Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition
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.
| Errataetall: |
CommentIn: Circulation. 2022 Aug 9;146(6):463-465. - PMID 35939546 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:146 |
|---|---|
| Enthalten in: |
Circulation - 146(2022), 6 vom: 09. Aug., Seite 450-462 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lytvyn, Yuliya [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 10.08.2022 Date Revised 12.12.2022 published: Print-Electronic ClinicalTrials.gov: NCT02632747 CommentIn: Circulation. 2022 Aug 9;146(6):463-465. - PMID 35939546 Citation Status MEDLINE |
|---|
| doi: |
10.1161/CIRCULATIONAHA.122.059150 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM343821028 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM343821028 | ||
| 003 | DE-627 | ||
| 005 | 20231226021337.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCULATIONAHA.122.059150 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1146.xml |
| 035 | |a (DE-627)NLM343821028 | ||
| 035 | |a (NLM)35862082 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lytvyn, Yuliya |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 10.08.2022 | ||
| 500 | |a Date Revised 12.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02632747 | ||
| 500 | |a CommentIn: Circulation. 2022 Aug 9;146(6):463-465. - PMID 35939546 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a REGISTRATION: URL: https://www | ||
| 520 | |a CLINICALTRIALS: gov; Unique identifier: NCT02632747 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a angiotensin-converting enzyme inhibitors | |
| 650 | 4 | |a glomerular filtration rate | |
| 650 | 4 | |a hemodynamics | |
| 650 | 4 | |a sodium-glucose transporter 2 inhibitors | |
| 650 | 7 | |a Angiotensin-Converting Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a Angiotensins |2 NLM | |
| 650 | 7 | |a Sodium-Glucose Transporter 2 |2 NLM | |
| 650 | 7 | |a Sodium |2 NLM | |
| 650 | 7 | |a 9NEZ333N27 |2 NLM | |
| 650 | 7 | |a Glucose |2 NLM | |
| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
| 650 | 7 | |a Ramipril |2 NLM | |
| 650 | 7 | |a L35JN3I7SJ |2 NLM | |
| 700 | 1 | |a Kimura, Karen |e verfasserin |4 aut | |
| 700 | 1 | |a Peter, Nuala |e verfasserin |4 aut | |
| 700 | 1 | |a Lai, Vesta |e verfasserin |4 aut | |
| 700 | 1 | |a Tse, Josephine |e verfasserin |4 aut | |
| 700 | 1 | |a Cham, Leslie |e verfasserin |4 aut | |
| 700 | 1 | |a Perkins, Bruce A |e verfasserin |4 aut | |
| 700 | 1 | |a Soleymanlou, Nima |e verfasserin |4 aut | |
| 700 | 1 | |a Cherney, David Z I |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation |d 1950 |g 146(2022), 6 vom: 09. Aug., Seite 450-462 |w (DE-627)NLM000039020 |x 1524-4539 |7 nnns |
| 773 | 1 | 8 | |g volume:146 |g year:2022 |g number:6 |g day:09 |g month:08 |g pages:450-462 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1161/CIRCULATIONAHA.122.059150 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 146 |j 2022 |e 6 |b 09 |c 08 |h 450-462 | ||