Flozins: The Latest Guard of the Kidneys

Mohamad Alkadi, MD

Nephrology and kidney transplantation consultant

Hamad Medical Corporation

Assistant professor of clinical medicine

Weill Cornell Medicine-Qatar

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD) and end stage kidney disease (ESKD) worldwide. Since the early 2000’s there have been no new interventions or approved medications for the treatment of diabetic kidney disease (DKD); however, flozins have revolutionized management of DKD over the last few years. Flozins are derivatives of phlorizin that inhibit sodium-glucose cotransporters (SGLT) with increased oral bioavailability and higher selectivity to SGLT2 over SGLT1. SGLT2 is responsible for > 90% glucose reuptake in kidneys, with SGLT1 reabsorbing the remainder of the filtered glucose. Inhibition of SGLT2 decreases glucose and sodium chloride reabsorption in the proximal tubules of nephrons and increases delivery of solutes to the macula densa “salt sensors” in tubules. This results in vasoconstriction of glomerular afferent arteriole via tubuloglomerular feedback and decreased intraglomerular hypertension and hyperfiltration. It also leads to decreased plasma volume, systemic blood pressure, inflammation, and oxidative stress. The net effects of SGLT2 inhibition are reduction of hyperglycemia, albuminuria, and the risk of heart failure decompensation.

Over the last few years, several randomized, placebo-controlled, multicenter studies and metanalyses demonstrated cardiorenal benefits of SGLT-2 inhibitors. EMPA-REG OUTCOME was the first study to show empagliflozin was associated with lower risk of death from cardiovascular causes, death from any cause and hospitalization for heart failure in patients with type 2 diabetes (T2DM) and established cardiovascular disease. Empagliflozin was also found to lower the risk of worsening nephropathy, defined as progression to macroalbuminuria, doubling of creatinine, accompanied by an eGFR of ≤45 ml/min/1.73m² or the initiation of renal replacement therapy, by 39%. In 2019, CREDENCE was the first study to have renal outcomes in patients with T2DM and CKD as the primary outcome. It showed that canagliflozin was associated with a 30% lower risk of a primary composite of ESKD, doubling of creatinine, or death from renal or cardiovascular causes. A year later, DAPA-CKD, the first study to assess the long-term efficacy and safety of dapagliflozin in patients with chronic kidney disease without T2DM, was published. Dapagliflozin lowered the risk of a primary composite of sustained decline in eGFR ³ 50%, ESKD, or death from renal or cardiovascular causes by 50% in patients with eGFR between 25-75 ml/min/1.73m². The most reported adverse events of SGLT2 inhibitors in clinical trials were genital infections and volume depletion, but there was no increased risk of hypoglycemia, diabetic ketoacidosis, amputation, acute kidney injury or fractures. SGLT2 was found to induce an acute reduction in eGFR of ~ 5 ml/min/1.73m² over a few weeks and then the eGFR tends to return towards baseline and remains more stable over time than in patients receiving placebo. This effect is seen in patients with or without chronic kidney disease, with or without established cardiovascular disease, and in those with or without T2DM. The dip in eGFR is reversed within 2 weeks of drug discontinuation.

Given the overwhelming evidence of cardiorenal benefits of SGLT-2 inhibitors, both the Kidney Disease Improving Global Outcomes guidelines (KDIGO) and the American Diabetes Association (ADA) now recommend the use of SGLT2 inhibitors as a first line therapy in patients with diabetes and chronic kidney disease (eGFR ³ 25 ml/min/1.73m²). When SGLT2 inhibitors are initiated, patients should be educated about potential volume depletion, and they should be advised to hold them in periods of illness accompanied by decreased oral intake or increased volume losses. SGLT-2 inhibitors can be continued until kidney replacement therapy needs to be started.

References:

• Cowie, M.R., Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 17, 761–772 (2020). https://doi.org/10.1038/s41569-020-0406-8
• Giugliano, D., Longo, M., Scappaticcio, L. et al. SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs. Cardiovasc Diabetol 20, 236 (2021). https://doi.org/10.1186/s12933-021-01430-3
• Wanner, Christoph. "EMPA-REG OUTCOME: the nephrologist's point of view." The American journal of cardiology 120.1 (2017): S59-S67.
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