Kidney Hemodynamic Effects of Angiotensin Receptor Blockade, Sodium-Glucose Cotransporter-2 Inhibition Alone, and Their Combination: A Crossover Randomized Trial in People With Type 2 Diabetes

HomeCirculationVol. 146, No. 24Kidney Hemodynamic Effects of Angiotensin Receptor Blockade, Sodium-Glucose Cotransporter-2 Inhibition Alone, and Their Combination: A Crossover Randomized Trial in People With Type 2 Diabetes Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBKidney Hemodynamic Effects of Angiotensin Receptor Blockade, Sodium-Glucose Cotransporter-2 Inhibition Alone, and Their Combination: A Crossover Randomized Trial in People With Type 2 Diabetes Rosalie A. Scholtes, Anne C. Hesp, Charlotte M. Mosterd, Frank Geurts, Ewout J. Hoorn, Daan J. Touw, Merle M. Krebber, Jaap A. Joles, Hiddo J.L. Heerspink and Daniël H. van Raalte Rosalie A. ScholtesRosalie A. Scholtes Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, the Netherlands (R.A.S., A.C.H., C.M.M., D.H.v.R.). Search for more papers by this author , Anne C. HespAnne C. Hesp Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, the Netherlands (R.A.S., A.C.H., C.M.M., D.H.v.R.). Search for more papers by this author , Charlotte M. MosterdCharlotte M. Mosterd https://orcid.org/0000-0002-1309-5155 Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, the Netherlands (R.A.S., A.C.H., C.M.M., D.H.v.R.). Search for more papers by this author , Frank GeurtsFrank Geurts Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (F.G., E.J.H.). Search for more papers by this author , Ewout J. HoornEwout J. Hoorn https://orcid.org/0000-0002-8738-3571 Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (F.G., E.J.H.). Search for more papers by this author , Daan J. TouwDaan J. Touw https://orcid.org/0000-0002-1429-4789 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, the Netherlands (D.J.T., H.J.L.H.). Search for more papers by this author , Merle M. KrebberMerle M. Krebber https://orcid.org/0000-0001-9856-6907 Department of Nephrology and Hypertension, University Medical Center, Utrecht, the Netherlands (M.M.K., J.A.J.). Search for more papers by this author , Jaap A. JolesJaap A. Joles https://orcid.org/0000-0003-2565-242X Department of Nephrology and Hypertension, University Medical Center, Utrecht, the Netherlands (M.M.K., J.A.J.). Search for more papers by this author , Hiddo J.L. HeerspinkHiddo J.L. Heerspink https://orcid.org/0000-0002-3126-3730 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, the Netherlands (D.J.T., H.J.L.H.). Search for more papers by this author and Daniël H. van RaalteDaniël H. van Raalte Correspondence to: Daniël H. van Raalte, MD, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2894-6124 Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, the Netherlands (R.A.S., A.C.H., C.M.M., D.H.v.R.). Search for more papers by this author Originally published12 Dec 2022https://doi.org/10.1161/CIRCULATIONAHA.122.061033Circulation. 2022;146:1895–1897Renin-angiotensin system (RAS) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors improve kidney outcomes in people with type 2 diabetes.1 Lowering of glomerular pressure, clinically characterized by an acute estimated glomerular filtration rate (eGFR) decline, contributes to the kidney-protective properties of these drugs.2 In all trials studying their kidney effects, SGLT2 inhibitors were introduced on top of standard of care, including RAS inhibition. The effect of the combination of these drugs on kidney hemodynamic function remains unstudied. Therefore, we investigated the effects of monotherapy and combination therapy with the SGLT2 inhibitor empagliflozin and the RAS inhibitor losartan on kidney hemodynamic function, particularly, measured GFR (mGFR), in individuals with type 2 diabetes.We conducted a phase 4, monocenter, randomized, double-blind, comparator-controlled, 4-armed, crossover mechanistic study. The study was approved by our institutional review committee, and participants provided informed consent. Data are available on reasonable request. We included 24 overweight or obese individuals with type 2 diabetes (age, 66±6 years; hemoglobin A1c, 7.4±0.9%) treated with metformin (100%) and/or sulfonylurea (46%). Systolic blood pressure was 145±16 mm Hg. Hypertension (58%) was regulated by α- or β-blockers. Participants were randomized to a 1-week treatment with 10 mg of empagliflozin once daily, 50 mg of losartan once daily, empagliflozin+losartan once daily, and matching placebo, with 4-week washout periods between each treatment period (Figure [A]). Primary end points were fasting mGFR and effective renal plasma flow. mGFR and were determined by iohexol and para-aminohippurate clearances, respectively. A linear mixed-model analysis was used to compare outcome measures between treatment sequences.Download figureDownload PowerPointFigure. Kidney hemodynamic effects of empagliflozin and losartan in the RECOLAR study. A, A crossover study design was used for the present trial. The washout period was 4 weeks between treatments. B through I, Treatment-induced changes in kidney hemodynamic function. B, Measured glomerular filtration rate (GFR). C, Effective renal plasma flow (ERPF). D, Renal vascular resistance (RVR). E, Preglomerular resistance. F, Postglomerular resistance. G, Filtration fraction (FF). H, Adapted plot based on calculations in the article by Carmines et al,3 which related changes in preglomerular and postglomerular resistance to FF. Placebo-placebo treatment was used as reference with values set at 100%. I, Estimated intraglomerular pressure. J, Systolic blood pressure. Data represent mean with SEM. Statistical analyses carried out by linear mixed model, which included a random intercept for the subject, taking into account the dependency of the observations within one subject and included treatment order as a factor to exclude carryover effects. Significant findings compared with placebo are indicated. Statistically significant mean differences of treatments compared with placebo are indicated with brackets. E indicates empagliflozin; L, losartan; and P, placebo.All treatments reduced mGFR compared with placebo (107 mL/min [SD, 20 mL/min]): empagliflozin by 7.2 mL/min (95% CI, −13.9 to −0.6), losartan by 7.5 mL/min (95% CI, −14.1 to −0.9), and empagliflozin+losartan by 10.9 mL/min (95% CI, −17.5 to −4.3; Figure [B]). Compared with empagliflozin, empagliflozin+losartan reduced GFR by 3.7 mL/min (95% CI, −13.7 to 6.4), whereas compared with losartan, empagliflozin+losartan reduced GFR by 3.4 mL/min (95% CI, −13.5 to 6.6). Effective renal plasma flow (placebo, 624 mL/min [SD, 158 mL/min]) was not changed by any treatment (Figure [C]), whereas renal vascular resistance tended to decline (Figure [D]). Both preglomerular (Figure [E]) and postglomerular (Figure [F]) reductions in arteriolar resistance were noted, with filtration fraction kept constant (Figure [G and H]).We demonstrate that, compared with placebo, RAS and SGLT2 inhibition combination therapy induced a numerically greater reduction in mGFR and estimated glomerular pressure (Figure [I]) than either treatment alone. The study was not powered to compare the monotherapy arms with the combination therapy arm; however, we could observe clinically relevant mGFR reductions of 3 to 4 mL/min between these conditions. An interesting point is that both drugs showed similar kidney hemodynamic effects that contribute to mGFR and glomerular pressure reductions.Losartan monotherapy reduced mGFR and estimated glomerular pressure without increasing renal vascular resistance. Estimated preglomerular and postglomerular resistances were reduced, supporting vasoconstrictive actions of angiotensin II on both preglomerular and postglomerular vessels. Because postglomerular arterioles have smaller diameters than preglomerular arterioles, the hemodynamic impact in response to angiotensin II of these arterioles is larger compared with the preglomerular arterioles, according to the equation of Hagen-Poisseulle4 and as proposed in the nomogram by Carmines et al,3 in which smaller changes in efferent arteriolar resistance have larger kidney hemodynamic effects. This effect explains the observed overall reduction in mGFR with constant filtration fraction (Figure [G and H]). The reduction in systolic blood pressure may also contribute to the observed kidney hemodynamic profile (Figure [J]).Empagliflozin induced a similar kidney hemodynamic profile. In contrast to stimulating afferent vasoconstriction in hyperfiltering individuals with type 1 diabetes, SGLT2 inhibition induces an overall vasodilative response in people with type 2 diabetes.5 SGLT2 inhibitors activate tubuloglomerular feedback secondary to increased distal sodium and chloride uptake, triggering the macula densa to secrete adenosine, inducing vasodilatory endothelial responses in people with type 2 diabetes. In addition, SGLT2 inhibitors are known to cause systemic and intrakidney RAS activation. It has been suggested that an SGLT2 inhibitor–induced increase in angiotensin II could activate the nonclassic RAS pathways independent of simultaneous RAS inhibition. This nonclassic pathway generally opposes the classic RAS pathway and is considered to induce general vasodilation.These different mechanisms of action, that is, direct endothelial effects related to angiotensin II receptor blockade of RAS inhibitors and tubular-mediated endothelial effects of SGLT2 inhibitors, lead to additive effects when used in combination, although, as stated, we had insufficient power to reach statistical significance for these differences.Our study is limited by its short duration, although hemodynamic effects with both agents occur very rapidly and remain stable over time. In addition, we included mostly White men with preserved kidney function, therefore limiting generalizability. Furthermore, we could only estimate glomerular pressure and resistance with the Gomez formulas.In conclusion, we show that the SGLT2 inhibitor empagliflozin, combined with the RAS blocker losartan, has additional beneficial kidney hemodynamic effects compared with either drug alone in people with type 2 diabetes. These data support the combined use of these agents to reduce the kidney disease burden in this population.Article InformationSources of FundingBoehringer Ingelheim provided the empagliflozin and empagliflozin-placebo tablets.Disclosures R.A.S., A.C.H., C.M.M., F.G., E.J.H., M.M.K., and J.A.J. report no conflicts. D.H.vR. has acted as a consultant for and received honoraria from Boehringer Ingelheim-Eli Lilly Alliance, Merck, Sanofi, and AstraZeneca, and has received research operating funds from Boehringer Ingelheim-Lilly Diabetes Alliance, AstraZeneca, and Merck. All honoraria are paid to his employer (Amsterdam University Medical Centers, location VUMC). D.J.T. reports grants from ZONMW and Chiesi Pharmaceuticals, as well as fees to his institution from ZONMW and PurelMS. H.J.L.H. has received research support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen, as well as fees to his institution for his participation on advisory boards from Merck, Mitsubishi Tanabe, Janssen, and Mundipharma; for consulting from AbbVie, Retrophin, Boehringer Ingelheim, and Novo Nordisk; and for participation in steering committees from Janssen, Gilead, Bayer, Chinook, and CSL Pharma.FootnotesFor Sources of Funding and Disclosures, see page 1897.Circulation is available at www.ahajournals.org/journal/circRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04238702.Correspondence to: Daniël H. van Raalte, MD, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands. Email d.[email protected].nlReferences1. Scholtes RA, van Baar MJB, Kok MD, Bjornstad P, Cherney DZI, Joles JA, van Raalte DH. Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: interaction with SGLT2 inhibitors.Nephrology (Carlton). 2021; 26:377–390. doi: 10.1111/nep.13839CrossrefMedlineGoogle Scholar2. Meraz-Munoz AY, Weinstein J, Wald R. eGFR decline after SGLT2 inhibitor initiation: the tortoise and the hare reimagined.Kidney360. 2021; 2:1042–1047. doi: 10.34067/KID.0001172021CrossrefMedlineGoogle Scholar3. Carmines PK, Perry MD, Hazelrig JB, Navar LG. Effects of preglomerular and postglomerular vascular resistance alterations on filtration fraction.Kidney Int Suppl. 1987; 20:S229–S232.MedlineGoogle Scholar4. Denton KM, Fennessy PA, Alcorn D, Anderson WP. Morphometric analysis of the actions of angiotensin II on renal arterioles and glomeruli.Am J Physiol. 1992; 262(pt 2):F367–F372. doi: 10.1152/ajprenal.1992.262.3.F367CrossrefMedlineGoogle Scholar5. van Bommel EJM, Muskiet MHA, van Baar MJB, Tonneijck L, Smits MM, Emanuel AL, Bozovic A, Danser AHJ, Geurts F, Hoorn EJ, et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.Kidney Int. 2020; 97:202–212. doi: 10.1016/j.kint.2019.09.013CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. 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