Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data.
Hallow K Melissa,Greasley Peter J,Helmlinger Gabriel,Chu Lulu,Heerspink Hiddo J,Boulton David W
American journal of physiology. Renal physiology
The mechanisms of cardiovascular and renal protection observed in clinical trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) are incompletely understood and likely multifactorial, including natriuretic, diuretic, and antihypertensive effects, glomerular pressure reduction, and lowering of plasma and interstitial fluid volume. To quantitatively evaluate the contribution of proposed SGLT2i mechanisms of action on changes in renal hemodynamics and volume status, we coupled a mathematical model of renal function and volume homeostasis with clinical data in healthy subjects administered 10 mg of dapagliflozin once daily. The minimum set of mechanisms necessary to reproduce observed clinical responses (urinary sodium and water excretion, serum creatinine and sodium) was determined, and important unobserved physiological variables (glomerular pressure, blood and interstitial fluid volume) were then simulated. We further simulated the response to SGLT2i in diabetic virtual patients with and without renal impairment. Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of Na/H exchanger 3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage. The model also showed that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and mild blood pressure reduction, in agreement with clinical observations. The simulations suggest that these effects are more significant in diabetic patients than healthy subjects and that while glucose excretion may diminish with renal impairment, improvements in glomerular pressure and blood volume are not diminished at lower glomerular filtration rate, suggesting that cardiorenal benefits of SGLT2i may be sustained in renally impaired patients.
10.1152/ajprenal.00202.2018
What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors?
Sridhar Vikas S,Rahman Habib U,Cherney David Z I
Diabetes, obesity & metabolism
Over the past 5 years, sodium-glucose cotransport 2 (SGLT2) inhibitors have been increasingly regarded as glycaemic agents with cardiovascular (CV) and renal protective effects. The CV benefits of SGLT2 inhibitors have been well established in patients with type 2 diabetes (T2D) and a range of CV comorbidities at baseline. Subsequently, the renal benefits of SGLT2 inhibitors were established in the CREDENCE trial, a dedicated renal outcome trial where canagliflozin reduced the primary composite renal outcome by 30%. In light of these trials, clinical practice guidelines have rapidly evolved, recommending the use of SGLT2 inhibitors as renal and cardioprotective agents in appropriate patient populations. Accordingly, it is important to have an in-depth understanding of the evidence underlying the use of SGLT2 inhibitors in patients with T2D based on published clinical trials and real-world evidence (RWE) studies, as well as information related to potential safety concerns. To accomplish this, we reviewed the evidence for renal protection and safety with SGLT2 inhibitors in the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 CV safety trials, and in the growing body of evidence emerging from real-world studies. This body of work has shown that SGLT2 inhibitors reduce the risk of surrogate renal endpoints such as albuminuria and mitigate the risk of hard renal endpoints including doubling of serum creatinine and end-stage kidney disease in patients with T2D.
10.1111/dom.13965
Renal protection: a leading mechanism for cardiovascular benefit in patients treated with SGLT2 inhibitors.
Margonato Davide,Galati Giuseppe,Mazzetti Simone,Cannistraci Rosa,Perseghin Gianluca,Margonato Alberto,Mortara Andrea
Heart failure reviews
Initially developed as glucose-lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have demonstrated to be effective agents for the risk reduction of cardiovascular (CV) events in patients with type 2 diabetes mellitus (T2DM). Subsequently, data has emerged showing a significant CV benefit in patients treated with SGLT2i regardless of diabetes status. Renal protection has been initially evaluated in CV randomized trials only as secondary endpoints; nonetheless, the positive results gained have rapidly led to the evaluation of nephroprotection as primary outcome in the CREDENCE trial. Different renal and vascular mechanisms can account for the CV and renal benefits enlightened in recent literature. As clinical guidelines rapidly evolve and the role of SGLT2i appears to become pivotal for CV, T2DM, and kidney disease management, in this review, we analyze the renal effects of SGLT2, the benefits derived from its inhibition, and how this may result in the multiple CV and renal benefits evidenced in recent clinical trials.
10.1007/s10741-020-10024-2
Recent advances in the treatment of chronic heart failure.
Buckley Leo F,Shah Amil M
F1000Research
After more than a decade of relatively modest advancements, heart failure therapeutic development has accelerated, with the PARADIGM-HF trial and the SHIFT trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization for sacubitril-valsartan and in heart failure hospitalization alone for ivabradine. Several heart failure therapies have since received or stand on the verge of market approval and promise substantive advances in the treatment of chronic heart failure. Some of these improve clinical outcomes, whereas others improve functional or patient-reported outcomes. In light of these rapid advances in the care of adults living with chronic heart failure, in this review we seek to update the general practitioner on novel heart failure therapies. Specifically, we will review recent data on the implementation of sacubitril-valsartan, treatment of functional mitral regurgitation, sodium-glucose co-transporter-2 (SGLT-2) inhibitor therapy, agents for transthyretin amyloid cardiomyopathy, treatment of iron deficiency in heart failure, and the use of biomarkers or remote hemodynamic monitoring to guide heart failure therapy.
10.12688/f1000research.20447.1
Sodium-Glucose Cotransporter-2 Inhibitors, Reverse J-Curve Pattern, and Mortality in Heart Failure.
Imprialos Konstantinos,Stavropoulos Konstantinos,Papademetriou Vasilios
Heart failure clinics
The prevalence of diabetes mellitus and heart failure is increasing. The novel sodium-glucose cotransporters 2 inhibitors offer multidimensional ameliorating effects on cardiovascular and heart failure risk factors. Several studies have assessed the impact on cardiovascular events, with data suggesting beneficial effects on cardiovascular events in high-risk patients with diabetes in patients with heart failure. The reverse J-curve pattern between blood pressure levels and mortality has emerged as an important topic in the field of heart failure. There is no significant evidence to propose any potential effect of sodium-glucose co-transporter 2 inhibitors on the J-shape-suggested mortality in patients with heart failure.
10.1016/j.hfc.2019.06.004
[Outcome studies on SGLT-2 inhibitors].
Seufert J,Laubner K
Der Internist
BACKGROUND:Inhibitors of sodium-glucose cotransporters type 2 (SGLT-2) are a class of oral antidiabetic drugs with a novel specific mode of action in the kidneys. OBJECTIVE:The effects of SGLT-2 inhibitors on cardiovascular (CV) and renal endpoints in outcome trials with type 2 diabetes patients. MATERIAL AND METHODS:Differential analysis and interpretation of the results of outcome trials with the SGLT-2 inhibitors empagliflozin, canagliflozin and dapagliflozin in type 2 diabetes mellitus. RESULTS:In the EMPA-REG OUTCOME trial, empagliflozin demonstrated a significant reduction in major cardiac adverse events (MACE), hospitalization for heart failure (HHI), renal endpoints, CV and total mortality vs. placebo in >7000 patients with type 2 diabetes and established CV disease over 3.1 years. In the CANVAS program, canagliflozin demonstrated a significant reduction of MACE, HHI and renal endpoints vs. placebo in >10,000 patients with type 2 diabetes and high CV risk over 2.4 years. In the CREDENCE trial, canagliflozin demonstrated a significant reduction of a combined renal endpoint and CV endpoints vs. placebo in >4000 patients with type 2 diabetes and established kidney disease with albuminuria over 2.6 years. In the DECLARE-TIMI 58 trial, dapagliflozin demonstrated a significant reduction in a combined endpoint of CV death and HHI vs. placebo in >17,000 patients with type 2 diabetes and established CV disease or with multiple CV risk factors over 3.1 years. CONCLUSION:Outcome trials with SGLT-2 inhibitors have collectively demonstrated cardioprotective and nephroprotective effects in patients with type 2 diabetes and high CV risk. The use of SGLT-2 inhibitors is recommended in current guidelines and consensus statements as primary combination partners for metformin in patients with type 2 diabetes and established CV disease, high CV risk, heart failure or kidney disease.
10.1007/s00108-019-0656-x
Novel oral hypoglycemic agents SGLT-2 inhibitors: cardiovascular benefits and potential mechanisms.
Li Wei,Yu Kewei,Sun Shujuan
Die Pharmazie
Diabetes is an independent risk factor for cardiovascular events, and cardiovascular diseases (CVD) increase the risk of death when combined with diabetes. Diabetes and coronary heart disease are like two sides of a coin, which increase each other's long-term cardiovascular events. Therefore, a glucose-lowering regimen that can change the cardiovascular outcome has become a hot spot in the cardiovascular field in recent years. SGLT-2 (sodium-glucose cotransporter type 2) inhibitors have a novel hypoglycemic mechanism that reduces blood glucose by promoting glucose excretion. Clinical studies have shown that SGLT-2 inhibitors such as dapagliflozin and empagliflozin can reduce major cardiovascular adverse events, CV mortality, all-cause mortality, and hospitalization for heart failure. The pharmacological mechanisms by which SGLT-2 inhibitors achieve cardiovascular benefits have also become hot spots. Possible mechanisms for the cardiovascular benefits of SGLT-2 inhibitors known so far include lowering blood pressure, improving heart function and atherosclerosis, reducing inflammation and oxidative stress. This review discusses the clinical trials and possible pharmacological mechanisms of cardiovascular benefits of SGLT2 inhibitors.
10.1691/ph.2020.9634
Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice.
Diabetes, metabolic syndrome and obesity : targets and therapy
PURPOSE:This study investigates the possible effect and central mechanism of novel antidiabetic medication sodium glucose transporter-2 (SGLT-2i) on the cardiovascular activity. MATERIAL AND METHODS:Thirty-four normal male C57BL/6 mice were randomly assigned to 2 groups to receive single Dapagliflozin (1.52mg/kg) dose via intragastric gavage or a comparable dose of saline. Glycemic level (BG), blood pressure (BP) and heart rate (HR) were measured 2 hours after administration of the respective treatments. Immunohistochemical tests were performed to determine the effect of SGLT-2i on neural localization of SGLT-2 and c-Fos, a neural activator. The distributional relationships of SGLT-2 and c-Fos were examined by immunofluorescence. RESULTS:Administration of SGLT-2i significantly decreased BP but did not affect the HR. There was no difference in BG between the two groups. Results showed that SGLT-2 was localized to specific regions involved in autonomic control. Expression of c-Fos was significantly higher in major critical nuclei in the aforementioned regions in groups treated with Dapagliflozin. CONCLUSION:This study demonstrates that SGLT-2 is expressed in CNS tissues involved in autonomic control and possibly influence cardiovascular function. Dapagliflozin influences central autonomic activity via unidentified pathways by inhibiting central or peripheral SGLT-2. These results provide a new concept that sympathetic inhibition by SGLT-2i can be mediated by central autonomic system, a mechanism that explains how SGLT-2i improves the cardiovascular function.
10.2147/DMSO.S258593
Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury.
Cardiovascular diabetology
BACKGROUND:A sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established. METHODS:The effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function. RESULTS:Dapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy. CONCLUSIONS:Acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.
10.1186/s12933-020-01066-9
SGLT-2 Inhibitors in Heart Failure: Implications for the Kidneys.
Verbrugge Frederik H,Martens Pieter,Mullens Wilfried
Current heart failure reports
PURPOSE OF REVIEW:This review aims to summarize the renal effects of sodium-glucose transporter-2 (SGLT-2) inhibitors and their potential implications in heart failure pathophysiology. RECENT FINDINGS:In patients with diabetes and established atherosclerosis, the SGLT-2 inhibitor empagliflozin versus placebo significantly reduced the rate of heart failure admissions with 35%. Moreover, empagliflozin slowed kidney disease progression and reduced the need for renal replacement therapy. SGLT-2 inhibitors inhibit proximal tubular sodium and chloride reabsorption, leading to increased nephron flux throughout the distal renal tubules, most notably at the level of the macula densa. Afferent arteriolar vasoconstriction is promoted through tubulo-glomerular feedback and reduces glomerular capillary hydrostatic pressure, relieving podocyte stress and explaining renal preservation. Further, plasma volume is contracted and natriuresis promoted without inducing neurohumoral activation. Finally, SGLT-2 inhibitors may improve endothelial function and energy metabolism efficiency. Together, these promising features place them as a potential novel treatment for heart failure.
10.1007/s11897-017-0345-9
Sodium glucose cotransporter (SGLT)-2 inhibitors alleviate the renal stress responsible for sympathetic activation.
Sano Motoaki
Therapeutic advances in cardiovascular disease
This review focuses on the pathogenic role of sodium glucose cotransporter (SGLT)-2 in the development of renal dysfunction and heart failure in patients with diabetes, by emphasizing the concept of reno-cardiac syndrome (kidney injury worsens cardiac condition) and by substantiating the deleterious effect of sympathetic overdrive in this context. Furthermore, the review proposes a mechanistic hypothesis to explain the benefits of SGLT2 inhibitors, specifically that SGLT-2 inhibitors reduce sympathetic activation at the renal level. To illustrate this point, several examples from both animal experiments and clinical observations are introduced. The bidirectional interaction of the heart and kidney were deeply implicated as an exacerbator of heart failure and renal failure without diabetes. Renal cortical ischemia and abnormal glucose metabolism of tubular epithelial cells are likely to exist as common pathologies in nondiabetic heart failure patients. It is no wonder why SGLT-2 inhibitors are specifically being studied even in the absence of diabetes, both for heart failure and also for renal failure.
10.1177/1753944720939383
Are SGLT-2 Inhibitors the Future of Heart Failure Treatment? The EMPEROR-Preserved and EMPEROR-Reduced Trials.
Diabetes therapy : research, treatment and education of diabetes and related disorders
Heart failure is frequently associated with diabetes, and therapies which reduce mortality in people with heart failure and reduced ejection fraction (HFrEF) are often limited to drugs which modulate the renin-angiotensin-aldosterone system or heart rate control and occasionally to device therapy. Treatment is even more challenging in people with heart failure and preserved ejection fraction (HFpEF), with currently no approved therapy demonstrating a mortality-improving effect, limiting treatment to diuretics for the alleviation of the symptoms of fluid overload and risk factor management. Previous cardiovascular outcome trials for sodium-glucose co-transporter-2 (SGLT-2) inhibitors have demonstrated significant favourable outcomes for cardiovascular disease, heart failure hospitalisation and all-cause mortality. The aim of the nearly completed EMPEROR-preserved and EMPEROR-reduced trials is to determine the impact of empagliflozin on cardiovascular and heart failure outcomes in people with HFpEF or HFrEF with or without diabetes. The trials will add substantially to our understanding of SGLT-2 inhibitors in the treatment of HFrEF and may have major implications for the treatment of people with HFpEF. The study will also be powered to address the impact of empagliflozin on changes in renal function in people with and without diabetes and incident diabetes in the participants without diabetes at baseline. In this article we discuss the rationale for using SGLT-2 inhibitors in people with heart failure and explore the potential findings and importance of the ongoing EMPEROR-preserved and EMPEROR-reduced trials.
10.1007/s13300-020-00889-9