Effects Of Sodium-glucose Cotransporter Research Articles

Effect of sodium-glucose cotransporter 2 inhibitors on left atrial remodeling and prognosis in patients with type 2 diabetes and heart failure with reduced ejection fraction.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been found to minimize hospitalization for heart failure and cardiovascular death. Cardiac reverse remodeling may be a mechanism responsible for the favorable clinical efficacy of SGLT2is on heart failure. To date, few studies have examined their effects on the left atrium. Therefore, the purpose of this study was to explore whether SGLT2is improve left atrial adverse remodeling in patients with type 2 diabetes and heart failure with reduced ejection fraction (HFrEF). A single-center, retrospective, observational study was conducted. Consecutive patients with type 2 diabetes and HFrEF hospitalized at the First Affiliated Hospital of Dalian Medical University for acute decompensated heart failure between 1 January 2019 and 1 March 2022 were identified. On the basis of their treatment strategies, the enrolled participants were classified into SGLT2i and non-SGLT2i groups. The primary end point was all-cause mortality. Changes in left atrial echocardiographic indices from baseline to follow-up were also assessed. A total of 198 patients (mean age: 63.96 ± 12.11 years, 20.71% women) were included. Greater reductions from baseline were seen with SGLT2i in the left atrial diameter (P < 0.001), left atrial superior-inferior diameter (P = 0.027), left atrial transverse diameter (P = 0.020), left atrial volume (P = 0.005), and left atrial volume index (P = 0.004). Moreover, 48 cases (48.48%) in the SGLT2i group and 33 (33.33%) in the non-SGLT2i group showed left atrial reverse remodeling (P = 0.003). Survival analysis demonstrated significantly lower overall mortality in the SGLT2i group compared with the non-SGLT2i group. This study found that SGLT2i therapy promoted left atrial structure reverse remodeling. This beneficial effect may be a vital mechanism by which SGLT2i improved clinical outcomes in patients with HFrEF.

Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury.

Association of sodium-glucose cotransporter 2 inhibitors with post-discharge outcomes in patients with acute heart failure with type 2 diabetes: a cohort study

BackgroundGiven the cumulative evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on chronic heart failure, demand is emerging for further information on their effects in patients who are hospitalized for acute heart failure. However, there is still limited evidence about the class effect of SGLT2is on acute heart failure. We investigated whether initiating treatment with SGLT2is after an episode of acute heart failure reduces the risks of post-discharge heart failure readmission or cardiovascular mortality among patients with type 2 diabetes.MethodsA retrospective cohort study was conducted in a cohort of patients with type 2 diabetes who hospitalized for heart failure, using Korean Health Insurance Review & Assessment database (2015–2020). The exposure was defined as initiation of SGLT2is during hospitalization or at discharge. We assessed hazards of post-discharge heart failure readmission and cardiovascular death at 1-year, and 30-, 60-, and 90-day from the date of discharge in the SGLT2is users and non-users. Cox proportional hazards models with propensity score-based inverse probability of treatment weighting were used to estimate hazard ratios and 95% confidence intervals.ResultsAmong 56,343 patients with type 2 diabetes hospitalized for heart failure, 29,290 patients were included in the study cohort (mean [SD] age, 74.1 [10.8] years; 56.1% women); 818 patients (2.8%) were prescribed SGLT2is during index hospitalization or at discharge. Patients with a prescription for SGLT2i vs. those without prescription had lower rates of heart failure readmission or cardiovascular death at 1 year (22.4% vs. 25.3%; adjusted hazard ratio, 0.90 [95% confidence interval, 0.87–0.93]), and also at 30 days (7.0% vs. 7.7%%; 0.74 [0.69–0.79]).ConclusionsAmong patients with type 2 diabetes, initiating SGLT2i treatment after an episode of acute heart failure was significantly associated with a reduced combined risk of heart failure readmission and cardiovascular mortality in a nationwide cohort reflecting routine clinical practice.

Foetal recapitulation of nutrient surplus signalling by O-GlcNAcylation and the failing heart.

The development of the foetal heart is driven by increased glucose uptake and activation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α), which drives glycolysis. In contrast, the healthy adult heart is governed by sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK), which promote fatty-acid oxidation and the substantial mitochondrial ATP production required for survival in a high-workload normoxic environment. During cardiac injury, the heart recapitulates the foetal signalling programme, which (although adaptive in the short term) is highly deleterious if sustained for long periods of time. Prolonged increases in glucose uptake in cardiomyocytes under stress leads to increased flux through the hexosamine biosynthesis pathway; its endproduct-uridine diphosphate N-acetylglucosamine (UDP-GlcNAc)-functions as a critical nutrient surplus sensor. UDP-GlcNAc drives the post-translational protein modification known as O-GlcNAcylation, which rapidly and reversibly modifies thousands of intracellular proteins. Both O-GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O-GlcNAcylation is regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which adds or removes GlcNAc (N-acetylglucosamine), respectively, from target proteins. Recapitulation of foetal programming in heart failure (regardless of diabetes) is accompanied by marked increases in O-GlcNAcylation, both experimentally and clinically. Heightened O-GlcNAcylation in the heart leads to impaired calcium kinetics and contractile derangements, arrhythmias related to activation of voltage-gated sodium channels and Ca2+ /calmodulin-dependent protein kinase II, mitochondrial dysfunction, and maladaptive hypertrophy, microvascular dysfunction, fibrosis and cardiomyopathy. These deleterious effects can be prevented by suppression of O-GlcNAcylation, which can be achieved experimentally by upregulation of AMPK and SIRT1 or by pharmacological inhibition of OGT or stimulation of OGA. The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the heart are accompanied by reduced O-GlcNAcylation, and their cytoprotective effects are reportedly abrogated if their action to suppress O-GlcNAcylation is blocked. Such an action may represent one of the many mechanisms by which enhanced AMPK and SIRT1 signalling following SGLT2 inhibition leads to cardiovascular benefits. These observations, taken collectively, suggest that UDP-GlcNAc functions as a critical nutrient surplus sensor (which acting in concert with mTOR and HIF-1α) can promote the development of cardiomyopathy.

Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: An updated meta-analysis of randomized controlled trials

Background and aimSodium-glucose co-transporter 2 inhibitors (SGLT2i) has been verified to improve Non-alcoholic fatty liver disease (NAFLD) in previous clinical practice. We mainly aim to investigate the effects of SGLT2i on liver fibrosis in NAFLD patients with type 2 diabetes mellitus (T2DM). MethodsWe conducted a comprehensive literature search utilizing the databases PubMed, Embase, Web of Science, and Cochrane Library, and extracted continuous data in the form of mean and standard deviation of the difference before and after treatment. RevMan 5.3 software was used to chart the pooled forest plot and perform heterogeneity, sensitivity and subgroup analysis. This study is conducted under the protocol registered with the Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY protocol 4946, INPLASY202360058). ResultsA total of 16 articles involving 699 patients were included. Indicators of liver fibrosis, containing Liver Stiffness Measurement (LSM), Controlled Attenuation Parameter (CAP), Serum ferritin, Serum type 4 collagen 7s, and FIB-4 index, were found to be considerably reduced by SGLT2i medication and subgroup analysis manifested pronounced dose-dependence. Additionally, SGLT2i therapy decreased BMI, lipid buildup and insulin resistance. ConclusionsSGLT2 inhibitors significantly ameliorated liver fibrosis and liver fat content, improved body conditions and insulin resistance, demonstrating that SGLT2i might reduce the risk of the progression of liver fibrosis and have a positive effect on NAFLD patients with T2DM.

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.

Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation.

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

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.

Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering

IntroductionRelationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain.Research design and methodsWe analyzed 4395 individuals with prebaseline and postbaseline hemoglobin...

Left Ventricular Systolic Function After 3 Months of SGLT2 Inhibitor Therapy in Heart Failure Patients with Reduced Ejection Fraction.

Not much is known about the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on echocardiographic parameters of left ventricular (LV) systolic function in patients with heart failure and reduced ejection fraction (HFrEF).We prospectively included 59 outpatients with HFrEF: 41 patients received SGLT2i with OMT (SGLT2i+ group), whereas eighteen patients received OMT without SGLT2i (SGLT2i- group). Myocardial work index (MWI), 3D ejection fraction (3D LVEF), and global longitudinal strain (GLS) were measured at baseline and after 3 months following treatment. At 3-month follow-up, the SGLT2i+ group showed significantly greater improvement in MWI than the SGLT2i- group. In both groups, there was a significant improvement in 3D LVEF and LV GLS, circulating NT-proBNP levels, and NYHA functional class, with significantly greater improvement in the SGLT2i+ group.In conclusion, the addition of SGLT2i to fully optimized background medical therapy resulted in a greater improvement of LV systolic function among outpatients with HFrEF.

Meta-analysis on the effectiveness of SGLT2 inhibitors in heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Aims We aimed to carry out a meta-analysis on the effectiveness of sodium-glucose co transporter 2 (SGLT2) inhibitors in heart failure patients (HF) with preserved and reduced ejection fraction. Methods and results From their inception till September 2022, MEDLINE, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov were searched for placebo-controlled randomized controlled trials of SGLT2 inhibitors. Randomized controlled studies were chosen if they included HF patients and reported at least one of the predetermined outcomes. A random effects model was used to pool hazard ratios (HRs) or risk ratios together with the appropriate 95% confidence intervals. There were fourteen trials in total, with 42409 HF patients participating (N = 21678 in the SGLT2 inhibitor arms and N = 20731 in the placebo arms). In the overall HF cohort, SGLT2 inhibitors significantly reduced the composite of first HF hospitalization or cardiovascular death [HR: 0.75 (0.71–0.79); P &amp;lt;0.001; I2 = 0%]. Also resulted in a significant reduction in total hospitalizations for heart failure [HR: 0.70 (0.66–0.75); P &amp;lt; 0.001; I2 = 0%] and reduced the occurrence of cardiovascular death [HR: 0.86 (0.81–0.92); P &amp;lt; 0.001; I2 = 43%]. Sub-group analysis was conducted to based on HF status at baseline, ejection fraction, diabetes status at baseline, and gender. SGLT2 inhibitors significantly reduced the composite heart failure hospitalization and cardiovascular death for all the subgroups except for patients with HFpEF at baseline [HR: 0.87 (0.74–1.03); P = 0.11; I2 = 60%] and no diabetes status at baseline [HR: 0.92 (0.73–1.16); P = 0.50; I2 = 78%]. SGLT2 inhibitors seemed to have no risk of hypovolaemia, hyperkalaemia, or hypotension when compared to the placebo. Conclusions In patients with HF, SGLT2 inhibitors substantially increase cardiovascular outcomes, including all-cause and cardiovascular mortality. In this meta-analysis, SGLT2 inhibitors did not show reduction in composite heart failure in patients with heart failure with preserved ejection fraction (HFpEF) at baseline.

Abstract #1368667: Effects of Sodium-Glucose Co-transporter 2 Inhibitors on Adipokines and Inflammatory Markers in People Living with Type 2 Diabetic Mellitus

Type 2 diabetes mellitus is a chronic metabolic disease associated with high cardiovascular disease (CVD) risks. SGLT-2 inhibitors reduce HbA1c and show favorable effects on body weight, blood pressure, lipid profile, arterial stiffness, and endothelial function. More importantly, SGLT-2 inhibitors have demonstrated impressive cardioprotective and renoprotective effects. The main mechanisms of cardioprotective effects have been attributed to improvement in cardiac cell metabolism, improvement in ventricular loading conditions, inhibition of the Na+/H+ exchanger in myocardial cells, alteration in adipokines and cytokines production. This research aimed to observe the effects of SGLT-2 inhibitors on select inflammatory biomarkers, adiponectin, chosen metabolic and anthropometric variables. Compare changes of serum adiponectin between baseline with 16-week after SGLT-2 inhibitors therapy and other variables such as BMI, fasting plasma glucose, HbA1c, for instance, among people with type 2 diabetic mellitus. At 16-week after SGLT-2 inhibitors treatment, a striking increment in mean serum adiponectin by 1.25 mcg/mL (95% CI: 0.02, 2.48) or 81% was revealed. Furthermore, they showed a reduction of mean BMI 1.12 % (95% CI: -1.74%, -0.50%), systolic blood pressure 1 mmHg (95% CI: -1.85, -0.72), diastolic blood pressure 1 mmHg (95% CI: -1.65, -0.52), fasting plasma glucose 34 mg/dL (95% CI: -51.66, -17.10), and HbA1c 0.73% (95% CI: -1.25%, -0.21%). No between-group differences were expressed with the other biomarkers. Serious side effects such as ketoacidosis, hypoglycemic status, genitourinary tract infection, or acute kidney injury were not appeared. SGLT-2 inhibitors can improve changes in serum adiponectin which appreciatively benefit in cardiovascular outcomes among type 2 diabetes.

Effects of sodium glucose cotransporter 2 inhibitors and pioglitazone on FIB-4 index in metabolic-associated fatty liver disease.

The antidiabetic drugs sodium glucose cotransporter 2 inhibitors (SGLT2is) and thiazolidinediones have beneficial effects on the liver dysfunction of patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus (T2DM). We aimed to determine the efficacy of these drugs for the treatment of liver disease in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and T2DM. We undertook a retrospective study of 568 patients with MAFLD and T2DM. Of these, 210 were treating their T2DM with SGLT2is (n=95), 86 with pioglitazone (PIO), and 29 with both. The primary outcome was the change in Fibrosis-4 (FIB-4) index between baseline and 96weeks. At 96weeks, the mean FIB-4 index had significantly decreased (from 1.79±1.10-1.56±0.75) in the SGLT2i group, but not in the PIO group. The aspartate aminotransferase to platelet ratio index, serum aspartate and alanine aminotransferase (ALT), hemoglobin A1c, and fasting blood sugar significantly decreased in both groups (ALT: SGLT2i group, -17±3IU/L; PIO group, -14±3IU/L). The bodyweight of the SGLT2i group decreased, but that of the PIO group increased (-3.2kg and +1.7kg, respectively). When the participants were allocated to two groups according to their baseline ALT (>30IU/L), FIB-4 index significantly decreased in both groups. In patients taking pioglitazone, the addition of SGLT2i improved liver enzymes but not FIB-4 index for 96weeks. Treatment with SGLT2i causes a larger improvement in FIB-4 index than PIO in patients with MAFLD over 96weeks.

Sodium-glucose cotransporter-2 inhibitors and cardiovascular clinical outcomes in acute heart failure: A narrative review.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. This review describes the evidence from randomized controlled trials (RCTs) regarding the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular (CV) clinical outcomes when therapy is initiated during acute heart failure (HF). SGLT2 inhibitors have become a cornerstone of guideline-directed medical therapy (GDMT) for type 2 diabetes mellitus, chronic kidney disease, and HF. Because of their ability to promote natriuresis and diuresis as well as other potentially beneficial CV effects, use of SGLT2 inhibitors has been investigated when therapy is initiated during hospitalization for acute HF. We identified 5 placebo-controlled RCTs that reported CV clinical outcomes incorporating one or more components of all-cause mortality, CV mortality, CV hospitalization, HF worsening, and hospitalization for HF in patients treated with empagliflozin (n = 3 trials), dapagliflozin (n = 1 trial), and sotagliflozin (n = 1 trial). Nearly all CV outcomes in these trials showed benefit with SGLT2 inhibitor use during acute HF. Incidence of hypotension, hypokalemia, and acute renal failure was generally similar to that with placebo. These findings are limited by heterogeneous outcome definitions, variation in time to SGLT2 inhibitor initiation, and small sample sizes. SGLT2 inhibitors may have a role in inpatient management of acute HF, provided there is close monitoring for fluctuations in hemodynamic, fluid, and electrolyte status. Initiation of SGLT2 inhibitors at the time of acute HF may promote optimized GDMT, continued medication adherence, and reduced risk of CV outcomes.

Effect of Sodium-Glucose Cotransporter 2 Inhibitors on Clinical and Laboratory Variables in Heart Failure Patients with Reduced Left Ventricular Ejection Fraction in a Latin American Hospital: A Retrospective Study

Heart failure (HF) is a syndrome suffered by more than 26 million people worldwide. SGLT2 inhibitors are drugs that have been shown to positively affect the management of HF patients, regardless of their diabetes status. A retrospective observational study was conducted on heart failure patients with reduced ejection fraction (HFrEF) enrolled at the HF clinic, who were on SGLT2 inhibitors. For these patients, baseline and follow-up data were collected and analyzed over time. Changes over time were quantified and statistical analysis was conducted to validate whether the changes were significant. After the screening of all the HF program patients, 24 met the inclusion criteria, with an average age of 68 years. Through the study, it was possible to find a statistically significant difference in the values of NT-ProBNP before and after adding a SGLT2 inhibitor in 14 patients (p = 0.0214). In addition, there was an improvement in the NYHA functional scale of 71% and no significant change in renal function or other laboratory values. Based on the studied parameters and throughout the clinical changes during the follow-up period, it was possible to establish an improvement in HFrEF patients on SGLT2 inhibitors as part of their therapy.

Association of adverse respiratory events with sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors among patients with type 2 diabetes in South Korea: a nationwide cohort study

BackgroundImpaired respiratory function remains underrecognized in patients with type 2 diabetes (T2D), despite common pulmonary impairment. Meanwhile, there is little data available on the respiratory effects of sodium glucose cotransporter 2 inhibitors (SGLT2i). Hence, we examined the association between SGLT2i use and the risk of adverse respiratory events in a real-world setting.MethodsWe conducted a population-based, nationwide cohort study using an active-comparator new-user design and nationwide claims data of South Korea from January 2015 to December 2020. Among individuals aged 18 years or older, propensity score matching was done to match each new user of SGLT2is with dipeptidyl peptidase 4 inhibitors (DPP4is), with patients followed up according to an as-treated definition. The primary outcome was respiratory events, a composite endpoint of acute pulmonary edema, acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure. Secondary outcomes were the individual components of the primary outcome and in-hospital death. Cox models were used to estimate hazard ratios (HRs) and 95% CIs.ResultsOf 205,534 patient pairs in the propensity score matched cohort, the mean age of the entire cohort was 53.8 years and 59% were men, with a median follow-up of 0.66 years; all baseline covariates achieved balance between the two groups. Incidence rates for overall respiratory events were 4.54 and 7.54 per 1000 person-years among SGLT2i and DPP4i users, respectively, corresponding to a rate difference of 3 less events per 1000 person-years (95% CI − 3.44 to − 2.55). HRs (95% CIs) were 0.60 (0.55 to 0.64) for the composite respiratory endpoint, 0.35 (0.23 to 0.55) for acute pulmonary edema, 0.44 (0.18 to 1.05) for ARDS, 0.61 (0.56 to 0.66) for pneumonia, 0.49 (0.31 to 0.76) for respiratory failure, and 0.46 (0.41 to 0.51) for in-hospital death. Similar trends were found across individual SGLT2is, subgroup analyses of age, sex, history of comorbidities, and a range of sensitivity analyses.ConclusionsThese findings suggest a lower risk of adverse respiratory events associated with patients with T2D initiating SGLT2is versus DPP4is. This real-world evidence helps inform patients, clinicians, and guideline writers regarding the respiratory effects of SGLT2i in routine practice.

Effects of sodium glucose cotransporter 2 inhibitors on the risk of hyperkalemia in patients on mineralocorticoid receptor antagonist: a systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Background Occurrence of hyperkalemia has been a great limitation in the full implementation of a guideline-directed medical therapy especially in patients with heart failure. Recent developments have exhibited the positive role of SGLT2 inhibitors, not only on the cardiovascular outcomes but also conferred renal protection. Purpose We explored the effects of SGLT2i and MRA combination on the risk of developing hyperkalemia. Methods Randomized controlled trials on SGLT2i versus placebo in patients already on MRA regardless of heart failure status reporting outcomes of potassium homeostasis were searched using Pubmed, CENTRAL, and ScienceDirect. Outcome of interest was the effects on the risk of hyperkalemia. Pooled hazard ratios with 95% confidence intervals were used as effect estimates using fixed-effects model. Results Five studies were included with a total of 11,123 patients. There was a significant reduction on the risk of hyperkalemia in the MRA with SGLT2i group (HR 0.61, 95% CI 0.50-0.75, p&amp;lt;0.00001) compared to MRA without SGLT2i group. Conclusion SGLT2i provides significant risk reduction on the development of hyperkalemia in patients already on a mineralocorticoid receptor antagonist.

Effect of sodium-glucose co-transporter 2 inhibitors on plasma potassium: A meta-analysis

AimsThere has been uncertainty whether SGLT2 inhibition predisposes to hyperkalaemia or is protective from it. We therefore performed a meta-analysis to assess effects of SGLT2 inhibition on serum-potassium and hyperkalaemia-events in T2DM. MethodsMEDLINE and PubMed databases were searched for ‘hyperkalaemia’ or ‘potassium’, with SGLT2 inhibitors in T2DM, to 31st December 2020. Randomised controlled trials, with potassium or hyperkalaemia as primary or secondary outcomes, were included. Cochran’s Q test and I2 statistic assessed statistical heterogeneity. Meta-analyses were performed using Cochrane-RevMan with two outcomes: i) Odds ratio (OR) of hyperkalaemia-events between SGLT2 inhibitor and placebo (fixed-effects), ii) Mean difference (MD) in change from baseline potassium between SGLT2 inhibitor and placebo (random-effects). ResultsOf 1724 identified publications, nine were included in the meta-analysis (n = 3 hyperkalaemia event; n = 5 serum-potassium; n = 1 reported both outcomes). Pooled OR for hyperkalaemia-events for SGLT2 inhibitor vs placebo was 0.72 [95% confidence interval (CI) 0.61 to 0.85, P < 0.001], I2 of 9%. The pooled MD in serum-potassium concentration with SGLT2 inhibitor vs placebo was −0.04 mmol/L [95% CI −0.08 to 0.00 mmol/L; P = 0.04], I2 of 89%. ConclusionsUse of SGLT2 inhibitors in T2DM reduced odds of inducing hyperkalaemia but had a minimal effect of lowering serum potassium.

Canagliflozin promotes osteoblastic MC3T3-E1 differentiation via AMPK/RUNX2 and improves bone microarchitecture in type 2 diabetic mice.

Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone metabolic disorders and bone fracture due to disease progression and clinical treatment. The effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors, now greatly prescribed for the treatment of T2DM, on bone metabolism is not clear. This study aimed to explore the possible influence of bone metabolic disorder and the underlying mechanism through a comparison of three different SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) in the treatment of type 2 diabetic mice. For the in vivo experiments, four groups (DM, DM+Cana, DM+Dapa, and DM+Empa) were established using micro-CT to detect the bone microarchitecture and bone-related parameters. The study results indicated that canagliflozin, but not dapagliflozin or empagliflozin, increased bone mineral density (p<0.05) and improved bone microarchitecture in type 2 diabetic mice. Furthermore, canagliflozin promoted osteoblast differentiation at a concentration of 5 μM under high glucose concentration (HG). Phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) α (Thr172) has been confirmed to activate run-related transcription factor-2 (RUNX2) to perform this function. This effect can be partially reversed by the AMPK inhibitor dorsomorphin (compound C) and strengthened by the AMPK activator acadesine (AICAR) in vitro. The level trend of RUNX2 and p-AMPK in vivo were consistent with those in vitro. This study suggested that canagliflozin played a beneficial role in bone metabolism in type 2 diabetic mice compared with dapagliflozin and empagliflozin. It provides some theoretical support for the chosen drugs, especially for patients with osteoporosis or a high risk of fracture.