When and How to Use Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction or Chronic Kidney Disease

The role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in preventing heart failure (HF) in people with type 2 diabetes (T2DM) is now part of current treatment recommendations. Two large clinical trials (DAPA-HF and EMPEROR-Reduced) have recently highlighted the important impact of SGLT2 inhibitors in patients with HF and a reduced ejection fraction (HFrEF), with significant outcome benefits on HF hospitalisations and cardiovascular mortality, and similar effects in patients with and without T2DM. These benefits were observed on top of excellent background HF therapy, and there were no treatment interactions between SGLT2 inhibitors and background HF therapy. There were no increases in adverse events of interest in the SGLT2 inhibitor arm, including volume depletion, adverse renal events, hypoglycemia, amputation, and ketoacidosis, demonstrating the favourable safety profile of this treatment in HFrEF. Approximately 40%-50% of patients with HFrEF have chronic kidney disease (CKD), and the recently reported results of the DAPA-CKD trial indicate that dapagliflozin can prevent renal and cardiovascular outcomes in patients with established CKD, whether diabetes is present or not. Although the mechanisms of action of SGLT2 inhibitors are not fully understood, the hypotheses that have been proposed for their HF outcome benefits include a reduction of preload via osmotic diuresis, lowering of afterload, reduction in myocardial mass, alteration of myocardial energy substrate toward a more efficient glucose metabolism, modulation of renal sympathetic afferent tone, and increased erythropoiesis. We here present a summary of the evidence as well as a practical perspective on prescribing SGLT2 inhibitors in patients with HFrEF, with or without diabetes.     

Use of sodium–glucose co‐transporter‐2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure

Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF), with recent reports indicating that HF with preserved ejection fraction (HFpEF) may be more common than HF with reduced ejection fraction (HFrEF) in patients with T2D. T2D and HF result in worse outcomes than either disease alone. Sodium–glucose co‐transporter‐2 inhibitors (SGLT‐2is) have significantly improved HF outcomes in patients with T2D and may represent a new therapeutic alternative for patients with T2D at risk for or with HF. Current guidelines recommend prevention of HF through risk factor management. Once developed, treatment of HFrEF should include neurohormonal and haemodynamic modulations; however, there are no specific treatments available for HFpEF. SGLT‐2is are the first class of glucose‐lowering therapy to prevent HF in clinical trials and real‐world studies in patients with T2D (with or without established cardiovascular disease and with or without baseline HF). Mechanistic studies suggest that SGLT‐2is have beneficial effects on both systolic and diastolic function and additional systemic effects that could benefit HF outcomes. In patients with HFrEF, SGLT‐2i treatment as add‐on to standard HF therapy has had beneficial effects on HF outcomes, irrespective of T2D status. These results and those of ongoing outcomes trials with SGLT‐2is may help establish this drug class as a treatment for HF in patients with HFrEF and HFpEF, as well as HF in patients without T2D.     

The Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists on Cardiorenal Outcomes: Systematic Review and Meta-analysis

BackgroundEvidence for the cardiorenal risk reduction properties of antihyperglycemic medications originally prescribed for type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is rapidly emerging. We completed a meta-analysis of recent literature to provide evidence-based estimates of benefit across various populations and outcomes.MethodsWe searched Medline and Cochrane databases from 2015 to September 2021 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. Reviewers screened citations, extracted data, and assessed the risk of bias and certainty of evidence. We assessed statistical and methodological heterogeneity and performed a meta-analysis of studies with similar interventions and components.ResultsA total of 137,621 adults (51% male) from 19 studies were included; 14 studies with unclear risk of bias and 5 with low risk of bias. Compared with standard of care, use of SGLT2i showed significant reductions for the outcome of cardiovascular (CV) mortality (14%), any-cause mortality (13%), major adverse CV events (MACE) (12%), heart failure (HF) hospitalization (31%), CV death or HF hospitalization (24%), nonfatal myocardial infarction (10%), and kidney composite outcome (36%). Treatment with GLP-1RA was associated with significant reductions for the outcome of CV mortality (13%), any-cause mortality (12%), MACE (14%), CV death or HF hospitalization (11%), nonfatal stroke (16%), and kidney composite outcome (22%).ConclusionsThe use of GLP-1RA and SGLT2i leads to a statistically significant benefit across most cardiorenal outcomes in the populations studied. This review shows a role for SGLT2i and GLP-1RA in cardiorenal protection in adults, independent of type 2 diabetes status.     

Cardiorenal disease management in type 2 diabetes: An expert consensus

Background and aimThe interplay between cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes (T2D) is well established. We aim at providing an evidence-based expert opinion regarding the prevention and treatment of both heart failure (HF) and renal complications in people with T2D.Methodology: The consensus recommendations were developed by subject experts in endocrinology, cardiology, and nephrology. The criteria for consensus were set to statements with ≥80% of agreement among clinicians specialized in endocrinology, cardiology, and nephrology. Key expert opinions were formulated based on scientific evidence and clinical judgment.ResultsAssessing the risk factors of CVD or CKD in people with diabetes and taking measures to prevent HF or kidney disease are essential. Known CVD or CKD among people with diabetes confers a very high risk for recurrent CVD. Metformin plus lifestyle modification should be the first-line therapy (unless contraindicated) for the management of T2D. Glucagon-like peptide 1 (GLP-1) agonists can be preferred in people with atherosclerotic cardiovascular disease (ASCVD) or with high-risk indicators, along with sodium–glucose cotransporter-2 inhibitors (SGLT2i), whereas SGLT2i are the first choice in HF and CKD. The GLP-1 agonists can be used in people with CKD if SGLT2i are not tolerated.ConclusionCurrent evidence suggests SGLT2i as preferred agents among people with T2D and HF, and for those with T2D and ASCVD. SGLT2i and GLP-1RA also lower CV outcomes in those with diabetes and ASCVD, and the treatment choice should depend on the patient profile.     

2022 Canadian Cardiovascular Society Guideline for Use of GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults

This guideline synthesizes clinical trial data supporting the role of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors (SGLT2i) for treatment of heart failure (HF), chronic kidney disease, and for optimizing prevention of cardiorenal morbidity and mortality in patients with type 2 diabetes. It is on the basis of a companion systematic review and meta-analysis guided by a focused set of population, intervention, control, and outcomes (PICO) questions that address priority cardiorenal end points. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system and a modified Delphi process were used. We encourage comprehensive assessment of cardiovascular (CV) patients with routine measurement of estimated glomerular filtration rate, urinary albumin-creatinine ratio, glycosylated hemoglobin (A1c), and documentation of left ventricular ejection fraction (LVEF) when evaluating symptoms of HF. For patients with HF, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy for the reduction of hospitalization for HF when LVEF is > 40% and for the reduction of all-cause and CV mortality, hospitalization for HF, and renal protection when LVEF is ≤ 40%. In patients with albuminuric chronic kidney disease, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy to reduce all-cause and CV mortality, nonfatal myocardial infarction, and hospitalization for HF. We provide recommendations and algorithms for the selection of glucagon-like peptide-1 receptor agonists and SGLT2i for patients with type 2 diabetes and either established atherosclerotic CV disease or risk factors for atherosclerotic CV disease to reduce all-cause and CV mortality, nonfatal stroke, and for the prevention of hospitalization for HF and decline in renal function. We offer practical advice for safe use of these diabetes-associated agents with profound cardiorenal benefits.     

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.     

改善心血管和肾脏结局的新型抗高血糖药物临床应用中国专家建议

动脉粥样硬化性心血管病(ASCVD)和(或)慢性肾脏病(CKD)不但是2型糖尿病(T2DM)常见合并疾病,也是T2DM患者致残和致死的首要原因。近年来一系列临床研究证据表明,新型抗高血糖药物胰高糖素样肽-1受体激动剂(GLP-1 RA)和钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)类药物能显著改善心血管和肾脏结局的临床获益,且安全性良好。为促使T2DM的治疗模式从单纯控制血糖转移到改善心血管和肾脏临床结局,中国心血管病学、内分泌学、肾脏病学和神经病学专家组成的专家组梳理了GLP-1 RA或SGLT2i的心血管保护的临床证据、可能机制和常见不良反应,提出了对这两类药物在临床实践中的合理定位、应用建议和注意事项,鼓励临床医师在临床实践中对T2DM患者及早启动并长期维持能够改善心血管和肾脏结局的新型抗高血糖药物治疗。     

Bloqueantes del receptor mineralcorticoide en la enfermedad renal crónica

There are many experimental data supporting the involvement of aldosterone and mineralcorticoid receptor (MR) activation in the genesis and progression of chronic kidney disease (CKD) and cardiovascular damage.Many studies have shown that in diabetic and non-diabetic CKD, blocking the renin- angiotensin-aldosterone (RAAS) system with conversion enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) decreases proteinuria, progression of CKD and mortality, but there is still a significant residual risk of developing these events.In subjects treated with ACEi or ARBs there may be an aldosterone breakthrough whose prevalence in subjects with CKD can reach 50%. Several studies have shown that in CKD, the aldosterone antagonists (spironolactone, eplerenone) added to ACEi or ARBs, reduce proteinuria, but increase the risk of hyperkalemia. Other studies in subjects treated with dialysis suggest a possible beneficial effect of antialdosteronic drugs on CV events and mortality. Newer potassium binders drugs can prevent / decrease hyperkalemia induced by RAAS blockade, and may reduce the high discontinuation rates or dose reduction of RAAS-blockers.The nonsteroidal MR blockers, with more potency and selectivity than the classic ones, reduce proteinuria and have a lower risk of hyperkalemia. Several clinical trials, currently underway, will determine the effect of classic MR blockers on CV events and mortality in subjects with stage 3b CKD and in dialysis patients, and whether in patients with type 2 diabetes mellitus and CKD, optimally treated and with high risk of CV and kidney events, the addition of finerenone to their treatment produces cardiorenal benefits.Large randomized trials have shown that sodium glucose type 2 cotransporter inhibitors (SGLT2i) reduce mortality and the development and progression of diabetic and nondiabetic CKD. There are pathophysiological arguments, which raise the possibility that the triple combination ACEi or ARBs, SGLT2i and aldosterone antagonist provide additional renal and cardiovascular protection.     

Sodium glucose cotransporter (SGLT)-2 inhibitors: Do we need them for glucose-lowering,for cardiorenal protection or both?

Sodium glucose cotransporter (SGLT)-2 inhibitors are the newest addition to our treatment armamentarium for the management of hyperglycemia in type 2 diabetes. Glucose-lowering per se reduces the risk of microvascular complications, but not the risk of cardiovascular disease, including heart failure and cardiovascular mortality. Also, even when embedded in optimal cardiovascular prevention, a large residual risk remains with respect to progression of diabetic kidney disease. SGLT-2 inhibitors lower blood glucose levels by inducing glucosuria. Through various proposed mechanisms, among which diuretic and natriuretic effects, SGLT-2 inhibitors decrease heart failure hospitalization, reduce cardiovascular mortality, and mitigate progression of diabetic kidney disease. In this perspective, we will discuss the glucose-lowering and other protective effects of SGLT-2 inhibitors on the cardiorenal axis, both in primary and secondary prevention. By comparing the glycemic and pleiotropic effects of these agents to other glucose-lowering drugs, we will address questions around whether SGLT-2 inhibitors should be considered primarily as glucose-lowering agents, cardiorenal drugs or both.     

中国成人2型糖尿病患者糖化血红蛋白控制目标及达标策略专家共识

糖化血红蛋白(HbA1C)控制目标应遵循患者为中心的个体化原则,即根据患者的年龄、病程、健康状况、药物不良反应风险等因素实施分层管理。本共识建议一般成人2型糖尿病(T2DM)患者的HbA1C控制目标为<7.0%,并对其他情况下的HbA1C目标值作出推荐。本共识建议将二甲双胍作为T2DM患者单药治疗的首选,α-糖苷酶抑制剂(AGI)或胰岛素促泌剂作为单药治疗的备选。进行联合治疗时,建议根据患者是否合并动脉粥样硬化性心血管疾病(ASCVD)、心力衰竭(HF)或慢性肾脏疾病(CKD)进行分层。如患者合并ASCVD,建议在具备条件的情况下联合有心血管获益证据的胰升糖素样肽-1受体激动剂(GLP-1RA)或钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)。如患者合并CKD,建议联合用药时在条件允许的情况下首选有肾脏获益证据的SGLT2i,在患者不能使用SGLT2i时可选择有肾脏获益证据的GLP-1RA。如患者合并HF,建议在条件允许时选择SGLT2i。如患者未合并ASCVD、HF或CKD时,可根据基线HbA1C水平、低血糖风险、体重、经济状况、药物可及性等因素选择联合的药物。     

Review of glucagon‐like peptide‐1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD), and when it causes CKD it is collectively referred to as diabetic kidney disease. One of the newer therapies for managing hyperglycemia is the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) drug class. This review summarizes the effects of GLP‐1RAs in patients with T2DM with CKD and evidence for renoprotection with GLP‐1RAs using data from observational studies, prospective clinical trials, post hoc analyses, and meta‐analyses. Evidence from some preclinical studies was also reviewed. Taken together, subgroup analyses of patients with varying degrees of renal function demonstrated that glycemic control with GLP‐1RAs was not markedly less effective in patients with mild or moderate renal impairment vs that in patients with normal function. GLP‐1RAs were associated with improvements in some cardiorenal risk factors, including systolic blood pressure and body weight. Furthermore, several large cardiovascular outcome studies showed reduced risks of composite renal outcomes, mostly driven by a reduction in macroalbuminuria, suggesting potential renoprotective effects of GLP‐1RAs. In conclusion, GLP‐1RAs effectively reduced hyperglycemia in patients with mild or moderately impaired kidney function in the limited number of studies to date. GLP‐1RAs may be considered in combination with other glucose‐lowering medications because of their ability to lower glucose in a glucose‐dependent manner, lowering their risk for hypoglycemia, while improving some cardiorenal risk factors. Potential renoprotective effects of GLP‐1RAs, and their renal mechanisms of action, warrant further investigation.     

Impact of SGLT2 inhibitors on major clinical events and safety outcomes in heart failure patients: a meta-analysis of randomized clinical trials

BACKGROUNDSodium-glucose co-transporter-2 inhibitors (SGLT2i) significantly reduce the risk of cardiovascular (CV) and renal adverse events in patients with diabetes mellitus, heart failure (HF) and/or chronic kidney disease. We performed a meta-analysis to explore the impact of several different SGLT2i on all-cause mortality, CV mortality, HF hospitalizations and the combined outcome CV death/HF hospitalization in HF patients across the spectrum of left ventricular ejection fraction (LVEF) phenotypes.METHODSA systematic search in MEDLINE database and Cochrane library through March 2021 was performed without limitations. Randomized clinical trials that provided data about the impact of SGLT2i on all-cause mortality, CV mortality, HF hospitalizations or the combined outcome of CV death/HF hospitalization in HF patients were included. A random effects model was used for calculating the effect estimates.RESULTSNine studies (n = 16,723 patients, mean age: 65.9 years, males: 70.7%) were included in the quantitative synthesis. Compared to placebo, SGLT2i use was associated with 14% lower risk of all-cause mortality [hazard ratio (HR) = 0.86, 95% CI: 0.78−0.94,I² = 0, P = 0.0008], 32% lower risk of HF hospitalizations (HR = 0.68, 95% CI: 0.62−0.74,I² = 0, P < 0.001), 14% lower risk of CV mortality (HR = 0.86, 95% CI: 0.77−0.95, I² = 0, P = 0.003) and 26% lower risk of CV death/HF hospitalization (HR = 0.74, 95% CI: 0.68−0.80,I² = 0, P < 0.001). Regarding the safety outcomes, our data revealed no significant differences between SGLT2i and placebo groups in drug related discontinuations, amputations, severe hypoglycemia, hypotension, volume depletion, ketoacidosis and genital infections. By contrast, a protective role of SGLT2i against placebo was found for serious adverse events and acute kidney injury. CONCLUSIONSIn patients with HF, regardless of LVEF phenotype, all SGLT2i had an excellent safety profile and significantly reduced the risk of all-cause mortality, CV mortality, HF hospitalizations and CV deaths/HF hospitalizations compared to placebo.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) is an antidiabetic class category that acts by blocking glucose resorption in the proximal tubule of the kidney promoting glucosuria.^[1] Randomized clinical trials have shown the beneficial role of SGLT2i in cardiovascular (CV) and renal outcomes in patients with or without diabetes mellitus (DM), including patients with heart failure (HF) and/or chronic kidney disease (CKD).^[2–8] According to current guidelines, empagliflozin, canagliflozin and dapagliflozin are recommended in patients with type 2 DM (T2DM) and CV disease, or at very high/high CV risk to reduce CV events, while empagliflozin is also recommended in patients with T2DM and CV disease to reduce the risk of death.^[9] The protective role of SGLT2i on CV events is mainly driven by the reduction in HF hospitalizations.^[4] For that reason, SGLT2i (empagliflozin, canagliflozin and dapagliflozin) are also recommended to lower risk of HF hospitalization in patients with DM.^[9] Recent studies and meta-analyses have shown that empagliflozin and dapagliflozin can further improve CV and renal outcomes in HF patients with reduced left ventricular ejection fraction [LVEF, especially HF with reduced ejection fraction (HFrEF)], regardless of the presence of DM.^[8,10,11] In addition, the American College of Cardiology has already recommended SGLT2i for the treatment of HFrEF.^[12] However, there are still unanswered questions as to whether the observed favorable outcomes in efficacy and safety constitute a class effect of SGLT2i or an effect confined to specific agents and whether the benefit also extends to HF with preserved LVEF [especially HF with preserved ejection fraction (HFpEF)]. The aim of this meta-analysis is to shed some light on these open issues by pooling data from randomized controlled trials (RCTs) on all clinically available SGLT2i, while examining the effects of SGLT2i across the spectrum of LVEF phenotypes.     

Prevalence of SGLT2i and GLP1RA use among US adults with type 2 diabetes

AimsTo determine national prevalence of sodium-glucose contransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1RA) use among adults with type 2 diabetes mellitus (T2DM).MethodsWe studied adults with T2DM and eGFR ≥ 30 mL/min/1.73 m² who participated in the cross-sectional National Health and Nutrition Examination Survey (NHANES), focusing on the 2017–2020 examination cycle, a key time period prior to widespread dissemination of pivotal trial results and corresponding clinical practice guidelines. We tested prevalence of SGLT2i and GLP1RA use among subgroups based on demographic variables and relevant comorbidities, including chronic kidney disease (CKD), congestive heart failure (CHF), and atherosclerotic cardiovascular disease (ASCVD). We compared use of SGLT2i and GLP1RA to other glucose-lowering medications and assessed trends from prior NHANES cycles.ResultsAmong 1375 participants studied in 2017–2020, mean age was 60 years, 46% were women, 13% self-identified as non-Hispanic Black, 10% self-identified as Mexican American, 37% had CKD, 8.5% had CHF, and 23% had ASCVD. The prevalence of SGLT2i and GLP1RA use was 5.8% and 4.4%, respectively. Among adults with CKD, CHF, or ASCVD, SGLT2i were used by 7.7% and GLP1RA were used by 3.5%. Differences in SGLT2i or GLP1RA use were observed by age, race, ethnicity, health insurance status, body mass index, and by whether a single healthcare provider was identified as responsible for diabetes management. Biguanides, sulfonylureas, DPP-4 inhibitors, and insulin were used more frequently than SGLT2i or GLP1RA. Prevalence of SGLT2i but not GLP1RA use increased significantly from 2013–2014 to 2017–2020.ConclusionsSGLT2i and GLP1RA use is low among adults with T2DM, including among those with strong indications. Enhanced implementation of these agents is crucial to improving kidney and cardiovascular outcomes and mitigating health disparities in T2DM.     

Impact of demographic characteristics and antihyperglycemic and cardiovascular drugs on the cardiorenal benefits of SGLT2 inhibitors in patients with type 2 diabetes mellitus: A protocol for systematic review and meta-analysis

Background:It is unclear whether demographic characteristics and baseline use of hypoglycemic and cardiovascular drugs significantly affect the efficacy of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM).Methods:Randomized trials assessing the efficacy of SGLT2 inhibitors on cardiorenal outcomes in adult patients with T2DM were included in analysis. Three endpoints of interest were major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular death (HHF or CV death), and kidney composite outcome (KCO). We performed random-effects meta-analysis using the aggregate data of hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses were done according to 17 factors of interest, including 7 factors related to demographic characteristics and 10 related to baseline use of antihyperglycemic and cardiovascular drugs such as renin–angiotensin system (RAS) inhibitor. We conducted meta-regression analyses to calculate P values for subgroup differences.Results:Seven trials were included in this meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of MACE (HR 0.90, 95% CI 0.84–0.97) regardless of demographic characteristics and baseline use of insulin, statin or ezetimibe, RAS inhibitor, beta-blocker, and diuretic (P_subgroup from 0.088–0.981); that of HHF or CV death (HR 0.78, 95% CI 0.71–0.85) regardless of demographic characteristics and baseline use of 10 antihyperglycemic and cardiovascular drugs (P_subgroup from 0.147–0.999); and that of KCO (HR 0.63, 95% CI 0.57–0.69) regardless of demographic characteristics and baseline use of statin or ezetimibe, RAS inhibitor, and diuretic (P_subgroup from 0.073–0.918).Conclusions:The cardiorenal benefits of SGLT2 inhibitors were consistent in a broad population of T2DM patients. The findings of this meta-analysis suggest that SGLT2 inhibitors should be recommended in T2DM patients for the prevention of cardiorenal events, regardless of various demographic characteristics and baseline use of various hypoglycemic and cardiovascular drugs.     

A safety update on sodium glucose co-transporter 2 inhibitors

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are the first class of glucose lowering agent to be shown to reduce cardiovascular events. They are generally well tolerated with infrequent serious adverse events. The most frequent side effect is genital mycotic infections with candida species that are usually mild to moderate in severity, easily treated and infrequently recur. Urinary tract infections, although common in patients with diabetes, have not been shown to be increased in controlled studies with SGLT2i. Hypoglycaemia can occur when an SGLT2i is added to agents that cause hypoglycaemia, such as insulin or sulphonylureas. Volume depletion and hypotension is infrequent and can be minimized by adjusting diuretic and antihypertensive treatment in patients at risk. Acute renal failure or kidney injury was observed in early observational studies. However, in randomized controlled trials (RCTs) and in more recent observational studies a decreased incidence of acute kidney injury was observed in SGLT2-treated patients compared to those receiving either placebo or another class of glucose lowering agents. An increased incidence of amputation (largely feet and toes) was observed in the RCT with canagliflozin but not with the other SGLT2i. Observational studies have shown either an increased risk of amputation with other agents whereas another study showed no increase. Although the increased risk of amputation is very low, avoidance of SGLT2i in patients at high risk seems prudent. Increased incidence of fractures was observed with canagliflozin but not with SGLT2i nor in a meta-analysis that included canagliflozin, empagliflozin and dapagliflozin. No increased incidence of cancer has been observed in either RCTs or observational studies.     

Soluble Guanylate Cyclase Stimulators: a Novel Treatment Option for Heart Failure Associated with Cardiorenal Syndromes?

Heart failure in the setting of chronic kidney disease (CKD) is an increasingly common scenario and carries a poor prognosis. Clinicians lack tools for primary or secondary heart failure prevention in patients with cardiorenal syndromes. In patients without CKD, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) and statins mitigate cardiovascular risk in large part due to salutary effects on the endothelium. In the setting of CKD, use of these therapies is limited by adverse effects of hyperkalemia in pre-dialysis CKD (ACE-I/ARB), or potential increased risk of stroke in end-stage renal disease (statins). The soluble guanylate cyclase (sGC) stimulators are a novel class of medications that promote endothelial and myocardial function with no known risk of hyperkalemia or stroke. In this review, we discuss the evidence emerging from recent clinical trials of sGC stimulators in pulmonary hypertension and heart failure, the diseased pathways involved in cardiorenal syndromes likely to be restored by sGC stimulators, and several strategies for designing future clinical trials of cardiorenal syndromes that might shorten the timeline for discovery and approval of effective cardiovascular therapies in these high-risk patients.     

Sodium-glucose cotransporter 2 inhibitors as the first universal treatment of chronic kidney disease

In the last five years, the medical community was astonishingly surprised by the sequential large outcome trials that displayed the renal effects of sodium glucose co-transporter inhibitors (SGLT2Is) in type 2 diabetes mellitus (T2DM) patients with or without chronic kidney disease (CKD). This favorable effect was later disclosed in non-diabetic CKD patients. The EMPA-REG OUTCOME trial was the first trial that showed a reduction for the need for dialysis in patients suffering diabetic kidney disease (DKD) by 55%. This figure is double the score achieved by the angiotensin receptor blocker, Losartan, in RENAAL trial. The need for dialysis in DAPA-CKD trial was reduced in diabetic and non-diabetic CKD patients by 33%. The renal-specific composite outcome was reduced by 39% in EMPA-REG trial, 40% in CANVAS study, 47% in DECLARE-TIMI 58 study, 34% in CREDENCE trial, and 44% in DAPA-CKD trial. The greater surprise is the significant favorable effect of SGLT2Is on overall mortality in CKD patients with or without T2DM. Similar survival benefit was not previously encountered with any of the medications used in CKD patients with or without diabetes. In this review, we disclose the results of the DAPA-CKD trial, the CREDENCE trial and those of several cardiovascular outcome trials (CVOT) that used different SGLT2Is and showed that patients with lower eGFR levels may have greater benefit with respect to cardiovascular morbidity than patients with normal kidney function. In addition, we discuss the different mechanisms of action that explain the renal beneficial effects of SGLT2Is.     

Uric acid and the cardio-renal effects of SGLT2 inhibitors

Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardio-renal risk. Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the “metabolic syndrome” of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes.     

Finerenona: completando el abordaje del paciente con enfermedad renal y diabetes

Despite current treatments, that include renin angiotensin system blockers and SGLT2 inhibitors, the risk of renal disease progression among patients with diabetes and chronic kidney disease (CKD) remains unacceptably high. The pathogenesis of CKD in patients with diabetes is complex and includes hemodynamic and metabolic factors, as well as inflammation and fibrosis. Finerenone is a nonsteroidal highly selective mineralocorticoid antagonist that, in contrast to current therapies, may directly reduce inflammation and fibrosis, supporting an added value in the management of these patients. In fact, finerenone decreased albuminuria and slowed CKD progression in persons with diabetes. We now review the mechanisms of action of finerenone, the results of recent clinical trials and a practical approach to integrate the kidney and cardiovascular protection afforded by finerenone in the routine care of patients with diabetes and CKD.     

Front Cover

Patients with type 2 diabetes are at an increased risk of developing heart failure and chronic kidney disease. The presence of these co-morbidities substantially increases the risk of morbidity as well as mortality in patients with diabetes. The clinical focus has historically centred around reducing the risk of cardiovascular disease by targeting hyperglycaemia, hyperlipidaemia and hypertension. Nonetheless, patients with type 2 diabetes who have well-controlled blood glucose, blood pressure and lipid levels may still go on to develop heart failure, kidney disease or both. Major diabetes and cardiovascular societies are now recommending the use of treatments such as sodium-glucose co-transporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists, in addition to currently recommended therapies, to promote cardiorenal protection through alternative pathways as early as possible in individuals with diabetes and cardiorenal manifestations. This review examines the most recent recommendations for managing the risk of cardiorenal progression in patients with type 2 diabetes.