Sodium-glucose Linked Transporter-2 Inhibitors Research Articles

Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet.

Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.

Sodium-glucose linked transporter 2 inhibitors in liver cirrhosis: Beyond their antidiabetic use.

Type 2 diabetes mellitus (T2DM) and liver cirrhosis are clinical entities that frequently coexist, but glucose-lowering medication options are limited in cirrhotic patients. Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a class of glucose-lowering medication that act independently of insulin, by causing glycosuria in the proximal convoluted tubule. In this review, we aimed to briefly present the main data and to provide insight into the pathophysiology and potential usefulness of SGLT2 inhibitors in cirrhotic patients with or without T2DM. SGLT2 inhibitors have been proven useful as antidiabetic treatment in patients with metabolic liver disease, with most robust data from patients with metabolic dysfunction-associated steatotic liver disease (MASLD), where they also showed improvement in liver function parameters. Moreover, it has been suggested that SGLT2 inhibitors may have effects beyond their antidiabetic action. Accordingly, they have exhibited cardioprotective effects, expanding their indication in patients with heart failure without T2DM. Since decompensated liver cirrhosis and congestive heart failure share common pathophysiological features, namely renin-angiotensin-aldosterone axis and sympathetic nervous system activation as well as vasopressin secretion, SGLT2 inhibitors could also be beneficial in patients with decompensated cirrhosis, even in the absence of T2DM.

Are heart failure patients with mildly reduced ejection fraction treated according to current international guidelines?

Abstract Objective This study aims to investigate the guideline adherence and prognostic role of guideline recommended heart failure (HF) therapies in patients hospitalized with heart failure with mildly reduced ejection fraction (HFmrEF). Background Limited data regarding the guideline adherence and prognostic impact of different pharmacotherapies in patients with HFmrEF is available. Methods A large retrospective study was used including all consecutive hospitalized patients with HFmrEF (i.e., left ventricular ejection fraction (LVEF) 41 – 49%) from 2016 to 2022 according to current European guidelines. The prescription rates and the prognostic role of angiotensin-converting enzyme and receptor blockers (ACEi/ARB), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium glucose linked transporter 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitor"(ARNi) was assessed. The primary endpoint was the first heart-failure related re-hospitalization at 3 years. Secondary endpoints comprised amongst others cardiovascular re-hospitalization. Kaplan-Meier, uni- and multivariable Cox regression analyses were applied for statistics. Results 775 consecutive patients with HFmrEF surviving index hospitalization were included. Of those, 73% were discharged on ACEi/ARB, followed by BB (26%), 14% MRA, whereas only minor part was treated with SGLT2i (3%). In HFmrEF patients, no prognostic impact of BB (10% vs. 7%; log rank p=0.218; HR=1.474; 95% CI 0.792-2.742; p=0.220), ACEi/ARB (9% vs. 10%; log rank p=0.444; HR=0.822; 95% CI 0.497-1.359; p=0.445), SGLT2i (8% vs. 9%; log rank p=0.821; HR=0.851; 95% CI 0.209-3.470; p=0.445), MRA (8% vs. 9%; log rank p=0.748; HR=0.892; 95% CI 0.443-1.794; p=0.748) regarding the risk of heart-failure related re-hospitalization at 3 years was observed. In line, these pharmacotherapies were not associated with the risk of cardiovascular re-hospitalization. Conclusions In patients hospitalized with HFmrEF between 2016 and 2022, only infrequent treatment with guideline recommended HF therapies was observed, whereas non of the current HF therapies was associated with the risk of heart-failure related rehospitalization.

Cost-Effectiveness of New Quadruple Therapy Compared With Standard Treatment for Patients With Heart Failure in China.

This study aimed to compare the cost-effectiveness of the new quadruple therapy regimen of adding sodium-glucose-linked transporter 2 (SGLT2) inhibitors, with standard treatment for patients with heart failure (HF) in China. From the payer's perspective, the dates of cardiovascular event recurrences were extracted from a meta-analysis including 6 trials, combined with the treatment cost for patients with HF in China to construct a Markov model. The outcomes included per capita medical costs and incremental cost-effectiveness ratio, using quality-adjusted life years (QALYs) data. Single-factor, probability sensitivity analysis, and scenario analysis were used to explore the potential uncertainties of the model. The per capita costs of the new quadruple therapy regimen and standard treatment were $87441.26 and $87087.54, respectively. The new regimen was associated with a mean of 21.44 QALYs gained, compared with 18.60 QALYs gained with the standard treatment. The incremental cost-effectiveness ratio was $124.03 per QALY gained. The sensitivity analysis revealed that changes in the parameters within the set range did not affect the model results. In China, compared with standard treatment, the new quadruple therapy regimen with SGLT2 inhibitors reduce the frequency of cardiovascular events among patients with HF, and it has economic advantages.

Approaches to early diagnosis and prevention of cardiovascular toxicity induced by targeted drugs and immune checkpoint inhibitors in oncohematology: a literature review

The development of targeted drugs and immune checkpoint inhibitors (ICIs), as well as their implementation into clinical practice has allowed increasing the overall and event-free survival of oncohematological patients. Currently, assessment of the efficacy of a therapeutic strategy in each specific case includes the evaluation of an acceptable tolerability profile. The subject of discussion includes cardiovascular complications induced by target drugs and ICIs. The review mainly presents the issues of cardiovascular toxicity (CVT) in certain groups of oncohematological patients (with chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma). The spectrum of cardiovascular adverse effects associated with targeted and ICI therapy in oncohematological practice is quite wide — coronary artery disease, peripheral arterial disease, myocarditis, heart failure, arrhythmias, hypertension. The high importance of the problem of using targeted and immunosuppressive therapy dictates the need to predict adverse effects. The diagnosis of heart failure (one of CVT manifestations) is based on determining the decreased left ventricular ejection fraction during echocardiography, less often — during cardiac magnetic resonance imaging; global longitudinal myocardial strain is a significant parameter of preclinical heart failure, which is determined using the speckle tracking technique. To determine vascular toxicity, a special attention is paid to the vascular wall structure and microcirculation parameters — capillary density at rest, percentage of capillary recovery and perfused capillaries, stiffness index for large blood vessels, reflection index for small arteries, laboratory markers of inflammation and endothelial dysfunction (C-reactive protein, fibrinogen, homocysteine, endothelin 1, vascular endothelial growth factor). CVT prevention presumes the determination of the risk group, correction of risk factors, and administration of protective therapy to very high and high-risk patients. One of the promising directions for preventing vascular toxicity is the use of sodium-glucose linked transporter-2 inhibitors.

A practical approach to guideline-directed pharmacological treatment for heart failure with reduced ejection fraction

The 2021 guidelines of the European Society of Cardiology for the diagnosis and treatment of heart failure recommend the early implementation of all four mortality-lowering drug classes for heart failure with reduced ejection fraction (HFrEF), i. e. angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor II blocker-neprilysin inhibitor (ARNI), betablocker (BB), mineralocorticoid receptor-antagonists (MRA), and sodium-glucose linked transporter-2 inhibitors (SGLT2i). This article aims to give a practical compendium supporting physicians to enable safe and efficacious treatment for patients with HFrEF.

New aspects of pharmacological nephroprotection

Current estimates forecast that chronic kidney diseases will be the fifth most common cause of death worldwide by 2040. The prevalence of chronic renal diseases increases with age and, in many countries, affects patients with overweight, diabetes and hypertension. The primary objective of the treatment of chronic renal diseases is the delay of disease progression. Established markers for the deterioration of renal function include glomerular filtration rate and albuminuria. Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme inhibitors (ACE) or angiotensin receptor blockers (ARB) represents the cornerstone of drug-related nephroprotection. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend the use of ACEI or ARB for diabetic and non-diabetic patients with moderate and heavy albuminuria. In recent years, sodium-glucose linked transporter 2inhibitors (SGLT-2 ) have been established in the field of cardio- and nephroprotection. Their protective effects occur regardless of blood sugar reduction. Current data suggest that the use of SGLT‑2 inhibitors will soon be part of therapy in non-diabetic kidney disease. One of the first drugs in this substance class, dapagliflozin, is already approved in Germany for the treatment of chronic renal diseases in adults with and without type2 diabetes.

Ожирение и COVID-19: инсайты двух пандемий

Objective of the Review: To present the pathophysiological mechanisms of the coronavirus infection in obese patients, and approaches to obesity correction in this group of patients following an overview of large randomized clinical trials of cardiovascular safety from PubMed, Cochrane Library, Google Scholar. Key Points. Clinical trials have demonstrated that obesity is a significant risk factor of a number of comorbidities, including severe and fatal cases of the novel coronavirus infection. A higher prevalence and severity of the novel coronavirus infection in obese patients is caused by a set of factors, with the most significant factor being an increased cardiovascular risk, including tendency to blood-clotting, reduced respiratory efficiency, impaired immune response, and chronic inflammations. Main groups of medicinal products that can be used to manage lipotoxicity have been listed. Conclusion. It has been proven that a range of positive effects from new antihyperglycemic agents (glucagon-like peptide-1 receptor agonists and sodium-glucose linked transporter-2 inhibitors), combined with a well-studied efficiency and safety profile, is a new method to manage obesity during the coronavirus pandemic. Keywords: novel coronavirus infection, obesity, glucagon-like peptide-1 receptor agonists, sodium-glucose linked transporter-2 inhibitors, cardiovascular complications, prevention.

Safety of add-on sulfonylurea therapy in patients with type 2 diabetes using metformin: a population-based real-world study

IntroductionMetformin is the initial oral antihyperglycemic agent (OHA) of choice for most patients with type 2 diabetes (T2D). However, more than one agent is often required for optimal glucose control....

The effect of sodium-glucose link transporter 2 inhibitors on heart failure end points in people with type 2 diabetes mellitus: a systematic review and meta-analysis

Sodium-glucose linked transporter 2 inhibitors (SGLT2i) have been demonstrated to improve cardiovascular outcomes. In particular, SGLT2i appear to be beneficial in improving heart failure outcomes in people with and without diabetes. The aim of this review was to synthesis current evidence from randomised controlled trials (RCTs) comparing SGLT2i to placebo in adults with type 2 diabetes mellitus. The outcomes of interest were rate hospitalisation due to heart failure (primary), death due to heart failure (secondary) and incidence rates of heart failure (secondary).Methods: Searches were performed using recognised terms in MedLine, EMBASE, Pubmed and CINAHL. Studies were included if they compared an SGLT2i to inhibitor in an RCT and contained data for an outcome of interest. Studies were reviewed for inclusion by two people (TSJC and REJR) and data extraction and bias assessment were performed using a modified Cochrane’s data extraction tool and bias assessment tool. Meta-analysis of hazard ratios was performed in RevMan 5.4 using generic inverse variance and a fixed effects model where possible.Results: 2,850 records were identified of which 11 were eventually included, covering 9 clinical studies. Eight of these were suitable for meta-analysis for the outcome of hospitalisation due to heart failure – the pooled hazard ratio was found to be 0.69 (95% CI 0.63, 0.75). Interstudy heterogeneity was minimal (I2 0%) Only one study contained outcomes for death specifically due to heart failure, but its results were not significant. No current studies report incidence rates of new heart failure diagnosis.Conclusion: SGLT2is reduce the rates of hospitalisation due to heart failure in people with type 2 diabetes. This may help mediate the improvements seen in all cardiovascular outcomes, especially when assessed as a composite. More evidence is needed to support their use in reduce mortality due to heart failure and incidence rates of new heart failure in this high-risk cohort.

Neues zu Hypertonie und Diabetes

Hypertonie und Diabetes treten oft gemeinsam auf und erhöhen die kardiovaskuläre Mortalität. Beide Erkrankungen sind bei COVID-19-Patienten (COVID-19: „coronavirus disease 2019“) mit schweren Verläufen gehäuft anzutreffen. Hinsichtlich der Kausalität für COVID-19 ist die Datenlage widersprüchlich. Sicher ist ein Surrogateffekt, da meiste ältere COVID-19-Patienten einen schweren Verlauf aufgrund der Vorschäden aufweisen. Hemmer des Renin-Angiotensin-Aldosteron-Systems (RAAS-Blocker) erhöhen nicht die Wahrscheinlichkeit der positiven SARS-CoV-2-Testung (SARS-CoV-2: „severe acute respiratory syndrome coronavirus 2“). Sie haben keinen Einfluss auf die Schwere des Verlaufs und die Mortalität und sollten daher unter COVID-19 nicht pausiert/abgesetzt werden. Die renale Denervierung erfreut sich einer Renaissance, nachdem sich die Studiendesigns und Technologien stark weiterentwickelt haben. Bei den SGLT-2-Hemmern (SGLT-2: „sodium glucose linked transporter 2“) ist der Wissenszuwachs enorm. In den ersten beiden großen randomisierten kontrollierten Studien mit primären renalen Endpunkten verzögerten sie die Progression der chronischen Niereninsuffizienz (CKD) bis zum Dialysebeginn deutlich um zusätzliche ca. 12–13 Jahre. Sie sind prinzipiell bei Typ‑2- sowie Typ-1-Diabetes und auch bei herzinsuffizienten Patienten mit und ohne Diabetes einsetzbar und reduzieren den systolischen Blutdruck. Der nichtsteroidale Mineralokortikoidrezeptorantagonist (MRA) Finerenon wirkt bei Typ‑2-Diabetes reno- und kardioprotektiv bezüglich kardiovaskulärer Mortalität und Niereninsuffizienz. Wie bei den klassischen MRA kann es auch hier zur Hyperkaliämie in höheren CKD-Bereichen kommen. Größere Vergleichsstudien zu den klassischen MRA liegen nicht vor. Die Zulassung in Deutschland steht noch aus.

Cardiologist's approach to the diabetic patient: No further delay for a paradigm shift

Type 2 diabetes mellitus (DM) is constantly increasing worldwide and its most critical determinant of morbidity and mortality is still represented by cardiovascular (CV) complications. For years, cardiologists' approach to diabetic patients has been focused on risk factors optimization, with positive results. However, the management of DM per se was never truly considered in order to obtain prevention from major CV events, because medications used for glycemic control were not expected to gain CV benefit. Early trials concerning intensive versus conventional glycemia control did not prove useful in reducing the number of CV events. The introduction of new molecules led to a game change in DM treatment, as some new glucose-lowering drugs (GLDs), such as sodium-glucose linked transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA), showed not only to be safe but also to ensure CV benefit. A combination of anti-atherogenic effects and hemodynamic improvements are likely explanations of the observed reduction of CV events and mortality. These evidence opened a completely new era in the field of GLDs and of DM treatment.Nonetheless, the presence of residual cardiovascular risk despite optimal medical therapy remains an issue and an aggressive strategy against multiple risk factors is suggested. A paradigm shift toward a new approach to DM management should be made with no further delay with the use of medications that may prevent CV events in an integrated strategy of CV risk reduction.

Терапия сахарного диабета 2 типа в современных реалиях: на что должен обратить внимание врач на амбулаторном приеме

Objective of the Review: To discuss the problem of selecting antihyperglycemic drugs; to identify the trends in prescription of various groups of oral antihyperglycemic agents. Key Points. When type 2 diabetes mellitus (DM2) is diagnosed, a number of patients need prompt combined antihyperglycemic therapy because of a marked carbohydrate metabolism disorder. The prescription paradigm of initial therapy has shifted towards antihyperglycemic agents with established nephro- and cardioprotective effects (sodium-glucose linked transporter-2 inhibitors, glucagon-like peptide-1 receptor agonists). Drugs are recommended depending on presence or absence of a comorbid cardiovascular disease (CVD) and cardiovascular risk factors, and safety as regards hypoglycaemic events; therefore, very often selection of a therapeutic regimen can be challenging. Still, the first-line treatment for patients without CVD is metformin; however, a combined therapy is required in the majority of cases. Poor compliance, continued use of monotherapy, despite the need to boost the therapy, patient’s reluctance to take additional drugs can facilitate occurrence and progression of a lot of associated complications. In such cases, combined medications reducing the amount of tablets and improving compliance are useful. The most common combination of antihyperglycemic drugs is metformin and sulfonylureas. Still, care should be taken because of differences in pharmacokinetics and pharmacodynamics of the molecules in the latter group. High selectivity of some sulfonylureas can evidence their milder effect for glucose level reduction. Sulfonylureas are also cost-effective as compared to other antidiabetic medications. Conclusion. A wide choice of drugs allows a medical professional selecting an optimal antihyperglycemic regimen, taking into account individual characteristics of a patient. Prompt combined medications are a treatment of choice for the majority of patients with DM. Selection of antihyperglycemic drugs is affected by the cost as well. The most important thing is that the drugs are well-studied, efficient and safe. Keywords: type 2 diabetes mellitus, combined therapy, sulphonylurea, Glimepiride, metformin.

Современные подходы к терапии пациентов с сахарным диабетом 2 типа неинсулиновыми препаратами

Objective of the Review: To discuss possible therapies for patients with type 2 diabetes mellitus (DM2) using up-to-date initiation and therapy intensification algorithms with antihyperglycemic drugs. Key Points. DM is still a burning issue all over the world. The recommendations for therapy initiation and intensification for DM2 patients are reviewed annually. This article describes various antihyperglycemic drug regimens. Conclusion. Currently, the guideline is to use sodium-glucose linked transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists at early stages of DM2 therapy, irrespective of glycated haemoglobin levels, if the patient has an atherosclerotic cardiovascular disease (ASCVD), cardiac failure, chronic renal diseases or factors of ASCVD risk. Keywords: type 2 diabetes mellitus, non-insulin antihyperglycemic therapy, antihyperglycemic drug regimen.

Нефропротективные эффекты ингибиторов натрий-глюкозного котранспортера 2-го типа

Нефропротективные эффекты ингибиторов натрий-глюкозного котранспортера 2-го типа

Management of post-transplant diabetes: immunosuppression, early prevention, and novel antidiabetics.

SummaryPost‐transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus‐based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium–glucose‐linked transporter 2 inhibitors (SGLT2is) and glucagon‐like peptide 1 receptor agonists (GLP1‐RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1‐RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1‐RAs that have not brought forth major concerns, likely indicating that GLP1‐RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

Gut incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance secretion of insulin in a glucose-dependent manner, predominantly by elevating cytosolic levels of cAMP in pancreatic β-cells. Successful targeting of the incretin pathway by several drugs, however, suggests the antidiabetic mechanism is likely to span beyond the acute effect on hormone secretion and include, for instance, stimulation of β-cell growth and/or proliferation. Likewise, the antidiabetic action of kidney sodium-glucose linked transporter-2 (SGLT-2) inhibitors exceeds simple increase glucose excretion. Potential reasons for these ‘added benefits’ may lie in the long-term effects of these signals on developmental aspects of pancreatic islet cells. In this work, we explored if the incretin mimetics or SGLT-2 inhibitors can affect the size of the islet α- or β-cell compartments, under the condition of β-cell stress.To that end, we utilised mice expressing YFP specifically in pancreatic α-cells, in which we modelled type 1 diabetes by injecting streptozotocin, followed by a 10-day administration of liraglutide, sitagliptin or dapagliflozin.We observed an onset of diabetic phenotype, which was partially reversed by the administration of the antidiabetic drugs. The mechanism for the reversal included induction of β-cell proliferation, decrease in β-cell apoptosis and, for the incretin mimetics, transdifferentiation of α-cells into β-cells.Our data therefore emphasize the role of chronic incretin signalling in induction of α-/β-cell transdifferentiation. We conclude that incretin peptides may act directly on islet cells, making use of the endogenous local sites of ‘ectopic’ expression, whereas SGLT-2 inhibitors work via protecting β-cells from chronic hyperglycaemia.

Why Are SGLT2 Inhibitors Nephroprotective? Mechanisms of Action And Possible Benefits A Review

Recent researches have demonstrated that SGLT2i (Sodium-Glucose Linked Transporter 2 inhibitors) play a role in preventing the development and progression of chronic kidney disease (CKD). However, these studies have not to look into the mechanisms that justify this progress. In this document, we will approach the physiologic causes of the kidney response to SGLT2i treatment.
 SGLT2i were firstly designed as physiologic antidiabetic drugs due to its glucose anti-absorptive action in kidneys. Nevertheless, the effect on glucose levels has proved to be modest, so other different ways have to be involved in their renal benefits. After the commercialization of these drugs, their hypouricemic action, antihypertensive effects, and weight loss have been noticed. Although those actions are positive for the kidney, they are mild and hardly could induce a reduction of proteinuria and a kidney function stabilization effect.
 Other actions such as anti-inflammatory and metabolic could have more importance in the role of SGLT2i. SGLT2i have been shown to reduce hypoxia and fibrosis in the kidney by changing energetic balance and by reducing inflammatory activity. These two mechanisms are closely related to the settlement and progression of CKD.
 In addition, SGLT2i reduce proteinuria, which is probably the leading contribution of these drugs for renal function stabilization, due in part to its hemodynamic action by reducing intraglomerular pressure (tubule glomerular balance).
 In conclusion, SGLT2i kidney benefits could hardly be explained by a single effect. In fact, SGLT2i trigger several effects, that taken together explain the kidney improvements that have been described.

Sodium‐glucose linked transporter‐2 inhibitor renal outcome modification in type 2 diabetes: Evidence from studies in patients with high or low renal risk

Data from three completed cardiovascular outcome trials (CVOTs), EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58, add to the evidence supporting the potential renoprotective effects of sodium-glucose linked transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes. Despite recommendations in recent guidelines, it is difficult to support a view that definitive evidence for renoprotection exists from these SGLT2 inhibitor CVOT results. To date, the only dedicated trial to report definitive data on the renal impact of SGLT2 inhibition is CREDENCE. Notably, the total number of patient-relevant renal endpoint events (dialysis, transplant or renal death) observed in CREDENCE was significantly higher than the total for all three CVOTs collectively (183 events/4401 patients vs. 69 events/34 322 patients, respectively), which shows the increased statistical power of CREDENCE for these renal endpoints. Treatment with canagliflozin was associated with a 30% relative risk reduction (RRR) in the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular causes and a 34% RRR for the renal-specific elements of this primary endpoint (P <0.001). Canagliflozin has therefore become the first US-approved SGLT2 inhibitor to include an indication for RRR, in addition to type 2 diabetes glycaemic control and cardiovascular risk reduction. While confirmatory of the exploratory data from CVOTs, CREDENCE provides the first robust data on the effects of canagliflozin on patient-relevant renal endpoints. Extrapolation to a conclusion of a SGLT2 inhibitor class effect cannot be made until additional renal trials with other SGLT2 inhibitors are reported.

Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors.

Empaglifolzin, canagliflozin, and dapagliflozin are SGLT2 (sodium-glucose linked transporter type 2) inhibitors for treatment of type 2 diabetes mellitus that also reduce blood pressure, mortality, and cardiovascular disease and slow the loss of glomerular filtration rate. SGLT2 inhibitors inhibit the coupled reabsorption of sodium and glucose from the proximal tubules, thereby increasing renal glucose and sodium excretion, but they have more widespread renal effects, including inhibition of the sodium:proton exchanger. They increase the delivery of sodium to the loop of Henle and can thereby activate the tubuloglomerular feedback response to correct glomerular hyperfiltration. There are multiple potential mechanisms whereby these drugs lower blood pressure and preserve kidney function that are the focus of this review.