Kidney disease represents a true public health burden. Worldwide, there are more than 850 million people with chronic kidney disease (CKD). Nearly 4 million of them are on some form of renal replacement therapy. Sadly, too many of them may die without having access to any form of renal replacement therapy. Diabetes mellitus and hypertension are among the leading causes of CKD. An estimated 425 million adults are living with diabetes worldwide, and up to 40% of them may develop CKD during their lifespan. Further, CKD and proteinuria are recognized as strong cardiovascular risk factors, and in addition proteinuria, represents an independent risk marker for CKD progression. Prior studies have shown that angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-receptor-blockers (ARBs) offer kidney protection by lowering proteinuria and slowing the rate of progression of CKD. However, most of these studies were done on patients with diabetic kidney disease and did not show any mortality benefit. Until recently, there has been very limited data about other classes of medications to slow progression of CKD or improve mortality in this high-risk population.
Sodium-glucose cotransporter-2 Inhibitors
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were initially used to improve glucose control, which would in turn help slow progression of CKD in diabetic patients. However, more recently, it became clear that these novel medications, independent of their blood glucose lowering effect, also had renoprotective effect. Several potential mechanisms have been described. SGLT2is by decreasing inflammatory markers may contribute to lowering inflammation and fibrosis. The effects of these agents on blood pressure may also be beneficial. Further, SGLT2is have been shown to lower intraglomerular pressure given their effect on natriuresis and osmotic diuresis. Therefore, recent trials about SGLT2is included CKD patients regardless of their diabetes status.
CREDENCE was a multicenter randomized double-blinded placebo-controlled trial that compared canagliflozin vs placebo in Type 2 diabetic patients on stable renin-angiotensin system (RAS) blockade agents with an estimated glomerular filtration rate (eGFR) of 30-89 mL/min/1.73 m2 who had albuminuria (urine albumin/creatinine ratio between > 300 and 5,000 mg/g). The primary endpoint was a composite outcome of end-stage kidney disease (ESKD), doubling of serum creatinine, or kidney/cardiovascular related death. Importantly, the trial was stopped early after interim analysis because of clear benefits observed in the canagliflozin group after a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group compared to placebo. Similarly, cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure were also significantly lower in the canagliflozin group compared to placebo. This study revealed that canagliflozin significantly reduced the risk of kidney failure and major cardiovascular events in patients with Type 2 diabetes mellitus and CKD. Overall, the number needed to treat (NNT) was 22 (to avoid one event).
More recently, the DAPA-CKD trial randomized 4,304 patients with an eGFR between 25 and 75 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 200 to 5000 mg/g to receive 10 mg daily of dapagliflozin or placebo. Patients with or without diabetes were included in this study and were on stable RAS blockade agents for at least four weeks. About 67% of the participants in this trial had diabetes mellitus Type 2. The primary outcome was a composite of sustained decline in eGFR of at least 50%, ESKD, or death from kidney or cardiovascular causes. Similar to the CREDENCE trial, the data monitoring committee stopped the trial early, after a median follow-up of 2.4 years because of efficacy in favor of dapagliflozin. For the primary composite outcome, the hazard ratio was 39% lower in the dapagliflozin group compared to the placebo group with a NNT of 19 (to prevent one outcome). Also, the composite of death from cardiovascular causes or hospitalization for heart failure was significantly lower in the dapagliflozin group compared to placebo. Of note and for the first time, this study showed that the beneficial effects of dapagliflozin were similar in patients with and without diabetes Type 2.
Additionally, the EMPEROR-Reduced Trial randomized 3,730 patients with class II, III, IV heart failure and an ejection fraction of < 40% in a 1-to-1 fashion to either receive empagliflozin 10 mg daily or matching placebo. The primary outcome in this study was a composite of cardiovascular death or hospitalization for worsening heart failure. During a short median follow-up time of one month, the hazard ratio of the primary composite outcome was 25% lower in the patients randomized to empagliflozin compared to those receiving placebo. The benefit was independent of the patient’s diabetes status and above baseline guideline-directed medical therapy for heart failure. Study participants mean eGFR was 62 mL/min/1.73m2 with 48% having eGFR below 60 mL/min/1.73m2. Notably, among its secondary endpoints, the adverse renal outcomes were also significantly lower in the empagliflozin group compared to the placebo group, with an annual decline of 0.55 versus 2.28 mL/min/1.73m2.
None of the recent SGLT2is trials discussed above showed an increased risk of bone fracture, lower-extremity amputation, hyperkalemia, kidney dysfunction, or hypoglycemia. The CREDENCE trial, however, showed, although low, a statistically significant increased risk of diabetic ketoacidosis with canagliflozin vs placebo. Most experts agree to avoid STGL2is in patients with recurrent genito-urinary tract infections, patients with urinary bladder catheterization or suprapubic catheters, or when there is any concern of volume depletion. It is certainly reasonable to withhold SGLT2is during times of prolonged fasting, surgery, or critical medical illness. More studies are certainly needed to determine the safety and efficacy of using STGL2is in polycystic kidney disease patients or patients with a functioning kidney transplant who are immunosuppressed and potentially at increased risk for infections.
Selective Inhibitor of the Mineralocorticoid Receptors
Aldosterone is a mineralocorticoid hormone that is released from the adrenal zona glomerulosa as a result of many factors, including: angiotensin II, corticotropin, potassium concentration, nitric oxide, and endothelin. Aldosterone binds to the mineralocorticoid receptor in the distal tubule of the kidney and within glomeruli on podocytes and mesangial cells leading to sodium and water retention, potassium urinary loss, and increased in the levels of inflammatory cytokines and profibrotic factors. Finerenone, a nonsteroidal selective inhibitor of the mineralocorticoid receptor, has been shown to have an antiproteinuric effect independent of blood pressure control and also has the potential to reduce inflammation and fibrosis, and as a result, slowing CKD progression.
The FIDELIO-DKD trial randomized 5,734 patients with CKD and diabetes mellitus Type 2 to receive finerenone or placebo. Patients enrolled in the study either had a urinary albumin-to-creatinine ratio of 30 to less than 300 mg/g, eGFR between 25 and 59 mL/min/1.73 m2 and diabetic retinopathy or had a urinary albumin-to-creatinine ratio between 300 and 5000 mg/g with eGFR of 25 to 74 mL/min/1.73 m2. All patients at baseline were treated with maximally tolerated RAS blockade agents. The primary composite endpoint included kidney failure, a sustained eGFR decrease of at least 40%, or death from renal causes. Also, important secondary endpoints included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure-related hospitalization. During 2.6 years of median follow-up time, the finerenone group experienced a statistically significant 18% lower risk of the primary composite endpoint compared to the placebo group. For the primary composite endpoint, the NNT was 29 (to prevent one outcome). Similarly, patients in the finerenone group had a statistically significant 14% lower risk of cardiovascular events compared to the patients in the placebo group; in this case, the NNT was 42 (to prevent one outcome). Additionally, finerenone was associated with a 31% greater reduction in the urinary albumin-to-creatinine ratio from baseline to month four compared to placebo; this antiproteinuric benefit persisted throughout the study period. The incidence of all serious adverse events and acute kidney injury were similar in both groups. However, patients in the finerenone group had a mean increase in serum potassium level of 0.2 mmol/L with more incidence of hyperkalemia leading to discontinuation of the trial regimen compared to the placebo group (2.3% vs 0.9%).
Future Directions
The clinical approach to diabetic kidney disease should still rely on comprehensive care, including RAS blockade whenever possible, and lifestyle modifications, in addition to diabetes and blood pressure control. Current 2020 Kidney Disease Improving Global Outcomes (KDIGO - Diabetes in CKD) guidelines recommend adding STGL2is to the recommended therapy in patients with Type 2 diabetes, CKD, and eGFR > 30 ml/min/1.73 m2. We anticipate those guidelines in the near future to include finerenone in the management of diabetic kidney disease given its role in slowing CKD progression in patients with diabetes mellitus Type 2. Soon, we also expect these criteria to possibly expand and to include non-diabetic CKD patients based on the results of the DAPA-CKD trial. More studies are needed to assess the benefit of finerenone in non-diabetic CKD patients. It may also be of value to study and determine the benefits of using STGLT2is and finerenone in other types of kidney diseases with proteinuria, such as membranous nephropathy, IgA nephropathy, but also in genetic kidney diseases such as autosomal dominant polycystic kidney disease. In addition, these medications will likely have a prominent role in future heart failure management guidelines.
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