Sodium Glucose Co-Transporter 2 Inhibitors and Kidney Disease: The Past, Present, and Future
By: Sai Santhoshini Achi, MD MBA (@SaiAchi01)
For decades, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were the main agents available to slow the progression of diabetic kidney disease (DKD). More recently, sodium glucose co-transporter 2 inhibitors (SGLT-2i) emerged as central players in CKD progression reduction, essentially stealing the limelight from our tried and true renin-angiotensin-aldosterone system inhibitor (RAASi) mainstays.
The first SGLT2i study with primary renal endpoints, the CREDENCE trial, showed that canagliflozin slows the progression of CKD to ESKD and cardiovascular or renal death in patients with type 2 diabetes with albuminuria. In DAPA-CKD, summarized beautifully in this NephJC article, investigators demonstrated that dapagliflozin reduced progression of CKD regardless of diabetes mellitus status. Along with numerous other cardiovascular SGLT2i trials, CREDENCE and DAPA-CKD were foundational in placing SGLT2i center stage in the management of CKD and establishing it as a mainstay in goal directed therapy.
In the same year as DAPA-CKD, results of the FIDELIO-DKD trial were released, which looked at the effect of finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) in chronic kidney disease and type 2 diabetes. The association of mineralocorticoid receptor overactivation with renal and cardiovascular disease has been well-described. Non-steroidal MRAs are thought to have greater antifibrotic and anti-inflammatory effects with fewer gonadal effects compared to their steroidal MRA counterparts. Steroidal MRAs like spironolactone and eplerenone have been effective in reducing albuminuria in patients with chronic kidney disease and type 2 diabetes clinically, but have fallen short in demonstrating statistical benefit in reducing the risk of kidney disease progression. Results of the FIDELIO-DKD trial demonstrated that finerenone resulted in lower risk of CKD progression and cardiovascular events compared to placebo in patients with CKD and type 2 diabetes. The FIGARO-DKD trial studied the effects of finererone in patient populations that were understudied or excluded in the FIEDLIO-DKD trial. FIGARO-DKD showed a reduction of cardiovascular events in patients with CKD, and a slowing of the progression to ESKD, even in patients with more mild kidney disease.
Which brings us to our current study, The Kidney Protective Effects of the Sodium–Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists by Provenzano et al, which examined the benefits of SGLT-2 inhibitors in combination with MRAs. Specifically, investigators sought to determine if there are additive benefits in CKD similar to the combination therapy recommended for patients with heart failure with reduced ejection fraction.
The study was a subgroup analysis of the DAPA-CKD trial evaluating the efficacy of dapagliflozin in those patients who were treated with MRAs compared with patients who only received SGLT-2 inhibitors. It was a time-to-event analysis assessing the effects of dapagliflozin compared with placebo. Eligible members were adults with or without DM, eGFR between 25 to 75 ml/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) 200 to 5000 mg/g. All patients were on an ACEi or ARB for at least 4 weeks prior to study initiation and could be on MRAs as well. Participants were followed for 2 weeks after study initiation, at 2 and 4 months, and then at 4 month intervals afterwards. Of the 4304 participants, 229 were treated with MRAs at baseline, 109 were in the dapagliflozin group and 120 were in the placebo group. Table 1 below highlights the baseline characteristics of the participants.
Interestingly, those patients included for evaluation were more frequently males and more likely to have histories of heart failure, DM, higher BMI, and higher UACR. Those receiving MRAs were also more likely to be receiving other cardiovascular therapies. The benefits of dapagliflozin in patients with CKD with and without type 2 DM were still seen whether or not the patients were on MRAs.
Regardless of MRA use, those patients in the dapagliflozin group had a slower decline eGFR versus placebo. The study concluded that the use of SGLT-2 inhibitors and MRAs in combination appears beneficial and warrants further study.
The nephro-protective effects of SGLT-2 inhibitors and MRAs may be explained through a few mechanistic pathways. Both affect hemodynamics and decrease the intraglomerular pressure thereby allowing for the long term stabilization of the kidney function. The improvement of systemic blood pressure is also beneficial in decreasing cardiovascular and kidney disease. In addition, SGLT-2 inhibitors have been shown to improve tubular oxygen and reduce tubular hypoxic stress. Finally, MRAs deactivate the mineralocorticoid receptors in the fibroblasts, thereby leading to a reduction in renal fibrosis and glomerulosclerosis.
Other interesting data suggest promise in studying the combination effects of MRAs and SGLT-2 inhibitors. First, MRAs have been shown to cause hyperkalemia and SGLT-2 inhibitors provide the opposite effect. In the DAPA-CKD trial, regardless of MRA use, fewer patients experienced hyperkalemia thereby giving a rationale for the efficacy of combination of SGLT-2 inhibitors and MRA therapies in those patients with CKD and heart failure. While MRAs block the effects of aldosterone in the kidney, leading to hyperkalemia, SGLT-2 inhibitors increase tubule sodium delivery to the distal nephron, leading to potassium excretion.
The current study does have significant limitations. Given the small number of patients on combination MRA and SGLT-2 inhibitors, and the fact that some were on MRAs prior to study initiation, makes interpretation of the combined effect of these medications difficult.
That being said, the study showed no harm from the combined effect of MRAs and SGLT-2 inhibitors. There has already been a preclinical rat study of the cardio-renal disease pattern which showed that a combination of finererone and empagliflozin have a synergistic effect on lowering albuminuria and improved survival in comparison to single agent therapy.
This study highlighted that in patients receiving MRAs and SGLT-2 inhibitors, the combination therapy was safe and efficacious in reducing unfavorable kidney outcomes. Further prospective studies, in patients with varying severity of cardiovascular and kidney disease, will help determine which patients are most likely to benefit from combination therapy.
The visual abstract below wonderfully summarizes the study.
Visual abstract by Sophia Ambruso (@Sophia_Kidney)