Postprandial renal haemodynamic effect of lixisenatide vs once-daily insulin-glulisine in patients with type 2 diabetes on insulin-glargine: An 8-week, randomised, open-label trial

Lennart Tonneijck*, Marcel H.A. Muskiet, Mark M. Smits, Trynke Hoekstra, Mark H.H. Kramer, A. H.Jan Danser, Michaela Diamant, Jaap A. Joles, Daniël H. van Raalte

*Corresponding author for this work

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Abstract

Aim: To determine whether lixisenatide, a prandial short-acting glucagon-like peptide receptor agonist (GLP-1RA), ameliorates postprandial glomerular hyperfiltration in patients with type 2 diabetes mellitus (T2DM) compared with insulin-glulisine (iGlu). Methods: Postprandial renal haemodynamic effects of 8-week treatment with lixisenatide 20 µg vs once-daily titrated iGlu were measured in 35 overweight patients with T2DM inadequately controlled on insulin-glargine, with or without metformin [mean ± SD age 62 ± 7 years, HbA1c 8.0% ± 0.9%, estimated glomerular filtration rate (GFR) 85 ± 12 mL/min/1.73 m2, median (IQR) urinary albumin/creatinine ratio 1.5 (0.9-3.0) mg/mmol]. After a standardised breakfast, GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid renal clearance, respectively, based on timed urine sampling. Intrarenal haemodynamic functions were estimated using Gomez equations. Results: Compared with iGlu, lixisenatide did not affect GFR [+0.1 mL/min/1.73 m2 (95% CI −9 to 9)], ERPF [−17 mL/min/1.73 m2 (−61 to 26)], other (intra-)renal haemodynamics or renal damage markers, but increased fractional sodium excretion [+0.25% (0.09-0.41)] and urinary pH [+0.7 (0.3-1.2)]. Plasma renin, angiotensin-II and aldosterone were unchanged. Lixisenatide and iGlu reduced HbA1c similarly, by 0.8% ± 0.1% and 0.6% ± 0.1%, respectively, while postprandial glucose was lower with lixisenatide (P =.002). Compared with iGlu, lixisenatide reduced bodyweight [−1.4 kg (−2.5 to −0.2)] and increased postprandial mean arterial pressure [+9 mm Hg (4-14)]. Conclusion: Eight-week lixisenatide treatment does not affect postprandial (intra-)renal haemodynamics compared with iGlu when added to insulin-glargine in patients with T2DM without overt nephropathy. Prolonged lixisenatide treatment has a sustained natriuretic effect, which is in contrast to previous reports on long-acting GLP-1RA, reduces body weight and increases postprandial blood pressure compared with iGlu. 

Original languageEnglish
Pages (from-to)1669-1680
Number of pages12
JournalDiabetes, Obesity and Metabolism
Volume19
Issue number12
Early online date27 Apr 2017
DOIs
Publication statusPublished - Dec 2017

Funding

The authors thank all the patients for their dedicated participation in the demanding study protocol. The authors also thank J. Boerop and S. Gassman (Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands) for their excellent practical support during the test visits. The technical laboratory assistance of A. Dijk and N. Willekes-Koolschijn (Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands) was much appreciated. The authors thank R.G. IJzerman for his clinical guidance whenever that was needed during the study. Parts of these data were presented at the Annual Dutch Diabetes Research Meeting in Oosterbeek, the Netherlands, in December 2016. D. H. v. R. serves on the Sanofi-Aventis advisory board. Through M. H. H. K. the VU University Medical Center received research grants from AstraZeneca, Boehringer Ingelheim, Novo Nordisk and Sanofi-Aventis. The other authors declare no competing interests relevant to this manuscript. L. Tonneijck designed the study, performed the measurements, analysed and interpreted the data, and drafted and completed the final manuscript. M. H. A. Muskiet designed the study, performed measurements and interpreted the data, and contributed to the drafting and critical revision of the manuscript. M. Diamant designed the study, and was initially involved in the discussion and supervision. T. Hoekstra was involved in the statistical analyses and contributed to the critical revision of the manuscript. M. M. Smits, M. H. H. Kramer, A. H. J. Danser, J. A. Joles and D. H. van Raalte contributed to the interpretation of the data, discussion of the intellectual content and critical editing of the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. L. Tonneijck takes responsibility for the integrity of the data and the accuracy of the data analyses.

FundersFunder number
AstraZeneca
Sanofi
Boehringer Ingelheim
Novo Nordisk

    Keywords

    • diabetes
    • glomerular filtration rate
    • glomerular hyperfiltration
    • glomerular pressure
    • GLP-1 receptor agonist
    • glucagon-like peptide-1
    • insulin-glulisine
    • lixisenatide
    • natriuresis
    • renal function
    • renal haemodynamics
    • type 2 diabetes

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