Update on Perioperative Medication Management for the Hand Surgeon: A Focus on Diabetes, Weight Loss, Rheumatologic, and Antithrombotic Medications.

Diabetes mellitus and obesity are growing health concerns. New pharmacologic interventions have recently begun to play a more notable role in the treatment pathway of these separate but related conditions. In particular, glucagon-like peptide-1 receptor agonists, such as semaglutides (Ozempic, Wegovy) and tirzepatide (Mounjaro), and sodium glucose co-transporter 2 inhibitors, such as dapagliflozin (Farxiga) and empagliflozin (Jardiance), have emerged as treatment options. Multiple clinical trials have demonstrated their efficacy in regulating metabolism, improving glycemic control, and managing long-term weight reduction. However, glucagon-like peptide-1 receptor agonists have also been associated with gastrointestinal side effects, including delayed gastric emptying as well as regurgitation and aspiration during general anesthesia or deep sedation, and sodium glucose co-transporter 2 inhibitors have been associated with severe diabetic ketoacidosis. Therefore, discontinuation of these medications before surgery is imperative. Given the popularity of these medications among the general public, it is essential for hand surgeons, to understand how to appropriately manage them perioperatively. The objective of this article was to review these new diabetes mellitus and weight loss medications, including their mechanisms of action, indications for use, and perioperative management guidelines. Additionally, we will take this opportunity to review perioperative guidelines for other common medications relevant to patients undergoing procedures involving the hand and upper extremity such as antithrombotic medications and rheumatoid arthritis-related immunosuppressive medications. Finally, we will describe how the electronic medical record system can be used to optimize perioperative medication management in this population.

The Effect of Sodium Glucose Cotransporter-2 Inhibitors on Hemoglobin A1c Variability and Acute Kidney Injury: A Causal Mediation Analysis.

PURPOSE: The role of lower hemoglobin A1c (HbA1c) variability in the effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on acute kidney injury (AKI) remains unclear. We compared AKI risk between SGLT2i and dipeptidyl peptidase 4 inhibitors (DPP4i) initiators. Additionally, we aimed to explore the extent to which SGLT2i's influence on AKI risk is mediated by reducing long-term HbA1c variability. METHODS: Using 2018-2022 year data in Yinzhou Regional Health Care Database, we included adult, type 2 diabetes patients who were new users of SGLT2i or DPP4i. The effect of SGLT2i versus DPP4i on AKI, HbA1c variability, and AKI through HbA1c variability was compared using inverse probability of treatment weighted Cox proportional hazards models, median regression models, and causal mediation analysis. RESULTS: With a median follow-up of 1.76 years, 19 717 adults (for SGLT2i, n = 6008; for DPP4i, n = 13 709) with type 2 diabetes were included. The adjusted hazard ratio for SGLT2i versus DPP4i was 0.79 (95% confidence interval [CI] 0.64-0.98) for AKI. The adjusted differences in median HbA1c variability score (HVS) and HbA1c reduction were -16.67% (95% CI: -27.71% to -5.62%) and -1.98% (95% CI: -14.34% to 10.38%), respectively. Furthermore, lower AKI risk associated with SGLT2i was moderately mediated (22.77%) through HVS. The results remained consistent across various subgroups and sensitivity analyses. CONCLUSIONS: Compared to DPP4i, lower AKI risk associated with SGLT2i is moderately mediated through HbA1c variability. These findings enhance our understanding of the effect of SGLT2i on AKI and underscore the importance of considering HbA1c variability in diabetes treatment and management.

SGLT1 contributes to glucose-mediated exacerbation of ischemia-reperfusion injury in ex vivo rat heart.

Hyperglycaemia is common during acute coronary syndromes (ACS) irrespective of diabetic status and portends excess infarct size and mortality, but the mechanisms underlying this effect are poorly understood. We hypothesized that sodium/glucose linked transporter-1 (SGLT1) might contribute to the effect of high-glucose during ACS and examined this using an ex-vivo rodent heart model of ischaemia-reperfusion injury. Langendorff-perfused rat hearts were subjected to 35 min ischemia and 2 h reperfusion, with variable glucose and reciprocal mannitol given during reperfusion in the presence of pharmacological inhibitors of SGLT1. Myocardial SGLT1 expression was determined in rat by rtPCR, RNAscope and immunohistochemistry, as well as in human by single-cell transcriptomic analysis. High glucose in non-diabetic rat heart exacerbated reperfusion injury, significantly increasing infarct size from 45 ± 3 to 65 ± 4% at 11-22 mmol/L glucose, respectively (p < 0.01), an association absent in diabetic heart (32 ± 1-37 ± 5%, p = NS). Rat heart expressed SGLT1 RNA and protein in vascular endothelium and cardiomyocytes, with similar expression found in human myocardium by single-nucleus RNA-sequencing. Rat SGLT1 expression was significantly reduced in diabetic versus non-diabetic heart (0.608 ± 0.08 compared with 1.116 ± 0.13 probe/nuclei, p < 0.01). Pharmacological inhibitors phlorizin, canagliflozin or mizagliflozoin in non-diabetic heart revealed that blockade of SGLT1 but not SGLT2, abrogated glucose-mediated excess reperfusion injury. Elevated glucose is injurious to the rat heart during reperfusion, exacerbating myocardial infarction in non-diabetic heart, whereas the diabetic heart is resistant to raised glucose, a finding which may be explained by lower myocardial SGLT1 expression. SGLT1 is expressed in vascular endothelium and cardiomyocytes and inhibiting SGLT1 abrogates excess glucose-mediated infarction. These data highlight SGLT1 as a potential clinical translational target to improve morbidity/mortality outcomes in hyperglycemic ACS patients.

Value of the triglyceride-glucose index and related parameters in heart failure patients.

The triglyceride-glucose (TyG) index, proven to be a crucial insulin resistance biomarker (better than the Homeostasis Model Assessment for Insulin Resistance), is simple and non-invasive. Recently, indisputable evidence has shown that the TyG index is strongly associated with cardiovascular disease [CVD, including atherosclerosis, heart failure (HF), and hypertension] prognosis and mortality. Nevertheless, the value of the TyG index in HF patients treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) has not been systematically evaluated. Therefore, in this review, we summarized the value of the TyG index and its related parameters as markers of CVD, especially HF. Furthermore, we addressed the use of SGLT2is and GLP-1 receptor antagonists in HF patients. Finally, we summarized the mechanism of the "obesity paradox."

Association of sodium glucose co-transporter-2 inhibitors with risk of diabetic ketoacidosis among hospitalized patients: A multicentre cohort study.

INTRODUCTION: Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are increasingly being used among hospitalized patients. Our objective was to assess the risk of diabetic ketoacidosis (DKA) among hospitalized patients receiving an SGLT-2i. RESEARCH DESIGN AND METHODS: We conducted a multicentre cohort study of patients hospitalized at 19 hospitals. We included patients over 18 years of age who received an SGLT-2i or a dipeptidyl peptidase-4 inhibitor (DPP-4i) in hospital. The primary outcome was the risk of DKA during their hospitalization. RESULTS: 61,517 patients received a DPP-4i and 11,061 received an SGLT-2i. The risk of inpatient DKA was 0.07 % (N = 41 events) among adults who received a DPP-4i and 0.18 % (N = 20 events) among adults who received an SGLT-2i; adjusted odds ratio of 3.30 (95 % CI: 1.85-5.72). CONCLUSIONS: In hospitalized patients, the absolute risk of DKA was 0.2 %, which corresponded to a three-fold higher relative risk.

Treatment of Metabolic (Dysfunction)-Associated Fatty Liver Disease: Evidence from Randomized Controlled Trials-A Short Review.

Metabolic-associated fatty liver disease (MALFD) is a highly prevalent and progressive disease, strongly related to obesity, metabolic syndrome, and cardiovascular disease. It comprises a spectrum of liver pathology from steatosis (fat accumulation in the hepatocytes) to steatosis with inflammation (metabolic-associated steatohepatitis, MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. There is currently only one medication, resmetirom, US Food and Drug Administration approved for the treatment of MALFD. Evidence from randomized trials supports the efficacy of hypocaloric diets and exercise in MASH resolution. Moreover, substantial weight loss after bariatric surgery can lead to significant and longitudinally sustained MASH resolution, improvement in liver fibrosis, and decrease in the risk of major cardiovascular adverse events. Pioglitazone, an insulin sensitizer, initiated at the early stages, before the progression to fibrosis, may be effective in resolution of MASH in patients with or without type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), semaglutide and liraglutide, may also be effective in resolution of MASH but not of fibrosis. Preliminary data from interventions with tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide RA, and sodium-glucose cotransporter 2 inhibitors are encouraging, but more data based on liver biopsy are needed.

The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review.

Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.

Assessing the Effect of Sodium-Glucose Cotransporter 2 Inhibitor (SGLT2i) on Outcomes in Patients With Acute Myocardial Infarction: A Systematic Review and Meta-Analysis.

After acute myocardial infarction, patients are at increased risk for adverse outcomes, including heart failure and death. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits, but their efficacy in patients after myocardial infarction is not well established. This study aimed to evaluate the efficacy of SGLT2i in preventing cardiovascular outcomes in patients after myocardial infarction through a systematic review and meta-analysis. We conducted a comprehensive literature search of PubMed, Cochrane, EMBASE, and Web of Science for randomized controlled trials (RCTs) and retrospective and prospective studies evaluating SGLT2i in patients after myocardial infarction. The primary outcomes were major adverse cardiovascular events (MACEs) and all-cause mortality. Secondary outcomes included cardiovascular mortality, recurrent myocardial infarction, revascularization, and rehospitalization. Data were pooled using a random-effects model, and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. The meta-analysis included eight studies (three RCTs and five observational studies) with a follow-up duration ranging from 4 to 24 months. SGLT2i were associated with a significantly lower risk of MACE (RR: 0.71, 95% CI: 0.52-0.97, p = 0.03) and rehospitalization (RR: 0.64, 95% CI: 0.51-0.82, p<0.01) compared to controls. Although not statistically significant, the risk of all-cause mortality (RR: 0.79, 95% CI: 0.53-1.18, p = 0.25) and cardiovascular mortality was lower in the SGLT2i group. This meta-analysis suggests that SGLT2i may improve cardiovascular outcomes in patients after myocardial infarction, particularly by reducing the risk of MACEs and rehospitalization. However, larger trials with high-risk populations are needed to confirm these findings and elucidate the underlying mechanisms.

Proximal tubule hypertrophy and hyperfunction: a novel pathophysiological feature in disease states.

The role of proximal tubules (PTs), a major component of the renal tubular structure in the renal cortex, has been examined extensively. Along with its physiological role in the reabsorption of various molecules, including electrolytes, amino acids and monosaccharides, transcellular transport of different hormones and regulation of homeostasis, pathological events affecting PTs may underlie multiple disease states. PT hypertrophy or a hyperfunctioning state, despite being a compensatory mechanism at first in response to various stimuli or alterations at tubular transport proteins, have been shown to be critical pathophysiological events leading to multiple disorders, including diabetes mellitus, obesity, metabolic syndrome and congestive heart failure. Moreover, pharmacotherapeutic agents have primarily targeted PTs, including sodium-glucose cotransporter 2, urate transporters and carbonic anhydrase enzymes. In this narrative review, we focus on the physiological role of PTs in healthy states and the current understanding of the PT pathologies leading to disease states and potential therapeutic targets.

Case report: Two novel compound heterozygous variant of SLC12A3 gene in a gitelman syndrome family and literature review.

A 36-year-old unmarried male chef was incidentally diagnosed with hypokalemia during an evaluation for an acute perianal abscess. Despite potassium supplementation, he developed progressive weakness in his lower limbs, culminating in an inability to stand. Investigations confirmed severe hypokalemia, metabolic alkalosis, hypomagnesemia, secondary hyperaldosteronism, and low urinary calcium excretion, with normotension. The patient's long-standing stunted growth and lean physique since childhood were noted. Biochemical assays further identified type 2 diabetes mellitus and metabolic syndrome. Genetic analysis revealed three heterozygous SLC12A3 mutations (M1: c.421G>A: p.G141R, M2: c.509T>A:p.L170Q, and M3: c.704C>A: p.T235K), compound heterozygo us and derived from both parents, with M1 and M3 reported here for the first time. Treatment with spironolactone and oral potassium chloride stabilized his potassium levels. Following the administration of SGLT2 inhibitors in patients receiving hypoglycemic therapy, we observed a mild decrease in serum sodium levels. This case highlights the criticality of vigilant metabolic surveillance in Gitelman syndrome and advises prudence with SGLT2 inhibitors in those with concurrent type 2 diabetes, given the risk of potentially aggravate sodium loss.

A Case of BRASH (Bradycardia, Renal Dysfunction, Atrioventricular Node Blockade, Shock, and Hyperkalemia) Syndrome Following Initiation of a Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitor and a Loop Diuretic.

BRASH (bradycardia, renal dysfunction, atrioventricular node blockade, shock, and hyperkalemia) syndrome is a recently recognized clinical process that can be fatal if not adequately and promptly treated. As such, it is important for clinicians to recognize the syndrome. This case demonstrates an example of BRASH syndrome in a 73-year-old patient with heart failure occurring after initiation of dapagliflozin, a drug not previously associated with this phenomenon in the literature. Given the increasingly appreciated clinical utility of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, prescribers must respect their potential side effects in patients with underlying comorbidities and remember the importance of re-evaluating renal function after initiation of these medications. Here, we review the pathophysiology of BRASH, the renal effects of SGLT-2 inhibitors, and the importance of educating patients on volume management and diuretic dose titration at home.

Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors for the treatment of diabetes mellitus in liver transplant recipients.

AIM: To investigate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors in liver transplant (LT) recipients with diabetes. METHODS: A single-centre, retrospective analysis of prospectively collected data from an LT recipient database (1990-2023) was conducted. We included adults with pre-existing diabetes and post-transplant diabetes, newly started on GLP-1RAs and/or SGLT2 inhibitors after LT. Metabolic and biochemical parameters and outcomes were collected for up to 12 months after starting medications and were compared to those in patients receiving dipeptidyl peptidase-4 (DPP-4) inhibitors. Statistical analysis included descriptive statistics and linear mixed models. RESULTS: We included participants on GLP-1RAs (n = 46), SGLT2 inhibitors (n = 87), combination therapy (n = 12), and a DPP-4 inhibitor comparator (n = 217). Both GLP-1RAs and combination therapy decreased mean glycated haemoglobin (HbA1c) levels, and combination therapy remained significant when adjusted for DPP-4 inhibitor treatment (-3.5%, 95% CI [-6.1, -0.95]; p = 0.0089) at 12 months. All three groups had significant decreases in mean weight and body mass index, but these remained significant in the GLP-1RA (-5.2 kg, 95% CI [-8.7, -1.7], p = 0.0039 and 1.99 kg/m2, 95% CI [-3.4, -0.6], p = 0.0048) and combination therapy groups (-5.4 kg, 95% CI [-10.5, -0.36], p = 0.04 and -3.4 kg/m2, 95% CI [-5.5, -1.3], p = 0.0015) when adjusted for DPP-4 inhibitor treatment at 12 months. Alanine aminotransferase levels decreased with GLP-1RA and combination therapy. There were two (1.4%) cases of graft rejection. CONCLUSION: We found that GLP-1RAs, SGLT2 inhibitors, and their combination, led to significant weight loss in LT recipients with diabetes. Combination therapy, in particular, lowered HbA1c and alanine aminotransferase levels compared to DPP-4 inhibitors. Further studies are needed to assess long-term safety and efficacy.

Impact of SGLT2 inhibition on markers of reverse cardiac remodelling in heart failure: Systematic review and meta-analysis.

INTRODUCTION: Several landmark randomized-controlled trials (RCTs) have demonstrated the efficacy of sodium-glucose co-transport 2 (SGLT2) inhibitors in reducing all-cause mortality, cardiovascular (CV) mortality and heart failure (HF) hospitalizations. Much interest surrounds their mechanism of action and whether they have direct effects on reverse cardiac remodelling. Therefore, we conducted a meta-analysis of placebo controlled RCTs evaluating the impact of SGLT2 inhibition on imaging derived markers of reverse cardiac remodelling in patients with HF. METHODS: We performed a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement and Cochrane Collaboration. Data interrogation of each major database including PubMed, EMBASE, MEDLINE and Cochrane Library was performed. RCTs evaluating HF patients >18 years comparing SGLT2 inhibitor versus placebo-control were included. Outcome measures included left ventricular end-diastolic volume and volume index (LVEDV/LVEDVi), left ventricular end-systolic volume and volume index (LVSDV/LVSDVi), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMi), left atrial volume index (LAVi) and left ventricular global longitudinal strain (LV GLS). Studies with an HF with preserved ejection fraction population were excluded from analysis of parameters, which would be significantly affected by baseline LVEF, such as volumes and LVEF. The mean difference and standard error were extracted from each study and a random effects model used pool the mean difference and standard error across studies. A pre-specified sub-group analysis was performed to stratify results according to imaging modality used (cardiac magnetic resonance imaging and echocardiography). This study is registered on PROSPERO: CRD42023482722. RESULTS: Seven randomized, placebo-controlled trials in patients with HF comprising a total population of 657 patients were included. Overall LVEF of included studies ranged from 29 ± 8.0% to 55.5 ± 4.2%. In studies included in analysis of HFrEF parameters, baseline LVEF ranged from 29 ± 8% to 45.5 ± 12%. Pooled data demonstrated SGLT2 inhibition, compared with placebo control, resulted in significant improvements in mean difference of LVEDV [-11.62 ml (95% confidence interval, CI -17.90 to -5.25; z = 3.67, P = 0.0004)], LVEDVi [-6.08 ml (95% CI -9.96 to -2.20; z = 3.07; P = 0.002)], LVESV [-12.47 ml (95% CI -19.12 to -5.82; z = 3.68; P = 0.0002)], LVESVi [-6.02 ml (95% CI -10.34 to -1.70; z = 2.73; P = 0.006)], LVM [-9.77 g (95% CI -17.65 to -1.89; z = 2.43; P = 0.02)], LVMi (-3.52 g [95% CI -7.04 to 0.01; z = 1.96; P = 0.05)] and LVEF [+2.54 mL (95% CI 1.10 to 3.98; z = 3.62; P = 0.0005)]. No significant difference in GLS (n = 327) [+0.42% (95%CI -0.19 to 1.02; P = 0.18)] or LAVi [-3.25 ml (95% CI -8.20 to 1.69; z = 1.29; P = 0.20)] was noted. CONCLUSION: This meta-analysis provides additional data and insight into the effects of SGLT2 inhibition on reverse cardiac remodelling in patients with HF. Compared with placebo control, we found that treatment with a SGLT2 inhibitor produced significant improvements in several markers of reverse cardiac remodelling.

MAFLD Pandemic: Updates in Pharmacotherapeutic Approach Development.

With around one billion of the world's population affected, the era of the metabolic-associated fatty liver disease (MAFLD) pandemic has entered the global stage. MAFLD is a chronic progressive liver disease with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC), and for which to date there are almost no approved pharmacologic options. Because MAFLD has a very complex etiology and it also affects extrahepatic organs, a multidisciplinary approach is required when it comes to finding an effective and safe active substance for MAFLD treatment. The optimal drug for MAFLD should diminish steatosis, fibrosis and inflammation in the liver, and the winner for MAFLD drug authorisation seems to be the one that significantly improves liver histology. Saroglitazar (Lipaglyn®) was approved for metabolic-dysfunction-associated steatohepatitis (MASH) in India in 2020; however, the drug is still being investigated in other countries. Although the pharmaceutical industry is still lagging behind in developing an approved pharmacologic therapy for MAFLD, research has recently intensified and many molecules which are in the final stages of clinical trials are expected to be approved in the coming few years. Already this year, the first drug (Rezdiffra™) in the United States was approved via accelerated procedure for treatment of MAFLD, i.e., of MASH in adults. This review underscores the most recent information related to the development of drugs for MAFLD treatment, focusing on the molecules that have come furthest towards approval.

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Transcription Regulation of AgRP and POMC Genes.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors regulate plasma glucose levels in patients with type 2 diabetes mellitus (T2DM) by inhibiting renal glucose reabsorption. This study investigated the impact of empagliflozin (EMPA), an SGLT2 inhibitor, on hypothalamic energy regulation. To directly investigate the role of SGLT2 inhibitors in the hypothalamus, we administered EMPA through intracerebroventricular (i.c.v.) injections into the murine ventricles. After dental cementing the i.c.v. cannula onto the skull, the mice were given 5 days to recover before receiving vehicle or EMPA (50 nM/2 µL) injections. In a high-fat diet (HFD)-induced obesity model, we determined the gene expression levels of agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) in the hypothalamus. Additionally, we assessed FoxO1 expression, which regulates AgRP and POMC gene transcription in hypothalamic cell lines. We found that EMPA directly influenced the expression of endogenous mRNA of POMC and AgRP, which are critical for energy homeostasis, and modulated their transcription in high-fat diet-induced obese mice. Additionally, EMPA affected the expression of FoxO1, a key transcriptional regulator of glucose homeostasis, thereby regulating the transcriptional activity of POMC and AgRP. These results indicate that EMPA significantly influences hypothalamic energy homeostasis, highlighting its potential as a regulator in obesity and T2DM management.

Dapagliflozin improves skeletal muscle insulin sensitivity through SIRT1 activation induced by nutrient deprivation state.

Lipid peroxidation and mitochondrial damage impair insulin sensitivity in skeletal muscle. Sirtuin-1 (SIRT1) protects mitochondria and activates under energy restriction. Dapagliflozin (Dapa) is an antihyperglycaemic agent that belongs to the sodium-glucose cotransporter-2 (SGLT2) inhibitors. Evidence shows that Dapa can induce nutrient deprivation effects, providing additional metabolic benefits. This study investigates whether Dapa can trigger nutrient deprivation to activate SIRT1 and enhance insulin sensitivity in skeletal muscle. We treated diet-induced obese (DIO) mice with Dapa and measured metabolic parameters, lipid accumulation, oxidative stress, mitochondrial function, and glucose utilization in skeletal muscle. ß-hydroxybutyric acid (ß-HB) was intervened in C2C12 myotubes. The role of SIRT1 was verified by RNA interference. We found that Dapa treatment induced nutrient deprivation state and reduced lipid deposition and oxidative stress, improved mitochondrial function and glucose tolerance in skeletal muscle. The same positive effects were observed after ß-HB intervening for C2C12 myotubes, and the promoting effects on glucose utilization were diminished by SIRT1 RNA interference. Thus, Dapa promotes a nutrient deprivation state and enhances skeletal muscle insulin sensitivity via SIRT1 activation. In this study, we identified a novel hypoglycemic mechanism of Dapa and the potential mechanistic targets.

Long-term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52-week extension of a Phase 3 randomized controlled trial.

AIMS: To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52. RESULTS: A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0% (53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively. CONCLUSIONS: Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.

Cardiovascular and non-renal complications of chronic kidney disease: Managing risk.

Chronic kidney disease (CKD) currently affects approximately 850 million people globally and is continuing to increase in prevalence as well as in importance as a cause of death. The excess mortality related to CKD is mostly caused by an increase in cardiovascular disease. This includes atherosclerotic cardiovascular disease as many promoters of atherosclerosis, such as blood pressure, lipid levels and hypercoagulation, are increased in people with CKD. Diabetes is a leading cause of CKD contributing to the risk of CVD, and obesity is also increasingly prevalent. Management of these risk factors is therefore very important in CKD, and to reduce risk of CKD progression. Heart failure is also more prevalent in CKD and, again, many risk factors are shared. The concept of foundational pillars in the management of heart failure has been adapted to the treatment of CKD, with many organ-protective interventions, such renin-angiotensin system blockade, sodium-glucose cotransporter-2 inhibition and mineralocorticoid receptor antagonism, reducing the risk for mortality in heart failure with reduced ejection fraction, but also for progression of CKD. Atrial fibrillation is also more common with CKD and affects the management of the former. In this review these non-renal complications of CKD are discussed, along with how the risk of these complications should be managed. Many new opportunities have demonstrated heart and kidney organ protection, but implementation is a challenge.

Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

BACKGROUND AND PURPOSE: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. EXPERIMENTAL APPROACH: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols. KEY RESULTS: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology. CONCLUSIONS AND IMPLICATIONS: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.