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1.
Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.
Liu, H, Sridhar, VS, Boulet, J, Dharia, A, Khan, A, Lawler, PR, Cherney, DZI
Metabolism: clinical and experimental. 2022;:154918
Abstract
Type 2 diabetes (T2D) is one of the most common causes of chronic kidney disease (CKD) and cardiovascular (CV) disease. Until recently, glycemic and BP control were the cornerstones for preventing progression of CKD and CV disease associated with T2D. However, there has been a paradigm shift in treatment since the publication of the first clinical trial demonstrating benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in 2015. SGLT2 inhibitors have been shown to reduce the risk of major adverse CV events and progression of kidney disease in the setting of T2D. However, the elucidation of mechanisms of underlying these clinical benefits is the subject of ongoing investigation. Experimental studies have shown that SGLT2 inhibitors have diverse pleiotropic effects such as modulation of neurohormones such as the renin-angiotensin-aldosterone system, increasing hematocrit, altering energy substrate use, and attenuating systemic inflammation and oxidative stress, all of which have been implicated in the CV and kidney protective effects of SGLT2 inhibitors. In this review, we highlight biomarkers linked with diabetic kidney disease and heart failure and discuss how SGLT2 inhibitor-associated changes potentially mediate the cardiorenal protection observed with these therapies.
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2.
Renoprotection with sodium-glucose cotransporter-2 inhibitors in children: Knowns and unknowns.
Jiang, B, Cheng, Z, Liu, F, Li, Q, Fu, H, Mao, J
Nephrology (Carlton, Vic.). 2022;(2):126-132
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent novel hypoglycemic drugs for the treatment of adult diabetes that have shown considerable potential for cardioprotection and renoprotection. This new drug can inhibit SGLT2 at the proximal tubule, increase glucosuria and natriuresis, and thus decreases the serum glucose level and blood pressure. Furthermore, the tubuloglomerular feedback activated by the natriuresis can decrease glomerular hyperfiltration, acknowledged as the main foundation of renoprotection. Several studies have confirmed the protective effects of SGLT2 inhibitors on the kidneys of adult diabetic patients and those with non-diabetic nephropathy; however, limited researches are seen in paediatric patients. In this review, we have summarized the mechanisms of action of SGLT2 inhibitors, the current experiences in adults, results of exploratory studies in children, and adverse events & obstacles of paediatric use. We further explore the potential and possible future research direction of SGLT2 inhibitors in paediatric diseases.
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3.
Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat.
Iacobellis, G, Baroni, MG
Journal of endocrinological investigation. 2022;(3):489-495
Abstract
Epicardial adipose tissue is a novel cardiovascular risk factor. It plays a role in the progression of coronary artery disease, heart failure and atrial fibrillation. Given its rapid metabolism, clinical measurability, and modifiability, epicardial fat works well as therapeutic target of drugs modulating the adipose tissue. Epicardial fat responds to glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). GLP-1A and SGLT2i provide weight loss and cardiovascular protective effects beyond diabetes control, as recently demonstrated. The potential of modulating the epicardial fat morphology and genetic profile with targeted pharmacological agents can open new avenues in the pharmacotherapy of diabetes and obesity, with particular focus on cardiovascular risk reduction.
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4.
SGLT2 Inhibitors and Their Antiarrhythmic Properties.
Kolesnik, E, Scherr, D, Rohrer, U, Benedikt, M, Manninger, M, Sourij, H, von Lewinski, D
International journal of molecular sciences. 2022;(3)
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are gaining ground as standard therapy for heart failure with a class-I recommendation in the recently updated heart failure guidelines from the European Society of Cardiology. Different gliflozins have shown impressive beneficial effects in patients with and without diabetes mellitus type 2, especially in reducing the rates for hospitalization for heart failure, yet little is known on their antiarrhythmic properties. Atrial and ventricular arrhythmias were reported by clinical outcome trials with SGLT2 inhibitors as adverse events, and SGLT2 inhibitors seemed to reduce the rate of arrhythmias compared to placebo treatment in those trials. Mechanistical links are mainly unrevealed, since hardly any experiments investigated their impact on arrhythmias. Prospective trials are currently ongoing, but no results have been published so far. Arrhythmias are common in the heart failure population, therefore the understanding of possible interactions with SGLT2 inhibitors is crucial. This review summarizes evidence from clinical data as well as the sparse experimental data of SGLT2 inhibitors and their effects on arrhythmias.
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5.
Mitochondrion-driven nephroprotective mechanisms of novel glucose lowering medications.
Afsar, B, Hornum, M, Afsar, RE, Ertuglu, LA, Ortiz, A, Covic, A, van Raalte, DH, Cherney, DZI, Kanbay, M
Mitochondrion. 2021;:72-82
Abstract
Therapy for diabetic kidney disease (DKD) is undergoing a revolution with the realization that some glucose-lowering drugs have nephroprotective actions that may be intrinsic to the drugs and not dependent on the impact on diabetes control, as demonstrated with the sodium glucose co-transporter-2 (SGLT-2) inhibitors. Mitochondria are a critical factor required for the maintenance of kidney function, given its high energy demanding profile, with extensive use of adenosine triphosphate (ATP). Consequently, deficiency of the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1α predisposes to kidney disease. Perhaps as a result of key role of mitochondria in fundamental cellular functions, mitochondrial dysfunction may play a role in the pathogenesis of common conditions such as DKD. Finding pharmacological agents to influence this pathway could therefore lead to early implementation of therapy. Importantly, glucose-lowering drugs such as glucagon-like peptide-1 receptor activators and SGLT2 inhibitors have kidney and/or cardioprotective actions in patients with diabetes. Accumulating evidence from preclinical studies has suggested a protective effect of these drugs that is in part mediated by normalizing mitochondrial function. We now critically review this evidence and discuss studies needed to confirm mitochondrial protective benefits across a range of clinical studies.
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6.
Practical Considerations and Rationale for Glucagon-Like Peptide-1 Receptor Agonist Plus Sodium-Dependent Glucose Cotransporter-2 Inhibitor Combination Therapy in Type 2 Diabetes.
Goldenberg, RM, Ahooja, V, Clemens, KK, Gilbert, JD, Poddar, M, Verma, S
Canadian journal of diabetes. 2021;(3):291-302
Abstract
Glucagon-like peptide-1 receptor agonists and sodium-dependent glucose cotransporter-2 inhibitors have demonstrated clinically significant benefits on glycated hemoglobin, weight, blood pressure and cardiorenal outcomes. The emerging evidence from clinical trials and meta-analyses that assessed the combination of these 2 classes of drugs has been promising. An expert forum that included individuals with expertise in endocrine, cardiology and nephrology issues was held in May 2020 to review the literature on the metabolic and cardiorenal benefits of these 2 classes, independently and in combination, in adults with type 2 diabetes mellitus. Although hard outcome data are not available, the group concluded that the combination of glucagon-like peptide-1 receptor agonists with sodium-dependent glucose cotransporter-2 inhibitors is an emerging option for managing adults with type 2 diabetes as long as cost is not a barrier. Ongoing research may offer further insights on hard cardiorenal outcomes for this therapeutic combination as well as provide direction on the potential of this approach in obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and populations without diabetes.
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7.
Incorporating SGLT2i and GLP-1RA for Cardiovascular and Kidney Disease Risk Reduction: Call for Action to the Cardiology Community.
Nelson, AJ, Pagidipati, NJ, Aroda, VR, Cavender, MA, Green, JB, Lopes, RD, Al-Khalidi, H, Gaynor, T, Kaltenbach, LA, Kirk, JK, et al
Circulation. 2021;(1):74-84
Abstract
Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.
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8.
SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.
Tuttle, KR, Brosius, FC, Cavender, MA, Fioretto, P, Fowler, KJ, Heerspink, HJL, Manley, T, McGuire, DK, Molitch, ME, Mottl, AK, et al
Diabetes. 2021;(1):1-16
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Abstract
Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2 To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.
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Cardiovascular Protection With Sodium-Glucose Cotransporter-2 Inhibitors and Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease: A Milestone Achieved.
Sarafidis, P, Papadopoulos, CE, Kamperidis, V, Giannakoulas, G, Doumas, M
Hypertension (Dallas, Tex. : 1979). 2021;(5):1442-1455
Abstract
Chronic kidney disease (CKD) and cardiovascular disease are intimately linked. They share major risk factors, including age, hypertension, and diabetes, and common pathogenetic mechanisms. Furthermore, reduced renal function and kidney injury documented with albuminuria are independent risk factors for cardiovascular events and mortality. In major renal outcome trials and subsequent meta-analyses in patients with CKD, ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) were shown to effectively retard CKD progression but not to significantly reduce cardiovascular events or mortality. Thus, a high residual risk for cardiovascular disease progression under standard-of-care treatment is still present for patients with CKD. In contrast to the above, several outcome trials with SGLT-2 (sodium-glucose cotransporter-2) inhibitors and MRAs (mineralocorticoid receptor antagonists) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article discusses existing evidence on the effects of SGLT-2 inhibitors and MRAs on cardiovascular outcomes in patients with CKD that open new roads in cardiovascular protection of this heavily burdened population.
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10.
Effects of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Renin-Angiotensin-Aldosterone System.
Puglisi, S, Rossini, A, Poli, R, Dughera, F, Pia, A, Terzolo, M, Reimondo, G
Frontiers in endocrinology. 2021;:738848
Abstract
Sodium-glucose cotransporters inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA) are glucose-lowering drugs that are proved to reduce the cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM). In this process, the renin-angiotensin-aldosterone system (RAAS) is assumed to play a role. The inhibition of SGLT2 improves hyperglycemia hampering urinary reabsorption of glucose and inducing glycosuria. This "hybrid" diuretic effect, which couples natriuresis with osmotic diuresis, potentially leads to systemic RAAS activation. However, the association between SGLT2-i and systemic RAAS activation is not straightforward. Available data indicate that SGLT2-i cause plasma renin activity (PRA) increase in the early phase of treatment, while PRA and aldosterone levels remain unchanged in chronic treated patients. Furthermore, emerging studies provide evidence that SGLT2-i might have an interfering effect on aldosterone/renin ratio (ARR) in patients with T2DM, due to their diuretic and sympathoinhibition effects. The cardio- and reno-protective effects of GLP-1-RA are at least in part related to the interaction with RAAS. In particular, GLP1-RA counteract the action of angiotensin II (ANG II) inhibiting its synthesis, increasing the inactivation of its circulating form and contrasting its action on target tissue like glomerular endothelial cells and cardiomyocytes. Furthermore, GLP1-RA stimulate natriuresis inhibiting Na+/H+ exchanger NHE-3, which is conversely activated by ANG II. Moreover, GLP1 infusion acutely reduces circulating aldosterone, but this effect does not seem to be chronically maintained in patients treated with GLP1-RA. In conclusion, both SGLT2-i and GLP1-RA seem to have several effects on RAAS, though additional studies are needed to clarify this relationship.