Sodium–Glucose Cotransporter 2 Inhibitors and Lower Risk of Depression in Population with Type 2 Diabetes Mellitus: A Population-Based Active Comparator, New-User Design

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.

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.

e19515 Background: The prevalence of diabetes mellitus (DM) is significantly higher in patients with multiple myeloma (MM) compared to the general population. DM has been associated with worse outcomes in MM, including reduced overall survival and increased mortality. The impact of diabetes in patients with MM is further compounded by cardiotoxicity from proteasome inhibitors and the increased thromboembolic risk linked to immunomodulatory agents. Given the potential benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors, we hypothesized that their use in MM patients with DM could improve clinical outcomes and mitigate adverse events in this population. Methods: We utilized the TriNetX network to identify patients (≥18 years old) with MM and DM between January 1, 2013, and January 1, 2019. We categorized the patients into SGLT2 inhibitors users and SGLT2 inhibitors users. Inclusion in the SGLT2 inhibitors group required exposure to SGLT2 inhibitors for at least 1 year. 1:1 Propensity score matching was performed to match these two groups based on comorbidities, medications, baseline hemoglobin A1c, low-density lipoprotein, and left ventricular ejection fraction to produce two comparable cohorts. The study outcomes include all-cause mortality, all-cause hospitalization, acute venous thromboembolism (VTE), acute heart failure (HF), acute myocardial infarction (MI), cardiac arrhythmia, and cardiac arrest over the 5-year follow-up duration. Results: A total of 43,078 patients were identified, including 3,640 SGLT2 inhibitors users and 39,438 non-SGLT-2 inhibitors users. After 1:1 propensity-score matching, there were 3,379 SGLT-2 inhibitor users (68.9 ± 10.3 years of age, 38.0% female, 23.9% African American [AA]) and 3,379 non-SGLT-2 inhibitor users (68.9 ± 11.0 years of age, 35.9% female, 22.2% AA). SGLT-2 inhibitors users were associated with lower rates of all-cause mortality (odds ratio [OR]: 0.34, 95% confidence interval [CI]: 0.30-0.39) and all-cause hospitalization (OR: 0.52, 95% CI: 0.47-0.58). Lower odds of acute VTE (OR: 0.59, 95% CI: 0.49-0.70), acute HF (OR: 0.89, 95% CI: 0.81-0.98), acute MI (OR: 0.81, 95% CI: 0.69-0.95), cardiac arrhythmia (OR: 0.82, 95% CI: 0.70-0.97), and cardiac arrest (OR: 0.57, 95% CI: 0.44-0.74) were reported among SGLT-2 inhibitors users compared to non-SGLT2 inhibitor users. Conclusions: Our study revealed that only 8.4% of patients with DM and MM were prescribed an SGLT-2 inhibitor. Our study also demonstrated that SGLT2 inhibitor use was associated with lower odds of all-cause mortality and hospitalization, reduced risk of VTE, and favorable cardiovascular outcomes in this patient population.

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

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.

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,...

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.

Objective To assess the association between the use of sodium–glucose cotransporter 2 inhibitor (SGLT2i) and the incidence of diabetic retinopathy (DR). Research design and methods PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov were searched from inception to October 2021. Randomized controlled trials (RCTs) with reports of incidence of DR and other eye disorders between SGLT2i and non-SGLT2i users with type 2 diabetes mellitus were included. Results In general, the incidences of DR were comparable between SGLT2i and non-SGLT2i users (OR = 0.80, 95%CI 0.61 to 1.06, P = 0.12). However, compared with non-SGLT2i users, the incidence of DR was significantly reduced in SGLT2i users with diabetes duration less than 10 years (OR = 0.32, 95%CI 0.13 to 0.76, P = 0.01). Weight reduction in SGLT2i users was associated with a decreased risk of retinal detachment. Moreover, longer study duration was associated with lower incidence of cataract and retinal vasculopathy in SGLT2i users. Conclusions In general, the use of SGLT2i was not associated with the incidence of DR. However, a reduced risk of DR was observed in SGLT2i users with diabetes duration less than 10 years. An early initiation of SGLT2i might be more likely to provide with ocular benefits.

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.

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

IntroductionThe risk of new onset depression associated with sodium-glucose co-transporter 2 inhibitor (SGLT2I) use in patients with type 2 diabetes mellitus (T2DM) remains unclear. This study investigated the risk of new onset depression between SGLT2I and dipeptidyl peptidase 4 inhibitor (DPP4I) users.MethodsThis was a population-based cohort study of T2DM patients in Hong Kong between January 1st, 2015, and December 31st, 2019. T2DM patients over 18 with either SGLT2I or DPP4I use were included. 1:1 propensity-score matching using the nearest-neighbour method was conducted based on demographics, past comorbidities and non-DPP4I/SGLT2I medication use. Cox regression analysis models were used to identify significant predictors for new onset depression.ResultsThe study cohort included a total of 18,309 SGLT2I users and 37,269 DPP4I users (55.57% male, mean age: 63.5 ± 12.9 years) with a median follow-up duration of 5.56 (IQR: 5.23–5.8) years. After propensity score matching, SGLT2I use was associated with a lower risk of new onset depression compared to DPP4I use (HR: 0.52, 95% CI: [0.35, 0.77], P = 0.0011). These findings were confirmed by Cox multivariable analysis and sensitive analyses.ConclusionSGLT2I use is associated with significantly lower risk of depression compared to DPP4 use in T2DM patients using propensity score matching and Cox regression analyses.

To investigate the risk of diabetic macular oedema (DMO) associated with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM). We conducted a retrospective cohort study by analysing a large multi-institutional electronic medical records database in Taiwan. We included adult patients with T2DM without DMO newly receiving either SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1RAs) during the period 2016 to 2018. We used propensity scores with inverse probability of treatment weighting to generate comparable groups. The study outcome was incident DMO, determined by clinical diagnosis during outpatient visits or admissions. We followed patients from the index date to either DMO occurrence, last clinical visit, patient death, or December 31, 2020. We performed Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of DMO. We included 9986 new users of SGLT2 inhibitors (mean [SD] age 59.6 (12.1) years, median [interquartile range {IQR}] glycated haemoglobin [HbA1c] 70 (61-81)mmol/mol, estimated glomerular filtration rate [eGFR] 89.1 [71.4-108.7] mL/min/1.73 m2 and urine albumin-creatinine ratio [UACR] 26.1 [9.7-117.6] mg/g) and 1067 new users of GLP-1RAs (mean [SD] age 58.4(41.5) years, median [IQR] HbA1c 73 [64-84] mmol/mol, eGFR 91.6 [68.6-114.0] mL/min/1.73 m2 and UACR 37.6 [11.1-153.2] mg/g) with similar baseline characteristics. Lower DMO risks were observed among patients newly receiving SGLT2 inhibitors (7.9/1000 person-years), compared to those receiving GLP-1RAs (10.7/1000 person-years) with an HR of 0.75 (95% CI 0.64-0.88). Our findings suggest use of SGLT2 inhibitors was associated with lower risk of DMO in T2DM patients in clinical practice, compared to use of GLP-1RAs. Future studies are necessary to confirm this observation.

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.

&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;