SGLT2 Inhibitors Research Articles

Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients With IgA Nephropathy

IntroductionEndothelin A (ETA) receptor activation is a driver of proteinuria, kidney inflammation and fibrosis in IgA nephropathy (IgAN). Atrasentan, a selective ETA receptor antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. ALIGN (NCT04573478) is a phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss. MethodsEligibility criteria for the ALIGN main stratum included patients with biopsy-proven IgAN, total protein excretion ≥1g/d, eGFR ≥30 mL/min/1.73m2, receiving a maximally-tolerated stable dose of a renin-angiotensin system inhibitor (RASi). An exploratory stratum enrolled participants also receiving a stable dose of sodium glucose cotransporter-2 inhibitors (SGLT2i). Participants were randomized to 0.75 mg atrasentan or placebo orally daily for 132 weeks followed by a 4-week wash-out period. The primary outcome is proteinuria change from baseline (24h urine protein–creatinine ratio UPCR) to Week 36 in the main stratum. Key secondary endpoints include eGFR change from baseline to Week 136, safety and tolerability. ResultsEnrolment occurred across 20 countries; 404 patients are randomized: 340 in the main stratum and 64 in the SGLT2i stratum. At baseline in the main stratum, mean age was 44.7 years, 42.4% were female, mean eGFR and median UPCR were 58.9 mL/min/1.73 m2 and 1.4 g/g, respectively. ConclusionThe ongoing ALIGN trial evaluates the efficacy and safety of atrasentan in a representative global IgAN population at risk for disease progression despite optimized RASi therapy and includes an exploratory stratum evaluating atrasentan use in combination with an SGLT2i.

Assessing 1-year sodium-glucose co-transporter-2 inhibitor tolerance in older adults.

Evidence concerning tolerability of sodium-glucose co-transporter-2 (SGLT2) inhibitors in older adults is limited due to under-representation in clinical trials. Our study aimed to determine the extent to which SGLT2 inhibitor intolerance increases with age and explore additional factors associated with intolerance. This retrospective observational study included patients in the Veterans Health Administration who initiated an SGLT2 inhibitor between 1 January 2013 and 31 December 2021. One-year discontinuation served as a proxy for intolerance. Relative risk (RR) for 1-year discontinuation was contrasted across age groups using log-binomial regression to adjust for confounding. Of 232 495 patients who initiated an SGLT2 inhibitor, 60 582 (26.1%) discontinued within one year. A difference was observed across age groups, <65, 65-74, 75-84 and ≥85years, where 25.8%, 25.3%, 28.5% and 34.9% of patients discontinued, respectively (P < .001). After adjustment for confounding factors, patients 75-84 and ≥85years were at 8% (RR = 1.08; 95% CI: 1.05, 1.10) and 21% increased risk (RR = 1.21; 95% CI: 1.15, 1.26) for discontinuation, respectively, relative to patients <65years. Additional risk factors were identified: female (RR = 1.41; 95% CI: 1.37, 1.45), estimated glomerular filtration rate stage 4 (RR = 1.49; 95% CI: 1.39, 1.60), underweight (RR = 1.15; 95% CI: 1.03, 1.29), urinary tract infection history (RR = 1.25; 95% CI: 1.21, 1.30) and yeast infection history (RR = 1.39; 95% CI: 1.27, 1.51). No clinically meaningful differences in SGLT2 inhibitor intolerance were observed in patients up to 84years. Our findings support having closer follow-up when initiating in patients 85years and older.

Leveraging metabolism for better outcomes in heart failure.

Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium glucose cotransporter 2 inhibitor (SGLT2i) therapy as one of the four "pillars" of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.

Efficacy and safety of henagliflozin combined with continuous subcutaneous insulin infusion in the treatment of Chinese inpatients with type 2 diabetes mellitus based on a continuous glucose monitoring system: protocol of a multicentre, open-label, inpatient, randomised, controlled trial

IntroductionThe role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in diabetes treatment is expanding; however, few studies have investigated the efficacy and safety of combining SGLT2is with insulin pump therapy. Notably,...

Review on the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway in diabetes: mechanistic insights and therapeutic implications.

This review explores the pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of diabetes and its complications, highlighting the therapeutic potential of various oral hypoglycemic drugs targeting this pathway. NLRP3 inflammasome activation, triggered by metabolic stressors like hyperglycemia, hyperlipidemia, and free fatty acids (FFAs), leads to the release of pro-inflammatory cytokines interleukin-1β and interleukin-18, driving insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. These processes contribute to diabetic complications such as nephropathy, neuropathy, retinopathy, and cardiovascular diseases (CVD). Here we discuss the various transcriptional, epigenetic, and gut microbiome mediated regulation of NLRP3 activation in diabetes. Different classes of oral hypoglycemic drugs modulate NLRP3 inflammasome activity through various mechanisms: sulfonylureas inhibit NLRP3 activation and reduce inflammatory cytokine levels; sodium-glucose co-transporter 2 inhibitors (SGLT2i) suppress inflammasome activity by reducing oxidative stress and modulating intracellular signaling pathways; dipeptidyl peptidase-4 inhibitors mitigate inflammasome activation, protecting against renal and vascular complications; glucagon-like peptide-1 receptor agonists attenuate NLRP3 activity, reducing inflammation and improving metabolic outcomes; alpha-glucosidase inhibitors and thiazolidinediones exhibit anti-inflammatory properties by directly inhibiting NLRP3 activation. Agents that specifically target NLRP3 and inhibit their activation have been identified recently such as MCC950, Anakinra, CY-09, and many more. Targeting the NLRP3 inflammasome, thus, presents a promising strategy for managing diabetes and its complications, with oral hypoglycemic drugs offering dual benefits of glycemic control and inflammation reduction. Further research into the specific mechanisms and long-term effects of these drugs on NLRP3 inflammasome activity is warranted.

Uric Acid and SGLT2 Inhibition With Empagliflozin in HeartFailure With Preserved Ejection Fraction: The EMPEROR-Preserved Trial.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcome in patients with heart failure (HF) and reduce serum uric acid (SUA). The relevance of this metabolic effect in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. The authors investigated the effect of empagliflozin on SUA levels in relation to the therapeutic efficacy in patients with HFpEF. This post hoc analysis of the EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; NCT03057951) trial assessed the clinical effect of SUA reduction in relation to the outcome endpoints of the trial (composite primary outcome of cardiovascular mortality or hospitalization for HF, its individual components, and all-cause mortality in patients with HFpEF). Hyperuricemia (SUA >5.7mg/dL for women, >7.0mg/dL for men) was prevalent in 49% of patients. Elevated SUA (highest tertile SUA 8.8 ± 1.4 g/dL) was associated with advanced HF severity and with higher risk of adverse outcome (primary endpoint HR: 1.23 [95%CI: 0.98-1.53]; P = 0.07; HF hospitalization HR: 1.42 [95%CI: 1.08-1.86]; P= 0.01). SUA was reduced early (after 4weeks vs placebo-0.99 ± 0.03mg/dL; P< 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR: 0.62 [95%CI: 0.51-0.76]; P< 0.0001). The treatment benefit on the primary endpoint was not influenced by baseline SUA (HR: 0.79 [95%CI: 0.69-0.90]; P = 0.0004). The change in SUA was an independent correlate of the treatment benefit on the primary endpoint (P = 0.07). Hyperuricemia is a common complication in HFpEF and is related to advanced disease severity and adverse outcome. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricemia.

Protocolo terapéutico de la diabetes mellitus tipo 2 con obesidad y riesgo cardiovascular

The management of type 2 diabetes mellitus (DM2) with obesity and cardiovascular risk is a growing challenge due to the high prevalence of both conditions. This protocol describes therapeutic recommendations based on glycemic control and the cardiovascular benefits of certain drugs. Two classes of drugs with weight and cardiometabolic efficacy stand out: glucagon-like peptide-1 agonists (GLP-1a) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). This document suggests the joint use of both to reduce cardiovascular risk and promote weight loss. It also describes the role of metabolic surgery as an effective option for the management of DM2 and obesity, as it significantly improves glycemic outcomes and reduces cardiovascular risk. Continuous follow-up is recommended to adjust treatment according to the patient's clinical response and to avoid therapeutic inertia.

Sodium-glucose Cotransporter-2 Inhibition And Exercise Affect Pathways Related To Nonalcoholic Fatty Liver Disease

Sodium-glucose Cotransporter-2 Inhibition And Exercise Affect Pathways Related To Nonalcoholic Fatty Liver Disease

Should SGLT2 inhibitors be prescribed after myocardial infarction with left ventricular dysfunction?

Should SGLT2 inhibitors be prescribed after myocardial infarction with left ventricular dysfunction?

EMMY trial: What we know and what we need to know

ABSTRACT SGLT-2 inhibitors are a class of antidiabetic drugs with additional cardiovascular benefits. Though initially developed for glycemic control, subsequent studies in the heart failure (HF) population also demonstrated positive outcomes. Currently, they are approved for use in HF with both reduced and preserved ejection fraction. More recently, encouraging data have emerged on acute HF. Following an episode of acute myocardial infarction, patients are also at high risk for developing HF and experiencing recurrent events despite optimal therapy. The PARADISE MI study failed to demonstrate any benefits of ARNI in this scenario. The EMMY trial explored the role of SGLT-2i in &gt;450 odds patients with acute MI. At 26 weeks SGLT-2i (empagliflozin) use led to a higher fall in NT-pro-BNP levels compared to standard treatment. There was additional improvement in left ventricular echocardiographic parameters with empagliflozin too. However, it was a small trial, had a short follow-up and there were no clinical endpoints. But none the least, it attested to the safety of SGLT-2i in the post-MI scenario. Because the primary care physician frequently encounters patients in the post-MI scenario, the manuscript provides insights into their practice. Based on contemporary evidence, the universal use of SGLT-2 inhibitors in patients following acute MI is not warranted. A further role of these drugs in post-MI HF will be clarified in ongoing trials.

Sparsentan (SPAR) in Combination with SGLT2 Inhibitors (SGLT2i) in Patients with IgA Nephropathy (IgAN): A Case Series

Sparsentan (SPAR) in Combination with SGLT2 Inhibitors (SGLT2i) in Patients with IgA Nephropathy (IgAN): A Case Series

SGLT2 Inhibitors and Fracture Risk in Individuals with Advanced CKD

SGLT2 Inhibitors and Fracture Risk in Individuals with Advanced CKD

Estrategia terapéutica en el paciente diabético (II). Tratamiento farmacológico del paciente con diabetes mellitus tipo 2. Criterios de selección y evidencia actual de los fármacos antidiabéticos no insulínicos

The management of type 2 diabetes mellitus is complex and requires a multifaceted approach that combines nonpharmacological interventions with pharmacological treatments. Non-insulin antidiabetics (NIA) have evolved considerably, progressing from traditional agents such as biguanides and sulfonylureas to newer ones such as SGLT-2 inhibitors and GLP-1 agonists and from a glucocentric approach to management based on comorbidities. Metformin continues to be the first-line treatment due to its efficacy and safety profile. However, the variety of NIAs allows for personalizing treatment according to each patient's specific needs, considering factors such as the presence of comorbidities, cardiovascular risk, and patient preference. This document reviews the different pharmacological groups of NIAs and their mechanisms of action, efficacy, and side effects. It also addresses the selection criteria for these drugs, emphasizing the importance of an informed decision based on the most recent evidence and individual patient characteristics, in addition to updated evidence on these pharmacological groups.

Glomerular Diameter Is Associated with Reduction in Urinary Protein during Treatment with Dapagliflozin, a SGLT2 Inhibitor, in Patients with CKD

Glomerular Diameter Is Associated with Reduction in Urinary Protein during Treatment with Dapagliflozin, a SGLT2 Inhibitor, in Patients with CKD

Racial Disparities in SGLT2 Inhibitor (SGLT2i) and Glucagon-Like Peptide 1 Receptor Agonist (GLP-1 RA) Use in the US Military Health System (MHS)

Racial Disparities in SGLT2 Inhibitor (SGLT2i) and Glucagon-Like Peptide 1 Receptor Agonist (GLP-1 RA) Use in the US Military Health System (MHS)

SGLT2 Inhibitors, Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists, and the Risk of Hypokalemia and Hyperkalemia in a National Cohort of Veterans with Type 2 Diabetes

SGLT2 Inhibitors, Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists, and the Risk of Hypokalemia and Hyperkalemia in a National Cohort of Veterans with Type 2 Diabetes

Insulin Glargine Compared with Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) or SGLT2 Inhibitors Is Associated with Higher Risk of Alzheimer Disease and Alzheimer Disease-Related Dementias (AD/ADRD) in CKD

Insulin Glargine Compared with Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) or SGLT2 Inhibitors Is Associated with Higher Risk of Alzheimer Disease and Alzheimer Disease-Related Dementias (AD/ADRD) in CKD

Concomitant Sparsentan (SPAR) and SGLT2 Inhibitors in Adults with IgA Nephropathy in the Ongoing Phase 2 SPARTACUS Trial

Concomitant Sparsentan (SPAR) and SGLT2 Inhibitors in Adults with IgA Nephropathy in the Ongoing Phase 2 SPARTACUS Trial

SGLT2 Inhibitor Use and Kidney Outcomes in Persons Receiving Cisplatin

SGLT2 Inhibitor Use and Kidney Outcomes in Persons Receiving Cisplatin

SGLT2 Inhibitors Are Associated with Lower Risk of CKD Progression in Type 2 Diabetes (T2D) than Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs): An Emulated Clinical Trial

SGLT2 Inhibitors Are Associated with Lower Risk of CKD Progression in Type 2 Diabetes (T2D) than Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs): An Emulated Clinical Trial