Effects Of SGLT2 Inhibitors Research Articles

Differential effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular and renal outcomes according to renal function: a dose-response meta-analysis involving 10 randomized clinical trials and 71 553 individuals.

The main target of sodium-glucose cotransporter 2 inhibitors (SGLT2i), the sodium-glucose cotransporters 2, is found in the kidneys, and their activity is reduced in patients with chronic kidney disease (CKD). How the efficacy of SGLT2i may vary in patients with different levels of renal impairment has not been fully elucidated. We searched the PubMed databases for relevant studies published through May 25, 2022. Randomized control trials comparing SGLT2i with placebo and reporting cardiovascular or renal outcomes were included. The primary outcome was the composite of major adverse cardiovascular events (MACE), which were defined as cardiovascular death (CV death), nonfatal myocardial infarction (MI), and nonfatal ischemic stroke. Secondary outcomes included the components of MACE, all-cause mortality, hospitalization for heart failure (HHF), the composite of CV death and HHF, and composite renal outcomes. Linear meta-regression analysis was used to assess the effects of estimated glomerular filtration rate (eGFR) on the risks associated with SGLT2i treatment vs placebo for all outcomes. Nonlinear meta-regression analysis was also performed for MACE to investigate the combined influence of reduced drug efficacy in CKD but possible greater risk reduction in a population with higher risk at baseline. Further analyses were performed by including additional study-level covariates, including the prevalence of diabetes mellitus (DM), heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD). Risk ratios for MACE, CV death, nonfatal MI, HHF, and composite renal outcomes associated with SGLT2i treatment were not significantly related to baseline eGFR values. A positive association was observed between eGFR values and the risk of stroke with SGLT2i use (regression coefficient β = .0109, 95% confidence interval [CI] 0.0029-0.0188). A similar positive association was observed between eGFR values and the composite outcome of CV death and HHF (β = .0025, 95% CI 0.0000-0.0051). The results of the meta-regression analyses, including the additional covariates of DM, HF, and ASCVD, were consistent with the results of the primary analyses for most outcomes. The protective effects of SGLT2i for reducing most adverse cardiovascular and renal outcomes persisted in patients with variable degrees of renal impairment. The observed benefits such as preventing CV death, HF worsening, or stroke may be greater for patients with more severe CKD. Considering the cardiovascular and renal benefits associated with SGLT2i treatment, patients with CKD should be treated aggressively to improve outcomes. CRD42021273500.

Effect of sodium glucose cotransporter 2 inhibitors on atrial tachy-arrhythmia burden in patients with cardiac implantable electronic devices.

Use of sodium glucose cotransporter 2 inhibitors (SGLT2i) was associated with a reduction in atrial fibrillation hospitalizations. Therefore, we aim to evaluate the effects of SGLT2i on atrial tachy-arrhythmias (ATA) in patients with cardiac implantable electronic devices (CIEDs). All 13 888 consecutive patients implanted with a CIED in two tertiary medical centers were enrolled. Treatment with SGLT2i was assessed as a time dependent variable. The primary endpoint was the total number of ATA. Secondary endpoints included total number of ventricular tachy-arrhythmias (VTA), ATA and VTA, and death. All events were independently adjudicated blinded to the treatment. Multivariable propensity score modeling was performed. During a total follow-up of 24 442 patient years there were 62 725 ATA and 10 324 VTA events. Use of SGLT2i (N = 696) was independently associated with a significant 22% reduction in the risk of ATA (hazard ratio [HR] = 0.78 [95% confidence interval {CI} = 0.70-0.87]; p < .001); 22% reduction in the risk of ATA/VTA (HR = 0.78 [95% CI = 0.71-0.85]; p < .001); and with a 35% reduction in the risk of all-cause mortality (HR = 0.65 [95% CI = 0.45-0.92]; p = .015), but was not significantly associated with VTA risk (HR = 0.92 [95% CI = 0.80-1.06]; p = .26). SGLT2i were associated with a lower ATA burden in heart failure (HF) patients but not among diabetes patients (HF: HR = 0.68, 95% CI = 0.58-0.80, p < .001 vs. Diabetes: HR = 0.95, 95% CI = 0.86-1.05, p = .29; p < .001 for interaction between SGLT2i indication and ATA burden). Our real world findings suggest that in CIED HF patients, those with SGLT2i had a pronounced reduction in ATA burden and all-cause mortality when compared with those not on SGLT2i.

Blood pressure-lowering effects of SGLT2 inhibitors and GLP-1 receptor agonists for preventing of cardiovascular events and death in type 2 diabetes: a systematic review and meta-analysis.

To investigate the lowering BP effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on the risk of major cardiovascular event stratified by glucose-lowering drugs, baseline BP, glycated hemoglobin (HbA1c), and history of cardiovascular disease in patients with type 2 diabetes. We performed a systematic review of the MEDLINE and EMBASE databases search up to December 31, 2022, (PROSPERO, CRD42023400899) to identify all large-scale cardiovascular outcomes (CVO) trials of SGLT2i and GLP-1 RAs in which more than 1,000 patient-years of follow-up in each randomized group. Outcomes included all-cause mortality, major adverse cardiovascular event (MACE) and its component (cardiovascular death, myocardial infarction [MI], and stroke), heart failure, and renal failure. A random-effects meta-analyses were used to pool the estimates. Eighteen CVOTs (ten for SGLT2i and eight for GLP-1 RAs) with 127,606 patients with type 2 diabetes were included. Over 2.5years median follow-up, the average reduction of systolic BP was 2.2mmHg (mean difference [MD] - 2.2; 95% CI - 2.7 to - 1.7) with more important reduction (Pinteraction = 0.001) with SGLT2 inhibitors (- 2.9; - 3.4 to - 2.5) than with GLP-1 RAs (- 1.4; - 1.8 to - 1). With SGLT2i, every 5-mmHg reduction in systolic BP was associated with a significantly lower risk of mortality (hazard ratio[HR], 0.77; 95% CI 0.65-0.90), MACE (HR 0.81 [0.74-0.89]), cardiovascular death (HR 0.72 [0.59-0.88]), MI (HR 0.82 [0.71-0.95]), heart failure (HR 0.49 [0.42-0.57]), and renal failure (HR 0.46 [0.38-0.55]), while the association was not significant for stroke (HR 0.91 [0.69-1.19]). The corresponding effects for every 5-mmHg reduction in SBP with GLP-1 RAs were 0.65 (0.51-0.84) for all-cause mortality, 0.65 (0.56-0.76) for MACE, 0.62 (0.45-0.85) for CV death, 0.71 (0.52-0.76) for MI, 0.49 (0.35-0.69) for stroke, and 0.49 (0.35-0.66) for renal failure, while the association was not significant for heart failure (HR 0.82 [0.63-1.08]). In patients with type 2 diabetes, the hypotensive effects of SGLT2i and GLP-1 RAs were significantly associated with a reduction in mortality and cardiorenal events. These findings suggest that the lowering BP effect could be seen as an additive indicator of cardiovascular protection by SGLT2i and GLP-1 RAs drugs.

Hospitalization of Patients With Diabetes Due to Ketoacidosis Before and After the Initiation of Sodium-Glucose Cotransporter-2 Inhibitors

ObjectiveDiabetic ketoacidosis (DKA) is a rare side effect related to sodium-glucose cotransporter-2 inhibitors (SGLT2I). This study investigated the incidence of people with diabetes hospitalized because of DKA after the implementation of SGLT2I (2015-2019), compared with the pre-SGLT2I era. MethodsIn this retrospective cohort study, medical records of all adult patients hospitalized with a diagnosis of DKA in a tertiary referral center from 2011-2019 were reviewed. The incidence of DKA was compared between the periods 2011-2014 and 2015-2019. Demographic and clinical data of patients hospitalized with DKA as well as SGLT2I use were extracted. ResultsDuring 2011-2019, there were 186 hospitalizations because of DKA. The rate of hospitalization was stable during 2011-2019 at 0.22% ± 0.04% (95% CI, 0.18-0.25). The clinical characteristics of people hospitalized with DKA in 2011-2014 were similar to those of people hospitalized during 2015-2019. Only 7 people (6.1%) in the 2015-2019 cohort had SGLT2I-related DKA, and their clinical characteristics were similar to those of the rest of the cohort. ConclusionsThe rate of hospitalizations because of DKA remained stable before and 5 years after SGLT2I were implemented for the treatment of type 2 diabetes mellitus. Larger, multi-institutional studies with longer follow-ups are needed to study the effect of SGLT2I on the rate of hospitalizations because of DKA among people with diabetes. Although DKA events associated with SGLT2I are rare, they should be strongly considered in the differential diagnosis of people treated with these medications.

Empagliflozin reduces endoplasmic reticulum stress associated TXNIP/NLRP3 activation in tunicamycin-stimulated aortic endothelial cells.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to be of therapeutic significance for cardiovascular diseases beyond the treatment of type 2 diabetes. Recent studies have demonstrated the beneficial effects of SGLT2i on endothelial cell (EC) dysfunction, but the underlying cellular mechanisms remain to be clarified. In this study, we sought to understand the effect of empagliflozin (EMPA; Jardiance®) on cell homeostasis and endoplasmic reticulum (ER) stress signaling. ER stress was induced by tunicamycin (Tm) in human abdominal aortic ECs treated with EMPA over 24 h. Tm-induced ER stress caused increases in the protein expression of thioredoxin interacting protein (TXNIP), NLR-family pyrin domain-containing protein 3 (NLRP3), C/EBP homologous protein (CHOP), and in the ratio of phospho-eIF2α/eIF2α. EMPA (50-100 µM) resulted in a dampened downstream activation of ER stress as seen by the reduced expression of CHOP and TXNIP/NLRP3 in a dose-dependent manner. Nuclear factor erythroid 2-related factor 2 (nrf2) translocation was also attenuated in EMPA-treated ECs. These results suggest that EMPA improves redox signaling under ER stress which in turn attenuates the activation of TXNIP/NLRP3.

Effect of Sodium-Glucose Cotransporter-2 Inhibitor Administration on Cardiac Rehabilitation in Patients with Type 2 Diabetes Mellitus with Heart Failure.

Cardiac rehabilitation in patients with diabetes mellitus and heart failure may be affected by anti-diabetic drugs. However, there are few reports on the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on cardiac rehabilitation. Thus, we retrospectively investigated the patient backgrounds and effects of cardiac rehabilitation in 44 patients admitted to our hospital with heart failure and pre-existing diabetes mellitus. Our results showed that the patients tended to be older, and those who received SGLT2 inhibitors had lower systolic blood pressure and left ventricular ejection fraction on admission than those who did not. Cardiac rehabilitation significantly improved the Short Physical Performance Battery (SPPB) score in all patients, and there was no significant difference in body mass index or in body weight. There were no significant differences in SPPB score at admission, discharge, or change from admission to discharge with or without SGLT2 inhibitors. These results suggest that SGLT2 inhibitors do not affect the change in SPPB scores. SGLT2 inhibitors may thus be used safely without affecting cardiac rehabilitation while adhering to the necessary safety precautions.

Comparative effectiveness of sodium-glucose co-transporter 2 inhibitors and dipeptidyl peptidase-4 inhibitors on cardiorenal function and treatment adherence: A Prevalent New-User Design Study in tertiary hospitals

Abstract Objectives Data on the long-term effects comparing sodium-glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i) are scarce, especially from middle-income countries. To examine the effects of SGLT2i and DPP4i on the cardiorenal function and treatment adherence for people with type 2 diabetes (T2D) using prevalent new-user design in real-world setting. Methods We conducted a retrospective cohort study in two tertiary hospitals in Malaysia and matched T2D patients initiated on SGLT2i or DPP4i from 2010 to 2021 using time-conditional propensity score. Outcomes of interest included cardiovascular and renal outcomes, as well as clinical lab outcomes, adherence and non-persistence. The hazard ratios for cardiorenal outcomes was inferred using Cox proportional hazards model. Key findings The cohort included 1528 patients, with 406 SGLT2i users matched with 406 DPP4i users. Over a median follow-up of 1.52 years, no differences in cardiorenal outcomes were observed. Patients initiated with SGLT2i had lower HbA1c at 12-month (-0.79%,p&amp;lt;0.001) compared to DPP4i (-0.49%,p&amp;lt;0.05; difference:-0.30%,p&amp;lt;0.05). No differences in the renal, lipid, weight and blood pressure parameters were observed between both groups. Higher medication persistence was noted among SGLT2i users compared to DPP4i users (92% vs 87%,P=0.03). Conclusions Both medications were comparable in exerting distinct effects on cardiorenal risk factors, with better HbA1c control and medication persistence among SGLT2i users. The long-term cardiorenal outcomes remains undetermined.

The potential of sodium-glucose cotransporter 2 inhibitors for the treatment of systemic right ventricular failure in adults with congenital heart disease.

Given the compelling evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the conventional heart failure population, SGLT2i deserve exploration in systemic right ventricular (sRV) failure. The initial experience with dapagliflozin in sRV failure patients is described, with a focus on tolerability and short-term effects on clinical outcomes. Ten patients (70% female, median age 50 years [46.5-52]) with symptomatic sRV failure who received dapagliflozin 10 mg per day on top of optimal medical therapy between 04-2021 and 01-2023 were included. Within 4 weeks, no significant changes in blood pressure, electrolytes, or serum glucose occurred. Creatinine and estimated glomerular filtration rate (eGFR) showed a slight decline (88 ± 17 to 97 ± 23 µmol/L, p = 0.036, and 72 ± 14 vs. 66 ± 16 ml/min/1.73m2, p = 0.020, respectively). At 6 months follow-up (n = 8), median NT-proBNP decreased significantly from 736.6 [589.3-1193.3] to 531.6 [400.8-1018] ng/L (p = 0.012). Creatinine and eGFR recovered to baseline levels. There were no significant changes in echocardiographic systolic sRV or left ventricular function. New York Heart Association class improved significantly in 4 out of 8 patients (p = 0.046), who also showed an improvement in the 6-minute walk test or bicycle exercise test performance. One female patient developed an uncomplicated urinary tract infection. No patients discontinued treatment. Dapagliflozin was well-tolerated in this small cohort of sRV failure patients. While the early results on the reduction of NT-proBNP and clinical outcome parameters are encouraging, large-scale prospective studies are warranted to thoroughly evaluate the effects of SGLT2i in the growing sRV failure population.

880-P: Effects of Sodium–Glucose Cotransporter-2 Inhibitors on the Risk of Atrial Fibrillation in Older Adults with Type 2 Diabetes

Clinical evidence suggested a protective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the risk of atrial fibrillation (AF) in type 2 diabetes (T2D) patients, but the results were mixed. We aimed to compare the risk of AF in SGLT2i users compared to dipeptidyl peptidase-4 inhibitors (DPP4i) users and determine the effect in different subgroups. Using a 15% random sample of 2017-2018 Medicare claims data, we identified individuals with T2D, no preexisting AF, and initiated SGLT2i or DPP4i. The index date was defined as the date of the first filled prescription of SGLT2i or DPP4i. The outcome was the first incident of diagnosed AF. Inverse probability treatment weighted Cox regression models were used for analyses. Of the 97,660 eligible individuals (age 71.2±9.8 years, 54.6% women), 1.01% (n=989) had incident AF over a median follow-up of 361 days. The crude incidence rate was 8.39 (95% CI: 6.67-9.99) and 11.70 (95% CI: 10.9-12.55) per 1000 person-years in the SGLT2i group and DPP4i group, respectively. SGLT2i was associated with a significantly lower risk of incident AF (HR 0.72 [95% CI 0.56-0.89]) than DPP4i. The risk reduction of incident AF was more pronounced in Hispanic individuals and subgroups with existing cardiovascular (CV) and renal conditions. (Figure) Use of SGLT2i was associated with a lower risk of AF in individuals with T2D. Disclosure Y.Li: None. Y.Guo: None. S.Kimmel: Consultant; GlaxoSmithKline plc., Other Relationship; Janssen Research &amp; Development, LLC. J.Bian: None. D.Schatz: Advisory Panel; Medtronic, Avotres Inc., QuLab Medical Ltd., Kriya Therapeutics. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health.

266-LB: SGLT2 Inhibition Improved Endurance Performance of db/db Mice Accompanied by an Increased Endogenous AMPK Activator in Skeletal Muscles

Background: Diabetes is associated with loss of skeletal muscle mass and function. Specifically, diabetes may affect the function of oxidative muscle fibers with lower fatigability and higher oxidative capacity in skeletal muscle. The effects of SGLT2 inhibition on skeletal muscle metabolism and function in patients with type 2 diabetes remain unclear. Methods: Male db/db (diabetic) and db/+ (non-diabetic) mice at 8 weeks of age were fed a normal chow diet or a diet containing canagliflozin (CANA) for 4 weeks. Grip strength and running distance were assessed during CANA treatment. At the end of CANA treatment, we measured muscle weight and analyzed metabolites in skeletal muscle. Results: The weights of the oxidative soleus and glycolytic extensor digitorum longus muscles were reduced by approximately 50% in the diabetic group compared to the non-diabetic group, but neither was altered by CANA treatment. Grip strength did not differ between the CANA-treated diabetic, diabetic, and non-diabetic groups. However, the running distance decreased in the diabetic group compared to the non-diabetic group (89 ± 60 m vs. 1980 ± 276 m). This was partially restored by CANA treatment (89 ± 60 m vs. 415 ± 140 m). Metabolomic analysis revealed that long-chain acyl-CoA increased and medium-chain and short-chain acyl-CoA decreased in diabetic soleus muscle. In contrast, CANA treatment increased medium-chain and short-chain acyl-CoA. Furthermore, CANA increased 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5’-monophosphate (AICARP), an endogenous AMPK activator, by approximately 3-fold in diabetic soleus muscle with increased levels of AMPK phosphorylation (Thr172). Conclusion: These results suggest that SGLT2 inhibitors may activate the AICARP/AMPK pathway and improve impaired oxidative muscle function in patients with type 2 diabetes. Disclosure S. Nakamura: None. Y. Miyachi: None. H. Yokomizo: None. H. Otsuka: None. R. Sakamoto: None. M. Takahashi: None. Y. Izumi: None. T. Miyazawa: None. T. Bamba: None. Y. Ogawa: None.

877-P: Effects of SGLT2 Inhibitors on Gut Microbiota in Japanese Patients with Type 2 Diabetes

SGLT2 inhibitors (SGLT2is) promote urinary glucose excretion, thereby lowering blood glucose. In addition, SGLT2is have been reported to reduce body weight. However, the mechanism underlying the reduction in the body weight induced by SGLT2i remains to be elucidated. In this study, we investigated the effects of SGLT2is on the gut microbiota. A total of 36 Japanese patients with type 2 diabetes received SGLT2is for 3 months, and the prevalences of balance-regulating bacteria (12 types), which regulate the balance of the gut microbiota to maintain health, and balance-disturbing bacteria (6 types), which disturb the balance of the gut microbiota to cause disease, in the feces of the patients before and after 3 months of SGLT2i treatment were determined. Furthermore, the prevalences of short-chain fatty acid-producing bacteria (6 types), which are thought to be involved in body weight gain and weight loss, were also analyzed individually. The SGLT2i treatment was associated with a significant increase of the overall prevalence of the 12 types of balance-regulating bacteria. In addition, significant increases in the prevalences of the short-chain fatty acid-producing bacteria among the balance-regulating bacteria were also observed. However, the SGLT2i treatment had no effect on the balance-disturbing bacteria. Individual analyses of the balance-regulating bacteria revealed that the SGLT2i treatment was associated with a significant increase in the prevalence of Ruminococci, which are balance-regulating bacteria classified as short-chain fatty acid-producing bacteria. In conclusion, SGLT2i treatment was associated with an overall increase in the prevalence of balance-regulating bacteria. Among the balance-regulating bacteria, the prevalences of short-chain fatty acid-producing bacteria increased. Since short-chain fatty acids have been reported to prevent obesity, these results suggest that SGLT2is might induce body weight reduction via their actions on the gut microbiota. Disclosure M.Kusunoki: Research Support; Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, Kaken Pharmaceutical Co., Ltd., Eli Lilly Japan K.K. F.Hisano: None. S.Matsuda: None. T.Miyata: None.

98-LB: Effects of SGLT2 Inhibition on Skeletal Muscle Bioenergetics and Myocellular Lipids in Patients with T2D and HFrEF

Background: The CV benefits of SGLT2i are well established. However, how skeletal muscle (SkM) bioenergetics respond to SGLT2i in T2D and HFrEF remains largely unknown. Objective: To explore the effects of empagliflozin on SkM bioenergetics (phosphorus metabolites &amp; myocellular lipid content) at rest and post-exercise (31P &amp; 1H MRS) and cardiac function (MRI). Methods: Subjects with T2D &amp; HFrEF (&amp;lt;40%) (n=6) were randomized 2:1 to empagliflozin 25mg (SGLT2i) or placebo for 12 wks (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3, EF 28±4%). A cardiac MRI, &amp; static/dynamic 31P &amp; 1H SkM by MRS, were performed before &amp; after treatment. Results: In the empagliflozin group, SkM 31P MRS at rest, showed decrease in phosphodiesterase [PDE]. 31P MRS post-exercise, showed significant improvement in Phosphocreatinine (PCr) recovery, expressed by the K value. 1H MRS showed a reduction of saturated intramyocellular lipids (IMCL-CH2:CH3 ratio). Conclusion: Empagliflozin in subjects with T2D and HFrEF had beneficial effects in SkM energy utilization and muscle recovery post-exercise as determined by a decrease in PDE and increase in K value. Additionally, empagliflozin decreased saturated IMCL, which could be expected to improve mitochondrial function and energy utilization. If similar findings were to occur in cardiac muscle, this could provide a novel mechanism for the beneficial CV effects of SGLT2i. Disclosure Y. Qin: None. N. D. Sanchez: None. A. Moody: None. F. M. Acosta: None. S. Neppala: None. M. Brown: None. H. Honka: None. L. A. Cruz Moreno: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. G. D. Clarke: None. E. Cersosimo: None. R. A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck &amp; Co., Inc. C. Solis-Herrera: None. Funding Doris Duke Charitable Foundation; Voelcker Foundation; National Institutes of Health

97-LB: Empagliflozin Improves Cardiopulmonary Function and VE/VCO2 in Patients with T2D and HFrEF

Background: Cardioprotective benefits of SGLT2 inhibitors (SGLT2i) are well established. However, their effects on cardiopulmonary function measured by CPET in patients with T2D and HFrEF continue to be largely unknown. Objective: Examine the effects of SGLT2i on cardiopulmonary function measured by cardiopulmonary exercise test (CPET) &amp; 6MWT in patients with T2D &amp; HFrEF. Methods: Six subjects with T2D with HFrEF (&amp;lt;40%) (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3, EF 28±4%) were randomized to empagliflozin 25mg (SGLT2i) vs. placebo in a 2:1 fashion for 12 weeks. Cardiac MRI, 6MWT, and CPET were performed pre- and post-intervention. Results: SGLT2i group showed an increase in EF. All subjects reached submaximal cardiovascular effort (RER≤1.10). The Ventilatory Anaerobic Threshold (VT, submaximal index of exercise capacity) showed a significant increase in VT time with SGLT2i (p=0.05). The rest of the parameters trended toward improvement including Ve/VCO2 slope and 6MWT. Conclusion: Subjects with T2D and HFrEF, treated with an SGLT2i had improved EF, a decrease in the worsening of the Ve/VCO2 slope (a predictor of mortality in HF patients), an increase in 6MWT, and significantly improved VT time (aerobic metabolism) compared to placebo. These findings may represent a novel mechanism of CV protection and warrants further investigation. Disclosure Y. Qin: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. G. D. Clarke: None. E. Cersosimo: None. S. E. Espinoza: None. R. A. Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck &amp; Co., Inc., Speaker's Bureau; AstraZeneca. C. Solis-herrera: None. F. M. Acosta: None. S. Neppala: None. T. M. Cortes: None. A. Stepanenko: None. A. Moody: None. N. D. Sanchez: None. M. Brown: None. L. A. Cruz moreno: None. Funding Doris Duke Charitable Foundation; Voelcker Foundation; National Institutes of Health

Serum uric acid lowering and effects of sodium-glucose cotransporter-2 inhibitors on gout: A meta-analysis and meta-regression of randomized controlled trials.

To pool the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on gout and to investigate the association of these effects with baseline serum uric acid (SUA), SUA lowering, and underlying conditions, such as type 2 diabetes mellitus (T2DM)/heart failure (HF). PubMed, Embase, Web of Science, Cochrane Library and clinical trial registry websites were searched for randomized controlled trials (RCTs) or post hoc analyses (≥1-year duration; PROSPERO:CRD42023418525). The primary outcome was a composite of gouty arthritis/gout flares and commencement of anti-gout drugs (SUA-lowering drugs/colchicine). Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using a generic inverse-variance method with a random-effects model. Mixed-effects model univariate meta-regression analysis was performed. Five RCTs involving 29 776 patients (T2DM, n = 23 780) and 1052 gout-related events were identified. Compared to placebo, SGLT2 inhibitor use was significantly associated with reduced risk of composite gout outcomes (HR 0.55, 95% CI 0.45-0.67; I2 = 61%, P < 0.001). Treatment benefits did not differ between trials being conducted exclusively in baseline HF versus those conducted in patients with T2DM (P-interaction = 0.37), but were greater with dapagliflozin 10 mg and canagliflozin 100/300 mg (P < 0.01 for subgroup differences). Sensitivity analysis excluding trials that evaluated the effects of empagliflozin 10/25 mg (HR 0.68, 95% CI 0.57-0.81; I2 = 0%) accentuated the benefits of SGLT2 inhibitors with no between-trial heterogeneity (HR 0.46, 95% CI 0.39-0.55; I2 = 0%). Univariate meta-regression found no impact of baseline SUA, SUA lowering on follow-up, diuretic use, or other variables on their anti-gout effects. We found that SGLT2 inhibitors significantly reduced the risk of gout in individuals with T2DM/HF. Lack of an association with SUA-lowering effects suggests that metabolic and anti-inflammatory effects of SGLT2 inhibitors may predominantly mediate their anti-gout benefits.

#3895 COMPARABLE RENO-CARDIAC PROTECTIVE EFFECTS OF SGLT2 INHIBITION VERSUS DPP-4 INHIBITION IN DIABETIC KIDNEY TRANSPLANT RECIPIENTS: KUWAIT EXPERIENCE

Abstract Background and Aims Diabetes is the most common cause of chronic kidney disease (CKD) globally. The renal and cardio-vascular benefits of the new anti-diabetic agents are not assessed comprehensively. We aimed to evaluate the short term renal and cardio-protective effects of Sodium-Glucose Cotransporter-2 Inhibition (SGLT2i) Vs. Dipeptidyl peptidase-4 Inhibition (DPP4i) among diabetic kidney transplant recipients. Method In this observational trial, 222 diabetic kidney transplants recipients (NODAT or type 2 diabetes) were enrolled and were categorized into two groups. Group 1 (n = 99) received SGLT2i while group 2(n = 123) received DPP4i as an add on antidiabetic medications. All patients in the two groups were followed up for 12 months. Results Most patients in the two groups (1&amp;2) were men (59.6 vs. 61.7%, p = 0.73) in their middle age (58.5±11.9 vs. 54.4±12.9, p = 0.016) years respectively. The two groups were matched regarding their demographics especially the type of donor, type of immunosuppression (induction or maintenance), number of cardiovascular events before enrollment in the study and the number of patients who were maintained on ACEi or ARB(p&amp;gt;0.05). The minority of patients were smokers (12.9 vs.8.7%), and chronic glomerulonephritis was the original disease in 36.4 vs. 35.4% in the two groups, respectively. Most of the enrolled patients (72.8 vs. 78.6%) underwent hemodialysis pre-transplant. During follow up period, patients in both groups were comparable regarding mean blood pressure, body weight, HbA1C, 24-hour urine protein, and graft function (represented by the mean serum creatinine) at different time intervals and compared to base line values(p&amp;gt;0.05). However, the mean HbA1C was significantly higher in group 1 during the whole follow up period of the study (p&amp;lt;0.05) but it did not drop significantly compared to baseline values (p&amp;gt;0.05). We did not report any macroangiopathic events (cerebral stroke, acute myocardial infection, or peripheral arterial disease) in the two groups during the study. Conclusion Both GLT2i and DPP-4 I are comparable regarding renal and cardio-vascular protection among diabetic kidney transplant recipients.

The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials.

Type 2 Diabetes Mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are part of metabolic syndrome and share multiple causal associations. Both conditions have an alarmingly increasing incidence and lead to multiple complications, which have an impact on a variety of organs and systems, such as the kidneys, eyes, and nervous and cardiovascular systems, or may cause metabolic disruptions. Sodium-glucose cotransporter 2-inhibitors (SGLT2-i), as an antidiabetic class with well-established cardiovascular benefits, and its class members have also been studied for their presumed effects on steatosis and fibrosis improvement in patients with NAFLD or non-alcoholic steatohepatitis (NASH). The MEDLINE and Cochrane databases were searched for randomized controlled trials examining the efficacy of SGLT2-i on the treatment of NAFLD/NASH in patients with T2DM. Of the originally identified 179 articles, 21 articles were included for final data analysis. Dapagliflozin, empagliflozin, and canagliflozin are some of the most used and studied SGLT2-i agents which have proven efficacy in treating patients with NAFLD/NASH by addressing/targeting different pathophysiological targets/mechanisms: insulin sensitivity improvement, weight loss, especially visceral fat loss, glucotoxicity, and lipotoxicity improvement or even improvement of chronic inflammation. Despite the considerable variability in study duration, sample size, and diagnostic method, the SGLT2-i agents used resulted in improvements in non-invasive markers of steatosis or even fibrosis in patients with T2DM. This systematic review offers encouraging results that place the SGLT2-i class at the top of the therapeutic arsenal for patients diagnosed with T2DM and NAFLD/NASH.

Cost-Effectiveness of SGLT2 Inhibitors in a Real-World Population: A MICADO Model-Based Analysis Using Routine Data from a GP Registry.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce the risk of cardiovascular complications, which largely drive diabetes' health and economic burdens. Trial results indicated that SGLT2i are cost effective. However, these findings may not be generalizable to the real-world target population. This study aims to evaluate the cost effectiveness of SGLT2i in a routine care type 2 diabetes population that meets Dutch reimbursement criteria using the MICADO model. Individuals from the Hoorn Diabetes Care System cohort (N = 15,392) were filtered to satisfy trial inclusion criteria (including EMPA-REG, CANVAS, and DECLARE-TIMI58) or satisfy the current Dutch reimbursement criteria for SGLT2i. We validated a health economic model (MICADO) by comparing simulated and observed outcomes regarding the relative risks of events in the intervention and comparator arm from three trials, and used the validated model to evaluate the long-term health outcomes using the filtered cohorts' baseline characteristics and treatment effects from trials and a review of observational studies. The incremental cost-effectiveness ratio (ICER) of SGLT2i, compared with care-as-usual, was assessed from a third-party payer perspective, measured in euros (2021 price level), using a discount rate of 4% for costs and 1.5% for effects. From Dutch individuals with diabetes in routine care, 15.8% qualify for the current Dutch reimbursement criteria for SGLT2i. Their characteristics were significantly different (lower HbA1c, higher age, and generally more preexisting complications) than trial populations. After validating the MICADO model, we found that lifetime ICERs of SGLT2i, when compared with usual care, were favorable (<€20,000/QALY) for all filtered cohorts, resulting in an ICER of €5440/QALY using trial-based treatment effect estimates in reimbursed population. Several pragmatic scenarios were tested, the ICERs remained favorable. Although the Dutch reimbursement indications led to a target group that deviates from trial populations, SGLT2i are likely to be cost effective when compared with usual care.

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an overview of 36 systematic reviews.

The recently published randomized trials (RCTs) evaluating the effect of Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) led researchers to perform a plethora of systematic reviews (SRs), often providing contradictory conclusions. This overview of reviews was aimed at summarizing the evidence of these SRs, quantifying the overlap, re-analyzing the evidence in case new studies that were identified, and mapping knowledge gaps. Literature search was conducted through Medline, Scopus, and Cochrane until March 22, 2023. Overall, 36 SRs synthesizing results from 18 RCTs were identified. A substantial overlap was identified among the SRs synthesizing large heart failure or cardiovascular outcome trials (CVOTs). Regarding the composite outcome of cardiovascular (CV) mortality or hospitalization for heart failure (HHF), all authors reported a significant favorable effect. A beneficial effect was also noted for CV and all-cause mortality, albeit not significant. Our meta-analysis demonstrated a significant improvement in health-related quality-of-life (HRQoL) as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS, MD = 1.97, p < 0.001), Total Symptom Score (KCCQ-TSS, MD = 2.29, p < 0.001), Clinical Summary Score (KCCQ-CSS, MD = 1.59, p < 0.001), and the 6-min walking distance (MD = 10.78m, p = 0.032). Regarding safety, SGLT2i were associated with a significantly lower risk of serious adverse events compared to placebo (RR = 0.94, p = 0.002). The use of SGLT2i in HFpEF is both efficient and safe. Further research is required to clarify the impact of SGTL2i on different subphenotypes of HFpEF and the cardiorespiratory capacity of these patients.

Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis

AimsSteatosis reducing effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-alcoholic steatohepatitis (NASH) has been consistently reported in humans, but their mechanism remains uncertain. In this study, we examined the expression of SGLT2 in human livers and investigated the crosstalk between SGLT2 inhibition and hepatic glucose uptake, intracellular O-GlcNAcylation, and autophagic regulation in NASH. Materials and methodsHuman liver samples obtained from subjects with/without NASH were analyzed. For in vitro studies, human normal hepatocytes and hepatoma cells were treated with SGLT2 inhibitor under high-glucose and high-lipid conditions. NASH in vivo was induced by a high-fat, −fructose, and -cholesterol Amylin liver NASH (AMLN) diet for 10 weeks followed by an additional 10 weeks with/without SGLT2 inhibitor (empagliflozin 10 mg/kg/day). ResultsLiver samples from subjects with NASH were associated with increased SGLT2 and O-GlcNAcylation expression compared with controls. Under NASH condition (in vitro condition with high glucose and lipid), intracellular O-GlcNAcylation and inflammatory markers were increased in hepatocytes and SGLT2 expression was upregulated; SGLT2 inhibitor treatment blocked these changes by directly reducing hepatocellular glucose uptake. In addition, decreased intracellular O-GlcNAcylation by SGLT2 inhibitor promoted autophagic flux through AMPK-TFEB activation. In the AMLN diet-induced NASH mice model, SGLT2 inhibitor alleviated lipid accumulation, inflammation, and fibrosis through autophagy activation related to decreased SGLT2 expression and O-GlcNAcylation in the liver. ConclusionsThis study firstly demonstrates increased SGLT2 expression in NASH and secondly reveals the novel effect of SGLT2 inhibition on NASH through autophagy activation mediated by inhibition of hepatocellular glucose uptake and consequently decreased intracellular O-GlcNAcylation.

Effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on cardiovascular and kidney outcomes in Asian versus White patients with type 2 diabetes mellitus

BackgroundThe study aimed to assess the treatment effects of the two medications on cardiovascular and kidney outcomes in Asian compared with White patients with type 2 diabetes mellitus (T2DM). MethodsMEDLINE, EMBASE, and CENTRAL were searched up to October 31, 2022. We included the trials that assessed the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus placebo in Asian and White patients with T2DM on major adverse cardiovascular events (MACE) and kidney outcomes. The Bucher method was used to perform an indirect comparison for estimating the differences in treatment effects of GLP-1 RA and SGLT2i between Asian versus White patients. Interaction tests were also performed for treatment-by-race to assess the potential effect modification by race. ResultsWe included 22 publications from 13 randomized trials. For MACE, there were no differences in treatment effects of GLP-1 RA (HR = 0.84, 95% CI: 0.68–1.04) or SGLT2i (HR = 0.90, 95% CI: 0.72–1.13) in Asian versus White patients. No differences in treatment effects of SGLT2i on kidney outcomes in Asian versus White patients were found (HR = 1.01, 95% CI: 0.75–1.36). There was no significant effect modification by race on cardiovascular and kidney outcomes. ConclusionsThere were no significant differences in treatment effects of GLP-1 RA or SGLT2i for MACE between Asian and White patients with T2DM. Likewise, no significant differences in treatment effects of SGLT2i on kidney outcomes were found between Asian and White patients.