Sodium‐glucose cotransporter‐2 inhibitors and non‐steroidal mineralocorticoid receptor antagonists: Ushering in a new era of nephroprotection beyond renin‐angiotensin system blockade

Abstract

The therapeutic options for preventing or slowing the progression of chronic kidney disease (CKD) have been thus far limited. While angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are, without a doubt, safe and effective drugs, a significant proportion of patients with CKD still progress to end-stage kidney disease. After decades of negative trials, nephrologists have finally found cause for optimism with the introduction of sodiumglucose cotransporter-2 (SGLT2) inhibitors and non-steroidal mineralocorticoid receptor antagonists (MRAs). Recent trials such as EMPA-REG OUTCOME and CREDENCE have provided evidence of the renal benefits of SGLT2 inhibitors, which have now found widespread acceptance as first-line agents for diabetic CKD, in addition to ACEi/ARBs. Considering results from the DAPA-CKD study, it is expected that their use will soon be expanded to other causes of albuminuric CKD as well, although confirmation from further trials, such as the EMPA-KIDNEY study is awaited. Likewise, although the role of mineralocorticoid receptor overactivation in CKD progression has been known for decades, it is only now with the FIDELIO-DKD study that we have evidence of benefits of MRAs on hard renal endpoints, specifically in patients with diabetic CKD. While further research is ongoing, given the evidence of synergism between the three drug classes, it is foreseeable that a combination of two or more of these drugs may soon become the standard of care for CKD, regardless of underlying aetiology. This review describes pathophysiologic mechanisms, current evidence and future perspectives on the use of SGLT2 inhibitors and novel MRAs in CKD.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetes Mellitus Undergoing Treatment with Sodium-Glucose Cotransporter 2 Inhibitors (EAGLE-DH)

“…Similarly, in the FIDELIO-DKD study, combination therapy with finerenone and an SGLT2 inhibitor was also confirmed to have a reducing effect on BP and UACR [ 33 ]. The details of the mechanism by which the efficacy of each drug is not counteracted are unclear, but it may be that SGLT2 inhibitors and MRBs act in the proximal and distal renal tubules, respectively [ 39 – 43 ], so that their efficacy would be complementary.…”

Finerenone cardiorenal effects and its placement in treatment of chronic kidney disease in patients with type 2 diabetes mellitus: A review

“…Таким образом, тройная комбинация, во-первых, представляется наиболее патофизиологически обоснованной ХБП-модифицирующей терапией, а во-вторых, нсАМКР смягчает «прорыв» альдостерона и предотвращает повреждение почек, вызванное гиперактивацией МКР, при этом ингибирование НГЛТ-2 обеспечивает некоторую защиту от гиперкалиемии, вызываемой иАПФ и АМКР, что позволяет продолжить их использование. Вместе с тем, несмотря на результаты исследований финеренона, окончательный вывод об эффективности и безопасности его комбинации с иНГЛТ-2 может быть основан только на данных РКИ, которые мы получим в ближайшем будущем (исследование CONFIDENCE, NCT05254002: применение финеренона и эмпаглифлозина у больных СД 2 и ХБП) [4].…”

“…Однако, несмотря на их эффективность, остаточный риск прогрессирования ХБП в течение 4-5 лет остается высоким почти у 1/2 пациентов с СД 2. Это обусловлено рефлекторным повышением выработки ренина и так называемым феноменом «прорыва альдостерона», с повышением его до уровня, предшествовавшего назначению ингибиторов ангиотензинпревращающего фермента/блокаторов рецепторов ангиотензина II (иАПФ/БРА) [4].…”

Molecular Mechanisms Linking Empagliflozin to Renal Protection in the LLC-PK1 Model of Diabetic Nephropathy

“…Various studies showed beneficial effects of SGLT2i: reduction in fasting plasma glucose levels, glycaemic improvement, weight loss, reduction in plasma volume, glomerular filtration pressure, systemic blood pressure, and renal hypoxia [ 29 ]. Numerous large randomised controlled trials have been conducted over the past five years supporting these findings and changing the status of SGLT2i from a simple class of oral hypoglycemic agents to a paradigm-shifting class of medications with renal and cardiovascular benefits far beyond their antihyperglycemic effects [ 30 ].…”