New therapeutic agents may be the ‘holy grail’ for cardiovascular risk management in CKD
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Patients with chronic kidney disease are at high risk for adverse cardiovascular events, even after adjusting for traditional risk factors.
The decline in the eGFR is associated inversely with cardiovascular (CV) risk. Hypertension, diabetes, smoking and dyslipidemia are well-identified risk factors for atherosclerotic disease and contribute to CKD progression. Other non-traditional factors, like vascular calcification, inflammation and myocardial alteration, contribute to CV risk.
Thus, a therapeutic gap for drugs that improve CV mortality and reduce adverse events has prevailed. In search of a “holy grail,” novel therapies, like sodium-glucose transport protein 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs), have emerged as promising treatments for reducing heart failure risk, CV mortality and progression of CKD.
SGLT2i were initially utilized as novel oral hypoglycemic agents that increased urinary glucose secretions. Recent trials have shown the improvement of CV and renal outcomes by treatment with SGLT2i, including empagliflozin, canagliflozin and dapagliflozin.
CV outcomes
SGLT2i improve CV outcomes by hemodynamic effects through osmotic diuresis and natriuresis, although the actual mechanism remains unidentified. The prescriber hesitancy arises from the risk of eGFR decline, euglycemic diabetic ketoacidosis (DKA), genital mycotic infections and medical insurance coverage issues. Many clinicians, like me, struggle with monitoring the adverse events after initiating the drug.
In clinical practice, one may encounter the initial dip in eGFR. If these “dips” indicate AKI, progressing to CKD, the challenge of identifying and managing adverse events prevails.
Three recent analyses from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus (T2D) Patients (EMPA-REG OUTCOME), the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS-CV) and the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trials, shed light on this concern. These studies report no long-term decline in eGFR after the initial dip.
Laboratory parameters
Monitoring laboratory parameters 2 to 4 weeks after initiating SGLT2i is reasonable, especially if hemodynamic instability is suspected. Volume depletion or hypotension is associated with euglycemic DKA.
The diagnosis is established by ketonemia and high anion gap acidosis. We prescribe patients home point of care ketone strips. The SGLT2i are held until volume status is corrected, hence the ketoacidosis resolution. Then, the medication can be resumed cautiously at a lower dose.
Finerenone
The novel non-steroidal MRAs, such as finerenone, are a promising therapeutic option in diabetic kidney disease (DKD). The blocking of mineralocorticoid receptor activation in inflammatory cells, podocytes, fibroblasts, mesangial cells and vascular cells leads to protective action. The phase 3 clinical studies from the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELO-DKD) trial report slowing CKD progression and reduced risk of adverse CV outcomes when finerenone was compared with placebo in patients with T2D. Non-steroidal MRAs carry a lower risk of hyperkalemia than steroidal MRAs, and the large FIDELIO-DKD clinical trial showed that finerenone did as well. Encouragingly, other non-steroidal MRAs have anti-albuminuria properties in DKD.
Obstacles
The SGLT2i and non-steroidal MRAs have delayed CKD progression and reduced CV events in clinical trials. There is consensus among the medical fraternity regarding the mortality and morbidity benefit of these drugs. However, the frequent insurance coverage denials and high out-of-pocket costs hinder the wide adoption of these drugs. Among the four SGLT2i available, the cost is highly variable even with copay cards.
The kidney community sees the dawn of alternative payment models under the Advancing American Kidney Health initiative. It may be time to explore cost-sharing or coverage options for these drugs under these programs.
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- Nupur Gupta, MD, is a nephrologist with Indiana University Health Physicians in Indianapolis and is a member of the Editorial Advisory Board for Nephrology News & Issues. She can be reached at nugupta@iu.edu.
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