Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function

Abstract

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone.

Keywords: HFpEF; HFrEF; SGLT2 inhibitor; chronic kidney disease; diabetic nephropathy; heart failure.

Figure 1

Cellular processes linked to SGLT2 and its inhibition in the early proximal tubule. Hyperglycemia enhances filtered glucose and, via SGLT2, the reabsorption of glucose and Na⁺ (1). Diabetes can increase SGLT2 expression (2); proposed mechanisms include tubular growth, Ang II, and HNF-1α, which may respond to basolateral hyperglycemia sensed by GLUT2. Hyperinsulinemia and tubular growth upregulate proximal tubular transport systems, including SGLT2, NHE3, URAT1, and Na-K-ATPase (3). The apical transporters may be functionally coupled via scaffolding proteins, such as MAP17 (4). The resulting proximal tubular Na⁺ retention enhances the GFR via tubuloglomerular feedback, which by increasing brush border torque can further increase transporter density in the luminal membrane. Diabetes, in part due to the associated acidosis, can enhance gluconeogenesis (5). The increase in intracellular glucose may lower SGLT2 expression via negative feedback (6). HNF-1α and HNF-3β upregulate GLUT2 and thereby the basolateral exit of glucose (7). Excessive SGLT2-mediated glucose uptake may attenuate autophagy (8) and trigger apical translocation of GLUT2 (9). Increased glucose reabsorption maintains hyperglycemia (10). Hypoxia due to diabetes-induced hyperreabsorption or kidney injury may induce HIF-1α, which enhances basolateral glucose uptake via GLUT1, induces a metabolic shift to glycolysis, and inhibits apical transport (11). Induction of TGF-β1 and tubular growth may be particularly sensitive to basolateral glucose uptake via GLUT1 (12). Abbreviations: Ang II, angiotensin II; GFR, glomerular filtration rate; GLUT, facilitative glucose transporter; HIF-1α, hypoxia-inducible factor 1 alpha; HNF, hepatic nuclear factor; MAP17, 17-kDa membrane-associated protein; NHE3, Na-H-exchanger 3; OA, organic anion; TGF-β1, transforming growth factor β1; URAT1, urate transporter 1. Figure adapted with permission from Reference .

Figure 2

Potential kidney-protective effects of SGLT2 inhibition. SGLT2 inhibition counteracts the diabetes-induced hyperreabsorption of glucose and Na⁺ in the early proximal tubule and lowers blood glucose levels. This also increases the NaCl and K concentration ([Na-Cl-K]_MD) and fluid delivery (V) to the macula densa, which lowers glomerular filtration rate (GFR) through the physiology of tubuloglomerular feedback (1) and by increasing hydrostatic pressure in Bowman’s space (P_Bow) (2). The GFR-lowering effect of tubuloglomerular feedback includes afferent arteriole constriction (via adenosine A1 receptor) and potentially efferent arteriole dilation (via adenosine A2 receptor), which both reduce glomerular capillary pressure (P_GC). Lowering of GFR reduces tubular transport work (3), thereby lowering cortical oxygen demand (Q_O2) (4) and increasing cortical oxygen tension (P_O2) (5). Lowering GFR (6) and hyperglycemia (7) attenuates filtration of tubulo-toxic compounds, including albumin, and reduces tubular growth and kidney inflammation. Tubular transport work is further reduced by lowering blood glucose and by cellular SGLT2 blockade itself, which reduces tubular gluco-toxicity and has also been linked to inhibition of the Na-H-exchanger NHE3 (8). SGLT2 inhibition shifts glucose reabsorption downstream where SGLT1 compensates and reduces the risk of hypoglycemia (9). Shifting glucose and Na⁺ reabsorption downstream to S3 and mTAL segments increases Q_O2 (10) and lowers P_O2 in the outer medulla (OM) (5). Furthermore, lower medullary P_O2 may activate hypoxia-inducible factor (HIF) and enhance erythropoietin (EPO) release (11). The latter increases hematocrit (Hct) (12) and improves O₂ delivery to kidney medulla and cortex (13) and the heart (14). Enhanced delivery of NaCl and fluid downstream of early proximal tubule enhances responsiveness to atrial natriuretic peptide (ANP) and diuretics (15). The diuretic and natriuretic effects of SGLT2 inhibition further increase Hct (16) and reduce extracellular (ECV) and interstitial (ISV) volume and blood pressure (17). These effects, which are also evident by compensatory upregulation of renin and vasopressin levels (18), can help protect the failing kidney and heart (19). The increased cortical oxygen availability together with lesser hyperglycemia, tubular gluco-toxicity, filtered albumin, and tubulointerstitial inflammation improves the integrity of the tubular and endothelial system, thereby allowing a higher tubular transport capacity and GFR to be maintained in the long term (20). The glucosuric effect lowers therapeutic and/or endogenous insulin levels and increases glucagon concentrations (21). This induces compensatory lipolysis and hepatic gluconeogenesis and ketogenesis. SGLT2 inhibitors are uricosuric, potentially involving urate transporter 1 (URAT1) inhibition and their glucosuric and insulin-lowering effect (22). These metabolic adaptations reduce urate levels, the hypoglycemia risk, and body and organ fat mass, which together with the resulting mild ketosis have the potential to further protect the kidney and heart (19, 23). Other abbreviations: UNaClV, urinary salt excretion; UV, urinary flow rate. Figure adapted with permission from Reference ; copyright 1999 Portland Press, Ltd.

Figure 3

Potential cardioprotective effects of SGLT2 inhibition. SGLT2 inhibitors enhance the cardiac oxygen and fuel supply while simultaneously reducing cardiac workload and cytotoxic and proinflammatory influences. The involved mechanisms are illustrated. Asterisks (*) denote urinary loss of calories, and glucose enhances lipolysis and thereby reduces peri-organ fat mass. Figure integrated and further developed from References , , , , . Abbreviations: AMPK, AMP-activated protein kinase; ANP, atrial natriuretic peptide; BIRC5, baculoviral IAP repeat-containing protein 5 or survivin; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; GFR, glomerular filtration rate; NLRP3, NLR family pyrin domain-containing 3; RAAS, renin-angiotensin-aldosterone system; SIRT1, Sirtuin 1; XIAP, X-linked inhibitor of apoptosis.