SGLT2 inhibitor canagliflozin reduces visceral adipose tissue in db/db mice by modulating AMPK/KLF4 signaling and regulating mitochondrial dynamics to induce browning.

Obesity is characterized by excessive accumulation of adipose tissue (mainly visceral). The morphology and function of mitochondria are crucial for regulating adipose browning and weight loss. Research suggests that the SGLT2 inhibitor canagliflozin may induce weight loss through an unknown mechanism, particularly targeting visceral adipose tissue. While Krueppel-Like Factor 4 (KLF4) is known to be essential for energy metabolism and mitochondrial function, its specific impact on visceral adipose tissue remains unclear. We administered canagliflozin to db/db mice for 8 weeks, or exposed adipocytes to canagliflozin for 24 h. The expression levels of browning markers, mitochondrial dynamics, and KLF4 were assessed. Then we validated the function of KLF4 through overexpression in vivo and in vitro. Adenosine monophosphate-activated protein kinase (AMPK) agonists, inhibitors, and KLF4 si-RNA were employed to elucidate the relationship between AMPK and KLF4. The findings demonstrated that canagliflozin significantly decreased body weight in db/db mice and augmented cold-induced thermogenesis. Additionally, canagliflozin increased the expression of mitochondrial fusion-related factors while reducing the levels of fission markers in epididymal white adipose tissue. These consistent findings were mirrored in canagliflozin-treated adipocytes. Similarly, overexpression of KLF4 in both adipocytes and db/db mice yielded comparable results. In all, canagliflozin mitigates obesity in db/db mice by promoting the brown visceral adipocyte phenotype through enhanced mitochondrial fusion via AMPK/KLF4 signaling.

Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin Attenuates Sorafenib-Induced Myocardial Inflammation and Toxicity.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1ß/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY.

BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Renal Function Improvement With Glucagon-Like Peptide-1 Receptor Agonist in a Patient With Type 2 Diabetes.

Diabetic kidney disease (DKD) includes hypertensive nephrosclerosis, aging, obesity, and atherosclerosis-related renal diseases, in addition to classical diabetic nephropathy. Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been approved for diabetic and non-diabetic patients at risk of chronic kidney disease progression. As the main mechanism for SGLT2i-mediated improvement of renal function, the normalization of tubulo-glomerular feedback (TGF) has been proposed. Enhanced TGF and resulting glomerular hypertension are observed in diabetic patients, and SGLT2is normalize TGF, reducing the intraglomerular pressure, which may reduce albuminuria and improve renal function. A type 2 diabetic patient with DKD complicated with hypertensive nephrosclerosis, whose renal function was deteriorated by SGLT2i and improved by glucagon-like peptide-1 receptor agonists (GLP-1RAs), was presented. In patients with hypertensive nephrosclerosis such as this case, the normalization of TGF by SGLT2i may further reduce afferent arteriolar blood flow which may worsen glomerular ischemia, resulting in deterioration of renal function. GLP-1RAs have no effect on TGF and have multiple effects to improve vascular endothelial function, which may be associated with an improvement in renal function in this patient.

Summary of Research: Efficacy and Safety of the SGLT2 Inhibitor Empagliflozin Versus Placebo and the DPP-4 Inhibitor Linagliptin Versus Placebo in Young People with Type 2 Diabetes (DINAMO): A Multicentre, Randomised, Double-Blind, Parallel Group, Phase 3 Trial.

The increasing occurrence of childhood overweight and obesity has been followed by a substantial increase in youth-onset type 2 diabetes (T2D). Pharmacological treatment options for youth-onset T2D remain limited, with a clear unmet need for additional oral agents. This summary of research reports on the efficacy and safety of empagliflozin and linagliptin on glycaemic control in children and adolescents aged 10-17 years with T2D in the randomised, double-blind, parallel group, phase 3 DINAMO trial. Empagliflozin provided a clinically relevant, statistically significant, and durable improvement in glycaemic control; however, linagliptin did not. The safety profile of both empagliflozin and linagliptin was comparable to those observed in studies in adults. These results suggest that empagliflozin could be a new oral therapy option for youth-onset T2D.

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post-hoc analysis of the PROCEED trial.

AIMS: To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHODS: This was a post-hoc analysis of the PROCEED trial, which evaluated the effect of 24-week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post-treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium-glucose co-transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. RESULTS: The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3-0.8; p < .001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3-3.1; p < .001) and erythropoietin (estimated log-transformed group difference, 0.1; 95% CI, 0.01-0.3; p = .036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (ß = 0.253, p < .001) or haematocrit (ß = 0.278, p < .001). Reductions in estimated plasma volume (estimated group difference, -7.94%; 95% CI, -11.6 to -4.26%; p < .001) and estimated extracellular volume (estimated group difference, -181.6 ml; 95% CI, -275.7 to -87.48 ml; p < .001) were significantly greater in the ipragliflozin group than those in the control group. CONCLUSIONS: Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. CLINICAL TRIAL: PROCEED trial (registration number: jRCTs071190054).

Cost-Effectiveness Analysis of Empagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction in the United States.

BACKGROUND: In the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction), empagliflozin plus standard of care reduced the composite of cardiovascular death or hospitalization for heart failure versus standard of care in adults with heart failure with reduced ejection fraction. This analysis investigated the cost-effectiveness of the 2 regimens from the perspective of US payors. METHODS AND RESULTS: A Markov cohort model was developed based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score quartiles and death. Transition probabilities between health states, risk of cardiovascular/all-cause death, hospitalization for heart failure and adverse events, treatment discontinuation, and health utilities were estimated from trial data. Medicare and commercial payment rates were combined for treatment acquisition, acute event management, and disease management. An annual discount rate of 3% was used. Empagliflozin plus standard of care yielded 18% fewer hospitalizations for heart failure and 6% fewer deaths versus standard of care over a lifetime, providing cost-offsets while adding 0.19 life years and 0.19 quality-adjusted life years at an incremental cost of $16 815/patient. The incremental cost-effectiveness ratio was $87 725/quality-adjusted life years gained. Results were consistent across payors, subpopulations, and in deterministic sensitivity analyses. In probabilistic sensitivity analyses, empagliflozin plus standard of care was cost-effective in 3%, 62%, and 80% of iterations at thresholds of $50 000, $100 000, and $150 000/quality-adjusted life years. CONCLUSIONS: Empagliflozin plus standard of care may prevent hospitalizations for heart failure, extend life, and increase quality-adjusted life years for patients with heart failure with reduced ejection fraction at an acceptable cost for US payors.

Impact of Dapagliflozin on the Renal Function and Damage in Patients with Heart Failure with a Reduced Ejection Fraction.

Objective Whether or not the initial dip in the glomerular filtration rate (GFR) after the initiation of sodium-glucose co-transporter 2 inhibitors (SGLT2is) is associated with renal tubular injury in patients with heart failure with a reduced ejection fraction (HFrEF) is unclear. We therefore investigated the relationship between changes in the estimated GFR (eGFR) and urine N-acetyl-ß-D-glucosaminidase (uNAG) after the initiation of dapagliflozin in patients with HFrEF. Methods We prospectively investigated 89 patients with HFrEF who were newly started on dapagliflozin 10 mg/day. Changes in the eGFR and uNAG-to-creatinine ratio (uNAG/Cre) were evaluated at 2 weeks and 2 months after the initiation of dapagliflozin. Results The eGFR was decreased at 2 weeks but had not declined further by 2 months. The uNAG/Cre was increased at 2 weeks but had not increased further by 2 months. There was no correlation between the changes in the eGFR and uNAG/Cre (r=-0.022, p=0.853 at 2 weeks and r=0.078, p=0.538 at 2 months). The relative change in the systolic blood pressure, hematocrit, plasma volume, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were correlated with the relative change in the eGFR. In a multiple linear regression analysis, the relative change in the eGFR at 2 weeks was significantly associated with NT-proBNP, and the relative change in the uNAG/Cre was significantly associated with the use of loop diuretics and the relative change in urine osmolality at 2 weeks. Conclusion A transient decrease in the eGFR after the initiation of dapagliflozin in patients with HFrEF was not generally associated with renal tubular injury and might have been the result of hemodynamic alteration.

Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis.

BACKGROUND: Empagliflozin (EMPA) ameliorates reactive oxygen species (ROS) generation in human endothelial cells (ECs) exposed to 10 % stretch, but the underlying mechanisms are still unclear. Pathological stretch is supposed to stimulate protein kinase C (PKC) by increasing intracellular calcium (Ca2+), therefore activating nicotinamide adenine dinucleotide phosphate oxidase (NOX) and promoting ROS production in human ECs. We hypothesized that EMPA inhibits stretch-induced NOX activation and ROS generation through preventing PKC activation. METHODS: Human coronary artery endothelial cells (HCAECs) were pre-incubated for 2 h before exposure to cyclic stretch (5 % or 10 %) with either vehicle, EMPA or the PKC inhibitor LY-333531 or PKC siRNA. PKC activity, NOX activity and ROS production were detected after 24 h. Furthermore, the Ca2+ chelator BAPTA-AM, NCX inhibitor ORM-10962 or NCX siRNA, sodium/potassium pump inhibitor ouabain and sodium hydrogen exchanger (NHE) inhibitor cariporide were applied to explore the involvement of the NHE/Na+/NCX/Ca2+ in the ROS inhibitory capacity of EMPA. RESULTS: Compared to 5 % stretch, 10 % significantly increased PKC activity, which was reduced by EMPA and PKC inhibitor LY-333531. EMPA and LY-333531 showed a similar inhibitory capacity on NOX activity and ROS generation induced by 10 % stretch, which was not augmented by combined treatment with both drugs. PKC-ß knockdown inhibits the NOX activation induced by Ca2+ and 10 % stretch. BAPTA, pharmacologic or genetic NCX inhibition and cariporide reduced Ca2+ in static HCAECs and prevented the activation of PKC and NOX in 10%-stretched cells. Ouabain increased ROS generation in cells exposed to 5 % stretch. CONCLUSION: EMPA reduced NOX activity via attenuation of the NHE/Na+/NCX/Ca2+/PKC axis, leading to less ROS generation in HCAECs exposed to 10 % stretch.

Evaluation of Inpatient Sodium-Glucose Co-Transporter-2 Inhibitor Use in Patients Hospitalized for Acute Heart Failure.

Hospitalization for acute heart failure (HF) represents an important opportunity for initiation and up-titration of guideline-directed medical therapy. This study aimed to determine whether sodium-glucose co-transporter-2 inhibitor (SGLT2I) use is safe in patients hospitalized for acute HF and whether its use is associated with improved clinical outcomes. We conducted a single-center, retrospective cohort study of adults hospitalized for acute HF with any ejection fraction and separated them into 2 matched groups based on inpatient SGLT2I use. The matching yielded 110 patients in the SGLT2I group and 110 patients in the control group. A total of 101 patients (91.8%) in the SGLT2I group were treated with dapagliflozin, whereas 9 (8.2%) were treated with empagliflozin. The mean age was 71 years, 37.7% were women, 70.9% were White, 22.7% were Black, and 64.1% were Hispanic or Latino. The length of stay was 10 days in the SGLT2I group and 11 days in the control group (p = 0.43). A total of 2 patients (1.8%) in the SGLT2I group and 13 patients (11.8%) in the control group died within 30 days of discharge (hazard ratio 0.15, 95% confidence interval [CI] 0.03 to 0.66, p = 0.012). A total of 17 patients (15.5%) in the SGLT2I group and 11 patients (10.0%) in the control group had an all-cause readmission within 30 days (hazard ratio 1.58, 95% CI 0.74 to 3.37, p = 0.239). In addition, 11 patients (10.0%) in the SGLT2I group and 3 patients (2.7%) in the control group had an HF readmission within 30 days (hazard ratio 3.75, 95% CI 1.05 to 13.44, p = 0.042). Acute kidney injury (54.5% vs 18.2%, p <0.001) and hypotension (12.7% vs 2.7%, p = 0.005) occurred significantly more frequently in the control group. In conclusion, SGLT2I use in patients hospitalized for acute HF was associated with decreased 30-day all-cause mortality and lower rates of acute kidney injury and hypotension; however, the rate of 30-day HF readmission increased.

Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor.

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.

Comparison of the efficacy of anti-diabetic medications as add-on to metformin in type 2 diabetes mellitus from a real-world database.

BACKGROUND: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A1c levels. METHODS: This retrospective cohort study used a medical information database in Japan. Non-insulin anti-hyperglycemic agents with different mechanisms of action were classified into eight drug classes. A monotherapy cohort and a combination therapy added to the metformin cohort were defined. The change in hemoglobin A1c levels was evaluated to compare the treatment effect between the cohorts. RESULTS: A total of 13,359 patients with type 2 diabetes mellitus in the monotherapy cohort and 1,064 in the metformin combination therapy cohort were identified. A comparison of the change from baseline HbA1c level by drug class between the two cohorts showed a similar trend. Among those treated with dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter-2 inhibitor, no clinically significant difference was observed between the two cohorts (0.00% and -0.07% for unadjusted, 0.15% and -0.03% for propensity score matching-adjusted, and 0.09% and -0.01% for inverse probability treatment weighting-adjusted analysis). CONCLUSIONS: According to the results of this study, the effect of dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor added to metformin seems to be additive with respect to the reduction in hemoglobin A1c.

Sodium-glucose co-transporter 2 inhibitor use in patients with diabetes mellitus undergoing endovascular therapy for symptomatic peripheral artery disease.

BACKGROUND: This study aimed to reveal the prevalence of sodium-glucose co-transporter 2 (SGLT2) inhibitor treatment and its association with restenosis risk in patients with diabetes mellitus undergoing endovascular therapy for symptomatic peripheral artery disease. METHODS: We used the database of a multicenter prospective study registering patients with symptomatic peripheral artery disease undergoing femoropopliteal drug-coated balloon treatment in Japan. The current analysis included 1058 patients with diabetes mellitus free from end-stage renal disease. The association of clinical characteristics with SGLT2 inhibitor use was investigated using the logistic regression model. The propensity score matching was adopted to compare the primary patency, i.e., freedom from restenosis, after endovascular therapy between patients treated with and without a SGLT2 inhibitor. RESULTS: The proportion of SGLT2 inhibitor treatment at revascularization was 14.8% (95% confidence interval, 12.8-17.1%). Younger age, increased body mass index, and increased hemoglobin A1c levels were independently associated with SGLT2 inhibitor use (all P < 0.05). The proportion of SGLT2 inhibitor reached 38.2% (95% confidence interval, 25.4-52.3%) in patients with the three associated factors. The propensity score-matching analysis demonstrated that primary patency was not different between patients treated with a SGLT2 inhibitor and those without it (72.0% [95% confidence interval, 64.1-80.9%] versus 67.8% [62.7-73.3%] at 2 years; P = 0.45). CONCLUSIONS: SGLT2 inhibitors were not rarely used in patients with diabetes mellitus who underwent femoropopliteal endovascular therapy using a drug coated balloon for symptomatic peripheral artery disease in real-world settings. SGLT2 inhibitor treatment was not associated with an increased risk of restenosis.

Short-term effects of canagliflozin on glucose and insulin responses in insulin dysregulated horses: A randomized, placebo-controlled, double-blind, study.

BACKGROUND: Decreasing hyperinsulinemia is crucial in preventing laminitis in insulin dysregulated (ID) horses. Complementary pharmacological treatments that efficiently decrease postprandial hyperinsulinemia in ID horses are needed. OBJECTIVES: Compare short-term effects of canagliflozin vs placebo on glucose and insulin responses to an oral sugar test (OST) as well as the effects on body weight and triglyceride concentrations in horses with ID. ANIMALS: Sixteen privately-owned ID horses. METHODS: A single-center, randomized, double-blind, placebo-controlled, parallel design study. The horses were randomized (ratio 1:1) to either once daily PO treatment with 0.6 mg/kg canagliflozin or placebo. The study consisted of an initial 3-day period for obtaining baseline data, a 3-week double-blind treatment period at home, and a 3-day follow-up period similar to the initial baseline period but with continued double-blind treatment. Horses were subjected to an 8-sample OST in the morning of the third day on both visits. RESULTS: Maximal geometric least square (LS) mean insulin concentration (95% confidence interval [CI]) during the OST decreased after 3 weeks of canagliflozin treatment compared with placebo (83.2; 55.4-125.0 vs 215.2; 143.2-323.2 µIU/mL). The geometric LS mean insulin response (insulin AUC0-180 ) for canagliflozin-treated horses was >66% lower compared with placebo. Least square mean body weight decreased by 11.1 (4-18.1) kg and LS mean triglyceride concentrations increased by 0.99 (0.47-1.5) mmol/L with canagliflozin treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Canagliflozin is a promising drug for treatment of ID horses that requires future studies.

Unsuspected diabetic ketoacidosis after myocardial infarction in a patient treated with SGLT2 inhibitor increased length of stay in the hospital: how can it be prevented? A case report.

Background: As the use of sodium-glucose co-transporter 2 inhibitors (SGLT2is) has expanded beyond glucose-lowering therapy in type 2 diabetes mellitus (T2DM), including chronic kidney disease and heart failure, there has also been an increase in reported cases of diabetic ketoacidosis (DKA) associated with SGLT2i. Case summary: A 77-year-old woman with T2DM presented to the emergency department with ST-segment elevation myocardial infarction (MI) complicated by atrial fibrillation. Her medications included empagliflozin, an SGLT2i, initiated for T2DM. Diabetic ketoacidosis was suspected on the basis of a large anion gap, despite a plasma glucose level below 200 mg/dL (11.1 mmol/L) and the absence of symptoms, including nausea and vomiting. Laboratory tests confirmed metabolic acidosis and high ketones. However, the diagnosis of euglycaemic DKA (eu-DKA) was delayed due to lack of symptoms and moderate hyperglycaemia. The patient was successfully treated according to DKA management guidelines. She was discharged on insulin, and SGLT2i was discontinued. Discussion: This is a case of asymptomatic eu-DKA after acute MI (AMI). We discuss the use of SGLT2is in AMI and arrhythmias from a review of the literature and the prophylaxis of eu-DKA. Regular monitoring of blood glucose and ketones should be performed in hospitalized T2DM patients treated with SGLT2i. The SGLT2i should be stopped as soon as possible in the event of critical illness or suspected DKA in the setting of an acute illness such as AMI. To help clinicians prevent this potentially fatal disease, we propose a flowchart for the prophylactic management of eu-DKA among inpatients.

Canagliflozin alleviates experimentally induced benign prostate hyperplasia in a rat model: exploring potential mechanisms involving mir-128b/EGFR/EGF and JAK2/STAT3 signaling pathways through in silico and in vivo investigations.

Benign prostatic hyperplasia (BPH) poses a significant health concern amongst elderly males. Canagliflozin (Cana), a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has a powerful anti-inflammatory influence. Nevertheless, its role in treating BPH has not been clarified. Therefore, the study aimed to investigate the potential ameliorative effect of Cana on experimentally induced BPH in rats and explore the underlying mechanisms compared to the standard finasteride (Fin). The study employed histological analysis, biochemical assays using ELISA, and western blotting. Animals were categorized into four groups: Control (2.5 ml/kg CMC, orally + 3 ml/kg olive oil, subcutaneous), BPH (3 mg/kg testosterone, subcutaneous + CMC orally), Fin-treated BPH (5 mg/kg, orally), and Cana-treated BPH (5 mg/kg, orally), for 28 days. The BPH group showed obvious BPH manifestations including an increase in prostate weight (PW), prostate index (PI), dihydrotestosterone (DHT) level, and histological aberrations compared to control. Fin and Cana therapy had a comparable impact. Cana treatment significantly reduced PW and PI, besides it improved prostatic biochemical, and histopathological features compared to BPH, consistent with in silico study findings. Cana was associated with downregulation of the androgen axis, increased miR-128b expression, with a lowered expression of epidermal growth factor (EGF) and its receptor. Phosphorylation of STAT3 and its downstream proliferative markers were significantly reduced suggesting apoptotic activity. Cana markedly rescued the BPH-induced upregulation of IL-1ß, and iNOS levels. Altogether, the current study demonstrates that Cana could impede BPH progression, possibly by modulating miR-128b/EGFR/EGF and JAK2/STAT3 pathways and downregulating AR, cyclin D1, and PCNA immunoreactivity.

Long-term observation of estimated fluid volume reduction after the initiation of ipragliflozin in patients with type 2 diabetes mellitus: a sub-analysis from a randomized controlled trial (PROTECT).

BACKGROUNDS/AIM: Recent studies have shown that the addition of sodium-glucose co-transporter 2 (SGLT2) inhibitors gradually reduces the estimated fluid volume parameters in a broad range of patient populations, suggesting that this mediates the clinical benefits of SGLT2 inhibitors in preventing heart failure. Here, we sought to examine the long-term (24 months) effect of the SGLT2 inhibitor ipragliflozin on the estimated fluid volume parameters in patients with type 2 diabetes mellitus (T2DM). METHODS: In this prespecified sub-analysis of the PROTECT (Prevention of Atherosclerosis by SGLT2 Inhibitor: Multicenter, Randomized Controlled Study) trial, which was an investigator-initiated, multicenter, prospective, randomized, open-label, clinical trial primarily designed to evaluate the effect of ipragliflozin treatment administered for 24 months on carotid atherosclerosis in patients with T2DM, we evaluated serial changes in estimated plasma volume (ePV, %) calculated using the Straus formula and estimated extracellular volume (eEV, mL) calculated by the body surface area by 24 months following the initiation of 50-mg ipragliflozin once daily and compared them with those following standard care for T2DM (non-SGLT2 inhibitor use). RESULTS: This sub-analysis included 464 patients (ipragliflozin, n = 232; control, n = 232), a full analysis set of the PROTECT trial. In an analysis using mixed-effects models for repeated measures, relative to the control group, ipragliflozin significantly reduced ePV by - 10.29% (95% confidence interval [CI] - 12.47% to - 8.11%; P < 0.001) at 12 months and - 10.76% (95% CI - 12.86% to - 8.67%; P < 0.001) at 24 months. Additionally, ipragliflozin significantly reduced eEV by - 190.44 mL (95% CI - 249.09 to - 131.79 mL; P < 0.001) at 12 months and - 176.90 mL (95% CI - 233.36 to - 120.44 mL; P < 0.001) at 24 months. The effects of ipragliflozin on these parameters over 24 months were mostly consistent across various patient clinical characteristics. CONCLUSIONS: This prespecified sub-analysis from the PROTECT trial demonstrated that ipragliflozin treatment, compared with the standard care for T2DM, reduced two types of estimated fluid volume parameters in patients with T2DM, and the effect was maintained for 24 months. Our findings suggest that SGLT2 inhibitor treatment regulates clinical parameters incorporated into the calculating formulas analyzed and consequently fluid volume status for the long-term, and this may be at least partly associated with clinical benefits from chronic use of SGLT2 inhibitors. Trial registration Japan Registry of Clinical Trials, ID jRCT1071220089.

The proteinuria-lowering effects of dapagliflozin are associated with an initial decline in estimated glomerular filtration rate in patients with chronic kidney disease.

AIM: Sodium-glucose co-transporter-2 inhibitor, dapagliflozin (DAPA) reduced albuminuria and slowed down the decline in estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD) in the DAPA-CKD trial. However, proteinuria (albuminuria) does not necessarily decrease in all patients in real-world clinical settings. Therefore, we aimed to identify the clinical characteristics of patients with CKD and decreased proteinuria in response to DAPA treatment. METHODS: Of 106 patients with CKD, 54 patients were finally included who received 10 mg of DAPA once daily. Patients whose urinary protein-to-creatinine ratio (UPCR) decreased by >30% or ≤30% from baseline after 1 month of treatment were defined as responders and non-responders, respectively. RESULTS: At baseline, median eGFR and UPCR were 45.3 mL/min/1.73 m2 (interquartile range [IQR], 29.7, 54.6) and 1.09 g/gCr (IQR, 0.52, 1.91), respectively. After 1 month of treatment, the mean decline in eGFR and reduction in UPCR was 6.5% (standard deviation [SD], 7.2%) and 6.6% (SD, 42.1%) from baseline, respectively. Moreover, the blood pressure, eGFR, and uric acid decreased significantly from baseline, but haemoglobin and serum potassium did not change. The median UPCR decreased significantly in patients with UPCR ≥0.5 g/gCr, but not <0.5 g/gCr at baseline. UPCR responders had a greater initial decline in eGFR at 1 month than non-responders. CONCLUSION: The percent changes in UPCR were positively associated with the initial decline rate in eGFR in patients with CKD with a UPCR ≥0.5 g/gCr at baseline after 1 month of DAPA treatment.