SGLT2 inhibitors and the risk of incident chronic kidney disease in type 2 diabetes: a nationwide emulated target trial in Taiwan.

No studies have reported the long-term outcomes of initiating sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with estimated glomerular filtration rates less than 20 mL/min/1.73 m2 to predialysis. To compare the risk for dialysis, cardiovascular events, and death between SGLT2i users and nonusers in patients with type 2 diabetes (T2D) and stage 5 chronic kidney disease (CKD). Target trial emulation study. Taiwan's National Health Insurance Research Database (NHIRD). By applying sequential target trial emulation principle, 23 854 SGLT2i users and 23 892 SGLT2i nonusers were selected from the NHIRD for patients with T2D and stage 5 CKD from 1 May 2016 to 31 October 2021. Conditional Cox proportional hazards models were used to compare the risks for dialysis, hospitalization for heart failure, acute myocardial infarction (AMI), diabetic ketoacidosis (DKA), acute kidney injury (AKI), and all-cause mortality between SGLT2i users and nonusers. In the intention-to-treat model, compared with no SGLT2i use, SGLT2i use was associated with lower risks for dialysis (hazard ratio [HR], 0.34 [95% CI, 0.27 to 0.43]), hospitalization for heart failure (HR, 0.80 [CI, 0.73 to 0.86]), AMI (HR, 0.61 [CI, 0.52 to 0.73]), DKA (HR, 0.78 [CI, 0.71 to 0.85]), and AKI (HR, 0.80 [CI, 0.70 to 0.90]), but there was no difference in the risk for all-cause mortality (HR, 1.11 [CI, 0.99 to 1.24]). The Kaplan-Meier curves and subgroup analyses also showed that initiation of an SGLT2i in stage 5 CKD was associated with a lower risk for long-term dialysis than no SGLT2i use. This result may not apply to patients without T2D. This emulated target trial showed that SGLT2i use was associated with a lower risk for dialysis, cardiovascular events, DKA, and AKI than no SGLT2i use in patients with T2D and stage 5 CKD. National Health Research Institutes, Taiwan.

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

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.

Background: Sodium‒glucose cotransporter-2 (SGLT2) inhibitors offer glycaemic and cardiorenal benefits in the early stage of chronic kidney disease (CKD). However, the use of SGLT2 inhibitors may increase the risk of genitourinary tract infection (GUTI). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may also cause deterioration of kidney function. The long-term follow-up of cardiorenal outcomes and GUTI incidence in patients with advanced CKD receiving SGLT2 inhibitors combined with ACEIs/ARBs should be further investigated. Methods: We analysed data from 5,503 patients in Taiwan's Taipei Medical University Research Database (2016-2020) who were part of a pre-end-stage renal disease (ESRD) program (CKD stages 3-5) and received ACEIs/ARBs. SGLT2 inhibitor users were matched 1:4 with nonusers on the basis of sex, CKD, and program entry duration. Results: The final cohort included 205 SGLT2 inhibitor users and 820 nonusers. SGLT2 inhibitor users experienced a significant reduction in ESRD/dialysis risk (aHR = 0.35, 95% CI = 0.190.67), and SGLT2 inhibitor use was not significantly associated with acute kidney injury or acute kidney disease risk. Among SGLT2 inhibitor users, those with a history of cardiovascular disease (CVD) had greater CVD rates. Conversely, those without a CVD history had lower rates of congestive heart failure, arrhythmia, acute pulmonary oedema, and acute myocardial infarction, although the differences were not statistically significant. Notably, SGLT2 inhibitor usage was associated with a greater GUTI incidence (aHR = 1.78, 95% CI = 1.122.84) shortly after initiation, irrespective of prior GUTI history status. Conclusion: Among patients with CKD stages 3-5, SGLT2 inhibitor use was linked to increased GUTI incidence, but it also significantly reduced the ESRD/dialysis risk without an episodic AKI or AKD risk. Clinical physicians should consider a personalized medicine approach by balancing GUTI episodes and cardiorenal outcomes for advanced CKD patients receiving SGLT2 inhibitors.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve the cardiovascular outcomes of patients with type 2 diabetes (T2D). However, whether this effect extends to stroke prevention in high-risk patients remains unclear. This study aims to investigate the effect of SGLT2i in stroke prevention in patients with T2D and concomitant risk factors. Patients with T2D and various risk factors for stroke were identified from the TriNetX platform from 2013 to 2024. These patients were divided into two cohorts: one treated with SGLT2i, and the other with metformin or dipeptidyl peptidase-4 inhibitors. Propensity score matching was used to balance the patients' demographic characteristics, underlying comorbidities, and antiplatelet and anticoagulant drug use patterns. The primary outcome was the development of ischemic or hemorrhagic stroke or the onset of a transient ischemic attack (TIA) within 1 year. Unadjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs). Sensitivity analyses stratified by age, sex, and hemoglobin A1c (HbA1c) levels were performed, and interaction tests were used to assess potential effect modifiers. In addition, the two cohorts were compared for estimation of numbers needed to treat (NNTs). A total of 3,715,058 patients were identified, of whom 971,727 (26.2%) were SGLT2i users. After matching, 932,419 patients were included in each group. SGLT2i use was associated with a significantly reduced risk of ischemic stroke (HR: 0.84, 95% confidence interval (CI): 0.81-0.87; NNT: 669), hemorrhagic stroke (HR: 0.73, 95% CI: 0.68-0.79; NNT: 1837), and TIA (HR: 0.81, 95% CI: 0.77-0.86; NNT: 1615). The protective effect against ischemic stroke was more pronounced in males and individuals aged over 65 years. Greater benefit was observed in patients with chronic kidney disease (NNT: 466), atrial fibrillation (NNT: 492), and heart failure (NNT: 415). In contrast, the protective effect was attenuated in patients with obesity, among whom SGLT2i use was associated with a modestly increased risk of ischemic stroke after 1 year (HR: 1.05, 95% CI: 1.01-1.09). SGLT2i use is associated with a significant reduction in the risk of stroke among selected T2D patients. SGLT2i may be used as a first-line therapy for diabetes patients with concomitant chronic kidney disease, atrial fibrillation, and heart failure.

128-LB: Sodium–Glucose Cotransporter-2 Inhibitors and Risk of Retinal Vein Occlusion among Patients with Type 2 Diabetes: A Propensity Score–Matched Cohort Study

Introduction: Type 2 diabetes (T2D) is a strong risk factor for chronic kidney disease (CKD). Clinical trials have shown that intensive glycemic control prevents the development of kidney failure and decreases in eGFR in patients with T2D and CKD. Furthermore, sodium-glucose cotransporter-2 inhibitors (SGLT2i) slow the progression of CKD compared to other glucose lowering medications. However, it’s unknown whether SGLT2 inhibitors reduce the risk of incident CKD. Using data from the US MarketScan administrative databases (2014-21), we assessed the association between use of SGLT2i vs. other 2 nd line therapies and risk of incident CKD among patients with T2D on metformin. Methods: We included 428,814 matched patients with T2D on metformin and a 2 nd line therapy. SGLT2i users were matched with up to 5 other 2 nd line therapy users by age, sex, date of enrollment, and date of 2 nd line therapy initiation. Other 2 nd line therapies included dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sulfonylureas, thiazolidinediones, and insulin. Incident CKD was defined using ICD codes. Those with prevalent CKD were excluded. Cox proportional hazards models were used. Results: Participants were on average age 53±10 years at baseline and 46% were female. Over a median follow-up of 2.0 years, 6,024 patients were diagnosed with CKD. After multivariable adjustments, SGLT2i users had a lower risk of incident CKD than those taking other 2 nd line therapies (Table; HR [95% CI]: 0.43 [0.39-0.47]). When compared to users of each 2 nd line therapy individually, SGLT2i users consistently had a lower risk of CKD. Conclusion: In this analysis using real-world data, among patients with T2D on metformin, SGLT2i use was associated with a lower risk of incident CKD than other 2 nd line diabetes therapies (when assessed as a group and individually). Results from this study may inform clinical guidelines regarding treatment options for those with diabetes at high-risk for CKD.

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 impact of sodium-glucose co-transporter 2 inhibitors on the incidence of non-tuberculous mycobacteria infection in diabetes populations.

&lt;b&gt;OBJECTIVE&lt;/b&gt;&lt;b&gt;&lt;/b&gt; &lt;p&gt;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.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESEARCH DESIGN AND METHODS&lt;/b&gt;&lt;b&gt;&lt;/b&gt;&lt;/p&gt; &lt;p&gt;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). In the matched sample, we used the Cox proportional hazards model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for developing RVO. Based on the main outcome, exploratory subgroup analyses were undertaken.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESULTS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;During the 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 new 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 &lt;em&gt;age and estimated glomerular filtration rate (eGFR);&lt;/em&gt; the HR for RVO was higher in patients aged ≥ 60 years and those with eGFR &lt;60 mL/min/1.73m&lt;sup&gt;2&lt;/sup&gt; than in others.&lt;/p&gt; &lt;p&gt;&lt;b&gt;CONCLUSIONS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;In a matched cohort study, we found that SGLT2 inhibitors were associated with a significantly increased risk of RVO. The older patients and those with chronic kidney disease were at higher risk for RVO. &lt;/p&gt;

&lt;b&gt;OBJECTIVE&lt;/b&gt;&lt;b&gt;&lt;/b&gt; &lt;p&gt;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.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESEARCH DESIGN AND METHODS&lt;/b&gt;&lt;b&gt;&lt;/b&gt;&lt;/p&gt; &lt;p&gt;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). In the matched sample, we used the Cox proportional hazards model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for developing RVO. Based on the main outcome, exploratory subgroup analyses were undertaken.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESULTS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;During the 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 new 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 &lt;em&gt;age and estimated glomerular filtration rate (eGFR);&lt;/em&gt; the HR for RVO was higher in patients aged ≥ 60 years and those with eGFR &lt;60 mL/min/1.73m&lt;sup&gt;2&lt;/sup&gt; than in others.&lt;/p&gt; &lt;p&gt;&lt;b&gt;CONCLUSIONS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;In a matched cohort study, we found that SGLT2 inhibitors were associated with a significantly increased risk of RVO. The older patients and those with chronic kidney disease were at higher risk for RVO. &lt;/p&gt;

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

Decreased Risk of New-onset Osteoporosis in Patients with Type 2 Diabetes on SGLT-2 Inhibitors.

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.

ObjectiveTo investigate the association between sodium-glucose cotransporter-2 (SGLT-2) inhibitor use and risk of all cause mortality among patients with heart failure with reduced ejection fraction.DesignLinked database study.SettingNational registers in Denmark,...