Effects Of SGLT2 Inhibitors Research Articles

916-P: SGLT2 Inhibitors and Parkinson’s Disease (PD) Risk in Older Populations with Type 2 Diabetes (T2D)

Background: Diabetes increases the risk of Parkinson’s disease (PD). SGLT2 inhibitors show neuroprotective effects in animal models. Yet evidence is limited regarding the effect of SGLT2 inhibitors on PD risk. We thus aimed to assess the association between SGLT2 inhibitors and PD risk in T2D patients. Methods: In this retrospective cohort study, we used 2016-2020 national Medicare Claims data to identify beneficiaries with T2D and without preexisting PD. We compared the risk of PD between new users of SGLT2 inhibitors vs. DPP4 inhibitors. We employed 1:1 propensity score matching to balance the baseline confoundings between the treatment groups and applied Cox regression models to estimate the PD risk. Results: After 1:1 propensity score matching, 26,619 individuals were included in each of the two treatment groups, the PD incidence was 2.48 and 3.54 per 1000 person-years in the SGLT2 inhibitor group and DPP4 inhibitor group, respectively. In the Cox model (Figure), the SGLT2 inhibitor group was associated with a significantly lower risk of incident PD (HR 0.70 [95% CI 0.55-0.89]) than the DPP4 inhibitor group. The risk reduction of PD was particularly profound in non-Hispanic Black individuals (HR 0.24 [95% CI 0.07-0.86]) and insulin users (HR 0.49 [95% CI 0.32-0.77]). Conclusion: Compared to DPP4 inhibitors, SGLT2 inhibitors were associated with a significantly lower risk of indecent PD in people with T2D. Disclosure J. Guo: None. H. Tang: None. H. Shao: Consultant; Eli Lilly and Company. Y. Lu: None. L. Shi: None. V. Fonseca: Consultant; Abbott, Bayer Inc. Stock/Shareholder; BRAVO4HEALTH, LLC. Consultant; Corcept Therapeutics. Speaker's Bureau; Eli Lilly and Company. Research Support; Fractyl Health, Inc. Consultant; Sun Pharmaceutical Industries Ltd. Stock/Shareholder; Amgen Inc. Y. Guo: None. J. Bian: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465)

Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for new-onset gastric cancer and gastric diseases in patients with type 2 diabetes mellitus: a population-based cohort study

ObjectiveTo compare the risks of gastric cancer and other gastric diseases in patients with type-2 diabetes mellitus (T2DM) exposed to sodium-glucose cotransporter 2 inhibitors (SGLT2I), dipeptidyl peptidase-4 inhibitors (DPP4I) or glucagon-like peptide-1 receptor agonists (GLP1a).DesignThis was a population-based cohort study of prospectively collected data on patients with T2DM prescribed SGLT2I, DPP4I or GLP1a between January 1st 2015 and December 31st 2020 from Hong Kong. The outcomes were new-onset gastric cancer, peptic ulcer (PU), acute gastritis, non-acute gastritis, and gastroesophageal reflux disease (GERD). Propensity score matching (1:1) using the nearest neighbour search was performed, and multivariable Cox regression was applied. A three-arm comparison between SGLT2I, DPP4I and GLP1a was conducted using propensity scores with inverse probability of treatment weighting.ResultsA total of 62,858 patients (median age: 62.2 years old [SD: 12.8]; 55.93% males; SGLT2I: n = 23,442; DPP4I: n = 39,416) were included. In the matched cohort, the incidence of gastric cancer was lower in SGLT2I (Incidence rate per 1000 person-year, IR: 0.32; 95% confidence interval, CI 0.23–0.43) than in DPP4I (IR per 1000 person-year: 1.22; CI 1.03–1.42) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of gastric cancer (HR 0.30; 95% CI 0.19–0.48), PU, acute gastritis, non-acute gastritis, and GERD (p < 0.05) compared to DPP4I use. In the three-arm analysis, GLP1a use was associated with higher risks of gastric cancer and GERD compared to SGLT2I use.ConclusionsThe use of SGLT2I was associated with lower risks of new-onset gastric cancer, PU, acute gastritis, non-acute gastritis, and GERD after matching and adjustments compared to DPP4I use. SGLT2I use was associated with lower risks of GERD and gastric cancer compared to GLP1a use.Graphical abstract

Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach.

Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis. Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013-2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument. Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA1c reduction was similar between SGLT2i and DPP4i (-0.3 mmol/mol [-1.6, 1.1], -0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (-4 mmol/mol [4.8, -3.1], -0.4% [-0.4, -0.3]). Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes.

Effects of sodium-glucose cotransporter-2 inhibitors on inflammatory skin diseases in patients with type 2 diabetes

Effects of sodium-glucose cotransporter-2 inhibitors on inflammatory skin diseases in patients with type 2 diabetes

Effect of SGLT2 inhibitors in the management of moroccan patients with heart failure with reduced ejection fraction

Effect of SGLT2 inhibitors in the management of moroccan patients with heart failure with reduced ejection fraction

Short-term effects of dapagliflozin on biomarkers of bone and mineral metabolism in patients with diabetic kidney disease: A prospective observational study

BackgroundThere is still a lack of information regarding the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on bone and mineral metabolism in patients with diabetes and chronic kidney disease (CKD). Therefore, we aimed to investigate the effects of SGLT2i in a cohort of patients suffering from diabetic kidney disease (DKD). MethodsIn this prospective observational study, patients with type 2 diabetes and biopsy-proven diabetic nephropathy or presumptive DKD with eGFR levels ≥20 ml/min/1.73m2 and 25-OH vitamin D levels ≥20 ng/dl were included. 41 used SGLT2i (study group) and 39 continued their current treatment regimens (control group). Serum FGF-23, sclerostin, osteoprotegerin (OPG), and hydroxyproline levels were measured at baseline, 1 month and 3 months after treatment. ResultsMean age of all patients was 67±9.3 years, and 48 (60%) were female. All patients in the study group used dapagliflozin. Taking into account the renal functions at the commencement of the study, the eGFR values for the study group and the control group were 51.2±15.6 and 44.6±16.9ml/min/1.73m2, respectively (p=0.01). After three months, these values were observed to be 47.4±16.7 and 44.3±18.8 ml/min/1.73m2 (p=0.43), respectively. At baseline, OPG levels were higher in the study group (p=0.025) but there were no differences between the groups in terms of FGF-23 and sclerostin levels (p=0.670 and p=0.467, respectively). Levels of OPG, FGF-23, and sclerostin significantly decreased throughout 3 months of treatment with dapagliflozin (p<0.001 for all). Hydroxyproline levels also declined but did not reach to statistical significance (p=0.075). Multiple linear regression models revealed that treatment with SGLT2i was associated with the change in levels of sclerostin (β=0.303, p=0.011) and OPG (β=0.210, p=0.010), but not with FGF-23 (β=0.089, p=0.150). ConclusionsFGF-23, sclerostin and OPG levels significantly declined after treatment with dapagliflozin for 3 months.

The effect of SGLT2 inhibitors and GLP1 receptor agonists on arterial stiffness: A meta-analysis of randomized controlled trials

BackgroundPulse wave velocity (PWV) and augmentation index (AIx) are indices used to assess arterial stiffness. We evaluated the effect of sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) on arterial stiffness indices. MethodsWe searched PubMed (up to January 2024) for RCTs assessing the effect of SGLT2i or GLP1-RA on arterial stiffness with reporting outcomes PWV and AIx. Effect sizes of the included studies were expressed as weighted mean difference (WMD) and 95 % confidence interval. Subgroup analyses were performed based on comparator (placebo vs. active comparator), design (RCT vs. crossover), population (diabetic vs. all) and blindness (yes vs. no). ResultsA total of 19 studies (SGLT2i, 12 studies; GLP1-RA, 5 studies; SGLT2i/GLP1-RA combination, 2 studies) assessing 1212 participants were included. We did not find any statistically significant association between GLP1-RA or SGLT2i and PWV or AIx. None of the subgroup analyses showed any statistically significant result. ConclusionNo evidence of a favorable change in arterial stiffness indices (PWV, AIx) was found following the administration of SGLT2i or GLP1-RA.

Pharmacotherapy in patients with heart failure with reduced ejection fraction: A systematic review and meta-analysis.

Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated. PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI). We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI+BB+MRA+SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI+BB+MRA+SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI+BB+MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle "ACEI+BB+MRA" in improving LVEF. ACEI+BB+MRA+SGLT-2i was better than ACEI+BB+MRA (-8.05mL/m2, 95% CI: -14.88 to -1.23mL/m2) and ACEI+BB+SGLT-2i (-18.94mL/m2, 95% CI: -36.97 to -0.61mL/m2) in improving LVEDVI. ACEI+BB+MRA+SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB+BB+MRA in reducing NT-proBNP. Adding SGLT-2i to ARNI/ACEI+BB+MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI+BB+MRA+SGLT-2i" is superior to the golden triangle "ACEI+BB+MRA" in improving LVEF. PROSPERO; No. CRD42022354792.

Invasive Hemodynamic Changes Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to lower incident heart failure (HF) and HF hospitalizations, but the mechanisms of benefit in relation to invasive hemodynamics remain unclear. Using PRISMA guidelines, we systematically reviewed multiple online databases for randomized trials evaluating the effect of SGLT2i on invasive hemodynamics. Rest and peak exercise invasive hemodynamics were measured via right heart catheterization pre- and postintervention. Random effects model meta-analysis at a 95% confidence interval was done using RevMan 5.0. A total of 3 studies with a total of 145 patients were included in the meta-analysis. SGLT2i was significantly associated with a reduction in pulmonary capillary wedge pressure at rest and peak exercise. Similarly, SGLT2i reduced mean pulmonary artery pressure at rest and peak exercise, respectively; however, this was not statistically significant. This hypothesis-generating study offers mechanistic insights into the central hemodynamic effects of SGLT2i underpinning the HF benefits of SGLT2i.

Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

The effect of SGLT2 inhibitors on kidney stones; a systematic review and meta-analysis

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are among the antidiabetic drugs with unclear relationship effect on kidney stones. Accordingly, this study aimed to investigate the relationship between SGLT2 inhibitors treatment and kidney calculi incidence using systematic review and meta-analysis. Materials and Methods: The PRISMA statement was used to write this systematic review and meta-analysis. Databases, including ProQuest, PubMed, Web of Science, Cochrane, and Google Scholar, were used to access the resources without a lower time limit until November 5, 2023. Data analysis was conducted using STATA 14 software. Results: Results obtained from six studies with a total of 4963542 participants indicated that SGLT2 inhibitors administration reduced the possibility of kidney calculi in general (OR = 0.80, 95% CI: 0.72, 0.89), in men (OR = 0.92, 95% CI: 0.86, 0.98), and women (OR = 0.93, 95% CI: 0.89, 0.97). SGLT2 inhibitors treatment prevented kidney calculi in cross-sectional studies (OR = 0.92, 95% CI: 0.89, 0.96), cohort studies (OR = 0.71, 95% CI: 0.66, 0.77), RCT study (OR = 0.64, 95% CI: 0.48, 0.86), Japan (OR = 0.92, 95% CI: 0.89, 0.96), United States (OR = 0.72, 95% CI: 0.67, 0.76), Denmark (OR = 0.51, 95% CI: 0.37, 0.71), compared with DPP4i (OR = 0.74, 95% CI: 0.71, 0.77), compared with GLP1RA (OR = 0.62, 95% CI: 0.47, 0.82), compared with other antidiabetic drugs (OR = 0.92, 95% CI: 0.89, 0.96), and compared with placebo (OR = 0.64, 95% CI: 0.48, 0.86). Conclusion: Compared with placebo and other antidiabetic drugs, SGLT2 inhibitors reduce the risk of kidney calculi. However, considering the limited number of investigated studies, more studies in this field are required. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023483132) and Research Registry (UIN: reviewregistry1743) websites.

Effects of sodium glucose co-transporter-2 inhibitor on atrial tachyarrhythmia burden in patients with cardiovascular implantable electronic device

Abstract Introduction Previous studies showed that sodium glucose co-transporter-2 inhibitors (SGLT2i) were associated with a lower atrial fibrillation (AF) incidence. Purpose Since mitochondrial dysfunction has been linked with AF, we aimed to examine the effects of SGLT2i on AF burden and mitochondrial function in patients with cardiovascular implantable electronic device (CIED). Methods Patients with CIED were randomly assigned to receive either dapagliflozin 10 mg daily or placebo for 3 months. The AF burden was measured as atrial high-rate episodes (AHRE) via CIED interrogations, and data were collected at baseline and 3-months post-treatment. Oxidative stress and mitochondrial function were determined in peripheral blood mononuclear cells (PBMCs). Results The study enrolled 54 CIED patients. There were 9 (16.7%) patients with diabetes mellitus and 36 (66.7%) patients with history of clinical AF. The changes of AHRE burden after 3-month treatments did not differ between dapagliflozin and placebo groups. However, in those with clinical AF, dapagliflozin significantly decreased the number of AHRE per month as compared to placebo (-2.2 vs. +0.6 episodes per month, p=0.048) (Table 1). Mitochondrial spare respiratory capacity (SRC) percentage was significantly increased after treatment with dapagliflozin (162.1% to 203.2%, p=0.003), whereas this was not found in the placebo group (Figure 1). In the subgroup analysis of patients with clinical AF, dapagliflozin showed significant improvement in both the SRC percentage (165.7 to 201.7%, p=0.016) and a reduction in cellular oxidative stress (26,840.5 to 18,164.0 arbitrary unit, p=0.049). Conclusions Dapagliflozin significantly reduced the number of AHRE per month in patients with history of clinical AF. The improvement in PBMC’s mitochondrial function and reduced cellular oxidative stress among dapagliflozin users could be the mechanisms responsible for its anti-atrial arrhythmic effect.Table 1Figure 1

#1071 The effect and mechanism of SGLT2 inhibitor on improving inflammatory injury of glomerular endothelial cells in diabetes

Abstract Background and Aims ATP-binding cassette transporter A1 (ABCA1), which reduces intracellular cholesterol accumulation, is highly expressed in the kidney. Studies have shown that sodium-glucose co-transporter 2 inhibitors (SGLT2) inhibitors promote ABCA1 expression in multiple tissues and organs. However, the effect of SGLT2 inhibitors on ABCA1 expression in diabetic kidney disease (DKD) is unclear. In this study, the effect of empagliflozin, an SGLT2 inhibitor, on ABCA1 in glomerular endothelial cells(GECs) of DKD and the possible mechanisms linking ABCA1 to GECs inflammatory injury were investigated. Method Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. db/db mice were used as animal models of type 2 diabetes and the effects of SGLT2 inhibitors on ABCA1 were analyzed by treatment with empagliflozin. The effects of ABCA1 overexpression on glomerular lipid deposition and kidney injury were examined in a type 2 diabetic mouse model with ABCA1 overexpression (db/db + ABCA1 mice), and human renal glomerular endothelial cells (HRGECs) cultured in high glucose and high cholesterol conditions, which simulated type 2 diabetes in vitro. Results The expression of ABCA1 in the glomeruli of DKD patients and db/db mice was significantly decreased. Enhancing ABCA1 expression in the kidney tissue of diabetic mice by adenovirus transduction improved renal cholesterol deposition, inhibited the overactivation of C3a/C5a, and improved renal inflammatory injury. In addition, in cultured HRGECs under high glucose and high cholesterol conditions, ABCA1 deficiency increased the deposit of cellular cholesterol, contributed to overactivation of C3a/C5a, and induced inflammatory injury. Overexpression of ABCA1 enhancing cholesterol efflux or inhibition of C3a/C5a activation in vitro significantly protected against glomerular endothelial injury stimulated by high glucose and high cholesterol. Moreover, SGLT2 inhibitor empagliflozin up-regulated the expression of ABCA1 and down-regulated the levels of cholesterol, C3a/C5a and inflammatory cytokines in diabetic mice and HRGECs. Conclusion SGLT2 inhibitor (empagliflozin) might play a renal protective role by up-regulating ABCA1-mediated cholesterol outflow, inhibiting the activation of C3a/C5a, and then ameliorating the inflammatory injury of GECs.

Comparative safety and cardiovascular effectiveness of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in nursing homes.

Studies examining the safety and effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus glucagon-like peptide-1 receptor agonists (GLP-1RAs) among community-dwelling adults may not generalize to nursing home (NH) residents, who are typically older and more multimorbid. We compared the safety and cardiovascular effectiveness of SGLT2is and GLP-1RAs among US NH residents. Eligible individuals were aged ≥66 years with type 2 diabetes mellitus and initiated an SGLT2i or GLP-1RA in an NH between 2013 and 2018. Safety outcomes included fall-related injuries, hypoglycaemia, diabetic ketoacidosis (DKA), urinary tract infection or genital infection, and acute kidney injury in the year following treatment initiation. Cardiovascular effectiveness outcomes included death, major adverse cardiovascular events and hospitalization for heart failure. Per-protocol adjusted hazard ratios (HR) were calculated using stabilized inverse probability of treatment and censoring weighted cause-specific hazard regression models accounting for 127 covariates. The study population included 7710 residents (31.08% SGLT2i, 68.92% GLP-1RA). Compared with GLP-1RA initiators, SGLT2i initiators had higher rates of DKA (HR 1.95, 95% confidence limits 1.27, 2.99) and death (HR 1.18, 95% confidence limits 1.02, 1.36). Rates of urinary tract infection or genital infection, acute kidney injury, major adverse cardiovascular events, and heart failure were also elevated, while rates of fall-related injuries and hypoglycaemia were reduced, but all estimates were imprecise and highly compatible with no difference. SGLT2is do not have superior, and may have inferior, effectiveness compared with GLP-1RAs for cardiovascular and mortality outcomes in NH residents. Residents initiating SGLT2is should be monitored closely for DKA.

Sodium-glucose cotransporter-2 inhibitors and incidence of atrial fibrillation in older adults with type 2 diabetes: a retrospective cohort analysis

ObjectivesTo investigate the risk of atrial fibrillation (AF) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) compared to dipeptidyl peptidase-4 inhibitor (DPP4i) use in older US adults and across diverse subgroups.MethodsWe conducted a retrospective cohort analysis using claims data from 15% random samples of Medicare fee-for-service beneficiaries. Patients were adults with type 2 diabetes (T2D), no preexisting AF, and were newly initiated on SGLT2i or DPP4i. The outcome was the first incident AF. Inverse probability treatment weighting (IPTW) was used to balance the baseline covariates between the treatment groups including sociodemographics, comorbidities, and co-medications. Cox regression models were used to assess the effect of SGLT2i compared to DPP4i on incident AF.ResultsOf the 97,436 eligible individuals (mean age 71.2 ± 9.8 years, 54.6% women), 1.01% (n = 983) had incident AF over a median follow-up of 361 days. The adjusted incidence rate was 8.39 (95% CI: 6.67–9.99) and 11.70 (95% CI: 10.9–12.55) per 1,000 person-years in the SGLT2i and DPP4i groups, respectively. SGLT2is were associated with a significantly lower risk of incident AF (HR 0.73; 95% CI, 0.57 to 0.91; p = 0.01) than DPP4is. The risk reduction of incident AF was significant in non-Hispanic White individuals and subgroups with existing atherosclerotic cardiovascular diseases and chronic kidney disease.ConclusionCompared to the use of DPP4i, that of SGLT2i was associated with a lower risk of AF in patients with T2D. Our findings contribute to the real-world evidence regarding the effectiveness of SGLT2i in preventing AF and support a tailored therapeutic approach to optimize treatment selection based on individual characteristics.

#2549 Real world data of dapagliflozin effect on proteinuria in primary glomerulopathies in Croatia

Abstract Background and Aims SGLT2 inhibitors, namely dapagliflozin, proved to slow progression of kidney disease in randomized clinical trials. Our aim was to assess real world efficacy of dapagliflozin on proteinuria level in primary glomerulopathies (GN). Method adult patients with biopsy proven glomerulonephritis from all university hospitals in Croatia who started dapagliflozin as a standard of care were enrolled. Data were analyzed if patients had at least six months of follow up. None of the patients were on immunosuppression. Data are shown as N (%) or median with interquartile range (IQR) and accompanied p levels. Results Overall 118 patients, predominantly male 84 (71.8%) of average age of 52 years (min–max 20–76), were enrolled. Most of the patients had IgA nephropathy (IgAN) (N = 55;46.6%), followed by membranous nephropathy (N = 27;22.9%), FSGS (N = 19;16.1%), membranoproliferative GN (N = 8;6.8%), Alport syndrome (N = 8;6.8%). 95.8% of patients were on ACE inhibitors or angiotensin receptor blockers and 10.7% were on mineralocorticoid receptor inhibitors and RAAS blockage was not significantly upscaled during follow up. During the median follow up of 12.2 (7.5-18.6) months, proteinuria was significantly reduced from 1139 (534–2265) to 701 (305-1543) mg/dU; p &amp;lt; 0.001. When divided by glomerulonephritis type, statistically significant reduction of proteinuria was observed in patients with IgAN and Alport syndrome, while trend of reduction of proteinuria was observed in all types of GN. There was a slight reduction in eGFR levels (54 (43-78) vs. 52 (39–73) ml/min/1,73 m²; p &amp;lt; 0.001) and rise in creatinine values (122 (89–149) vs. 128 (91–159) μmol/l; p &amp;lt; 0.001). There was a significant reduction in systolic (130 (120-140) vs.125 (115-134) mmHg; p &amp;lt; 0.001) and diastolic blood pressure (80 (75-90) vs. 80 (70-85) mmHg; p &amp;lt; 0.001). Reduction of uric acid level was noticed (377 (313–460) vs.343 (294–422); p &amp;lt; 0.001), while there was no effect on LDL levels (2.6 (2.12–3.53) vs.2.3 (1.9–3.30); p = 0.073). Dapagliflozin was well tolerated, one patient discontinued the therapy due to intolerance, one due to urinary infection and two due to relapse of GN which needed immunosuppressive therapy. One patient was excluded from analysis due to non-adherence. Conclusion SGLT2 inhibitor dapagliflozin has significant effect on reduction of proteinuria in patients with primary glomerulonephritis. Our data support a growing body of evidence that SGLT2 inhibitors should be used as a standard of care in patients with glomerular kidney diseases, especially IgAN. Future research should address earlier use of SGLT2 inhibitors during the treatment of glomerulonephritis alongside immunosuppressive therapy as well as look into the effect of SGLT2 inhibitors on mesangial cells.

#462 Initiation of SGLT2i vs GLP1-RA and incidence of AKI in persons with type 2 diabetes mellitus

Abstract Background and Aims Adverse kidney outcomes, including acute kidney injury (AKI), are frequent complications in people with diabetes mellitus type 2. In large placebo-controlled randomized trials, both sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown efficacy in reducing the risk of kidney outcomes; however, no trial has compared the kidney protective effects of these drug classes head-to-head. We therefore conducted an emulated target trial to compare the effect of SGLT2i to that of GLP1-RA on the incidence of AKI. Method Using routinely collected data from nationwide Danish population-based registries, we included all adults with diabetes mellitus type 2 initiating SGLT2i or GLP1-RA in 2015-2020. Patients with prevalent kidney failure (defined as eGFR &amp;lt; 15 mL/min/1.73m2, dialysis, or kidney transplant), and patients initiating GLP1-RA marketed specifically for treatment of obesity were excluded. We assessed demographic and diabetes-related baseline characteristics along with comorbidities and comedication. We used propensity scores, estimated by logistic regression, to compute stabilized inverse probability of treatment weights, which were applied in all analyses to reduce confounding. Using an intention to treat approach, we followed patients from treatment initiation until the first of death, emigration, or end of follow-up (31 December 2021). Using creatinine measurements from in- and outpatient settings, we applied the KDIGO definition of AKI to record each episode of AKI during follow-up. We estimated the risk of a first AKI episode over time using the Aalen-Johansen estimator. Furthermore, to estimate the mean number of AKIs over time, i.e., including recurrent AKIs, we used the mean cumulative count estimator. Both estimators account for the competing risk of death. Comparing SGLT2i to GLP1-RA, we reported differences in risks and counts at 1, 3 and 5 years of follow-up. Finally, we estimated all-cause mortality using the Kaplan-Meier estimator. We used bootstrapping to obtain 95% confidence intervals (95% CI). Results We included 68 010 individuals, of which 44 034 (65%) initiated SGLT2i, and 23 976 (35%) initiated GLP1-RA. Initiators of SGLT2i were slightly older (median age 63 vs 62 years) and more often male (63% vs 56%) than initiators of GLP1-RA, but with similar diabetes duration (7 vs 7 years). The annual number of initiators of each drug in Denmark increased over the study period. Compared to GLP1-RA, initiators of SGLT2i generally had better estimated glomerular filtration rate (eGFR) at baseline (9% vs 18% had eGFR &amp;lt; 60 mL/min/1.73m2), more frequently used metformin (91% vs 84%), but less frequently insulin (11% vs 28%). Initiators of SGLT2i had a lower prevalence of hospital-diagnosed retinopathy (7% vs 9%), neuropathy (5% vs 6%), and obesity (13% vs 23%) than initiators of GLP1-RA. After inverse probability of treatment weighting, each variable was well balanced with absolute standardized mean differences below 0.02. During a median follow-up of 2.8 years, the weighted absolute risks of first time AKI at 1, 3, and 5 years were 4.8%, 11.2%, and 17.0% for initiators of SGLT2i, and 5.4%, 12.3%, and 19.1% for initiators of GLP1-RA, resulting in AKI risk differences of −0.6% (95% CI: −1.0% to −0.3%), −1.0% (95% CI: −1.7% to −0.5%), and −2.0% (95% CI: −3.0% to −1.1%). The mean cumulative counts showed a similar pattern, with SGLT2i initiators experiencing slightly fewer AKI episodes than GLP1-RA initiators on average (Fig. 1). After 5 years, an estimated 10.3% of SGLT2i initiators and 9.6% of GLP1-RA initiators had died, resulting in a risk difference of 0.7% (95% CI: -0.1% to 1.5%). Conclusion People with diabetes mellitus type 2 who initiated SGLT2i had slightly lower weighted incidence of AKI over 5 years than those initiating GLP1-RA.

#762 Hyperkalemia and discontinuation of RAS blockade after initiating SGLT-2i vs. DPP-4i in patients with type 2 diabetes; a population-based cohort study

Abstract Rate of hyperkalemia and discontinuation of renin-angiotensin system blockade after initiating SGLT-2 inhibitors vs. DPP-4 inhibitors in patients with type 2 diabetes; a population-based cohort study Background and Aims Post-hoc analyses of clinical trials have suggested that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the rate of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes and CKD. Whether these effects are generalizable to patients treated in routine clinical practice is unclear. Here, we evaluated the comparative effects of SGLT-2i and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the rate of hyperkalemia and RASi discontinuation. Method We conducted a population-based active-comparator, new-user cohort study using data from the Stockholm CREAtinine Measurements (SCREAM) project of people with type 2 diabetes who newly initiated SGLT-2i or DPP-4i between January 2014 and December 2021. The primary outcomes were time to first outpatient hyperkalemia (plasma potassium &amp;gt;5.0 mmol/L) occurrence and recurrent hyperkalemia. The secondary outcomes were mild (potassium &amp;gt;5-≤5.5 mmol/L) and moderate-severe (potassium &amp;gt;5.5 mmol/L) hyperkalemias. Among RASi users, we also studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate hazard ratios (HRs) and rate differences for time to first hyperkalemia. Weighted Poisson regression was used to estimate incidence rate ratios (IRRs) for hyperkalemia recurrence. Results We included 24 417 individuals (of which 14 470 initiated SGLT-2i and 9, 947 DPP-4i therapy), followed for median 2.0 (Q1-Q3 0.8-3.7) years. Mean age was 67 years and 37% were women. Compared with DPP-4i, initiation of SGLT-2i was associated with a lower rate of first hyperkalemia (adjusted hazard ratio [HR] 0.83; 95% CI 0.72-0.96) and recurrent hyperkalemia (incidence rate ratio [IRR] 0.75; 0.64-0.85). Similar findings were observed among people with eGFR ≥60 (HR 0.73; 95% CI 0.63-0.86) and &amp;lt;60 (HR 0.87; 95% CI 0.63-1.16) ml/min/1.73 m2, as well as for mild (HR 0.82; 95% CI 0.71-0.95) and moderate-severe (HR 0.67; 95% CI 0.52-0.84) hyperkalemias. Out of 15 746 participants that were prevalent RASi users, 17% discontinued RASi therapy during 2.0 (IQR 0.8-3.7) years of follow-up. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (HR: 1.00; 0.91-1.11). Conclusion In patients with type 2 diabetes managed in routine clinical care, the use of SGLT-2i was associated with a lower rate of first and recurrent hyperkalemia compared with DPP-4i. However, this was not accompanied by higher persistence on RASi therapy.

#1549 The effect of sglt2 inhibitors (dapaglifozin) on albuminuria in patients of diabetic nephropathy above standard of care

Abstract Background and Aims Albuminuria is the hallmark of diabetic nephropathy (DN) and progression of albuminuria denotes declining renal functions culminating in End Stage Renal Disease. Intensive blood glucose control (HbA1c &amp;lt;7%), intensive blood pressure control (&amp;lt;130/90 mmHg), blockade of Renin Angiotensin Aldosterone System (RAAS) by Angiotensin converting enzyme inhibitors (ACE-i) and Angiotensin receptor blockers (ARBs) constitute the standard line of care for treatment of DN with proteinuria. Sodium Glucose cotransporter 2 inhibitors (SGLT2i) are drugs are recently introduced for proteinuria reduction with no data available in this part of the world. Hence, I, observed the antiproteinuric effect of SGLT2i in patients who have type2 diabetes mellitus (T2DM) with albuminuria and who are already on maximum doses of ACE-I or ARBs. My study population was on dapaglifozin due to easy availability and low cost. Method it is an observational study including patients who attended the out-patient clinic of Nephrology, at Medica Hospital, Kolkata between July 2022 to February 2023. Inclusion criteria: Exclusion criteria: Quantitative estimation of urine albumin was performed using the VITROS Chemistry Products mALB Reagent along with the VITROS Chemistry Products Calibrator Kit 24 on the VITROS 5,1 FS Chemistry System and the VITROS 5600 Integrated System. Blood sugar was measured by glucose oxidase method. eGFR by CKD EPI equation. Statistical Methodology Continuous variables were presented with mean and standard deviation and tested for normal distribution by the Kolmogorov-Smirnov test. Categorical variables were summarized using frequency and percentages. For testing of related samples, Wilcoxon sign ranked test is used. Statistical analyses were performed using the SPSS software with version 26.0. Results A total of 100 patients were included in the study, of which 3 patients were lost to follow up and 2 patients discontinued the study at 3 months due to fall in eGFR below 25 ml/min/1.73 m2 and 4 patients discontinued after 3 months because of fungal genital infections. After Dapaglifozin administration, a significant reduction in Urine Albumin-creatinine ratio (UACR) was observed, by a percentage decrease of 37.3% (p&amp;lt;0.001) at 3 months and of 70.2% (p&amp;lt;0.001) at 6 months from baseline. Similarly, there was an acute reduction in eGFR from baseline. A percentage decrease by 5.16% (p&amp;lt;0.001) was observed at 3 months &amp; a decrease by 5.69% (p&amp;lt;0.001) at 6 months from baseline. Conclusion Conventional approaches reduce but have not been able to stop disease progression in Diabetic Kidney Disease (DKD). SGLT2i can protect against the onset of DKD, slow disease progression independently. They have an antiproteinuric effect in patients with diabetic nephropathy which was sustained throughout the follow-up period in my study. Studies have also shown that SGLT2i reduce major adverse cardiovascular events in patients with T2DM and established cardiovascular disease. With the new results of EMPA-KIDNEY trial, SGLT2i are being used at even lower eGFR (&amp;lt;25 ml/min/1.73 m2 till on hemodialysis) and such vast health benefits, invention of SGLT2i are is a boon to the mankind.

#1917 SGLT2-Inhibition in patients with Alport syndrome – an international, retrospective and in parts prospective observational large cohort study

Abstract Background and Aims Large-scale trials showed positive outcomes of SGLT2-inhibitors (SGLT2i) in elderly patients with CKD. Patients with Alport syndrome, a type IV collagen disease, develop CKD early in life. Whether the use of SGLT2i is safe and effective in patients with the type IV collagen disease Alport syndrome (and thus a different pathogenesis) has not yet been investigated specifically besides case reports. Method For the first time, this observational, multicenter, international study (NCT02378805) assessed 112 patients with AS from nine countries and 21 trial sites after start of SGLT2i at early stages of their chronic kidney disease (CKD). The study's primary endpoint was change of albuminuria in albumin/g creatinine after start of therapy with SGLT2i. Results Compared to the large randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this trial were much younger (38 ± 14 years; n = 101), had a better eGFR (63 ± 35 ml/min/1.73m2; n = 98) and had a higher albuminuria (1699 ± 1472 mg/g creatinine; n = 51). At a mean time on SGLT2i-therapy of 6 ± 1 months, albuminuria decreased significantly (1727 ± 1564 vs. 1203 ± 1165 mg/g creatinine; n = 33; p = 0.01). Compared to baseline, at the first three follow-up visits after initiation of SGLT2i-therapy, a significant reduction of albuminuria &amp;gt;30% was observed. Mean loss of eGFR was 9 ± 12 ml/min/1.73 m² almost one year after initiation of SGLT2i-therapy (n = 35). At a mean follow up of 12 ± 2 month after initiation of SGLT2i-therapy, serum-albumin increased significantly from 3.7 ± 0.7 to 4.0 ± 0.4 g/dL (n = 18; p = 0.019). At a total of 68 patient-years at risk, adverse events occurred in 11/85 patients (13%). Two very serious adverse events (acute necrotizing pancreatitis and Fournier's gangrene) occurred. Conclusion This study demonstrated that SGLT2i, when added to RASi, have the potential to reduce the rate of albuminuria in adult patients with Alport Syndrome. The study will be continued to provide valuable data on the long-term course of CKD under SGLT2i-therapy in AS to investigate if the promising reduction of albuminuria results in a clinical relevant delay in renal failure. This observational study successfully formed the scientific basis for the current randomized controlled trial with SGLT2i in children and young adults with AS Double Protect Alport.