Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial

Marcel H A Muskiet; Lennart Tonneijck; Mark M Smits; Mark H H Kramer; D Margriet Ouwens; Bolette Hartmann; Jens J Holst; Daan J Touw; A H Jan Danser; Jaap A Joles; Daniël H van Raalte

doi:10.2337/dc20-0902

Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial

Marcel H A Muskiet, Lennart Tonneijck, Mark M Smits, Mark H H Kramer, D Margriet Ouwens, Bolette Hartmann, Jens J Holst, Daan J Touw, A H Jan Danser, Jaap A Joles, Daniël H van Raalte

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

OBJECTIVE: To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM).

RESEARCH DESIGN AND METHODS: In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured.

RESULTS: HbA 1c reductions were similar with linagliptin (-0.45 ± 0.09%) and glimepiride (-0.65 ± 0.10%) after 8 weeks ( P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FE Na) and potassium, without affecting FE of lithium. Linagliptin-induced change in FE Na correlated with SDF-1α ( R = 0.660) but not with other DPP-4 substrates.

CONCLUSIONS: Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.

Original language	English
Pages (from-to)	2889-2893
Number of pages	5
Journal	Diabetes Care
Volume	43
Issue number	11
Early online date	8 Sept 2020
DOIs	https://doi.org/10.2337/dc20-0902
Publication status	Published - Nov 2020

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Muskiet, M. H. A., Tonneijck, L., Smits, M. M., Kramer, M. H. H., Ouwens, D. M., Hartmann, B., Holst, J. J., Touw, D. J., Danser, A. H. J., Joles, J. A., & van Raalte, D. H. (2020). Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial. Diabetes Care, 43(11), 2889-2893. https://doi.org/10.2337/dc20-0902

@article{1b82f74ca0ad4d588255de99735817dd,

title = "Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial",

abstract = "OBJECTIVE: To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODS: In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured.RESULTS: HbA 1c reductions were similar with linagliptin (-0.45 ± 0.09%) and glimepiride (-0.65 ± 0.10%) after 8 weeks ( P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FE Na) and potassium, without affecting FE of lithium. Linagliptin-induced change in FE Na correlated with SDF-1α ( R = 0.660) but not with other DPP-4 substrates. CONCLUSIONS: Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.",

author = "Muskiet, {Marcel H A} and Lennart Tonneijck and Smits, {Mark M} and Kramer, {Mark H H} and Ouwens, {D Margriet} and Bolette Hartmann and Holst, {Jens J} and Touw, {Daan J} and Danser, {A H Jan} and Joles, {Jaap A} and {van Raalte}, {Dani{\"e}l H}",

note = "Funding Information: Acknowledgments. In memory of Prof. Mi- chaela Diamant, whose experience and expertise were crucial for the design of this study. The authors extend gratitude to all study participants who took part in this study for their time and commitment to the demanding protocol. Furthermore, the authors thank the study nurses for their excellent practical support during the conduct of this study, with special thanks to Sandra Gassman and Jeannette Boerop (Diabetes Center, Department of Internal Medicine, VU University Medical Center). Finally, the authors thank Adele Dijk and Nel Willekes-Koolschijn (Department of Nephrology and Hypertension, University Medical Center), and Daniela Herzfeld de Wiza (Institute of Clinical Biochemistry and Pathobiochemistry) for much appreciated technical laboratory assistance. Duality of Interest. Funding for the study was provided by Boehringer Ingelheim. M.H.A.M. is a speaker/consultant for AstraZeneca, Eli Lilly & Co., Novo Nordisk, and Sanofi. L.T. consulted for Eli Lilly & Co. and Novo Nordisk. Through M.H.H.K., the Amsterdam University Medical Centers, location VUmc, received research grants from Boehringer Ingelheim, Novo Nordisk, and Sanofi. D.H.v.R. serves on advisory boards of Boehringer Ingelheim, Eli Lilly Alliance, Novo Nordisk, Sanofi, and Merck Sharp & Dohme (MSD) and received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Sanofi, and MSD. All authors from the Amsterdam University Medical Centers, location VUmc, declare that they did not receive personal fees in connection to these roles described above, and honoraria were paid to their employer. J.J.H. has been a member of advisory boards for Novo Nordisk. D.J.T. reports grants received from ZonMw, Chiesi Pharmaceuticals, and Astellasdall outside the scope of this study. No other potential conflicts of interest relevant to this article were reported. Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = nov,

doi = "10.2337/dc20-0902",

language = "English",

volume = "43",

pages = "2889--2893",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "11",

}

Muskiet, MHA, Tonneijck, L, Smits, MM, Kramer, MHH, Ouwens, DM, Hartmann, B, Holst, JJ, Touw, DJ, Danser, AHJ, Joles, JA & van Raalte, DH 2020, 'Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial', Diabetes Care, vol. 43, no. 11, pp. 2889-2893. https://doi.org/10.2337/dc20-0902

Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial. / Muskiet, Marcel H A; Tonneijck, Lennart; Smits, Mark M et al.
In: Diabetes Care, Vol. 43, No. 11, 11.2020, p. 2889-2893.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS)

T2 - A Randomized, Double-Blind Trial

AU - Muskiet, Marcel H A

AU - Tonneijck, Lennart

AU - Smits, Mark M

AU - Kramer, Mark H H

AU - Ouwens, D Margriet

AU - Hartmann, Bolette

AU - Holst, Jens J

AU - Touw, Daan J

AU - Danser, A H Jan

AU - Joles, Jaap A

AU - van Raalte, Daniël H

N1 - Funding Information: Acknowledgments. In memory of Prof. Mi- chaela Diamant, whose experience and expertise were crucial for the design of this study. The authors extend gratitude to all study participants who took part in this study for their time and commitment to the demanding protocol. Furthermore, the authors thank the study nurses for their excellent practical support during the conduct of this study, with special thanks to Sandra Gassman and Jeannette Boerop (Diabetes Center, Department of Internal Medicine, VU University Medical Center). Finally, the authors thank Adele Dijk and Nel Willekes-Koolschijn (Department of Nephrology and Hypertension, University Medical Center), and Daniela Herzfeld de Wiza (Institute of Clinical Biochemistry and Pathobiochemistry) for much appreciated technical laboratory assistance. Duality of Interest. Funding for the study was provided by Boehringer Ingelheim. M.H.A.M. is a speaker/consultant for AstraZeneca, Eli Lilly & Co., Novo Nordisk, and Sanofi. L.T. consulted for Eli Lilly & Co. and Novo Nordisk. Through M.H.H.K., the Amsterdam University Medical Centers, location VUmc, received research grants from Boehringer Ingelheim, Novo Nordisk, and Sanofi. D.H.v.R. serves on advisory boards of Boehringer Ingelheim, Eli Lilly Alliance, Novo Nordisk, Sanofi, and Merck Sharp & Dohme (MSD) and received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Sanofi, and MSD. All authors from the Amsterdam University Medical Centers, location VUmc, declare that they did not receive personal fees in connection to these roles described above, and honoraria were paid to their employer. J.J.H. has been a member of advisory boards for Novo Nordisk. D.J.T. reports grants received from ZonMw, Chiesi Pharmaceuticals, and Astellasdall outside the scope of this study. No other potential conflicts of interest relevant to this article were reported. Publisher Copyright: © 2020 by the American Diabetes Association. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/11

Y1 - 2020/11

N2 - OBJECTIVE: To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODS: In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured.RESULTS: HbA 1c reductions were similar with linagliptin (-0.45 ± 0.09%) and glimepiride (-0.65 ± 0.10%) after 8 weeks ( P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FE Na) and potassium, without affecting FE of lithium. Linagliptin-induced change in FE Na correlated with SDF-1α ( R = 0.660) but not with other DPP-4 substrates. CONCLUSIONS: Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.

AB - OBJECTIVE: To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODS: In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured.RESULTS: HbA 1c reductions were similar with linagliptin (-0.45 ± 0.09%) and glimepiride (-0.65 ± 0.10%) after 8 weeks ( P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FE Na) and potassium, without affecting FE of lithium. Linagliptin-induced change in FE Na correlated with SDF-1α ( R = 0.660) but not with other DPP-4 substrates. CONCLUSIONS: Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.

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U2 - 10.2337/dc20-0902

DO - 10.2337/dc20-0902

M3 - Article

C2 - 32900785

SN - 0149-5992

VL - 43

SP - 2889

EP - 2893

JO - Diabetes Care

JF - Diabetes Care

IS - 11

ER -

Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial

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