Clinical Implications of an Acute Dip in eGFR after SGLT2 Inhibitor Initiation.

Abstract

Glomerular hyperfiltration is one of the earliest mechanisms contributing toCKD initiation andprogression. Experimental and clinical studies have shown glomerular hyperfiltration is associated with kidney injury in many CKD etiologies, and is a consequence of complex interactions between growth factors, vasoactive substances, and tubuloglomerular feedback (1). Nephroprotective pharmacotherapies and dietary interventions, including dietary proteinmoderation and use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), generally reduce glomerular hyperfiltration by reducing glomerular pressure. This manifests clinically as an acute and reversible dip in eGFR, with greater dipping patterns associated with longterm kidney function preservation (2). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of drugs that are cardiovascular protective and reduce kidneydisease progression (3). SGLT2 inhibitors induce an acute, reversible reduction in GFR, which is often referred to as the GFR “dip.” This response pattern suggests these agents reduce glomerular hypertension—an effect that is reminiscent of ACE inhibitors/ARBs. The clinical implications of the acute eGFR dip were unknown and led to concerns about the safetyof SGLT2 inhibitors because observational reports suggested an increase in the risk of AKI with these therapies (4). Given the clear cardiorenal protective effects of SGLT2 inhibitors, it is important to resolve uncertainty around the safety and long-term consequences of eGFR dipping to avoid clinical inertia with these therapies (5). Fortunately, new experimental and clinical studies have provided important insights into themechanisms andclinical relevanceof theeGFRdip.SGLT2 inhibitors exert a variety of physiologic effects that are either attributable to glucosuria, such as HbA1c reduction and weight loss, or to simultaneous inhibition of proximal tubular sodium reabsorption (3). This leads to augmenteddistal nephron sodiumdelivery, an effect linked with macula densa sodium uptake, which generates adenosine from ATP breakdown (3). Adenosine binds to the adenosine type 1 receptor at the afferent arteriole, leading to vasoconstriction (3,6). As a result, this proximal natriuresis causes vasoconstriction and a reduction in glomerular hyperperfusion and hyperfiltration. In this model, when the adenosine receptor is pharmacologically antagonized, the acute hemodynamic effect of SGLT2 inhibition is abolished (6). The fact that SGLT2 inhibitors induce an acute dip in eGFR has been known for more than 8 years. Less clear, however, was the relevance of the eGFR dip, and whether it represented potential signals around kidney safety or, conversely, clinical benefit. It is for this reason that three recent analyses—one from Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), one from Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS-CV), and one from Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE)—are of importance. The first report was a post-hoc analysis fromEMPA-REGOUTCOME in participants with type 2 diabetes and cardiovascular disease. The analysis showed that after 4 weeks, 28% of empagliflozin-treated participants versus 13% placebotreated participants experienced an acute dip in eGFR $10% (odds ratio, 2.7; 95% confidence interval, 2.3 to 3.0). Diuretic use at baseline and a higher Kidney Disease: Improving Global Outcomes category were associated with higher likelihood of eGFR dipping. Importantly, long-term eGFR trajectories and safety outcomes, includingAKI,were similar regardless of the initial dip in eGFR with empagliflozin treatment (Figure 1) (7). Similar datawere reported in ananalysis from the VERTIS-CV randomized controlled trial in patients with type 2 diabetes and cardiovascular disease, presentedat theAmericanSocietyofNephrology in2020. In this analysis, patients treatedwith ertugliflozinwith the largest tertile for the initial eGFR dip at 6 weeks exhibited the lowest subsequent eGFR slope over time, suggesting a kidney protective effect (8). A third analysis from the CREDENCE trial characterized the acute dip in eGFR and its long-term consequences in patientswith type 2 diabetes andCKD (9). In this study, an acute dip in eGFR $10% was observed in 45% of patients treated with canagliflozin versus 21% of patients treated with placebo (odds ratio, 3.0; 95% confidence interval, 2.7 to 3.3). Long-term eGFR trajectories andkidneysafetyprofileswere similar, regardlessof the magnitude of the initial dip in eGFR after canagliflozin initiation. In the CREDENCE trial, an initial eGFR dip .30% was a rare event and occurred in only 0.5% of canagliflozin-treated participants. In this small Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Ontario, Toronto, Canada