Cardiac disease is the leading cause of death for patients with chronic kidney disease (CKD). Because the risk of cardiovascular disease increases with the progression of CKD, cardiac care is an essential component of comprehensive CKD management. Sodium glucose-co-transporter 2 (SGLT-2) inhibitors are a new class of medication initially developed to control hyperglycemia in people with type 2 diabetes mellitus. In addition to helping patients achieve glycemic and overall metabolic control, SGLT-2 inhibitors have been shown to have cardio-protective benefits for high-risk patients with diabetes, and recent studies indicate they also hold promise for slowing CKD progression and for treating heart failure and other cardiovascular conditions.
Slowing the progression of kidney disease is a key focus in nephrology research.1,2 The best results are achieved by combining dietary interventions, lifestyle modifications, and pharmacologic therapies with systemic and renal hemodynamic effects. Treatment optimization relies on a stepwise approach using several classes of medications to lower glomerular and vascular stress in addition to hypertension and proteinuria. In this context, anti-hypertensive drugs that block the renin angiotensin aldosterone system (RAAS) have been effective; however, more specific interventions based on the primary cause of kidney disease and/or the specific risk identified are also required.3,4
In the case of type 2 diabetes mellitus (T2DM), a leading cause of kidney disease, controlling hyperglycemia and related metabolic disorders remains important in slowing diabetic kidney disease (DKD) progression.5,6 Comparatively, for hypertensive and vascular nephropathy, the optimal control of hypertension and correcting aggravating factors, such as severe renal stenosis by angioplasty and stenting, may preserve kidney function.7 In addition to focusing on slowing kidney disease progression, comprehensive CKD management should also integrate cardiac health components.8,9
Cardiovascular disease (CVD) is the leading cause of death in individuals with CKD, accounting for between 40 and 60 percent of deaths in individuals with advanced kidney disease.10 The risk for CVD develops as CKD progresses, representing a mutually aggravating process with the same risk factors and benefiting from the same management approach (Figure 1).11 CKD is recognized as one of the most prominent cardiovascular risk factors.12
FIGURE 1 | Renal and cardiac burden in CKD patients follow the same pathways with mutual aggravation
SGLT-2 inhibitors are a new class of medication initially developed to facilitate glycemic control in T2DM by inducing glucosuria.13 In less than a decade, they have become the first-in-class treatment for diabetes, with impressive results on glycemic and overall metabolic control and outcomes.14,15 SGLT-2 inhibitors are associated with unexpected protective results on cardiac outcomes in this highly vulnerable population.16 Recent studies have identified that SGLT-2 inhibitors are associated with positive clinical benefits in various chronic diseases, such as heart failure and CKD, even among individuals without T2DM.17,18
Gliflozins are specific glucoside-based inhibitors of sodium-glucose co-transporters (SGLT).19,20 Sodium-dependent glucose transporters are a member of the protein family consisting of SGLT-2 and SGLT-1 located in the proximal kidney tubule. SGLT-2 proteins are mainly located in the initial part of the proximal tubule involved in 90 percent of glucose reabsorption filtered back to the systemic circulation (Figure 2). Inhibition of SGLT-2 increases the urinary glucose excretion with significant glucosuria (50 to 80 g per day in normoglycemic conditions, and up to 100 or 120 g per day in hyperglycemic conditions), facilitating glycemic control and inducing caloric loss and starvation adaptation. SGLT-2 inhibition increases urinary flow through its osmotic action but also natriuresis by blocking glucose-sodium protein cotransporters.21 Increase of natriuresis delivery at the macula densa site results in a deactivation of the tubuloglomerular feedback mechanism mediated by vasoconstriction of the glomerular afferent arteriole. Therefore, glomerular hypertension and hyperfiltration decreases, contributing to reduced glomerular stress and proteinuria, a hallmark of kidney dysfunction in diabetes.
FIGURE 2 | Tubular action of SGLT-2 inhibitors
As of August 2021, dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of T2DM.
Four major randomized controlled trials revealed the clinical benefits of SGLT-2 inhibition in T2DM patients (Figure 3).22
In brief, dapagliflozin, empagliflozin, and canagliflozin have remarkable and consistent class effects on renal outcomes. Baseline renal filtration function and degree of proteinuria are the most significant indicators of risk for both renal and cardiovascular events.
FIGURE 3 | Four major randomized controlled trials studied SGLT-2 inhibition in T2DM
Additional analysis of several SGLT-2 inhibitor trials shows a consistent benefit for treating patients with heart failure, in particular with reduced ejection fraction, and advanced kidney disease from DKD.23,24,25,26,27,28, 29,30,31 In these studies, recruited patients were receiving optimal treatment for T2DM and cardiac disease with SGLT-2 inhibitors considered an add-on treatment. In all studies, primary cardiac outcomes of cardiac death and hospitalization for heart failure were improved, with 15 percent risk reduction on average (range 3 to 25 percent) in patients receiving SGLT-2 inhibitors.
The ongoing Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) study is assessing the effects of dapagliflozin versus placebo in managing heart failure patients with preserved ejection fraction, using the same primary endpoint as the Dapagliflozin and Prevention of Adverse Outcomes (DAPA) in Heart Failure trial.32,33 This study will complement other cardiovascular outcome studies evaluating the benefits and risks of SGLT-2 inhibitors in various cardiac settings (e.g., acute decompensated heart failure, chronic reduced or preserved ejection fraction with and without T2DM). Findings of these studies may have enormous implications for future treatment approaches.34
In the Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes (DIAMOND) study, 58 CKD patients without diabetes (eGFR≥25 mL/min; m GFR 58 mL/min) with proteinuria (≥500-3500 mg/d, m 1110 mg/24h) receiving a renin-angiotensin system blockade agent were randomly assigned to receive dapagliflozin (10 mg/d) or a placebo.35 eGFR declined by –6.6 mL/min at week six in the dapagliflozin group, but this reduction was fully reversible within six weeks after dapagliflozin discontinuation. Body weight was reduced by 1.5 kg with dapagliflozin, while changes in blood pressure did not differ significantly between dapagliflozin and placebo treatment.
In the subanalysis of the DAPA in Chronic Kidney Disease (DAPA CKD) trial, of the 270 participants with IgA nephropathy (94 percent confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to a placebo.36,37 In this IgA subgroup, mean eGFR was 43.8 mL/min and median urinary albumin-to-creatinine ratio was 900 mg/g. Composite renal outcomes consisted of sustained eGFR, proteinuria, ESKD, or renal death. Relative risk reduction in a 50 percent sustained decrease in eGFR, ESKD, or death from renal causes was 46 percent, 39 percent in death from cardiovascular causes, and 26 percent for proteinuria in patients receiving dapagliflozin.
In this perspective, the ongoing EMPA-KIDNEY study, exploring cardio-renal effects of empagliflozin in CKD patients irrespective of whether the individual has diabetes, will be of tremendous interest.38 Potential risks of temporary or sustained eGFR decline associated with SGLT-2 inhibitors use in CKD with or without proteinuria deserve further trials to precisely assess the safety and renal protective effects of these drugs.39
Effects of SGLT-2 inhibitors are well documented and largely encompass their effects on glycemic homeostasis and DKD.40,41 SGLT-2 inhibitors facilitate glycemic control without stimulating insulin release, weight loss due to glucosuria and caloric loss, reduction of body fat facilitating insulin action, reductions of salt load and extracellular volume, lowering of systemic blood pressure, and reduction of glomerular pressure and filtration marked by a reduction of proteinuria.42 Interesting findings have been observed with proteinuric glomerular disease and CKD that require further confirmatory studies to defi ne new therapeutic options.
Beyond the scope of glycemic control and DKD, the use of SGLT-2 inhibitors is expanding with promising results in the treatment of other conditions such as heart failure and cardiorenal syndrome. Further studies are needed to validate safety of this approach in advanced kidney disease. SGLT-2 inhibitors are associated with sustained sodium removal facilitating restoration of the whole-body sodium homeostasis. Furthermore, SGLT-2 inhibitors induce profound metabolic changes including ketogenesis from liver and reprioritization of energetic oxidation metabolic pathways favoring cardiomyocytes activity and regenerative process. Interestingly, the common denominator and the main action point of SGLT-2 inhibitors seems to be a way of depleting total body salt excess, restoring sodium and water homeostasis that include sodium osmotically active (extracellular compartment) but also tissue sodium (third compartment of water-free sodium).43
Despite significant progress in cardiovascular disease management for advanced CKD patients, cardiac health remains one of the main challenges in this highly vulnerable population. Therapeutic approaches to reduce cardiac burden and slow kidney disease progression have steadily improved over recent years by effectively addressing the deleterious mechanical effects of fluid excess and hypertension on cardiac and kidney end organ damage. In this context, RAAS blockade agents have slowed down this process, but they have not been sufficient to halt it. SGLT-2 inhibitors beyond glucosuria and throughout their pleiotropic actions, offer a new and complementary approach for improving cardiac health in CKD patients without T2DM.44 Ongoing studies focusing on low eGFR patients are exploring the benefits and risks of these medications.45