Cardiovascular Benefits Of Sodium-glucose Co-transporter 2 Inhibitors Research Articles

Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

Understanding The Role of SGLT2 Inhibitors in Cardiovascular Risk Reduction for Type 2 Diabetes Patients-A Literature Review

Introduction: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular events and heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a novel class of antidiabetic agents with potential cardiovascular benefits. This systematic review aims to evaluate the impact of SGLT2 inhibitors on reducing cardiovascular events and heart failure hospitalizations in patients with T2DM. Aims: The review aims to comprehensively evaluate the impact of SGLT2 inhibitors on reducing cardiovascular events, including MACE, and HF hospitalizations in patients with T2DM. Methods: A comprehensive literature search was conducted in major electronic databases like PubMed, Google Scholar and Science Direct to identify relevant studies. Studies investigating the cardiovascular outcomes of SGLT2 inhibitors in T2DM patients were included. Data extraction and quality assessment were performed independently by three reviewers using predefined criteria. Results: A total of 17 studies met the inclusion criteria and were included in the review. The analysis of clinical trials, including EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58, demonstrated significant reductions in MACE and HF hospitalizations with SGLT2 inhibitors compared to placebo or standard care. Real-world evidence from studies such as the CVD-REAL and EASEL studies further supported these findings, showing consistent cardiovascular benefits of SGLT2 inhibitors in routine clinical practice. The findings suggest that SGLT2 inhibitors are associated with a reduction in cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality, as well as a decreased risk of heart failure hospitalizations in patients with T2DM. Conclusion: This systematic review provides evidence supporting the cardiovascular benefits of SGLT2 inhibitors in T2DM management. The findings underscore the importance of considering these agents as part of comprehensive cardiovascular risk reduction strategies in T2DM patients. Further research is necessary to explicate the mechanisms underlying these benefits and optimize their clinical use.

The effect of empagliflozin on ketone bodies in patients with heart failure with reduced ejection fraction (Empire HF)

Abstract Background The thrifty-substrate hypothesis suggests that Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors increase plasma levels of ketone bodies and create a salutary switch in myocardial fuel metabolism. Purpose We investigated the effect of SGLT2 inhibitor on plasma beta-hydroxybutyrate in patients with heart failure and reduced ejection fraction (HFrEF). Method This is a post hoc analysis of the Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction (Empire HF) trial, an investigator-initiated, double-blind, randomized, placebo-controlled trial which enrolled 190 stable HFrEF patients with a left ventricular ejection fraction (LVEF) of ≤40%. Patients were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo. Analyses were performed in patients with complete data using a linear-mixed effect-model with log-transformed beta-hydroxybutyrate, adjusted for baseline beta-hydroxybutyrate value, age, sex, and type 2 diabetes. Results A total of 188 (99%) patients had available data. The groups were well-matched with respect to baseline characteristics. Mean age was 64 (SD, 11) years; LVEF was 29 (SD, 8) %, 13% had type 2 diabetes, New York Heart Association (NYHA) class II was found in 78%. Median plasma levels of beta-hydroxybutyrate were 0.10 (inter quartile range (IQR) 0.05–0.18) mmol/l at baseline, and 0.11(IQR 0.07–0.2) mmol/l at follow-up in the empagliflozin group. In the placebo group, baseline and at follow-up concentrations were 0.10 (0.06–0.17) mmol/l and 0.09 (0.05–0.15) mmol/l, respectively. Empagliflozin increased plasma levels of beta-hydroxybutyrate compared to placebo (adjusted between-groups treatment effect; Ratio of change 1.45 [95%confidence interval (CI); 1.12–1.87], p = 0.005 (Figure 1). The effect of empagliflozin on beta-hydroxybutyrate outcomes was consistent across multiple subgroups analyses including baseline median age, sex, N-terminal-pro B-type natriuretic peptide (NT-proBNP) cut-off 600 pg/mL, treatment with sacubitril–valsartan or beta-blockers, measured glomerular filtration rate (GFR) level, hemoglobin A1c (HbA1c) level, and concomitant type 2 diabetes (all P interaction>0.05). Conclusion In patients with HFrEF, predominantly without diabetes, short-term treatment with empagliflozin increased the levels of beta-hydroxybutyrate. The absolute changes were modest and the exact contribution of ketone bodies to the cardiovascular benefits of SGLT2 inhibitors requires further clarification.Figure 1Table 1

Empagliflozin Improves Circulating Vascular Regenerative Cell Content in People Not Living With Diabetes But With Cardiovascular Risk Factors.

SGLT2 inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-month visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 months, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ pro-angiogenic cells (P=0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P=0.012) and decreased ALDHhiSSCmidCD86+CD163- pro-inflammatory monocyte (P=0.011) polarization compared to placebo. Empagliflozin promoted the recovery of multiple circulating pro-vascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.

The Role of SGLT2 Inhibitors in Cardiovascular Management.

Cardiovascular disease is a major cause of morbidity and mortality worldwide in patients with type 2 diabetes. Type 2 diabetes confers an elevated risk of developing heart failure and atherosclerotic cardiovascular disease. Until recently, there have been limited options to prevent and reduce the cardiovascular complications of type 2 diabetes. However, recent therapeutic advances have led to the adoption of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in cardiovascular management. Though SGLT2i were originally used for antihyperglycemic treatment, a series of landmark trials found that SGLT2i may confer cardio-protective effects in patients with heart failure and atherosclerotic cardiovascular disease, particularly a reduction in cardiovascular mortality and hospitalizations for heart failure. The cardiovascular benefits of SGLT2i were similarly demonstrated in patients with and without type 2 diabetes. Though previous trials found SGLT2i to be cardio-protective in heart failure with reduced ejection fraction, recent trials demonstrated that SGLT2i may also provide cardiovascular benefits in heart failure with mildly reduced and preserved ejection fraction. These advances have led SGLT2i to become an instrumental component of cardiovascular therapy.

Clinical Benefits of Sodium-Glucose Cotransporter 2 Inhibitors and the Mechanisms Underlying Their Cardiovascular Effects.

In addition to showing antidiabetic effects, sodium-glucose cotransporter 2 (SGLT2) inhibitors also reduce cardiovascular events in patients with type 2 diabetes mellitus. In major trials of cardiovascular outcomes, SGLT2 inhibitors have been shown to improve cardiovascular and renal outcomes, including reduced rehospitalization in patients with heart failure, regardless of the presence of diabetes. A recent report showed that the benefits of SGLT2 inhibitors in terms of cardiovascular deaths/admissions caused by heart failure and reduced ejection fraction were greater in Asians than in Whites. In this review, the first part demonstrates the results of recent clinical trials and their clinical implications and outlines current trials and upcoming research areas. The second part provides a general overview of the current understanding of the mechanisms of the cardiovascular benefits of SGLT2 inhibitors.

Alterations of sodium-hydrogen exchanger 1 function in response to SGLT2 inhibitors: what is the evidence?

This review summarizes and describes the current evidence addressing how sodium-glucose cotransporter 2 (SGLT2) inhibitors alter the function of sodium-hydrogen exchanger 1 (NHE-1), in association with their protective effects against adverse cardiovascular events. In the heart, SGLT2 inhibitors modulate the function of NHE-1 (either by direct inhibition or indirect attenuation of protein expression), which promotes cardiac contraction and an enhanced energy supply, in association with improved mitochondrial function, reduced inflammation/oxidative/endoplasmic reticulum stress, and attenuated fibrosis and apoptotic/autophagic cell death. The vasodilating effect of SGLT2 inhibitors has also been proposed due to NHE-1 inhibition. Moreover, platelet-expressed NHE-1 might serve as a target for SGLT2 inhibitors, since these drugs and selective NHE-1 inhibitors produce comparable activity against adenosine diphosphate-stimulated platelet activation. Overall, it is promising that the modulation of the functions of NHE-1 on the heart, blood vessels, and platelets may act as a contributing pathway for the cardiovascular benefits of SGLT2 inhibitors in diabetes and heart failure.

SGLT2 Inhibitors and Ketone Metabolism in Heart Failure.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as powerful drugs that can be used to treat heart failure (HF) patients, both with preserved and reduced ejection fraction and in the presence or absence of type 2 diabetes. While the mechanisms underlying the salutary effects of SGLT2 inhibitors have not been fully elucidated, there is clear evidence for a beneficial metabolic effect of these drugs. In this review, we discuss the effects of SGLT2 inhibitors on cardiac energy provision secondary to ketone bodies, pathological ventricular remodeling, and inflammation in patients with HF. While the specific contribution of ketone bodies to the pleiotropic cardiovascular benefits of SGLT2 inhibitors requires further clarification, ketone bodies themselves may also be used as a therapy for HF.

Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches.

Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

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.

Sodium-Glucose Cotransporter-2 Inhibitors in Vascular Biology: Cellular and Molecular Mechanisms.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new antidiabetic drugs that reduce hyperglycemia by inhibiting the glucose reabsorption in renal proximal tubules. Clinical studies have shown that SGLT2 inhibitors not only improve glycemic control but also reduce major adverse cardiovascular events (MACE, cardiovascular and total mortality, fatal or nonfatal myocardial infarction or stroke) and hospitalization for heart failure (HF), and improve outcome in chronic kidney disease. These cardiovascular and renal benefits have now been confirmed in both diabetes and non-diabetes patients. The precise mechanism(s) responsible for the protective effects are under intensive investigation. This review examines current evidence on the cardiovascular benefits of SGLT2 inhibitors, with a special emphasis on the vascular actions and their potential mechanisms.

Dapagliflozin decreases ambulatory central blood pressure and pulse wave velocity in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial.

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors reduce the incidence of heart failure and death in patients with type-2 diabetes mellitus. Arterial stiffness is a prominent risk factor for heart failure and overall mortality. The aim of this study was to evaluate the effects of dapagliflozin on ambulatory brachial and central blood pressure (BP) levels and arterial stiffness parameters in patients with type-2 diabetes mellitus. This is a double-blind, randomized, placebo-controlled clinical trial including 85 adult patients with type-2 diabetes mellitus on monotherapy or combination therapy with two of: metformin, sulphonylurea, DPP-4 inhibitor, or insulin. Patients were randomized in a 1 : 1 ratio to oral dapagliflozin 10 mg per day or placebo for 12 weeks. Study participants underwent 24-h ambulatory BP monitoring with the Mobil-O-Graph NG monitor at baseline and study-end. Baseline demographic, clinical and laboratory parameters were similar in the two groups. During follow-up, 24-h brachial SBP/DBP (129.0 ± 12.6/77.3 ± 7.3 vs. 123.2 ± 12.4/75.1 ± 6.4 mmHg; P < 0.001/P = 0.008) and central SBP/DBP (117.4 ± 10.5/78.9 ± 7.3 vs. 113.3 ± 8.8/77.3 ± 6.5 mmHg; P = 0.002/P = 0.047) significantly decreased in dapagliflozin but not in the placebo group. Corresponding reductions of 24-h brachial SBP (-5.8 ± 9.5 vs. -0.1 ± 8.7, P = 0.005) and central SBP (-4.1 ± 8.0 vs. -0.7 ± 7.8; P = 0.046) were greater with dapagliflozin than placebo. Twenty-four-hour heart-rate adjusted augmentation index significantly decreased with dapagliflozin and insignificantly with placebo. Importantly, there was a significant difference in change of estimated 24-h PWV (-0.16 ± 0.32 vs. 0.02 ± 0.27; P = 0.007) favoring dapagliflozin. In generalized linear mixed models including 24-h brachial SBP as a random covariate, the adjusted marginal means of delta 24-h central SBP and delta 24-h PWV were not significantly different between-groups. Treatment with dapagliflozin significantly reduces ambulatory brachial and central BP levels and PWV in patients with type-2 diabetes mellitus. Improvement in these parameters may substantially contribute to the cardiovascular benefits of SGLT-2 inhibitors.

SO036THE EFFECT OF DAPAGLIFLOZIN ON AMBULATORY AORTIC BLOOD PRESSURE AND ARTERIAL STIFFNESS PARAMETERS IN PATIENTS WITH TYPE-2 DIABETES MELLITUS: A DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL

Abstract Background and Aims Arterial stiffness is a prominent risk factor for heart failure and overall mortality in patients with type-2 diabetes mellitus (DM). Sodium-glucose co-transporter 2 (SGLT-2) inhibitors reduce the incidence of heart failure and death in these patients. The aim of this study is to evaluate the effects of dapagliflozin on ambulatory central blood pressure (BP) levels and arterial stiffness parameters in patients with type-2 DM. Method This is a double-blind, randomized, placebo-controlled clinical trial including 85 adult patients with type-2 DM on monotherapy or combination therapy with two of: metformin, sulphonylurea, DDP-4 inhibitor, or insulin. Patients were randomized in a 1:1 ratio to oral dapagliflozin 10 mg per day or placebo for 12 weeks. Study participants underwent 24-h ambulatory BP monitoring with the Mobil-O-Graph NG monitor at baseline and study-end. Results Baseline demographic, clinical and laboratory parameters were similar in the two groups (age 61.74±6.73 vs 60.64±9.35; p=0.534). During follow-up, 24-hour central SBP/DBP significantly decreased in dapagliflozin (117.41±10.52/78.88±7.25 vs 113.30±8.75/77.25±6.54; p=0.002/p=0.047), but not in the placebo group. Corresponding reductions of 24-hour central SBP (-4.12±8.00 vs -0.65±7.77; p=0.046) were greater with dapagliflozin than placebo. Aortic pulse pressure (PP) decreased only in the dapagliflozin group (38.53±7.44 vs 36.05±6.59 mmHg; p=0.004). 24-hour heart-rate adjusted augmentation-index significantly decreased with dapagliflozin. Importantly, there was a significant difference in the change of 24-hour PWV (-0.16±0.32 vs 0.02±0.27; p=0.007) favoring dapagliflozin. Conclusion Treatment with dapagliflozin significantly reduces ambulatory central BP and PWV levels in type-2 diabetics. Improvement in these parameters may substantially contribute to the cardiovascular benefits of SGLT-2 inhibitors.

Canagliflozin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration

Cardiovascular disease is the major cause of morbidity and mortality in diabetes. Although numerous factors contribute to the development of diabetes‐associated cardiovascular disease, excessive proliferation and migration of vascular smooth muscle cells (SMCs) plays a critical role. Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are the latest approved class of glucose lowering drugs. By blocking glucose uptake in the proximal tubule of the kidney, SGLT2 inhibitors induce glycosuria leading to decreases in fasting and postprandial glycemia. Notably, large multicenter clinical trials have demonstrated that SGLT2 inhibitors reduce cardiovascular disease and mortality in patients with type 2 diabetes. The mechanism underlying the cardiovascular benefits of SGLT2 inhibitors is not fully known; however, direct effects on vascular SMCs have not been considered. In the present study, we investigated the effect of three different SGLT2 inhibitors on vascular SMC function. Treatment of rat and human aortic SMCs with canagliflozin resulted in a potent, concentration‐dependent inhibition of cell proliferation and DNA synthesis. The anti‐proliferative effect of canagliflozin was observed at clinically relevant concentrations, and this was not seen with other SGLT2 inhibitors, including empagliflozin and dapagliflozin. The inhibition of SMC growth by canagliflozin occurred in the absence of cell death and was associated with the arrest of SMCs in the G0/G1 phase of the cell cycle. In addition, scratch‐wound assays found that vascular SMC migration was blocked by canagliflozin in a concentration‐dependent manner, whereas empagliflozin or dapagliflozin had no effect on SMC motility. In conclusion, the present study identified canagliflozin as a robust inhibitor of vascular SMC proliferation and migration. These inhibitory effects of canagliflozin are detected at pharmacologically relevant concentrations and are unique for this drug and not seen with other SGLT2 inhibitors. The ability of canagliflozin to exert these pleiotropic effects on vascular SMC function may contribute to the salutary cardiovascular actions of this drug in patients with type 2 diabetes.Support or Funding InformationSupported by American Diabetes Association grant #1‐17‐IBS‐290.

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors for Cardiovascular Disease Prevention.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Because of these associated risks, managing diabetes and CVD, including heart failure (HF), has become a joint effort to reduce the risk of adverse outcomes. Although many patients with T2DM are receiving preventive therapies for CVD, their residual risk remains high for atherosclerotic CVD (ASCVD). Recent data regarding the use of antidiabetic medications to prevent negative cardiovascular outcomes has revealed a positive association with reduced major adverse cardiovascular events (MACE). One class of medications, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, are at the forefront of the cardiovascular outcomes prevention discussion. The clinical data presented in this review indicate the potential cardiovascular benefits of SGLT-2 inhibitors in patients with CVD and its potential value as a treatment option in preventing CVD in various patient populations.

Bridging the Gap for Patients with Diabetes and Cardiovascular Disease Through Cardiometabolic Collaboration.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with type 2 diabetes (T2D). Recent cardiovascular outcome trials (CVOTs) have established sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1 RA) as powerful medications that can lower glucose as well as reduce the risk of complications of CVD in many individuals with T2D. The combination of glycemic and cardiovascular benefits of SGLT2i and GLP1 RA has highlighted the importance of collaborative care of patients by diabetes and cardiovascular specialists. We review several models of cardiometabolic care for patients with diabetes and CVD and discuss practical ways in which diabetes and cardiovascular specialists can work together to improve cardiometabolic care. CVOTs for SGLT2i and GLP1 RA have demonstrated a significant reduction in major adverse cardiovascular events in individuals with T2D and CVD, in addition to their beneficial effects on glucose lowering and weight loss. Additionally, several models of care, including population health screening models with or without a remote management intervention, multidisciplinary clinics, and combined cardiometabolic training, have been proposed to better facilitate the multifaceted care that individuals with diabetes and CVD require. Innovative models of cardiometabolic care have the potential to improve the quality of care that individuals with diabetes and CVD receive. Through collaboration and co-management, diabetes specialists, cardiovascular specialists, and primary care providers have the ability to optimize diabetes and cardiovascular care.

Empagliflozin's Ameliorating Effect on Plasma Triglycerides: Association with Endothelial Function Recovery in Diabetic Patients with Coronary Artery Disease.

Aim: So far, the mechanisms behind the cardiovascular benefits of sodium/glucose cotransporter 2 (SGLT2) inhibitors have not been fully clarified.Methods: In order to evaluate the effects of SGLT2 inhibitors on systemic hemodynamics, glucose metabolism, lipid profile, and endothelial function, 50 diabetic patients with established coronary artery disease (CAD) were included in this analysis and were given empagliflozin 10 mg/d. Cookie meal testing (carbohydrates: 75 g, fats: 28.5 g), endothelial function testing using flow-mediated dilatation (FMD), and body composition evaluation were performed before and after six months of treatment. Changes in %FMD between the treatment periods and its association with metabolic biomarkers were evaluated.Results: After six months of treatment, the body weight and body fat percentage decreased significantly, while the body muscle percentage increased significantly. The hemoglobin A1c level and fasting and postprandial plasma glucose levels were significantly decreased with treatment. Postprandial insulin secretion was also significantly suppressed and the insulin resistance index was significantly decreased. Furthermore, the fasting and postprandial triglyceride (TG) levels decreased significantly, while total ketone bodies increased significantly after the six-month treatment. While the plasma brain natriuretic peptide level was not changed, the C-reactive protein level was decreased and FMD was significantly improved after the six-month treatment. Multiple regression analysis showed that the strongest predictive factor of FMD improvement is change in the plasma TG levels.Conclusion: SGLT2 inhibitors improve multiple metabolic parameters. Of these, a reduction in plasma TGs was strongly associated with endothelial function recovery in diabetic patients with CAD, and this reduction may be related to the cardiovascular benefits of SGLT2 inhibitors.

Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies.

There is growing evidence from Phase III randomized clinical trials of the cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes mellitus. It is hypothesized that these benefits are mediated by mechanisms other than glucose control. To address this, we performed a systematic review of data from preclinical studies examining the direct cardioprotective effects of SGLT2 inhibitors. Medline, EMBASE, CINAHL, and International Pharmaceutical Abstracts databases were searched for preclinical studies that examined the potential cardioprotective effects of SGLT2 inhibitors. Submission documents to the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceutical and Medical Devices Agency for the registration of SGLT2 inhibitors were also reviewed. A total of 36 reports were included in the final analysis. The potential direct cardiovascular benefits of SGLT2 inhibitors include: augmentation of signal transducer and activator of transcription 3; inhibition of sodium hydrogen exchange; reduction of atherosclerosis; modulation of natriuretic peptides; vasodilation; modulation of sympathetic tone; and reduction of inflammation, oxidative stress, endoplasmic reticulum stress, and cardiac glucose uptake via down-regulation of SGLT1 expression. There are a number of mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits beyond glycaemic control.

Making sense of newer treatment options for type 2 diabetes.

Over the past decade, several new medications have been developed to treat type 2 diabetes mellitus. Large-scale outcome trials have been performed with patients at high cardiovascular risk to assess the cardiovascular safety of these agents. These trials are changing the landscape of diabetes therapy with evidence beyond safety to cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and some glucagon-like peptide-1 receptor agonists. This review provides an overview of incretin-based therapies and SGLT-2 inhibitors with a particular focus on the results of published cardiovascular outcome trials, which have also provided unique opportunities to evaluate uncommon but potentially serious adverse events of these newer agents. The cardiovascular benefits of SGLT-2 inhibitors and some glucagon-like peptide-1 receptor agonists suggest that they may be the preferred choice, usually as an add-on to metformin, for patients with type 2 diabetes mellitus at high cardiovascular risk.

Cardiovascular Benefit of SGLT2 Inhibitors in the Therapeutics of Diabetes Mellitus: A Close Look beyond the Horizon.

Cardiovascular complications are among the main reasons for the high morbidity and mortality in patients with type 2 diabetes, making the management of cardiovascular complications an integral component in the treatment of type 2 diabetes. Along the same line, the US Food and Drug Administration mandated all new diabetic drugs and therapies have a safe cardiovascular profile. Among various drugs available for the treatment against type 2 diabetes, the sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a class of newly developed anti-diabetic agents with properties of mitigating cardiovascular risk in patients with type 2 diabetes. Evidence from clinical trials has suggested that the SGLT2 inhibitors empagliflozin and canagliflozin are capable of reducing the overall risk of cardiovascular events and mortality in type 2 diabetic patients. In this mini-review, we will briefly discuss the various cardiovascular benefits of SGLT2 inhibitors, and the underlying mechanisms involved.