotype (150.0-141.5, P = 0.024). CONCLUSTIONS: In the C genotype, it might be easy to improve SBP through lifestyle intervention in free-living hypertensive Japanese men, however generalization could not be achieved by the small sample size.
Alleles ; Asian Continental Ancestry Group ; Blood Pressure* ; Cardiovascular Diseases ; Cooking ; Diet ; Follow-Up Studies ; Generalization (Psychology) ; Genotype* ; Humans ; Hypertension ; Life Style* ; Male ; Polymerase Chain Reaction ; Potassium ; Receptor, Angiotensin, Type 2* ; Resistance Training ; Sample Size ; Sodium ; Walking