Association of sodium-glucose cotransporter 2 inhibitors with the risk of incident anxiety and insomnia: a retrospective cohort study using the TriNetX database.

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.

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.

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

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.

While the kidney-protective effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors have attracted much attention, there are limited real-world clinical data examining the effects of SGLT2 inhibitors on kidney function in older individuals. We aimed to compare the kidney outcomes between SGLT2 inhibitor and dipeptidyl peptidase 4 (DPP4) inhibitor use in older adults with diabetes. Using a nationwide claims database, we studied 6354 older adults (≥60years of age) who had diabetes and were newly initiated on SGLT2 inhibitors or DPP4 inhibitors. A 1:4 propensity score matching algorithm was used to compare changes in estimated glomerular filtration rate (eGFR) between SGLT2 inhibitor and DPP4 inhibitor users. The primary outcome was a decrease in the rate of eGFR, which was obtained using a linear mixed-effects model with an unstructured covariance. Following propensity score matching, 6354 individuals including 1271 SGLT2 inhibitor users and 5083 DPP4 inhibitor users {median age 68years [interquartile range (IQR) 65-70], male 60.4%, median eGFR 69.0ml/min/1.73m2 [IQR 59.1-79.0], median haemoglobin A1c [HbA1c] 6.9% [IQR 6.5-7.4]} were analysed. SGLT2 inhibitor users had a slower eGFR decline than did DPP4 inhibitor users [-0.97ml/min/1.73m2/year (95% CI -1.24 to -0.70) versus -1.83ml/min/1.73m2/year (95% CI -1.97 to -1.69); P for interaction <.001]. This finding remained consistent across subgroups based on age, sex, body mass index, HbA1c level, renin-angiotensin system inhibitor use and baseline eGFR. Additionally, the risk of a ≥20%, ≥30% and ≥40% decrease in eGFR from baseline was significantly lower in SGLT2 inhibitor users than in DPP4 inhibitor users. Our analysis, utilizing a nationwide epidemiological dataset, demonstrated that the decrease in eGFR was slower in individuals ≥60years of age with diabetes who were prescribed SGLT2 inhibitors compared with those prescribed DPP4 inhibitors, suggesting a potential advantage of SGLT2 inhibitors for kidney outcomes even in older individuals with diabetes.

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.

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.

To conduct a pharmacoepidemiological study to explore the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and gout in patients with type 2 diabetes mellitus (T2DM). A retrospective open cohort study using the IQVIA Medical Research Data UK database was performed between November 1, 2012 and December 31, 2018, estimating the risk of gout in patients with T2DM who were new users of SGLT2 inhibitors, compared to propensity-score-matched new users of dipeptidyl peptidase-4 (DPP-4) inhibitors. A total of 85 incident cases of gout were recorded over 30 389 person-years of observation in 13 617 new users of SGLT2 inhibitors and 29 426 new users of DPP-4 inhibitors. Crude incidence rates (IRs) per 1000 person-years were 2.90 and 2.47 for new users of SGLT2 inhibitors and DPP-4 inhibitors, respectively. The unadjusted hazard ratio (HR) was 1.18 (95% confidence interval [CI] 0.76-1.83). The adjusted HR was 1.20 (95% CI 0.77-1.86). In the at-treatment analysis, crude IRs per 1000 person-years were found to be 2.68 and 2.53 for SGLT2 inhibitor and DPP-4 inhibitor users, respectively. In the adjusted model, the adjusted HR was 1.3 (95% CI 0.90-2.29). Sensitivity analyses did not change the findings. In this nationwide study, no difference in the incidence of gout was documented in patients treated with SGLT2 inhibitors compared to DPP-4 inhibitor users. This neutral finding remained consistent in sensitivity analyses.

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern with increasing prevalence and associated health impacts. Although no approved drugs are available for the NAFLD treatment, several hypoglycemic agents have been investigated as promising therapeutic agents. We aimed to compare the risk of occurrence of NAFLD with respect to the use of different hypoglycemic agents in patients with type 2 diabetes. This retrospective cohort study used data from the National Health Insurance Service-National Sample Cohort of South Korea. Participants newly diagnosed with type 2 diabetes (2003-2019) were included in this study. Two new user-active comparator cohorts were assembled: Cohort 1, new users of thiazolidinediones (TZD) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and Cohort 2, new users of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and DPP-4i. The occurrence of NAFLD was defined based claims that include diagnostic codes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models in 1:3 propensity score (PS)-matched cohorts. For 65,224 patients newly diagnosed with type 2 diabetes, the overall prevalence of NAFLD was 42.6%. The PS-matched Cohort 1 included 6,351 and 2,117 new users of DPP-4i and TZD, respectively. Compared to DPP-4i, TZD use was associated with the decreased risk of NAFLD (HR, 0.66; 95% CI: 0.55-0.78). Cohort 2 consisted of 6,783 and 2,261 new users of DPP-4i and SGLT-2i, respectively; SGLT-2i use was associated with a decreased risk of NAFLD (HR, 0.93; 95% CI: 0.80-1.08). This population-based cohort study supports the clinical implications of prioritizing TZD and SGLT-2i over DPP-4i in reducing the risk of occurrence of NAFLD in patients with type 2 diabetes. However, the findings lacked statistical significance, highlighting the need for further verification studies.

The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) vs dipeptidyl peptidase-4 inhibitors (DPP4I) on the risk of new-onset gout remains unknown. This study aims to compare the effects of SGLT2I against DPP4I on gout risks. This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus treated with SGLT2I or DPP4I between 1 January 2015 and 31 December 2020 in Hong Kong. The study outcomes are new-onset gout and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I was performed. Univariable and multivariable Cox regression models were conducted. Competing risks models and multiple approaches based on the propensity score were applied. This study included 43 201 patients [median age: 63.23 years old (Interquartile range, IQR): 55.21-71.95, 53.74% males; SGLT2I group: n = 16 144; DPP4I group: n = 27 057] with a median follow-up of 5.59 years (IQR: 5.27-5.81 years) since initial drug exposure. The incidence rate of developing gout [Incidence rate (IR): 2.5; 95% CI: 2.2, 2.9] among SGLT2I users was significantly lower than DPP4I users (IR: 5.2; 95% CI: 4.8, 5.8). SGLT2I was associated with 51% lower risks of gout (HR: 0.49; 95% CI: 0.42, 0.58; P-value < 0.0001) and 51% lower risks of all-cause mortality (HR: 0.49; 95% CI: 0.42, 0.58; P-value < 0.0001) after adjusting for significant demographics, past comorbidities, medications and laboratory results. The results remained consistent on competing risk and other propensity score approaches. SGLT2I use was associated with lower risks of new gout diagnosis compared with DPP4I use.

Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP-4 inhibitors: an analysis from the CVD-REAL 2 multinational cohort study

The benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the occurrence rate of adverse cardiac and renal outcomes in patients with type 2 diabetes has been well described in randomized trials. Whether this benefit extends to patients at the most severe end of the disease spectrum requiring admission to the ICU remains to be examined. Retrospective observational study. Data were obtained from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System). All adult patients (age ≥ 18 yr) with type 2 diabetes and newly prescribed SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors between January 1, 2015, and December 31, 2019. None. After 1:2 propensity score matching, a total of 27,972 patients (10,308 SGLT2 inhibitors vs 17,664 DPP-4 inhibitors) were included in the final analysis. The mean age was 59 ± 11 years, and 17,416 (62.3%) were male. The median follow-up period was 2.9 years. The use of SGLT2 inhibitors was associated with decreased ICU admission (286 [2.8%] vs 645 [3.7%]; hazard ratio [HR], 0.79; 95% CI, 0.69-0.91; p = 0.001) and lower risks of all-cause mortality (315 [3.1%] vs 1,327 [7.5%]; HR, 0.44; 95% CI, 0.38-0.49; p < 0.001), compared with DPP-4 inhibitors. The severity of illness upon ICU admission by Acute Physiology and Chronic Health Evaluation IV-predicted risk of death was also lower in SGLT2 inhibitors users. Admissions and mortality due to sepsis were lower in SGLT2 inhibitor users compared with DPP-4 inhibitor users (admissions for sepsis: 45 [0.4%] vs 134 [0.8%]; p = 0.001 and mortality: 59 [0.6%] vs 414 [2.3%]; p < 0.001, respectively). In patients with type 2 diabetes, SGLT2 inhibitors were independently associated with lower rates of ICU admission and all-cause mortality across various disease categories.

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 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.

BackgroundCharacteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018.MethodsWe conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018.ResultsOur cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%).ConclusionAlthough SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA.