Effect of Combination of Finerenone with Empagliflozin on Urinary Albumin to Creatinine Ratio and Estimated Glomerular Filtration Rate in Chronic Kidney Disease and Type 2 Diabetes

The prevalence of diabetes is increasing and today we have 101 million people with diabetes in India.[1] The incidence of diabetes is also high.[2] The BURDEN of hypertension is also HUGE in India as shown by the ICMR-INDIAB study.[3] The prevalence of diabetic kidney disease (DKD) and diabetic eye disease are also RISING IN INDIA.[4-7] It is therefore very important to prevent diabetic kidney disease. In this context, DKD is a known microvascular complication of diabetes. It affects individuals with both type 1 and type 2 diabetes, but is more prevalent in type 2 diabetes. It is the leading cause of end stage renal disease in the world.[8] As the disease progresses, it often leads to decreased quality of life. Hence it is essential to diagnose and treat in the early stage of the disease. DKD is diagnosed in people with long duration of diabetes in whom other causes of chronic kidney disease are ruled out and have increased urinary albumin to creatinine ratio (UACR) or reduced estimated glomerular filtration rate (eGFR) or both.[9] In the earlier days, lifestyle modification with diet and physical activity, blood pressure control and renin angiotensin system (RAS) inhibition with ACE inhibitors or ARBs was the treatment of choice which reduced the progression of microalbuminuria in DKD.[10] Recent trials have shown additional beneficial effects of non- steroidal mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transport inhibitors (SGLT2i) on regression of microalbuminuria in DKD in addition to the conventional treatment. However, these trials chiefly utilized either of these agents in isolation and did not evaluate the effects of starting treatment with a combination of the two. The recently published CONFIDENCE trial brought to the fore the benefits of initially starting with a combination therapy of finerenone and empagliflozin rather than a single drug therapy with either of these drugs in individuals with DKD already on RAS inhibition. In this trial, 800 participants with chronic kidney disease (CKD), eGFR between 30 to 90 mL per minute per 1.73 m2 of body surface area, albuminuria (measured by UACR) between 100 to <5000 mg/g and type 2 diabetes who were already taking RAS inhibitor were assigned in a ratio of 1:1:1 to receive finerenone (with empagliflozin matching placebo), empagliflozin (with finerenone matching placebo) or a combination of finerenone and empagliflozin. The dose of finerenone was 20 mg when the eGFR was ≥60 mL/min per 1.73 m2 and 10 mg when the baseline eGFR was <60 mL/min per 1.7 3 m2. At baseline, UACR and other characteristics were similar among participants in the three groups. At day 180, investigators reported that the reduction in UACR with combination therapy was 29% greater than that with finerenone alone and 32% higher than that with empagliflozin alone. This trial showed the beneficial effects of early combination therapy on albuminuria in DKD. A pertinent point to consider is that this trial included participants with modest proteinuria already on ACEI/ARB. Further, at day 30, there was a decrease in eGFR of greater than 30% in 6.3% participants in the combination group as compared to 3.8% participants in the finerenone group and 1.1% participants in the empagliflozin group. Combination therapy also resulted in a greater reduction in systolic blood pressure than either therapy although the incidence of symptomatic hypotension was low and change in blood pressure was reversible with drug discontinuation. While SGLT2 inhibitors help in reducing the glomerular hyperfiltration by altering hemodynamics, finerenone helps to reduce the renal inflammation and fibrosis thus perfecting their roles in preventing the progression of DKD when used as combination therapy.[11,12] Beyond reduction in proteinuria, this drug combination has also shown beneficial effects on regression of cardiac and renal fibrosis.[13] Currently, the KDIGO and ADA-EASD guidelines recommend the addition of SGLT2 inhibitor to maximally tolerated dose of ACEI/ARBs in DKD management. Finerenone can be added as a second line drug to ACEI/ARB if there is absolute contraindication or intolerance to SGLT2 inhibitor. In individuals with residual risk of DKD progression with declin ing eGFR and increasing microalbuminuria, finerenone can be added with SGLT2 inhibitor and ACEI/ARB. SGLT2i is now permitted to be used down to an eGFR of 20 mL/min and finerenone, to an eGFR 25 mL/min.[14] To conclude, combination therapy of non-steroidal MRA and SGLT2i remains a promising approach in preventing the progression of DKD given their additive effect on reducing microalbuminuria. However, we should pick our patients carefully as this combination has also been shown to reduce eGFR by more than 30% in the initial phase of treatment. Excessive reduction of blood pressure in some patients could also necessitate discontinuation of therapy. Financial support and sponsorship Nil. Conflicts of interests There are no conflicts of interest.