Effects of SGLT2 inhibitors on eGFR in type 2 diabetic patients—the role of antidiabetic and antihypertensive medications

Abstract

Recent randomized trials demonstrating the beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in type 2 diabetes suggest that early reductions in eGFR upon initiation of SGLT2i therapy are associated with improved renal outcomes. Multiple concomitant medications, including antidiabetic and antihypertensive agents, are commonly used, however, which may modify the renal hemodynamic action of SGLT2is. Here we found that background treatment with metformin diminished the SGLT2i-induced reductions in eGFR after 3 months of SGLT2i therapy in patients with type 2 diabetes and hypertension (−2.29 ± 0.90 vs −5.85 ± 1.27 mL/min/1.73 m2 for metformin users (n = 126) and nonusers (n = 97), respectively). Other antidiabetic agents (DPP4 inhibitors, sulfonylureas and insulin) had no effect on the eGFR response to SGLT2is. Antihypertensive drugs, including calcium channel blockers (CCBs) and β blockers, did not affect the SGLT2i-induced changes in eGFR, whereas renin-angiotensin system inhibitors (RASis) tended to enhance this response (p = 0.059). Next, we evaluated the interaction between metformin and RASis in the eGFR responses to SGLT2is. Under no background treatment with RASis, metformin abrogated the eGFR response to SGLT2is, but this response was preserved when RASis had been given along with metformin (decreases of 0.75 ± 1.28 vs. 4.60 ± 1.15 mL/min/1.73 m2 in eGFR, p = 0.028). No interaction between metformin and insulin or between metformin and DPP4 inhibitors was observed. In conclusion, metformin blunts the SGLT2i-induced decrease in eGFR, but coadministration of RASis ameliorates this response. Furthermore, the inability of CCBs to modify the SGLT2i-induced reduction in eGFR suggests that the SGLT2i-induced renal microvascular action is mediated predominantly by postglomerular vasodilation rather than preglomerular vasoconstriction.

Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS‐3150) and sodium–glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies

“…In both studies, SGLT2 and DPP‐4 inhibitors were required to have stable dosage and administration from 12 weeks before the start of esaxerenone treatment until the end of the study. SGLT2 inhibitors are known to decrease albuminuria 13 , 27 , blood pressure 28 and eGFR 29 with an initial dip, and all of these effects reach steady state at 12 weeks. Therefore, we consider that one possible reason for the observation that UACR, blood pressure and eGFR remained constant in the placebo group using SGLT2 inhibitors in the ESAX‐DN (J308) study might be that these parameters had already undergone their maximum decrease at the start of the study.…”

Impact of the initial decline in estimated glomerular filtration rate on the risk of new‐onset atrial fibrillation and adverse cardiovascular and renal events in patients with type 2 diabetes treated with sodium‐glucose co‐transporter‐2 inhibitors

“…30 Our analysis also showed that the use of metformin was associated with a numerically lower risk of an eGFR decline of more than 30% following SGLT2i treatment. Several studies showed that the simultaneous administration of metformin elevated eGFR and attenuated the SGLT2i-induced eGFR reduction, 31,32 possibly because of the nitric oxide-mediated vasodilatory property of metformin. 33 However, future studies should focus on investigating these issues.…”

Selection and Warning of Evidence-Based Antidiabetic Medications for Patients With Chronic Liver Disease

“…But close monitoring of SGLT2 inhibitors plus diuretics is necessary to avoid the risks of hypovolemia, hypotension, encephalopathy and hepatorenal syndrome in patients with cirrhosis ( 86 ). One study has reported that the coadministration of SGLT2 inhibitors and β blocker did not affect the eGFR response to SGLT2 inhibitors ( 88 ). Therefore, it may be safe to co-administer SGLT2 inhibitors with β blockers in patients with liver cirrhosis.…”