Combination Therapy for Kidney Progression in Patients With CKD From Type 2 Diabetes

From the Chair

 In my April Nephrology Times editorial titled “Imagine Halting Progression of Kidney Disease in Patients with Type 2 Diabetes,”¹ I wrote that we could be on the cusp of halting kidney progression if we use multiple agents to target different pathophysiologic mechanisms of kidney progression. I discussed the importance of randomized clinical trials (RCTs) to test whether combination therapy is superior to using individual drugs. Indeed, post hoc analyses of large randomized controlled trials do suggest that there may be complementary benefits of treating patients in a combination of an ACE inhibitor or an angiotensin receptor antagonist, an SGLT-2 inhibitor, and a non-steroidal mineralocorticoid antagonist.^2,3

Of course, the problem with post hoc or exploratory analyses is that they set up hypotheses to be tested rather than provide definitive evidence. Also post hoc analyses are often insufficient when looking at the safety of a particular treatment strategy.

In an article published in May 2022 in the Journal of the American Society of Nephrology,⁴ Michele Provenzano and colleagues conducted a pilot randomized crossover trial that examined the effects of dapagliflozin and eplerenone individually compared with in-combination in patients with CKD with or without type 2 diabetes already on maximal dose of either ACE inhibitor or ARB.

The study was small but generated important findings that need to be urgently tested in large RCTs. A total of 46 patients were randomly assigned to the three groups: dapagliflozin, eplerenone, and dapagliflozin-eplerenone. All patients were already being maximally treated with an ACE inhibitor or ARB. At baseline, the mean estimated glomerular filtration rate (eGFR) was 58.1 mL/min/1.73 m², and the median level of albuminuria (UACR) was 401 mg/g of creatinine. The primary end point was the individual 24-hour UACR change from baseline during treatment with dapagliflozin, eplerenone, and their combination. The investigators also examined the change in 24-hour UACR, systolic blood pressure, eGFR, and potassium from baseline during each treatment period.

The results supported a clinically meaningful benefit of combination therapy: the UACR reduction at week 4 compared to baseline was approximately 20%, 34%, and 53% for dapa, eplerenone, and dapa+ eplerenone therapy, respectively. A ≥50% reduction in UACR at week 4 occurred in 20%, 26%, and 56% of patients on dapagliflozin, eplerenone, and dapagliflozin-eplerenone treatment, respectively. There was a nearly 5-fold and 3.6-fold higher odds of patients treated with combination therapy of achieving a ≥50% UACR reduction compared with those treated with either dapagliflozin alone or eplerenone alone, respectively. The other interesting finding was that the benefit of reducing albuminuria was more pronounced among patients with type 2 diabetes compared with those without type 2 diabetes and in patients with baseline eGFR <60 ml/min per 1.73 m² compared with those with eGFR ≥60 mL/min/1.73 m².

The important question of hyperkalemia as a side-effect was also examined in the Provenzano study. Hyperkalemia was most common among patients randomized to eplerenone alone and surprisingly was quite low in the dapagliflozin-eplerenone groups (0.9%). A lower rate of hyperkalemia was recently reported in a post hoc study of patients on SGLT-2+finererone+ACE/ARB enrolled in the FIDELIO-DKD trial compared with those who were not on those three agents.⁵ The lower-than-expected rate of hyperkalemia in patients on combination therapy could be explained by increased distal sodium delivery from treatment with an SGLT-2 inhibitor, which then drives potassium secretion via principal cells in the cortical collecting duct.

So my take is that while the Provenzano study doesn’t prove that combination therapy is superior to treatment with individual agents in slowing kidney progression, it does show a powerful effect on albuminuria that might be a tantalizing signal. To explore this issue more definitively, we urgently need large RCTs. Second, the lower hyperkalemia with combination MRA+ACEI/ARB+SGLT-2 inhibitor therapy suggests that concerns regarding the risk of hyperkalemia with an MRA (especially a non-steroidal MRA) like finererone may be overblown when agents are used in combination.

Disclosure: Dr Singh consults for GSK, Bayer, and Zydus. He receives honoraria from Nephrology Times.

References

1. https://www.docwirenews.com/nephtimes/nephtimes-features/nephtimes-columns/nephtimes-from-the-chair/imagine-halting-progression-of-kidney-disease-in-patients-with-type-2-diabetes/ Accessed June 14, 2022
2. Rossing P, Filippatos G, Agarwal R, Anker SD, Pitt B, Ruilope LM, Chan JCN, Kooy A, McCafferty K, Schernthaner G, Wanner C, Joseph A, Scheerer MF, Scott C, Bakris GL; FIDELIO-DKD Investigators. Finerenone in Predominantly Advanced CKD and Type 2 Diabetes With or Without Sodium-Glucose Cotransporter-2 Inhibitor Therapy. Kidney Int Rep. 2021 Oct 14;7(1):36-45. doi: 10.1016/j.ekir.2021.10.008. PMID: 35005312; PMCID: PMC8720648.
3. Provenzano M, Jongs N, Vart P, et al.; DAPA-CKD Trial Committees and Investigators. The Kidney Protective Effects of the Sodium-Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists. Kidney Int Rep. 2021 Dec 14;7(3):436-443. doi: 10.1016/j.ekir.2021.12.013. PMID: 35257056; PMCID: PMC8897688.
4. Provenzano M, Puchades MJ, Garofalo C,et al.; ROTATE-3 study group. Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and their Combination in Patients with Chronic Kidney Disease: A Randomized Cross-Over Clinical Trial. J Am Soc Nephrol. 2022 Apr 19:ASN.2022020207. doi: 10.1681/ASN.2022020207. Epub ahead of print. PMID: 35440501.
5. Agarwal R, Joseph A, Anker SD, et al.; FIDELIO-DKD Investigators. Hyperkalemia Risk with Finerenone: Results from the FIDELIO-DKD Trial. J Am Soc Nephrol. 2022 Jan;33(1):225-237. doi: 10.1681/ASN.2021070942. Epub 2021 Nov 3. PMID: 34732509; PMCID: PMC8763180.