Uric acid and the cardio‐renal effects of SGLT2 inhibitors

Abstract

Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardiorenal risk.Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the "metabolic syndrome" of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes. K E Y W O R D Scardiac, gout, obesity, renal, sodium/glucose co-transporter-2 (SGLT2) inhibitor, type 2 diabetes, uric acid | CARDIO-RENAL EFFECTS OF SGLTINHIBITORSSeveral recent large prospective randomized studies in type 2 diabetes have observed reduced CV risk and improved renal function during treatment with an SGLT2 inhibitor. 3 In the EMPA-REG OUTCOME trial, treatment with empagliflozin was associated with a reduced composite 3-point MACE of CV death, nonfatal myocardial infarction (MI) and stroke by 14%; CV mortality was reduced by 38%, overall mortality by 32% and hospitalization for heart failure by 35%. 4 Empagliflozin also reduced by 39% the deterioration in nephropathy, measured as a composite of progression to macroalbuminuria, doubling of

Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, preserves renal function irrespective of acute changes in the estimated glomerular filtration rate in Japanese patients with type 2 diabetes

“…A recent clinical trial suggested that urate-lowering therapy might be associated with maintaining or improving eGFR in patients with chronic kidney disease without proteinuria [24]. Since SGLT2 inhibitors reduce serum uric acid levels, it is postulated that the urate-lowering effect of SGLT2 inhibitors may assist in retarding the progression of chronic kidney disease [25].…”

Lowering the risk of gout: Another benefits from the use of sodium–glucose cotransporter 2 inhibitors

“…Previous observational and interventional studies have shown that uric acid acts as a modifiable risk factor in the progression of chronic kidney disease for type 2 diabetes 1,2 . This is also true for those diabetes patients with lesser degrees of hyperuricemia.…”

“…Hyperuricemia and the risk of gout are commonly seen in patients with type 2 diabetes. It has also been reported that chronically elevated circulating uric acid concentrations are associated with an increased risk of hypertension, cardiovascular disease and chronic kidney disease, all of which are known diabetes‐associated complications 1,2 .…”

“…Presumably, the glycosuria caused by the use of SGLT2 inhibitors helps uric acid to be secreted into the urine. The most likely mechanism postulated was that, through SGLT2 inhibitors, an increase in uricosuria occurred by suppressing the activity of glucose transporter 9b, a hexose/urate transporter located at the proximal tubular cells across the basolateral membrane 1 . However, the exact mechanisms have not been fully illustrated.…”

“…However, the exact mechanisms have not been fully illustrated. It is estimated that the increased uric acid elimination through the use of SGLT2 inhibitors usually lowers circulating uric acid concentrations by approximately 35–45 μmol/L (0.60–0.75 mg/dL) in individuals with a baseline uric acid value in the normal concentration range of approximately 200–400 μmol/L (~3.3–6.7 mg/dL) 1 . In the Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk (EMPA‐REG OUTCOME) trial, patients who received empagliflozin showed a lower serum uric acid level of approximately 30 μmol/L compared with those who had been assigned a placebo 4 .…”