SGLT2 inhibitor and urothelial carcinoma incidence in type 2 diabetes patients.

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to acute exacerbations, cardiovascular disease, and premature death. To compare the risk of COPD exacerbation, cardiovascular diseases, and mortality between sodium-glucose cotransporter-2 (SGLT-2) inhibitor use and no use in patients with type 2 diabetes mellitus (T2DM) and COPD. The study included 299,168 patients diagnosed with T2DM and COPD in the National Health Insurance Research Database from January 1, 2009, to December 31, 2020. Cox proportional hazards models were used to examine the relative hazard of major adverse cardiovascular events, hospitalization for COPD, noninvasive positive pressure ventilation (NIPPV), invasive mechanical ventilation, lung cancer, and mortality between SGLT-2 inhibitor users and nonusers. We used propensity score matching to select 1288 pairs of SGLT-2 inhibitor users and nonusers. In the matched cohorts, SGLT-2 inhibitor use was associated with a significantly lower risk of mortality (aHR 0.64, 95% CI 0.43-0.95), NIPPV (aHR 0.48, 95% CI 0.27-0.87), and hospitalization for COPD (aHR 0.82, 95% CI 0.69-0.98) than SGLT-2 inhibitor non-use. Subgroup and dose-response analyses showed that SGLT-2 inhibitor use was associated with a significantly lower risk of mortality, NIPPV, and hospitalization for COPD (p<0.05) than no use of SGLT-2 inhibitors. This population-based cohort study showed that SGLT-2 inhibitors use was associated with a lower risk of COPD exacerbations, ventilator support, and mortality than non- SGLT-2 inhibitors use in patients with T2DM and COPD. SGLT-2 inhibitors may have a role in treating patients with COPD and diabetes.

The association between the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and the occurrence of drug-induced kidney injury has not been evaluated. This study assessed whether the use of SGLT-2 inhibitors decreases the risk of drug-induced acute kidney injury (AKI) using the US Food and Drug Administration's Adverse Event Reporting System and the Medical Data Vision database. The occurrence of AKI in SGLT-2 inhibitor users and dipeptidyl peptidase-4 (DPP-4) inhibitor users was compared using both databases. In the US Food and Drug Administration's Adverse Event Reporting System analysis, disproportionality for AKI was observed between DPP-4 inhibitor users and SGLT-2 inhibitor users administered nonsteroidal anti-inflammatory drugs (reporting odds ratio, 0.65; 95%CI, 0.48-0.88; P < .01) and thiazide diuretics (reporting odds ratio, 0.78; 95%CI, 0.67-0.90; P < .01). In Medical Data Vision analysis, SGLT-2 inhibitor users administered nonsteroidal anti-inflammatory drugs (odds ratio [OR], 0.46; 95%CI, 0.41-0.53; P < .01), anti-herpes simplex virus drugs (OR, 0.20; 95%CI, 0.07-0.53; P < .01), thiazide diuretics (OR, 0.50; 95%CI, 0.36-0.71, P < .01), and loop diuretics (OR, 0.71; 95%CI, 0.62-0.83; P < .01) had a lower incidence of AKI compared with DPP-4 inhibitor users receiving the same drugs. No differences were observed in the risk of AKI between SGLT-2 and DPP-4 inhibitor users administered vancomycin and cisplatin in both databases. The use of SGLT-2 inhibitors might reduce the risk of drug-induced AKI caused by some drugs.

BackgroundThere is a lack of recent data reflecting the actual use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for heart failure (HF) and type 2 diabetes (DM) in the superaged society. The present study investigated the association between the use of SGLT2 inhibitors and one-year prognosis in patients hospitalized across a broad spectrum of HF patients with DM in the superaged society using the Nationwide Electric Health Database in Japan.MethodsThe patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2019. A cohort of 2,277 users of SGLT2 inhibitors and 41,410 users of the active comparator, dipeptidyl peptidase-4 (DPP4) inhibitors were compared. A propensity score-matched cohort study of 2,101 users of each inhibitor was also conducted. A multivariable multilevel mixed-effects survival model was conducted with adjustments, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.ResultsAmong 300,398 patients discharged with HF in 4,176 hospitals, 216,016 (71.9%) were 75 years or older, and 60,999 (20.3%) took antidiabetic medications. Among them, the patients treated with SGLT2 inhibitors were younger and had a more severe status than those treated with DPP4 inhibitors. Kaplan–Meier analysis showed that patients treated with SGLT2 inhibitors had a lower mortality risk and HF readmission. In propensity-matched cohorts, SGLT2 inhibitor use was associated with a lower risk of mortality and HF readmission than DPP-4 inhibitor use (HR [95% CI]; 0.70 [0.56, 0.89] and 0.52 [0.45, 0.61], respectively). Very elderly (≥ 75 years) patients showed similar results. Favorable effects were also observed across all age groups, including ≥ 75 years, in patients with coronary artery disease or atrial fibrillation and with concomitant β-blocker, diuretics, or insulin.ConclusionThe use of SGLT2 inhibitors at discharge was associated with a lower risk of one-year mortality and HF readmission in patients across a broad spectrum of HF with DM in the superaged society. The findings further support the benefits of using SGLT2 inhibitors in very elderly HF care and complement the current evidence.

The effects of sodium-glucose co-transporter 2 inhibitors (SGLT-2i) on dementia risk have not been assessed in the Chinese population. We aimed to assess the association between the use of SGLT-2i and dementia incidence in a mainland Chinese population. A target trial of SGLT-2i vs. dipeptidyl peptidase 4 inhibitors (DPP-4i) was emulated, with cohorts of type 2 diabetes mellitus patients who were new users of SGLT-2i or DPP-4i being assembled using the Yinzhou Regional Health Care Database. Inverse probability of treatment weighting (IPTW) was applied to control potential confounding, and a Cox model was used to estimate the hazard ratio (HR) of the association between the use of SGLT-2i and incident dementia. The final cohort included 47 335 new users of DPP-4i or SGLT-2i. In the primary analysis, the incidence of dementia was 500.2 and 347.5 per 100 000 person-years in users of DPP-4i and SGLT-2i, respectively. SGLT-2i use was associated with a reduced risk of incident dementia after adjusting for potential confounding using IPTW, with an HR of 0.74 (95% CI, 0.60-0.93). The results were generally consistent in various subgroup analyses and sensitivity analyses. The use of SGLT-2i is associated with a decreased risk of dementia incidence in the study population in mainland China.

Frailty-stratified effectiveness of SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 receptor agonists on pulmonary outcomes in type 2 diabetes: a nationwide cohort study.

Comparative outcomes of adding SGLT2 inhibitors versus incretin-based therapies to insulin in type 2 diabetes.

The association between SGLT2 inhibitors and new-onset arrhythmias: a nationwide population-based longitudinal cohort study

Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a novel class of antidiabetic medication, have emerged as a key treatment option in diabetes management. Notably, SGLT2i promote glucose and sodium excretion through urine, a mechanism that may be implicated in the potential association between SGLT2i use and risk of atopic dermatitis (AD). To investigate the relationship between SGLT2i use and new-onset AD in people with diabetes. This nationwide active-comparator cohort study used data from the Taiwan National Health Insurance database to investigate the association between SGLT2i use and AD risk. The study included adults with type 2 diabetes mellitus who initiated SGLT2i or DPP4i between May 2016 and December 2018, with no prescriptions for other SGLT2i or DPP4i in the 12 months prior to cohort entry. A total of 148 354 SGLT2i users were identified as the study group, while 322 703 DPP4i users were designated as the active comparator group. The primary outcome was the incidence of AD. To minimize potential confounding, inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics, medical history and ever having used medication between the two groups. Additionally, sensitivity analyses, subgroup analyses and sex-specific assessments were conducted to further validate the findings. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of developing AD. SGLT2i users had a lower incidence of AD (9.742 vs. 12.070 per 1000 PY) than DPP4i users. SGLT2i users had a significantly lower risk of AD compared with DPP4i users (HR 0.847) after IPTW adjustment. Different types of SGLT2i also showed a consistent protective effect for AD. Notably, the highest SGLT2i dosage was associated with the lowest risk of AD (IPTW-adjusted HR 0.647), consistent across sensitivity analyses. Additionally, men who use SGLT2i exhibited a much lower risk of AD (IPTW-adjusted HR 0.750) than women who use SGLT2i. SGLT2i show a significant protective effect against AD in patients with diabetes compared with DPP4i. This robust finding, consistent across weighting and sensitivity analyses, supports SGLT2i use, with a strong protective effect also found in the dose-response analysis.

Moderating Effects in Randomized Trials—Interpreting the P Value, Confidence Intervals, and Hazard Ratios

Sodium-glucose co-transporter 2 inhibitors for heart failure: clinical trial efficacy and clinical practice effectiveness.

To investigate the risk of hyperkalaemia in new users of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes mellitus (T2DM). Patients with T2DM who commenced treatment with an SGLT2 or a DPP-4 inhibitor between 2015 and 2019 were collected. A multivariable Cox proportional hazards analysis was applied to compare the risk of central laboratory-determined severe hyperkalaemia, hyperkalaemia, hypokalaemia (serum potassium ≥6.0, ≥5.5, and <3.5mmol/L, respectively), and initiation of a potassium binder in patients newly prescribed an SGLT2 or a DPP-4 inhibitor. A total of 28599 patients (mean age 60±11 years, 60.9% male) were included after 1:2 propensity score matching, of whom 10586 were new users of SGLT2 inhibitors and 18013 of DPP-4 inhibitors. During a 2-year follow-up, severe hyperkalaemia developed in 122 SGLT2 inhibitor users and 325 DPP-4 inhibitor users. Use of SGLT2 inhibitors was associated with a 29% reduction in incident severe hyperkalaemia [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.88] compared with DPP-4 inhibitors. Risk of hyperkalaemia (HR 0.81, 95% CI 0.71-0.92) and prescription of a potassium binder (HR 0.74, 95% CI 0.67-0.82) were likewise decreased with SGLT2 inhibitors compared with DPP-4 inhibitors. Occurrence of incident hypokalaemia was nonetheless similar between those prescribed an SGLT2 inhibitor and those prescribed a DPP-4 inhibitor (HR 0.90, 95% CI 0.81-1.01). Our study provides real-world evidence that compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with lower risk of hyperkalaemia and did not increase the incidence of hypokalaemia in patients with T2DM.

Reports of amputations associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes. This multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71-1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.

To investigate whether sodium-glucose cotransporter-2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use as add-on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first-ever prescription for a DPP-4 inhibitor or an SGLT2 inhibitor as add-on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP-4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP-4 inhibitor use. A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP-4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP-4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91-1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64-1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP-4 inhibitor use.

CE-452774-3 SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITOR USE IN TYPE II DIABETES MELLITUS IS ASSOCIATED WITH A LOWER RATE OF ATRIAL ARRHYTHMIAS IN A REAL-WORLD POPULATION

Objective: To assess the association between use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and retinal vein occlusion (RVO) using data from the National Health Insurance Service in South Korea. Research Designs and Methods: We used an active comparator, new user design and nationwide data from 2014 to 2017. Based on a 1:1 propensity score match, we included 47 369 new users of SGLT2 inhibitors and 47 369 users of other glucose-lowering drugs (oGLD). The mean follow-up time for the primary intention-to-treat analysis was 2.57 years. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for RVO. Based on the main outcome, a prespecified subgroup analysis was undertaken. Results: During follow-up of 2.57 years, the incidence rate of RVO was 2.19 and 1.79 per 1000 person-years in patients treated with SGLT2 inhibitors and oGLD, respectively. The use of SGLT2 inhibitors was associated with an increased risk of RVO compared with oGLD use (HR 1.264, 95% CI 1.056-1.513). In the subgroup analyses, a significant interaction with SGLT2 inhibitors was observed for age and estimated glomerular filtration rate (eGFR); the HR for RVO was higher in patients aged ≥60 years and those with eGFR &amp;lt;60 mL/min/1.73m2 than in others. Conclusions: In a matched cohort study, we found that SGLT2 inhibitors were associated with a significantly increased risk of RVO. The elderly and patients with chronic kidney disease were at higher risk for RVO. Disclosure M. Lee: None. K. Han: None. H. Kwon: None. Y. Roh: None.