Action Of Sodium-glucose Cotransporter 2 Inhibitors Research Articles

Remission effect of Canagliflozin in patients with newly diagnosed type 2 diabetes mellitus: a protocol for a multicenter, parallel-group, randomized, controlled, open-label trial

BackgroundStudies reporting the effects of metabolic surgery, lifestyle intervention, and intensive insulin therapy for the remission of type 2 diabetes (T2DM) has been increasing, with fruitful results better conducted and yielded. However, there are only a few studies on the remission of T2DM using oral hypoglycemic drugs. Therefore, this study aims to investigate the remission effect of canagliflozin and metformin on participants with newly diagnosed T2DM and its possible underlying mechanism(s) through which these two medications elicit diabetes remission.MethodTo this end, we performed a multicenter, parallel-group, randomized, controlled, and open-label trial. A total of 184 participants with a ≤ 3-year course of T2DM will be enrolled and randomly assigned to the canagliflozin or metformin treatment group in a ratio of 1:1. Participants in each group will maintain their medication for 3 months after achieving the target blood glucose level and then stop it. These participants will be followed up for one year to determine remission rates in both groups.DiscussionIn this study, we will establish that whether canagliflozin is superior to metformin in terms of remission rate in participants with newly diagnosed T2DM. The results of this trial may provide robust evidence regarding the efficacy and mechanisms of the action of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in T2DM remission.Trial registrationChiCTR2100043770(February 28, 2021).

Cardiorenal Protections of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes.

Cardiovascular disease and renal complications raise the risk of death and morbidity in patients with type 2 diabetes (T2D). Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a novel class of glucose-lowering drug that increases urine glucose excretion while decreasing blood glucose levels in type 2 diabetes patients by inhibiting glucose reabsorption. In the present article, we review the discovery and development of SGLT2i as a new T2D treatment approach for T2D; thereafter, we consider different cell-based methods for the evaluation of SGLT2i. Finally, we provide evidences from both clinical and experimental studies which bring up the cardio-renal protective effects of SGLT2i. We performed a literature search using PubMed, Google Scholar, and Web of Science to identify publications on preclinical and clinical studies of cardiorenal protective action of SGLT2i and their suggested mechanisms. SGLT2i have shown good effects in the improvement of cardiovascular and renal complications independent of glucose lowering effects. Besides controlling blood glucose levels, SGLT2i were found to exhibit therapeutic benefits on the kidney and cardiovascular system by lowering diabetic glomerular hyperfiltration, blood pressure (BP), body weight, uric acid concentrations, lipid peroxidation, inflammation, etc. As a result of their distinct mode of action, SGLT2i have emerged as a promising treatment option for T2D and maybe T1D due to their increased urine excretion of glucose. It has been demonstrated that SGLT2i have considerable protective effects on diabetic nephropathy (DN) and cardiomyopathy in well-designed experimental and clinical investigations.

Sizing SGLT2 Inhibitors Up: From a Molecular to a Morpho-Functional Point of View.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), or gliflozins, have recently been shown to reduce cardiovascular death and hospitalization in patients with heart failure, representing a revolutionary therapeutic tool. The purpose of this review is to explore their multifaceted mechanisms of actions, beyond their known glucose reduction power. The cardioprotective effects of gliflozins seem to be linked to the maintenance of cellular homeostasis and to an action on the main metabolic pathways. They improve the oxygen supply for cardiomyocytes with a considerable impact on both functional and morphological myocardial aspects. Moreover, multiple molecular actions of SGLT2i are being discovered, such as the reduction of both inflammation, oxidative stress and cellular apoptosis, all responsible for myocardial damage. Various studies showed controversial results concerning the role of SGLT2i in reverse cardiac remodeling and the lowering of natriuretic peptides, suggesting that their overall effect has yet to be fully understood. In addition to this, advanced imaging studies evaluating the effect on all four cardiac chambers are lacking. Further studies will be needed to better understand the real impact of their administration, their use in daily practice and how they can contribute to benefits in terms of reverse cardiac remodeling.

The anti-inflammatory and immunological properties of SGLT-2 inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic oral drugs that act on proximal renal tubules promoting renal glucose excretion. Although SGLT-2i belong to the class of hypoglycemic agents, in the last years great interest has emerged in studying their pleiotropic effects, beyond their ability to lower glucose levels. In this review we are describing the anti-inflammatory and immunological properties of SGLT-2i; furthermore, we are addressing how the mechanisms associated with the aforementioned anti-inflammatory properties may contribute to the beneficial effects of SGLT-2i in diabetes. A systematic search was undertaken for studies related the properties of SGLT-2i in reducing the inflammatory milieu of acute and chronic disease by acting on the immune system, independently by glycemia. Recently, some data described the anti-inflammatory and immunological properties of SGLT-2 in both pre-clinical and clinical studies. Numerous data confirmed the cardio- and -renal protective effects of SGLT-2i in patients with heart failure and kidney diseases, with or without diabetes. SGLT-2i are promising drugs with anti-inflammatory and immunological properties. Despite the mechanism of action of SGLT-2i is not fully understood, these drugs demonstrated anti-inflammatory effects, which may help in keeping under control the variety of complications associated with diabetes.

Potential favorable action of sodium-glucose cotransporter-2 inhibitors on sudden cardiac death: a brief overview.

The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na+/H+ exchanger (NHE) activity, but also suppression of late Na+ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na+ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.

Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction.

SGLT2i (sodium-glucose cotransporter-2 inhibitors) improve clinical outcomes in patients with heart failure, but the mechanisms of action are not completely understood. SGLT2i increases circulating levels of ketone bodies, which has been demonstrated to enhance myocardial energetics and induce reverse ventricular remodeling. However, the role of SGLT2i or ketone bodies on myocardial ischemia reperfusion injury remains in the dark. The objective of this study is to investigate the cardioprotective potential of empagliflozin and ketone bodies during acute myocardial infarction (MI). We used a nondiabetic porcine model of ischemia reperfusion using a percutaneous occlusion of proximal left anterior descending artery for 45 minutes. Animals received 1-week pretreatment with either empagliflozin or placebo prior to MI induction. Additionally, a third group received intravenous infusion of the ketone body beta-hydroxybutyrate BOHB (beta-hydroxybutyrate) during the MI induction. Acute effects of the treatments were assessed 4-hour post-MI by cardiac magnetic resonance and histology (thioflavin for area at risk, triphenyltetrazolium chloride staining for MI size). All animals were euthanized immediately postcardiac magnetic resonance, and heart samples were collected. The area at risk was similar in all groups. Empagliflozin treatment increased BOHB levels. Empagliflozin-treated animals showed significantly higher myocardial salvage, smaller MI size (both by cardiac magnetic resonance and histology), less microvascular obstruction, and improved cardiac function (left ventricle ejection fraction and strain). Furthermore, empagliflozin-treated animals demonstrated reduced biomarkers of cardiomyocyte apoptosis and oxidative stress compared with placebo. The BOHB group showed similar results to the empagliflozin group. One-week pretreatment with empagliflozin ameliorates ischemia reperfusion injury, reduces MI size and microvascular obstruction, increases myocardial salvage, preserves left ventricle systolic function, and lowers apoptosis and oxidative stress. Periprocedural intravenous infusion of BOHB during myocardial ischemia also induces cardioprotection, suggesting a role for BOHB availability as an additional mechanism within the wide spectrum of actions of SGLT2i.

Study on the pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in obesity-related atrial fibrillation based on network pharmacology and experimental verification.

Obesity is an independently risk factor of atrial fibrillation (AF). It is likely that the global burden of AF will escalate due to the current obesity epidemic. Weight loss can effectively reduce the risk of AF, while sodium-glucose co-transporter 2 inhibitors (SGLT2i) can reduce body weight, so SGLT2i are potentially effective for obesity-related AF. SGLT2i are a novel type of oral medication. This current study used network pharmacology to examine the potential mechanisms of SGLT2i in the treatment of obesity-related AF, and the therapeutic effects were assessed in vivo. Potential gene targets for SGLT2i in treating obesity-related AF were identified from public database. Cytoscape V3.7.1 was used to construct the "Drug-Target" and "Drug-Target-Disease" networks. The STRING database was applied to investigate the protein-protein interactions (PPIs). Additionally, the Bioconductor tools were used to analyze the Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The efficacy of SGLT2i in treating obesity-related AF was investigated in vivo using a diet-induced obese C57BL/6J male mouse model. A number of indicators were assessed, including invasive electrophysiology, testing of blood samples, and expression detection of pathway targets. These experiments were used to verify the targets mined by network pharmacology. The results indicated that SGLT2i had 80 potential target genes during the treatment of obesity-related AF, and 10 hub genes were obtained by further screening. It was predicted that the treatment of obesity-related AF by SGLT2i involved the advanced glycation end product (AGE)-receptor for advanced glycation end product (RAGE) signaling pathway and other signaling pathways. In in vivo experiments, administration of SGLT2i (the SGLT2i + DIO group) resulted in a lower AF induction rate (P<0.05), decreased serum AGEs/soluble RAGE (sRAGE) ratio (P<0.01), and decreased expression of NADPH oxidase 2 (NOX2) (P<0.05) compared to untreated DIO mice (the DIO group). In this study, pharmacological network analysis and in vivo experiments demonstrated that SGLT2i acts on obesity-related AF by inhibiting the AGE-RAGE signaling pathway. These results offer fresh perspectives on the pharmacological actions of SGLT2i in treating obesity-related AF.

Mechanisms of renoprotective action of sodium-glucose cotransporter-2 inhibitors (gliflozins): a clinician’s view

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a group of drugs that block the enzyme responsible for the reabsorption of glucose and sodium in the proximal part of the nephron. They appeared in clinical practice about a decade ago for the treatment of type 2 diabetes mellitus, but the first clinical studies showed the potential of these agents in preventing cardiovascular and renal events. Among the main mechanisms of the renoprotective effect of SGLT2i, the following are distinguished now: 1)reduction of hyperfiltration/pressure in the glomerulus (narrowing of the afferent and dilation of the efferent arterioles); 2) metabolic shift towards the use of free fatty acids for obtaining energy (increasing energy efficiency and reducing lipotoxic damage to cells); 3) antihypoxic effect (direct— due to a decrease in oxygen needs and indirect— due to an increase in hemoglobin); 4) reduction of pressure and fluid overload; 5) anti-inflammatory and antifibrotic effects; 6)other effects (decrease in glycaemia, body weight, uric acid level, etc.). Presumably, SGLT2i administration causes a universal cellular reaction (autophagic flux), which leads to improved energy efficiency, reduces cellular stress and increases the resistance of cells to overload. The significance of various mechanisms in the formation of the overall effect differs depending on the main cause of kidney damage, concomitant pathology, metabolic characteristics of the patient, degree of kidney ischemia, etc. It is different not only in each individual patient, but, probably, in the same patient at different stages of the disease. However, the implementation of these mechanisms allows preventing the development/progression of kidney failure and prolonging the life of patients.

Remission of Proteinuria in a Patient Affected by Crescentic IgA Nephropathy with Rapidly Progressive Glomerulonephritis Treated by Sodium-Glucose Cotransporter-2 Inhibitors: Casual or Causal Relationship?

Crescentic IgA nephropathy (IgAN) with rapidly progressive glomerulonephritis (RPGN) is often associated with rapidly declining kidney function. Up to this date, specific therapy for crescentic IgAN is still unknown. Accumulating evidence suggests that sodium-glucose co-transporter-2 inhibitors (SGLT-2i) may have a role in standard therapy of glomerular diseases. However, it is unclear at what point in the natural history of specific glomerular diseases SGLT-2i can be beneficial. We report the clinical and histological features of a patient with crescentic IgAN that presented as an RPGN, who received intensive immunosuppression and renal replacement therapeutic (RRT). At the third month, the patient presented with significant improvement in his kidney function. At that point, we decided to start dapagliflozin in addition to his renin-angiotensin system (RAS) blocker, basing our decision on its proven renal benefits such as slowing the rate of decline in kidney function and reducing albuminuria. At the eighth month, the patient’s renal function gradually improved from serum Cr of 6.07 to 2.1 mg/dL; and urine albumin to creatinine ratio (UACR) declined from 5655 mg/g to 200 mg/g. The use of SGLT-2i in primary and secondary nondiabetic glomerular disease appears promising. It is crucial and necessary to accumulate more evidence for a more complete understanding of the mechanisms of the actions of SGLT-2i in non-diabetic glomerular disease.

Cardiac sodium/hydrogen exchanger (NHE11) as a novel potential target for SGLT2i in heart failure

Abstract Background Despite the cardiac benefits of sodium/glucose cotransporter 2 inhibitors (SGLT2i), their basic of action remains unclear. Sodium/hydrogen exchanger (NHE) has been proposed as mechanism of action of SGLT2i, but there are controversies related to its function and expression in heart failure (HF). Purpose We hypothesized that sodium transported-related molecules could be altered in human HF and they could be modulated through SGLT2i. Methods Transcriptome-level differences in genes involved in sodium transport between HF and control (CNT) were investigated in 36 heart samples with RNA-sequencing technology (HF, n=26; CNT, n=10). In addition, NHE11 and NHE1 protein levels were determined in 80 heart samples (HF, n=70; CNT, n=10) by ELISA assay. Furthermore, the effect of empagliflozin on NHE11 mRNA levels in rat left ventricular tissue (n=22) was studied through RT-qPCR. Results We observed alterations in several genes involved in sodium transport. Among them the overexpression in SLC9C2 (p=0.005) and SCL9A1 (p=0.020) genes, which encode the NHE11 and NHE1 proteins, respectively. In addition, cardiac protein levels of these molecules were determined. We found a significant increase in the concentration of NHE11 (p=0.042) and NHE1 (p=0.018) in HF. Moreover, NHE11 levels were correlated with left ventricular diameters. Due to the relevance of NHE11 changes observed, we studied the effect of SGLTi on its expression. NHE11 mRNA levels were reduced in rats treated with empagliflozin (p=0.010). Conclusions Our findings show alterations in several sodium transport, reinforce the importance of these channels in HF progression. We described upregulation in NHE11 and NHE1 in HF patients, but only NHE11 correlated with cardiac dysfunction. In addition, the most relevant finding is the change observed in the expression of the unknown NHE11 after treatment with empagliflozin. These results propose NHE11 as a potential target of SGLT2i in cardiac tissue. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health Carlos III European Regional Development Fund (ERDF)

SGLT-2 Inhibitors for Patients with Heart Failure: What Have We Learned Recently?

In this review, we discuss the mechanisms of action of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and the purported protective effects for mitigating heart failure (HF)-related outcomes. Major randomized clinical trials have demonstrated the cardiovascular safety and efficacy of SGLT-2i among patients without known HF and those with established HF with reduced ejection fraction or preserved ejection fraction (HFrEF and HFpEF respectively). Recent HF guidelines have incorporated SGLT-2i in HF treatment algorithms. SGLT-2i have emerged as a novel treatment for both prevention of HF and reduction of cardiovascular morbidity and mortality among patients with existing HFrEF or HFpEF.

The Effects of Sodium-Glucose Cotransporter-2 Inhibitors (SLGT-2i) on Cardiovascular and Renal Outcomes in Non-diabetic Patients: A Systematic Review.

Globally, cardiovascular disease (CVD) and chronic kidney disease (CKD) are the leading causes of mortality. Despite medical advances, these illnesses are still underdiagnosed and undermanaged. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have recently emerged as a potential class of medications with promising cardiovascular and renal safety in non-diabetic patients. In this systematic review, we explored the outcomes of cardiovascular and renal protective effects utilizing SGLT-2i in three large randomized clinical trials with a cohort of both diabetes and non-diabetes patients. In these studies, data conferred that there is a significant reduction in heart failure (HF) hospitalization, as well as cardiovascular and all-cause mortality. Moreover, SGLT-2i impede the progression to and death from CKD. Additionally, we reviewed trials solely done on non-diabetics which demonstrated benefits in patients with established HF with reduced ejection fraction, though the fact that these studies had a smaller sample size. We also discussed some of the potential mechanisms of action of SGLT-2i on cardiovascular and renal outcomes that are beyond anti-hyperglycemic control. There is ongoing research involving a larger number of non-diabetes patients that may provide more information about the efficacy of these drugs besides anti-diabetic medications in the future. Finally, this is the first systematic review that has provided a perspective on the currently available trials, which offer evidence supporting the potential benefits of SGLT-2i on cardiovascular and renal outcomes in non-diabetic individuals.

Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review.

Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.

Empagliflozin: a path from glycemic control to reduced cardiovascular mortality and heart failure-related hospitalizations

In the EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58 studies, in patients with type 2 diabetes and established cardiovascular diseases or risk factors, a decrease in the risk of cardiovascular events and development or worsening of heart failure course without an increase in hypoglycemia incidence was revealed in those receiving sodium-glucose co-transporter-2 (SGLT2) inhibitors compared with placebo. To date, various mechanisms of action of SGLT2 inhibitors have been described, which are considered from the standpoint of their influence on the course and prognosis of heart failure. In the EMPEROR-Reduced study in the group of patients receiving empagliflozin, a significant reduction in the risk of cardiovascular death and hospitalizations for heart failure, regardless of the type 2 diabetes presence, was revealed.

SGLT2 Inhibition for Diabetic and Non-diabetic Kidney Disease

Chronic kidney disease (CKD) can be progressive, and its prognosis is worse because of increased mortality when it is associated with diabetes and cardiac disease. The outcomes of diabetic kidney disease (DKD) need to be improved, despite multifactorial interventions including glucose and blood pressure (BP) control, and the use of renin-angiotensin system (RAS) inhibitors, statins, and aspirin. Recent clinical trials suggest that sodium-glucose cotransporter-2 (SGLT2) inhibitors offer additional cardiorenal protection in DKD and non-diabetic CKD on top of RAS inhibition. The action of SGLT2 inhibitors is derived from the proximal tubule of the kidney, but their systemic effects beyond glucose-lowering involve hemodynamic and non-hemodynamic mechanisms. First, SGLT2 inhibitors restore tubuloglomerular feedback and relieve glomerular hypertension and albuminuria. Second, natriuresis and renal glycosuria lead to fluid and weight loss, resulting in BP lowering and prevention of heart failure. Third, SGLT2 inhibitors have anti-inflammatory and anti-oxidative actions that can reduce renal and cardiac inflammation and fibrosis, probably via adenosine monophosphate-activated protein kinase and sirtuin-1 activation. Finally, the proximal tubular workload is relieved, accompanied by increased erythropoiesis. Hypoxia-inducible factor 1 may be stimulated by renal outer medullary hypoxia when tubular sodium transport shifts from the proximal convoluted tubule to the proximal straight tubule and thick ascending limb, due to SGLT2 inhibition. These effects may also be beneficial in non-diabetic CKD, and we anticipate that SGLT2 inhibitors will prove effective for albuminuria reduction and preservation of kidney function in primary kidney diseases, including glomerulonephritis.

Nephroprotective effect of novel oral sugar-reducing medicines: glyflosins

The review is devoted to the consideration of the nephroprotective effect and its mechanisms in new hypoglycemic drugs gliflozins, identified in largescale randomized placebo-controlled trials and experimental studies. It was found that inhibition of sodium-glucose co-transporter 2 (SGLT2) in the proximal tubules of the kidneys when using these drugs not only leads to a decrease in blood glucose levels, a decrease in blood pressure, body weight, and uric acid content in blood plasma but also delays the progression of chronic kidney disease, inhibiting the development of diabetic nephropathy. This beneficial effect is multifactorial. It is caused by the diuretic and natriuretic effects, a decrease in albuminuria, a decrease in glucotoxicity in the cells of the renal tubules, a hemodynamic effect on kidney function, and a direct anti-inflammatory effect. It is discussed why the use of SGLT2 inhibitors restores tubuloglomerular feedback, which is disrupted in the initial period of diabetic nephropathy and leads to hyperfiltration in the remaining nephrons. Information is provided on the restoration of impaired mitochon drial function due to the positive effect of drugs on the ionic composition of renal tubule cells. This greatly contributes to the enhancement of autophagy, the lysosome-mediated pathway of degradation and removal of damaged organelles, and normalizes intracellular homeostasis. The probable mechanism of autophagy enhancement through increased activity of energy deprivation sensors of AMPK and SIRT1 cells is considered. Possible mechanisms of development of anti-inflammatory and antioxidant action of SGLT2 inhibitors through inhibition of inflammasome activity are discussed. The question of the possible use of gliflozins in chronic kidney disease, the pathogenesis of which is not associated with diabetes mellitus, is considered.

Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.

Dapagliflozin Does Not Modulate Atherosclerosis in Mice with Insulin Resistance.

Type 2 diabetes mellitus (T2DM) increases morbimortality in humans via enhanced susceptibility to cardiovascular disease (CVD). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are drugs designed for T2DM treatment to diminish hyperglycaemia by reducing up to 90% of renal tube glucose reabsorption. Clinical studies also suggest a beneficial action of SGLT2i in heart failure and CVD independent of its hypoglycaemiant effect. In the present study, we explored the effect of SGLT2i dapagliflozin (DAPA) in the metabolism and atherosclerosis in Apoe−/−Irs2+/− mice, which display accelerated atherosclerosis induced by insulin resistance. DAPA treatment of Apoe−/−Irs2+/− mice, which were fed a high-fat, high-cholesterol diet, failed to modify body weight, plasma glucose or lipid. Carbohydrate metabolism characterisation showed no effect of DAPA in the glucose tolerance test (GTT) despite augmented insulin levels during the test. In fact, decreased C-peptide levels in DAPA-treated mice during the GTT suggested impaired insulin release. Consistent with this, DAPA treatment of Apoe−/−Irs2+/− isolated islets displayed lower glucose-stimulated insulin secretion compared with vehicle-treated islets. Moreover, insulin-signalling experiments showed decreased pAKT activation in DAPA-treated adipose tissue indicating impaired insulin signalling in this tissue. No changes were seen in lesion size, vulnerability or content of macrophages, vascular smooth muscle cells, T cells or collagen. DAPA did not affect circulating inflammatory cells or cytokine levels. Hence, this study indicates that DAPA does not protect against atherosclerosis in insulin-resistant mice in hypercholesterolemic conditions.

SGLT2 inhibitors, sodium and off-target effects: an overview.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that in addition to emerging as an effective antihyperglycemic treatment have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Actually, sodium and water depletion may contribute to some positive actions of SGLT2i but evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, several experimental studies have recently identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection.

The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis.