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Heart failure (HF) is a complex clinical syndrome caused by structural or functional dysfunction of the ventricular filling or blood supply. Diabetes mellitus (DM) is an independent predictor of mortality for HF. The increase in prevalence, co-morbidity and hospitalization rates of both DM and HF has further fueled the possibility of overlapping disease pathology between the two. For decades, antidiabetic drugs that are known to definitively increase the risk of HF are the thiazolidinediones (TZDs) and saxagliptin in the dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin, which causes sodium and water retention, and whether metformin is effective or safe for HF is not clear. Notably, sodium-glucose transporter 2 (SGLT2) inhibitors and partial glucagon-like peptide-1 receptor agonists (GLP-1 RA) all achieved positive results for HF endpoints, with SGLT2 inhibitors in particular significantly reducing the composite endpoint of cardiovascular mortality and hospitalization for heart failure (HHF). Further understanding of the mutual pathophysiological mechanisms between HF and DM may facilitate the detection of novel therapeutic targets to improve the clinical outcome. This review focuses on the association between HF and DM, emphasizing the efficacy and safety of antidiabetic drugs and HF treatment. In addition, recent therapeutic advances in HF and the important mechanisms by which SGLT2 inhibitors/mineralocorticoid receptor antagonist (MRA)/vericiguat contribute to the benefits of HF are summarized.

ABSTRACT Background Sodium glucose‐linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. Methods Two mouse models of diet‐induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. Results In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet‐matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. Conclusion These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor‐induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are filtered and secreted to their primary site of action in the proximal tubule of the kidney. At this site, SGLT2 inhibitors also reduce renal elimination of ketone bodies, a finding implicated in their propensity to cause ketoacidosis. Many commonly used medications have potential to diminish renal elimination of SGLT2 inhibitors and to compound the effects of SGLT2 inhibitors on renal elimination of ketone bodies by inhibiting tubular secretion of the SGLT2 inhibitor itself and/or ketone bodies. We present a case of severe diabetic ketoacidosis (DKA) in a patient with type 2 diabetes occurring several days after co-prescription of empagliflozin and probenecid. Other than the recent introduction of empagliflozin, no cause for the DKA episode was apparent. A pharmacokinetic interaction between probenecid and empagliflozin, involving organic anion transporter 3 (OAT3), reduces proximal tubular secretion of empagliflozin and increases patient exposure to the drug. Whether or not this phenomenon is sufficient to cause severe DKA is discussed. An alternative explanation as to the DKA aetiology is proposed, wherein probenecid may compound effects of empagliflozin on renal elimination of ketone bodies. We suggest that clinicians exercise caution when prescribing SGLT2 inhibitors alongside pharmacologic inhibitors of, or competitors for, proximal tubular organic anion transporters in patients with diabetes mellitus due to the risk of severe DKA.

Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it may be an important area of research and development as a therapeutic target for DCM. Cumulative cardiovascular trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in diabetic populations. Whether SGLT2 inhibitors improve DCM by enhancing ketone body metabolism remains and whether they help prevent oxidative damage remains to be clarified. Here, we present the combined results of nine GSE datasets for diabetic cardiomyopathy (GSE215979, GSE161931, GSE145294, GSE161052, GSE173384, GSE123975, GSE161827, GSE210612, and GSE5606). We found significant up-regulated gene 3-hydroxymethylglutaryl CoA synthetase 2 (HMGCS2) and down-regulated gene 3-hydroxybutyrate dehydrogenase (BDH1) and 3-oxoacid CoA-transferase1 (OXCT1), respectively. Based on the analysis of the constructed protein interaction network, it was found that HMGCS2 was in the core position of the interaction network. In addition, Gene ontology (GO) enrichment analysis mainly focused on redox process, acyl-CoA metabolic process, catalytic activity, redox enzyme activity and mitochondria. The activity of HMGCS2 in DCM heart was increased, while the expression of ketolysis enzymes BDH1 and OXCT1 was inhibited. In vivo, Empagliflozin (Emp) treated DCM group significantly decreased ventricular weight, myocardial cell cross-sectional area, and myocardial fibrosis. In addition, Emp further promoted the activity of BDH1 and OXCT1, increased the utilization of ketone bodies, further promoted the activity of HMGCS2 in DCM, and increased the synthesis of ketone bodies, prevented mitochondrial breakage and dysfunction, increased myocardial ATP to provide sufficient energy, inhibited oxidative stress and apoptosis of cardiac cells ex vivo, and improved the myocardial dysfunction of DCM. Emp can improve mitochondrial dysfunction in diabetic cardiomyopathy by regulating ketone body metabolism and oxidative stress. These findings provide a theoretical basis for evaluating Emp as a treatment for DCM.

Background: We aimed to assess the impact of adding sodium glucose co-transporters-2 inhibitors (SGLT-2I) on cardiac remodeling in type 2 diabetic patients with heart failure with mildly reduced ejection fraction (HFmrEF) that had been under-represented in most clinical trials through the analysis of left atrial (LA) phasic functions with 2-D speckle tracking echocardiography (2D- STE Methods: We enrolled 70 patients with type 2 diabetes (T2DM) and stable HFmrEF (35 patients received one of SGLT-2I either empagliflozin or dapagliflozin). Laboratory assessment and echocardiographic evaluation were carried out at baseline and after 6 months. LA volumes and deformation analysis were conducted using 2D-STE. Three LA strain parameters were obtained (LA reservoir strain, contractile strain, and conduit strain). Results: After 6 months of SGLT-2 I treatment, there was better control of HbA1C and improvement of diastolic functions (E/e′ ratio and LAV-I significantly decreased. P

Coronary heart disease is a narrowing or obstruction of the vascular cavity caused by atherosclerosis of the coronary arteries, which leads to myocardial ischemia and hypoxia. At present, percutaneous coronary intervention (PCI) is an effective treatment for coronary atherosclerotic heart disease. Restenosis is the main limiting factor of the long-term success of PCI, and it is also a difficult problem in the field of intervention. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral glucose-lowering agent used in the treatment of diabetes in recent years. Recent studies have shown that SGLT2 inhibitors can effectively improve the prognosis of patients after PCI and reduce the occurrence of restenosis. This review provides an overview of the clinical studies and mechanisms of SGLT2 inhibitors in the prevention of restenosis, providing a new option for improving the clinical prognosis of patients after PCI.

Background: Stroke represents a major burden in patients with type 2 diabetes. Yet, this cerebrovascular complication has been less well studied than coronary artery disease and heart failure. Some cardiovascular outcome data suggested that sodium-glucose cotransporter 2 inhibitors (SGLT2is) exert a less pronounced protection against stroke compared with glucagon peptide-1 receptor agonists (GLP-1RAs) despite similar efficacy regarding major cardiovascular events (MACE-3 points). However, this conclusion was derived from indirect comparisons of placebo- controlled trials (RCTs). Methods: The present comprehensive review analyses the effects of SGLT2is versus GLP-1RAs on nonfatal and fatal/nonfatal strokes in real-life studies carried out worldwide. Results: A large majority of retrospective observational cohort studies (19 out of 21) failed to find any significant difference in the risk of stroke between the two pharmacological classes, independently of the presence of established cardiovascular disease. Available, yet limited, findings suggested that SGLT2is could be more efficacious against haemorrhagic than ischaemic strokes, in patients at risk for atrial fibrillation or with chronic kidney disease. Conclusion: In contrast to what was reported in RCTs, most observational studies showed similar incidence of stroke in SGLT2i users versus GLP-1RA users. Because both indirect comparisons of RCTs and retrospective cohort studies have limitations, a head-to-head RCT comparing the effects on stroke of an SGLT2i versus a GLP-1RA is needed to draw any definite conclusion.

Atherosclerotic cardiovascular disease (ASCVD), heart failure (HF) and chronic kidney disease (CKD) are major complications of type 2 diabetes (T2DM). The objectives of preventing these complications are not fully reached in clinical practice. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their efficacy in reducing major cardiovascular events, diminishing hospitalization for HF and limiting the progression of CKD to end-stage kidney disease in placebo-controlled randomised trials in high-risk patients with T2DM. These evidence-based benefits were confirmed in real-life cohort studies worldwide compared with other glucose-lowering agents. However, real-world data showed that only a minority of eligible patients with T2DM received an SGLT2i, yet encouraging increase was observed in recent years. Surprisingly, in several studies less patients with comorbidities (especially CKD) were treated with SGLT2is compared with T2DM patients without these complications. Bridging the gap between evidence-based cardiorenal protection with SGLT2is and their underuse in daily clinical practice in patients with T2DM at high risk is crucial from a public health viewpoint. Multifaceted and coordinated interventions involving all actors should be implemented to incite the adoption of SGLT2is as part of routine cardiovascular and renal care among patients with T2DM at high risk for these comorbidities.

We present a 51-year-old male patient with a history of Child-Pugh Grade B alcoholic liver cirrhosis (ALC) who developed renal impairment (serum creatinine of 2.00 mg/dL) and nephrotic syndrome (a urinary protein level of 4.35 g/gCr). The patient was diagnosed with immunoglobulin A nephropathy (IgAN) associated with ALC based on findings from comprehensive evaluations, including markedly elevated serum IgA levels (883.7 mg/dL), a kidney biopsy revealing significant IgA deposition in the para-mesangial area, and a liver diagnosis showing long-standing advanced ALC. Our treatment approach involved initiating dapagliflozin therapy, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, alongside strict alcohol abstinence. Remarkably, the patient demonstrated a dramatic reduction in proteinuria within one week of dapagliflozin administration. No hypoglycemic events were observed. This case adds valuable clinical insights into the potential therapeutic role of SGLT2 inhibitors in IgAN associated with ALC. Specifically, in cases where conventional steroid therapies may be contraindicated due to coexisting comorbidities such as diabetes or obesity, dapagliflozin emerges as a potentially efficacious alternative. Further investigations are warranted to validate these preliminary observations.

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as novel cardioprotective agents. However, their direct impact on cardiomyocyte injury is yet to be studied. In this work, we investigate the underlying molecular mechanisms of empagliflozin (EMPA), an SGLT2 inhibitor, in mitigating palmitate (PA)-induced cardiomyocyte injury in H9c2 cells. We found that EMPA significantly attenuated PA-induced impairments in insulin sensitivity, ER stress, inflammatory cytokine gene expression, and cellular apoptosis. Additionally, EMPA elevated AMP levels, activated the AMPK pathway, and increased carnitine palmitoyl transferase1 (CPT1) gene expression, which collectively enhanced fatty acid oxidation and reduced stress signals. This study reveals a novel mechanism of EMPA's protective effects against PA-induced cardiomyocyte injury, providing new therapeutic insights into EMPA as a cardioprotective agent. [ABSTRACT FROM AUTHOR]

Herein, we measured the antidiabetic and nephroprotective effects of the sodium–glucose cotransporter-2 inhibitor (empagliflozin; SGLT2i) and synthetic active vitamin D (paricalcitol; Pcal) mono- and co-therapy against diabetic nephropathy (DN). Fifty mice were assigned into negative (NC) and positive (PC) control, SGLT2i, Pcal, and SGLT2i+Pcal groups. Following establishment of DN, SGLT2i (5.1 mg/kg/day) and/or Pcal (0.5 µg/kg/day) were used in the designated groups (5 times/week/day). DN was affirmed in the PC group by hyperglycaemia, dyslipidaemia, polyuria, proteinuria, elevated urine protein/creatinine ratio, and abnormal renal biochemical parameters. Renal SREBP-1 lipogenic molecule, adipokines (leptin/resistin), pro-oxidant (MDA/H2O2), pro-inflammatory (IL1β/IL6/TNF-α), tissue damage (iNOS/TGF-β1/NGAL/KIM-1), and apoptosis (TUNEL/Caspase-3) markers also increased in the PC group. In contrast, renal lipolytic (PPARα/PPARγ), adiponectin, antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL10) molecules decreased in the PC group. Both monotherapies increased insulin levels and mitigated hyperglycaemia, dyslipidaemia, renal and urine biochemical profiles alongside renal lipid regulatory molecules, inflammation, and oxidative stress. While SGLT2i monotherapy showed superior effects to Pcal, their combination demonstrated enhanced remedial actions related to metabolic control alongside renal oxidative stress, inflammation, and apoptosis. In conclusion, SGLT2i was better than Pcal monotherapy against DN, and their combination revealed better nephroprotection, plausibly by enhanced glycaemic control with boosted renal antioxidative and anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2D) usually show progressive deterioration in glycemic control and sequential additions of therapy are generally needed. Many new options for glucose lowering therapy have been introduced recently and it is becoming common practice to use fixed-dose combinations (FDCs) of glucose lowering agents from different classes. This article reviews the FDC of canagliflozin with metformin extended release. A literature search was performed to identify publications describing the efficacy and safety of canagliflozin and metformin when used separately and in combinations. Canagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor which has shown benefits in reducing progression of renal disease and heart failure in patients with T2D. There was an increased incidence of amputation with canagliflozin in one study, but canagliflozin results in weight loss and reduction of blood pressure which contribute to the overall benefit. Metformin has been the first line oral hypoglycemic agent for many years and is thought to have many advantages, but it should be avoided in patients with severely decreased renal function because of the risk of lactic acidosis. The combination in a single tablet given once daily should help to simplify therapy and improve medication adherence in T2D. [ABSTRACT FROM AUTHOR]

This study assessed the clinical safety and efficacy of bexagliflozin, a sodium-glucose cotransporter 2(SGLT2) inhibitor, in managing glycemia among patients with type 2 diabetes mellitus (T2DM). We examined RCTs with T2DM comparing the clinical effectiveness and safety of 20 mg once daily oral dose of bexagliflozin with placebo for managing glycemia till 28 May 2023, published on databases like ClinicalTrials.gov, PubMed, Embase, and Cochrane Library. Furthermore, reduction of body weight, fasting plasma sugarr(FPG), systolic blood pressure (SBP) and the percentage of individuals who achieved glycated hemoglobin (HbA1c) of < 7% from baseline were also evaluated. The Review Manager 5 was utilized to investigate the retrieved data. We involved eight RCTs. Bexagliflozin was significantly superior in reducing HbA1c[least squares mean difference(LSMD) = -0.45,95% confidence interval (CI =-0.55 to −0.34,p < 0.00001], FPG [LSMD= −1.37, 95%CI =-1.73 to −1.00, p < 0.00001], body weight (LSMD= −1.77, 95%CI =-2.44 to-1.10, p < 0.00001), and SBP(LSMD= −4.11,95%CI = -6.18 to −2.03,p = 0.0001) in comparison to placebo. The safety outcomes of bexagliflozin were consistent with the placebo arm. This study concluded that bexagliflozin seems to be a promising oral anti-diabetic drug for enhancing glycemic management in adult patients with T2DM. Bexagliflozin, a novel hypoglycemic agent, is an extremely effective SGLT2 inhibitor developed by TheracosBio to manage glycemia in T2DM. The United States Food and Drug Administration (USFDA) granted first approval of bexagliflozin on 20 January 2023, for usage as an adjunctive therapy agent alongside lifestyle changes and exercise in T2DM. All included RCTs have investigated the therapeutic efficacy and safety of bexagliflozin 20 mg concerning glycemic and extra-glycemic effects in T2DM. Bexagliflozin 20 mg significantly reduces HbA1c, FPG (glycemic effect), body weight, and SBP (extra-glycemic effect) compared to the placebo arm in T2DM. Safety data show that bexagliflozin was comparable to placebo arm and polyuria, urinary tract infection (UTI), nasopharyngitis or upper respiratory tract infection (URTI), hypoglycemia, nausea, and diarrhea were the most common non-serious adverse effects. Bexagliflozin 20 mg seems to be an effective SGLT2 inhibitor compared to the placebo arm to manage glycemia in patients with T2DM along with favorable extra-glycemic effects. [ABSTRACT FROM AUTHOR]

Dapagliflozin, a sodium–glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2–3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 μM), sGC inhibitor (ODQ, 5 μM), or COX inhibitor (indomethacin, 3 μM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca2+-activated K+ channel (KCa) blocker (TEA, 2 mM), voltage-dependent K+ channel (KV) blocker (4-AP, 2 mM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (3 μM), and inward-rectifier K+ channel (KIR) blocker (BaCl2, 30 μM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca2+ homeostasis via dapagliflozin administration. [ABSTRACT FROM AUTHOR]

Study Objective: The effects of the sodium‐dependent glucose transporter‐2 inhibitor ipragliflozin were compared with metformin in a previous study, which revealed that ipragliflozin reduced visceral fat content by 12%; however, the underlying mechanism was unclear. Therefore, this sub‐analysis aimed to compare metabolomic changes associated with ipragliflozin and metformin that may contribute to their biological effects. Design: A sub‐analysis of a randomized controlled study. Setting: Chiba University Hospital and ten hospitals in Japan. Patients: Fifteen patients with type 2 diabetes in the ipragliflozin group and 15 patients with type 2 diabetes in the metformin group with matching characteristics, such as age, sex, baseline A1C, baseline visceral fat area, smoking status, and concomitant medication. Interventions: Ipragliflozin 50 mg or metformin 1000 mg daily. Measurements: The clinical data were reanalyzed, and metabolomic analysis of serum samples collected before and 24 weeks after drug administration was performed using capillary electrophoresis time‐of‐flight mass spectrometry. Main Results: The reduction in the mean visceral fat area after 24 weeks of treatment was significantly larger (p = 0.002) in the ipragliflozin group (−19.8%) than in the metformin group (−2.5%), as were the subcutaneous fat area and body weight. The A1C and blood glucose levels decreased in both groups. Glutamic pyruvic oxaloacetic transaminase, γ‐glutamyl transferase, uric acid, and triglyceride levels decreased in the ipragliflozin group. Low‐density lipoprotein cholesterol levels decreased in the metformin group. After ipragliflozin administration, N2‐phenylacetylglutamine, inosine, guanosine, and 1‐methyladenosine levels increased, whereas galactosamine, glucosamine, 11‐aminoundecanoic acid, morpholine, and choline levels decreased. After metformin administration, metformin, hypotaurine, methionine, methyl‐2‐oxovaleric acid, 3‐nitrotyrosine, and cyclohexylamine levels increased, whereas citrulline, octanoic acid, indole‐3‐acetaldehyde, and hexanoic acid levels decreased. Conclusions: Metabolites that may affect visceral fat reduction were detected in the ipragliflozin group. Studies are required to further elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population‐specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial. Methods: Individual participant data were pooled and analysed in subgroups according to population‐specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed‐effect models were used. Results: A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (Pheterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95). Conclusions: The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population‐specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial. [ABSTRACT FROM AUTHOR]

Aim: Sodium‐glucose cotransporter 2 inhibitors (SGLT2is) are available for individuals with type 1 diabetes, but appropriate use is recommended to prevent ketosis or ketoacidosis. This study aimed to evaluate the risk of ketosis in people with type 1 diabetes, focusing on the relationship between nutritional assessment, glycaemic status, c‐peptide immunoreactivity (CPR) index and body composition. Materials and Methods: In total, 46 Japanese patients with type 1 diabetes were included, and dietary assessment from food photographs and ketone levels were evaluated before and after taking SGLT2is. The effect of diet on morning ketone levels was also investigated. Results: All patients had an increase in mean ketone concentrations after taking SGLT2is (before 0.12 ± 0.06 mmol/L, after 0.23 ± 0.16 mmol/L). A significant negative correlation was found between average morning ketone levels and age (r = −0.514, p <.001) and the CPR index (r = −0.523, p =.038) after taking SGLT2is. Using a mixed‐effects model based on the results before starting the inhibitors, it was noted that both patient‐to‐patient and age, or patient‐to‐patient and capacity of insulin secretion, influenced the ketone levels. Multiple regression analysis showed that factors associated with the risk of increasing ketone levels after taking SGLT2is were younger age (β = −0.504, p =.003) and a low ratio of basal to bolus insulin (β = −0.420, p =.005). Conclusions: When administering SGLT2is to patients with a low CPR index or younger patients with type 1 diabetes, adequate instructions to prevent ketosis should be given. [ABSTRACT FROM AUTHOR]

Aims: To assess post‐initiation predictors of discontinuation of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors compared to dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors in the United Kingdom. Materials and Methods: We conducted a comparative population‐based retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) with linked data to hospital and death records. We included new metformin users who initiated either SGLT2 inhibitors or DPP‐4 inhibitors between January 2013 and October 2019. The main outcome was treatment discontinuation, defined as the first 90‐day gap after the estimated treatment end date. We used a series of extended Cox models to assess which time‐dependent predictors were associated with treatment discontinuation. To test if the hazard ratio of discontinuation for each predictor was statistically different between SGLT2 and DPP‐4 inhibitors, an exposure‐predictor interaction term was added to each model. Results: There were 2550 new users of SGLT2 inhibitors and 8195 new users of DPP‐4 inhibitors. Approximately 69% of SGLT2 inhibitor and 74% of DPP‐4 inhibitor users had discontinued treatment by the end of follow‐up. Occurrence of fractures after treatment initiation was a significant predictor of discontinuation of SGLT2 inhibitors (hazard ratio [HR] 4.13, 95% confidence interval [CI] 2.12‐8.06) but not DPP‐4 inhibitors (HR 0.93, 95% CI 0.79‐1.11). The rate of treatment discontinuation was significantly higher for those with low estimated glomerular filtration rate and minimal contact with the healthcare system. Efficacy endpoints, such as heart failure and glycated haemoglobin level, were not associated with treatment discontinuation. Conclusions: Our findings reflect some discrepancy between the available evidence and prescribing behaviour for SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Aim: This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)‐determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). Materials and Methods: Patients were given dapagliflozin 10 mg once daily in a randomized, double‐blind, placebo‐controlled trial with short‐term (1 week) and long‐term (12 weeks) cross‐over periods. The primary outcome was the difference in test meal food intake between long‐term dapagliflozin and placebo treatment. Secondary outcomes included short‐term differences in test meal food intake, short‐ and long‐term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). Results: In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2, glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91‐16.27, p =.004], and body weight (−2.84 vs. −0.87 kg) versus placebo. There was no short‐ or long‐term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI −127.9 to 139.3, p =.933); 15.8 g (95% CI −147.7 to 116.1, p =.813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction −4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. Conclusions: The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure. [ABSTRACT FROM AUTHOR]

Aims: Whether to recommend specifically the glucose‐lowering therapies with cardiovascular benefit only in secondary prevention, or also in patients with multiple risk factors (MRF) but without established atherosclerotic cardiovascular disease (ASCVD), is controversial across the guidelines for diabetes. Materials and Methods: We performed a meta‐analysis of clinical trials with major adverse cardiovascular events (MACE) as an outcome. Results: The definitions of ASCVD and MRF were heterogeneous across trials; nevertheless, the incidence of MACE was 2.8‐fold higher in people with ASCVD in trials with sodium‐glucose cotransporter 2 inhibitors (SGLT2is), and 3.9‐fold in trials with glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA). Both SGLT2i and GLP‐1 RA were associated with a significant reduction in the incidence of MACE in people with previous ASCVD [inverse variance‐odds ratio 0.91, 95% confidence interval (0.86: 0.97) for SGLT2i, Mantel‐Haenszel odds ratio 0.85, 95% confidence interval (0.81: 0.90) for GLP‐1 RA], whereas no significant reduction was detected in those without; on the other hand, no significant difference in effect was found between the two groups as well. The sample of patients without ASCVD enrolled in clinical trials is insufficient to draw reliable conclusions in this population; however, even assuming the same benefit detected in people with ASCVD also in those with MRF, the number needed to treat would differ (35 for secondary, 99 for primary prevention of a MACE with a SGLT2i; 21 for secondary, 82 for primary prevention with a GLP‐1 RA, respectively), given the difference in absolute cardiovascular risk at baseline. Conclusion: The distinction between patients with ASCVD and those without ASCVD and MRF appears therefore justified by available evidence. [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter (SGLT)‐2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non‐diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia. To test this hypothesis, we used an integrative mathematical model of human physiology, HumMod. Stage 3 CKD conditions were simulated by reducing nephron mass which was associated with hypertension, low glomerular filtration rate (GFR) (55 mL/min), hyperfiltration of remnant nephrons, elevated albuminuria (500 mg/day), and minimal levels of urinary glucose (0.02 mmol/L). SGLT2 inhibition was associated with acute reductions in GFR associated with afferent arteriolar vasoconstriction due to TGF. After 12 months, glomerular pressure, nephron damage, and chronic GFR decline were reduced with SGLT2 inhibition with additional SGLT1 inhibitory effects further enhancing these effects. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes. [ABSTRACT FROM AUTHOR]

Aim: To estimate the lifetime benefit of a combination treatment of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors and mineralocorticoid‐receptor antagonists (MRA) in patients with type 2 diabetes and chronic kidney disease (CKD). Materials and Methods: The cumulative effect of combination treatment was derived from trial‐level estimates of the effect of an SGLT2 inhibitor (canagliflozin) and MRA (finerenone) from the CREDENCE (N = 4401) and FIDELIO (N = 5734) trials, respectively. The cumulative effect was applied to the control group of patients with type 2 diabetes in the DAPA‐CKD trial (N = 1451) to estimate long‐term gains in event‐free and overall survival. The analysis was repeated in an observational study. The primary outcome was a composite endpoint of doubling of serum creatinine, end‐stage kidney disease or death because of kidney failure. Results: The hazard ratio of combination treatment for the primary outcome was 0.50 [95% confidence interval (CI): 0.44, 0.57]. At age 50 years, the estimated event‐free survival from the primary outcome was 16.7 years (95% CI: 18.1, 21.0) with combination treatment versus 10.0 years (95% CI: 6.8, 12.3) with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers resulting in an incremental gain of 6.7 years (95% CI: 5.5, 7.9). In an observational study, the estimated gain in event‐free survival regarding primary outcome was 6.3 years (95% CI: 5.2, 7.3). In a conservative scenario, assuming low adherence (70% of the observed adherence) and less pronounced efficacy (70% of the observed efficacy with 2% yearly decline) of combination therapy, gain in event‐free survival regarding primary outcome was 2.5 years (95% CI: 2.0, 2.9). Conclusions: Combined disease‐modifying treatment with an SGLT2 inhibitor and MRA in patients with type 2 diabetes and CKD may substantially increase the number of years free from kidney failure and mortality. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether sodium‐glucose cotransporter‐2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase‐4 (DPP‐4) inhibitor use as add‐on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). Methods: A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first‐ever prescription for a DPP‐4 inhibitor or an SGLT2 inhibitor as add‐on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP‐4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP‐4 inhibitor use. Results: A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP‐4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP‐4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91‐1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64‐1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. Conclusion: Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP‐4 inhibitor use. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. Methods: We conducted post hoc analyses of a randomized, open‐label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin‐creatinine ratio ≥30 and ≤500 mg/g assigned to 4‐week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4‐week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR‐reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated‐measures linear mixed‐effects models were employed. Results: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best‐performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best‐performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best‐performing drug and the other three was −19.7% (95% CI −23.1, −16.3; P < 0.001). Conclusions: We demonstrated no overall effect of 4‐week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels. [ABSTRACT FROM AUTHOR]

Copyright of Hypertonia és Nephrologia is the property of LifeTime Media Kft. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Hypertonia és Nephrologia is the property of LifeTime Media Kft. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) are two major complications of type 2 diabetes (T2DM). Cardiovascular protection is a key objective, yet not fully reached in clinical practice. Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM and SGLT2is in reducing hospitalization for HF in placebo-controlled randomized trials. However, real-life studies worldwide revealed that only a minority of patients with T2DM receive either a GLP-1RA or an SGLT2i and surprisingly even less patients with established ASCVD or HF are treated with these cardioprotective antihyperglycemic agents. Bridging the gap between evidence-based cardiovascular protection with GLP-1RAs and SGLT2is and their underuse in daily clinical practice in patients with T2DM at high risk is crucial from a public health viewpoint. However, the task appears hazardous and the goal not attained considering the current failure. Education of specialists/primary care physicians and patients is critical. Multifaceted and coordinated interventions involving all actors (physicians, patients and broadly health-care system) must be implemented to stimulate the adoption of these cardioprotective antihyperglycemic medications as part of routine cardiovascular care among patients with T2DM. Type 2 diabetes can lead to major cardiovascular complications including cardiovascular disease linked to narrowing of the arteries (atherosclerosis), and heart failure. These complications are associated with lower quality of life and life expectancy. Thus, cardiovascular protection in people with type 2 diabetes is an important objective. However, clinical practice often fails in fully achieving this goal. Two types of medications that lower blood sugar (so-called antidiabetic agents) have shown efficacy in reducing major cardiovascular events (such as strokes and heart attacks) in high-risk patients with type 2 diabetes. One of them has also shown effectiveness in decreasing hospitalizations due to heart failure. However, in clinical practice, most patients with type 2 diabetes do not receive these medications, even people with known cardiovascular disease or heart failure, despite the proven effectiveness of these drugs. Many studies worldwide have highlighted socioeconomic inequities regarding the use of these medications, which can be expensive. From a public health perspective, it is imperative to bridge the gap between the under-use of cardioprotective antidiabetic agents in routine daily practice among high-risk patients with type 2 diabetes and the clear-cut recommendations of international guidelines. Given the current limitations, this task appears challenging. Education of physicians (both primary care practitioners and specialists, including cardiologists) and patients is most important in addressing this issue. Finally, in every country, the global health-care system should facilitate the use of these agents among patients with type 2 diabetes at high risk of atherosclerotic cardiovascular disease and heart failure. [ABSTRACT FROM AUTHOR]

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. Objective s : 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. [ABSTRACT FROM AUTHOR]

Background: A comprehensive network meta-analysis comparing the effects of individual sodium-glucose cotransporter 2 (SGLT2) inhibitors on patients with and without comorbidities including diabetes mellitus (DM), heart failure (HF), and chronic kidney disease (CKD) has not been previously conducted. Methods: We searched PubMed, Embase, Cochrane, and ClinicalTrials.gov for randomized controlled trials up to March 28, 2023. Network meta-analysis using a random-effects model was conducted to calculate risk ratios (RRs). Risk of Bias tool 2.0 was used to assess bias, and CINeMA to assess the certainty of evidence. In the subgroup analysis, the SGLT2 inhibitors were classified into highly (dapagliflozin, empagliflozin, and ertugliflozin) and less selective SGLT2 inhibitors (canagliflozin and sotagliflozin). Results: A total of fourteen trials with 75,334 patients were analyzed. Among these, 40,956 had taken SGLT2 inhibitors and 34,378 had not. One of the main results with particular findings was empagliflozin users had a significantly lower risk of all-cause death compared to dapagliflozin users in DM population (RR: 0.81, 95% CI 0.69–0.96). In HF population, sotagliflozin users had a borderline significantly lower risk of CV death or hospitalization for HF (HHF) than dapagliflozin users (RR: 0.90, 95% CI 0.80–1.01). In non-HF population, those who used canagliflozin had a significantly lower risk of CV death or HHF compared with those who used dapagliflozin (RR: 0.75, 95% CI 0.58–0.98). At last, for HF patients, those who used less selective SGLT2 inhibitors had a significantly lower risk of MACEs compared to those who used highly selective SGLT2 inhibitors (RR: 0.75, 95% CI 0.62–0.90). Conclusions: Our network meta-analysis revealed that empagliflozin users with diabetes experienced a lower risk of dying from any cause than those using dapagliflozin. Additionally, canagliflozin users demonstrated a reduced risk of cardiovascular death or HHF compared to dapagliflozin users in those without HF. In HF patients, less selective SGLT2 inhibitors showed superior CV composite outcomes, even surpassing the performance of highly selective SGLT2 inhibitors. Trial registration: PROSPERO [CRD42022361906]. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation. Methods: We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17th 2023 and the Teratology Information Service (TIS) of Switzerland on February 6th 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion. Results: We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP-1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available. Conclusion/interpretation: We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies. [ABSTRACT FROM AUTHOR]

Use of sodium-glucose transporter-2 (SGLT2) inhibitors has dramatically increased over the past decade. This medication class predisposes patients to euglycaemic diabetic ketoacidosis, particularly during times of physiologic stress, including fasting and surgery. Beyond case reports and series, a systematic description of perioperative metabolic effects of SGLT2 inhibitors is lacking. We examined the degree of anion gap acidosis, controlling for non-ketone anions, in patients undergoing surgery at Massachusetts General Hospital in 2016–22. We constructed a multivariable regression model incorporating known non-ketone contributors to the postoperative anion gap (albumin, lactate, estimated glomerular filtration rate, and preoperative anion gap), hold time, and interaction terms between hold time and three previously suggested risk factors for euglycaemic diabetic ketoacidosis: emergency surgery, cardiac surgery, and insulin use. In 463 patients on SGLT2 inhibitors, we observed a strong association between decreased hold time and postoperative anion gap (P <0.001 in a univariable analysis; −0.43, 95% confidence interval [−0.76 to −0.11] change in anion gap per day held, P =0.01 in a multivariable analysis). A significant interaction between hold time and emergency surgery was observed, whereas there was no apparent interaction with insulin use or cardiac surgery. These findings provide the first evidence that an anion gap acidosis, likely from ketoacids, develops in all patients who do not hold SGLT2 inhibitors before surgery rather than in an idiosyncratic few. If an SGLT2 inhibitor is unable to be stopped, postoperative monitoring of anion gap and serum ketones can help detect clinically significant euglycaemic diabetic ketoacidosis, particularly in those undergoing emergency surgery. [ABSTRACT FROM AUTHOR]

Keywords: body composition; clinical trial; metformin; obesity therapy; SGLT2 inhibitor; type 2 diabetes EN body composition clinical trial metformin obesity therapy SGLT2 inhibitor type 2 diabetes 3071 3075 5 09/06/23 20231001 NES 231001 BACKGROUND The Japanese Diabetes Society has released an algorithm for pharmacotherapy for patients with type 2 diabetes (T2D).[1] It recommends metformin and sodium-glucose co-transporter 2 (SGLT2) inhibitors for patients with obesity. Urinary 1 microglobulin level is useful for selecting sodium-glucose transporter 2 inhibitor or metformin for visceral fat reduction in patients with type 2 diabetes The results prove that ipragliflozin is effective for reducing VFA in patients with high fasting insulin, low urinary 1MG, or high GPT levels, while metformin is effective for reducing VFA in patients with high HbA1c or urinary 1MG levels. The sodium-glucose cotransporter 2 inhibitor ipragliflozin improves liver function and insulin resistance in Japanese patients with type 2 diabetes. [Extracted from the article]

Aims: To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type 2 diabetes (T2D) and high risk of cardiovascular events. Materials and Methods: In this prespecified substudy of the randomized, placebo‐controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between‐group change in mGFR, measured by the 51Cr‐EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included. Results: From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention‐to‐treat analysis. Treatment with empagliflozin reduced mGFR by −7.9 mL/min (95% confidence interval [CI] −11.1 to −4.7; P < 0.001), estimated ECV by −192.5 mL (95% CI −318.0 to −66.9; P = 0.003) and estimated PV by −128.9 mL (95% CI −218.0 to 39.8; P = 0.005) at Week 13. Conclusions: Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

2 Martin CL, Albers JW, Pop-Busui R. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Effects of baricitinib, empagliflozin, linagliptin and telmisartan on cardiovascular autonomic neuropathy in type 1 diabetes: An exploratory, randomized, open-label, crossover trial The primary aim was to determine the individual albuminuria-lowering response of four albuminuria-lowering drug classes in persons with type 1 diabetes. Keywords: clinical trial; diabetes complications; diabetic neuropathy; empagliflozin; linagliptin; SGLT2 inhibitor EN clinical trial diabetes complications diabetic neuropathy empagliflozin linagliptin SGLT2 inhibitor 3064 3067 4 09/06/23 20231001 NES 231001 INTRODUCTION Cardiovascular autonomic neuropathy (CAN) is a prevalent complication in type 1 diabetes and a risk factor for cardiovascular mortality.[1] CAN is preventable to some extent: Intensive glucose control demonstrated a 45% risk reduction of CAN in persons with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC).[2] To our knowledge, however, no treatment is available when CAN is incident. [Extracted from the article]

It has been shown that SGLT2 suppresses atherosclerosis (AS). Recent studies indicate that autophagy widely participates in atherogenesis. This study aimed to assess the effect of canagliflozin (CAN) on atherogenesis via autophagy. Macrophages and ApoE − / − mice were used in this study. In macrophages, the results showed that CAN promoted LC3II expression and autophagosome formation. Furthermore, the cholesterol efflux assay demonstrated that CAN enhanced cholesterol efflux from macrophages via autophagy, resulting in lower lipid droplet concentrations in macrophages. The western blot revealed that CAN regulated autophagy via the AMPK/ULK1/Beclin1 signaling pathway. CAN resulted in increased macrophage autophagy in atherosclerotic plaques of ApoE − / − mice, confirming that CAN could inhibit the progression of AS via promoting macrophage autophagy. The current study found that CAN reduced the production of atherosclerotic lesions, which adds to our understanding of how SGLT2 inhibitors function to delay the progression of AS. [ABSTRACT FROM AUTHOR]

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF. [ABSTRACT FROM AUTHOR]

Abstract Aims The duration of type 2 diabetes mellitus (T2DM) is an important determinant of diabetes severity. The EMPA‐HEART CardioLink‐6 trial reported significant left ventricular (LV) mass indexed to body surface area (LVMi) regression in patients treated with the sodium‐glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin for 6 months. This exploratory sub‐analysis of the same trial investigated the association between T2DM duration and LVMi regression. Methods and results A total of 97 individuals with T2DM and coronary artery disease (CAD) were randomly assigned to receive empagliflozin 10 mg daily or placebo. LVMi was measured at the baseline and 6 month visit using cardiac magnetic resonance imaging. The study population was divided into those with a baseline T2DM duration

Abstract Aims Given recent suggestions that serum levels of insulin‐like growth factor‐binding protein 7 (IGFBP7) may identify patients who derive greater cardiorenal benefits from treatment with sodium‐glucose transport 2 inhibitors (SGLT2i), this exploratory sub‐analysis of the EMPA‐HEART CardioLink‐6 randomized controlled trial evaluated the association between serum levels of IGFBP7 and empagliflozin‐mediated left ventricular mass regression. Methods and results The EMPA‐HEART CardioLink‐6 trial used gold‐standard cardiac magnetic resonance imaging to detect change in left ventricular mass indexed to body surface area (LVMi) following 6 months of treatment with empagliflozin or matching placebo in 97 patients with type 2 diabetes and coronary artery disease. Serum samples were collected at baseline and analysed for IGFBP7 using an enzyme‐linked immunosorbent assay. A multivariate linear regression model was used to assess the association between IGFBP7 and baseline LVMi. A linear model adjusting for baseline differences in LVMi was used to test the relationship between baseline IGFBP7 level, change in LVMi over 6 months, and treatment arm. Of the 97 patients enrolled, 74 had complete covariate data and were included in our analysis. No association between baseline IGFBP7 and baseline LVMi was found [baseline LVMi: 0.14 g/m2 (95% CI: −0.29 g/m2 to 0.57 g/m2) per 1 ng/mL higher baseline IGFBP7]. In addition, no difference between patients treated with empagliflozin versus matching placebo was found when evaluating the association between serum IGFBP7, 6 month change in LVMi, and treatment arm [empagliflozin 6 month change in LVMi: 0.25 g/m2 (95% CI: −0.17 g/m2 to 0.67 g/m2) per 1 ng/mL higher IGFBP7 vs. matching placebo 6 month change in LVMi: 0.07 g/m2 (95% CI: −0.21 g/m2 to 0.35 g/m2) per 1 ng/mL higher IGFBP7; Pinteraction = 0.49]. Additional sensitivity analysis assessing IGFBP7 as a categorical variable (above/below the median) showed no significant association between IGFBP7, 6 month change in LVMi, and treatment arm. Conclusions Our study provides insight into the generalizability of IGFBP7 as a surrogate marker of cardiac remodelling in patients with type 2 diabetes and coronary artery disease. Our results suggest that SGLT2i‐mediated reverse cardiac remodelling may be independent of IGFBP7 levels. Further investigations evaluating the association between IGFBP7 and SGLT2i are suggested to understand if and how IGFBP7 levels may modulate benefits received from SLGT2i.

Abstract In patients with glycogen storage disease type Ib (GSD Ib), quality of life is severely hampered by neutropenia and neutropenia‐associated symptoms. SGLT2 inhibitors are a new treatment option and have shown improved medical outcomes in more than 120 patients so far. The aim of this international questionnaire study was to assess patient‐reported outcomes of this new treatment in GSD Ib patients. Patients and caregivers of pediatric patients were invited to complete a web‐based questionnaire. This was designed to evaluate treatment effects of the SGLT2 inhibitor empagliflozin on clinical symptoms and important aspects of daily life including physical performance, sleep, social and work life, traveling, socioeconomic aspects, and quality of life. The questionnaire was completed by 73 respondents from 17 different countries. The mean duration of treatment was 15 months, the cumulative treatment time was 94.8 years. More than 80% of patients reported an improved quality of life. The number of hospitalizations was reduced (66% of patients), as well as the number of days absent from school or work. Granulocyte colony‐stimulating factor (G‐CSF) treatment could be stopped in 49% of patients and reduced in another 42%. Clear improvement of neutropenia and all neutropenia‐associated symptoms was reported by the majority of patients. Additionally, patients or caregivers reported positive effects on appetite (63%), level of activity (75%), overall well‐being (96%), and sleep (63%). Empagliflozin positively impacts many aspects of daily life including work and social life and thereby significantly improves quality of life of patients and caregivers.

Abstract Background Sodium glucose co-transporter-2 (SGLT2) inhibitors improve long-term cardiovascular and renal outcomes in individuals with type 2 diabetes. However, the safety of SGLT2 inhibitors in ICU patients with type 2 diabetes is uncertain. We aimed to perform a pilot study to assess the relationship between empagliflozin therapy and biochemical, and clinical outcomes in such patients. Methods We included 18 ICU patients with type 2 diabetes receiving empagliflozin (10 mg daily) and insulin to target glucose range of 10–14 mmol/l according to our liberal glucose control protocol for patients with diabetes (treatment group). Treatment group patients were matched on age, glycated hemoglobin A1c, and ICU duration with 72 ICU patients with type 2 diabetes exposed to the same target glucose range but who did not receive empagliflozin (control group). We compared changes in electrolyte and acid–base parameters, hypoglycemia, ketoacidosis, worsening kidney function, urine culture findings, and hospital mortality between the groups. Results Median (IQR) maximum increase in sodium and chloride levels were 3 (1–10) mmol/l and 3 (2–8) mmol/l in the control group and 9 (3–12) mmol/l and 8 (3–10) mmol/l in the treatment group (P = 0.045 for sodium, P = 0.059 for chloride). We observed no differences in strong ion difference, pH or base excess. Overall, 6% developed hypoglycemia in each group. No patient in the treatment group and one patient in the control group developed ketoacidosis. Worsening kidney function occurred in 18% and 29% of treatment and control group patients, respectively (P = 0.54). Urine cultures were positive in 22% of treatment group patients and 13% of control group patients (P = 0.28). Overall, 17% of treatment group patients and 19% of control group patients died in hospital (P = 0.79). Conclusions In our pilot study of ICU patients with type 2 diabetes, empagliflozin therapy was associated with increases in sodium and chloride levels but was not significantly associated with acid–base changes, hypoglycemia, ketoacidosis, worsening kidney function, bacteriuria, or mortality.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2–OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Objective To evaluate the effect of sodium-glucose cotransporter-2 inhibitor （SGLT2i） on the efficacy and safety of percutaneous coronary intervention （PCI） in patients with acute ST segment elevation myocardial infarction （STEMI） complicated with type 2 diabetes mellitus. Methods Four hundred and six patients with STEMI complicated with type 2 diabetes mellitus undergoing PCI were selected and divided into the conventional treatment group and SGLT2i group according to whether SGLT2i was used. Clinical data were collected. Patients were followed up by outpatient or telephone. Results The incidence of MACE and heart failure readmission rate in the SGLT2i group were lower than those in the conventional treatment group （both P < 0.01）. After the adjustment of all risk factors， SGLT2i could reduce the incidence of MACE（OR=3.59，95%CI 9.43-1.36）and the risk of heart failure readmission（OR=4.54，95%CI 15.30-1.35）compared with conventional treatment. Conclusion SGLT2i is a safe treatment for STEMI patients complicated with type 2 diabetes mellitus after PCI， which can lower the incidence of MACE and heart failure readmission after surgery.

Abstract Background Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors is a rare, relatively new and potentially fatal clinical entity, characterized by metabolic acidosis with normal or only moderately elevated glycemia. The mechanisms are not fully understood but involve increased ketogenesis and complex renal metabolic dysfunction, resulting in both ketoacidosis and hyperchloremic acidosis. We report a rare case of fatal empagliflozin-associated acidosis with profound hyperchloremia and review its pathogenesis. Case presentation A patient with type 2 diabetes mellitus treated with empagliflozin underwent an elective hip replacement surgery. Since day 4 after surgery, he felt generally unwell, leading to cardiac arrest on the day 5. Empagliflozin-associated euglycemic diabetic ketoacidosis with severe hyperchloremic acidosis was identified as the cause of the cardiac arrest. Conclusions This unique case documents the possibility of severe SGLT2 inhibitor-associated mixed metabolic acidosis with a predominant hyperchloremic component. Awareness of this possibility and a high index of suspicion are crucial for correct and early diagnosis.

Abstract Background Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently. Methods We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane's risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria. Results We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89–1.05), PAOD (RR = 0.98, 95% CI 0.78–1.24), or IS (RR = 0.95, 95% CI 0.79–1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77–0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82–0.94). Conclusion Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.

Abstract Aims Absolute treatment effects—i.e. numbers needed to treat (NNTs)—of novel antidiabetic drugs for cardiovascular outcomes have not been comprehensively evaluated. We aimed to perform a meta‐analysis of digitalized individual patient outcomes to display and compare absolute treatment effects. Methods and results Individual patient time‐to‐event information from Kaplan–Meier plots of cardiovascular mortality (CM) and/or hospitalization for heart failure (HHF) endpoints from cardiovascular outcome trials (CVOTs) evaluating dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide‐1 (GLP‐1) receptor agonists, and sodium glucose transporter 2 (SGLT2) inhibitors vs. placebo were digitalized using WebPlotDigitizer 4.2 and the R code of Guyot et al.; Weibull regression models were generated, validated, and used to estimate NNT for individual trials; random‐effects meta‐analysis generated Meta‐NNT with 95% confidence intervals. Sixteen CVOTs reported time‐to‐event information (14 in primary diabetes and 2 in primary heart failure populations). Thirteen studies including 96 860 patients were meta‐analysed for CM: At the median follow‐up of 30 months, Meta‐NNTs were 178 (64 to ∞ to −223) for DPP‐4 inhibitors, 261 (158 to 745) for GLP‐1 receptor agonists, and 118 (68 to 435) for SGLT2 inhibitors. Ten studies including 96 128 patients were meta‐analysed for HHF: At the median follow‐up of 29 months, estimated Meta‐NNTs were −644 (229 to ∞ to −134) for DPP‐4 inhibitors, 441 (184 to ∞ to −1100) for GLP‐1 receptor agonists, and 126 (91 to 208) for SGLT2 inhibitors. SGLT2 inhibitors were especially effective for HHF in primary heart failure populations [Meta‐NNT 25 (19 to 39)] vs. primary diabetes populations [Meta‐NNT 233 (167 to 385)] at 16 months of follow‐up. Conclusions We found only modest treatment benefits of GLP‐1 receptor agonists and SGLT2 inhibitors for CM and HHF in primary type 2 diabetes mellitus populations. In primary heart failure populations, SGLT2 inhibitor benefits were substantial and comparable in efficacy to established heart failure medication.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are emerging as an important therapy not only for type 2 diabetes (T2DM), but also for heart disease and kidney disease. As these medicines gain acceptance, the number of hospitalized patients receiving them is likely to rise. During clinical trials, SGLT2 inhibitors were noted to have a potential risk for diabetic ketoacidosis (DKA), particularly DKA with relatively normal blood glucose levels, ‘euglycemic DKA’. Similar to DKA that is not associated with SGLT2 inhibitors, most of these events seem to be related to acute illnesses or other changes in a patient’s medications or self-management circumstances. This creates a need among hospital providers to create strategies to prevent DKA in their hospitalized patient and guidance on monitoring and treating euglycemic DKA. Our combined experience concerning this phenomenon has given a great deal of insight into this problem and the knowledge needed to improve patient care, by augmenting patient education, inpatient surveillance, and early treatment for euglycemic DKA.

ObjectiveCheckpoint inhibitors (CPIs) can trigger complications related to the autoimmune process such as CPI-triggered diabetes mellitus. The typical treatment for CPI-triggered diabetes is insulin, but a detailed therapeutic method has not yet been established. To prevent severe symptoms and mortality of diabetic ketoacidosis in advanced-stage cancer patients, the establishment of effective treatment of CPI-triggered diabetes, other than insulin therapy, is required.MethodsWe present a case of a 76-year-old man with CPI-triggered diabetes who was treated with nivolumab and ipilimumab for lung cancer. We also conducted a systematic review of 48 case reports of type 1 diabetes associated with nivolumab and ipilimumab therapy before June 2023.ResultsThe patient’s hyperglycemia was not sufficiently controlled by insulin therapy, and after the remission of ketoacidosis, the addition of a sodium-glucose transporter (SGLT) 2 inhibitor, dapagliflozin, improved glycemic control. Most of the reported nivolumab/ipilimumab-induced type 1 diabetes was treatable with insulin, but very few cases required additional oral anti-diabetic agents to obtain good glucose control.ConclusionAlthough SGLT2 inhibitors have been reported to have adverse effects on ketoacidosis, recent studies indicate that the occurrence of ketoacidosis is relatively rare. Considering the pathological mechanism of CPI-triggered diabetes, SGLT2 inhibitors could be an effective choice if they are administered while carefully monitoring the patient’s ketoacidosis.