Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition

Abstract

Background: The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration.

Methods: Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress.

Results: Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m2 lower GFR compared with placebo-ramipril treatment (P=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (P=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (P=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (P=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure-lowering effects (clinic systolic blood pressure lower by 4 mm Hg [P=0.0112]; diastolic blood pressure lower by 3 mm Hg [P=0.0032]) in conjunction with a 94.5 dynes × sex/cm5 lower total peripheral resistance (P=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin.

Conclusions: Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT02632747.

Keywords: angiotensin-converting enzyme inhibitors; glomerular filtration rate; hemodynamics; sodium-glucose transporter 2 inhibitors.

Figures

Figure 1.

Postulated mechanisms in normal physiology and hyperfiltration in early stages of nephropathy and after combined inhibition of SGLT2 and RAAS. A, Under physiologic conditions, tubuloglomerular feedback (TGF) signaling maintains stable glomerular filtration rate (GFR) by modulation of preglomerular arteriole tone. In cases of conditional increases in GFR, the macula densa within the juxtaglomerular apparatus senses an increase in distal tubular sodium delivery and adjusts GFR through TGF accordingly. Neurohormonal signaling using the renin-angiotensin-aldosterone system (RAAS) contributes to maintenance of stable GFR by modulating postglomerular arteriole tone. B, Under chronic hyperglycemic conditions during diabetes, increased proximal sodium-glucose cotransporter 2 (SGLT2)–mediated reabsorption of sodium (Na+) and glucose impairs this feedback mechanism. Thus, despite increased GFR, the macula densa is exposed to lowered sodium concentrations and results in dilation of the afferent intrarenal arteriole. Increased activation of the renin-angiotensin-aldosterone neurohormonal system in diabetes causes constriction at the efferent intrarenal arteriole. Together, impairment of TGF and neurohormonal signaling likely leads to inadequate arteriole tone at the afferent and efferent arterioles and renal perfusion is increased. C, SGLT2 inhibition with empagliflozin treatment blocks proximal tubule glucose and sodium reabsorption, which leads to increased sodium delivery to the macula densa. This condition restores TGF by means of appropriate modulation of arteriolar tone (e.g., afferent vasoconstriction). Blockade of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor, ramipril, leads to efferent vasodilation. The overall effect of afferent vasocontraction with SGLT2 inhibition and efferent vasodilation with ACE inhibition reduces renal plasma flow and hyperfiltration. Modified from Cherney et al.

Figure 2.

Changes in glomerular filtration rate, absolute proximal fluid reabsorption rate, absolute proximal sodium reabsorption rate, systolic blood pressure, diastolic blood pressure, and total peripheral resistance during screening subtracted from randomization and placebo subtracted from empagliflozin in patients with type 1 diabetes at baseline and in response to ramipril treatment after addition of empagliflozin or placebo. Changes in (A) glomerular filtration rate (GFR), (B) absolute proximal fluid reabsorption rate, (C) absolute proximal sodium reabsorption rate, (D) systolic blood pressure (SYSBP), (E) diastolic blood pressure (DIABP), and (F) total peripheral resistance (TPR) during screening subtracted from randomization and placebo subtracted from empagliflozin in patients with type 1 diabetes at baseline and in response to ramipril treatment after addition of empagliflozin or placebo.

Figure 3.

Changes in plasma renin concentration, urine 8-isoprostane, and urine cyclic guanosine monophosphate during screening subtracted from randomization and placebo subtracted from empagliflozin in patients with type 1 diabetes at baseline and in response to ramipril treatment after addition of empagliflozin or placebo. Changes in (A) plasma renin concentration, (B) urine 8-isoprostane, and (C) urine cyclic guanosine monophosphate during screening subtracted from randomization and placebo subtracted from empagliflozin in patients with type 1 diabetes at baseline and in response to ramipril treatment after addition of empagliflozin or placebo.