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Fibrates may Cause an Abnormal Urinary Betaine Loss Which is Associated with Elevations in Plasma Homocysteine

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Abstract

Purpose

Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion.

Methods

We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups.

Results

Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013).

Conclusions

Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.

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References

  1. Lever M, Sizeland PC, Bason LM, Hayman CM, Robson RA, Chambers ST. Abnormal glycine betaine content of the blood and urine of diabetic and renal patients. Clin Chim Acta. 1994;230:69–79.

    Article  CAS  PubMed  Google Scholar 

  2. Dellow WJ, Chambers ST, Lever M, Lunt H, Robson RA. Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia. Diab Res Clin Pract. 1999;43:91–9.

    Article  CAS  Google Scholar 

  3. Lever M, Sizeland PC, Frampton CM, Chambers ST. Short and long-term variation of plasma glycine betaine concentrations in humans. Clin Biochem. 2004;37:184–90.

    Article  CAS  PubMed  Google Scholar 

  4. Lever M, George PM, Dellow WJ, Scott RS, Chambers ST. Homocysteine, glycine betaine, and N, N-dimethylglycine in patients attending a lipid clinic. Metabolism. 2005;54:1–14.

    Article  CAS  PubMed  Google Scholar 

  5. Broeders N, Knoop C, Antoine M, Tielemans AD. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent? Nephrol Dial Transplant. 2000;15:1993–9.

    Article  CAS  PubMed  Google Scholar 

  6. Lipscombe J, Lewis GF, Cattran D, Bargman JM. Deterioration in renal function associated with fibrate therapy. Clin Nephrol. 2001;55:39–44.

    CAS  PubMed  Google Scholar 

  7. Lin Y-H, Pao K-Y, Wu V-C, Lin Y-L, Chien Y-F, Hung C-S, et al. The influence of estimated creatinine clearance on plasma homocysteine in hypertensive patients with normal serum creatinine. Clin Biochem. 2007;40:230–4.

    Article  CAS  PubMed  Google Scholar 

  8. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99:3C–18C.

    Article  CAS  PubMed  Google Scholar 

  9. Brinton EA. Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio? Curr Atheroscler Rep. 2008;10:25–32.

    Article  CAS  PubMed  Google Scholar 

  10. Hottelart C, El Esper N, Archard JM, Pruna A, Fournier A. Fenofibrate increases blood creatinine, but dies not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie. 1999;20:41–4.

    CAS  PubMed  Google Scholar 

  11. Garcia-Perez A, Burg MB. Renal medullary organic osmolytes. Physiol Rev. 1991;71:1081–115.

    CAS  PubMed  Google Scholar 

  12. Schliess F, Häussinger D. The cellular hydration state: a critical determinant for cell death and survival. Biol Chem. 2002;383:577–83.

    Article  CAS  PubMed  Google Scholar 

  13. Slow S, Lever M, Chambers ST, George PM. Plasma dependent and independent accumulation of betaine in male and female rat tissues. Physiol Res in press (available on-line as pre-press article 1569).

  14. Storer MK. Development of laboratory tests for assessing vitamin status. PhD Thesis, University of Otago, Dunedin, New Zealand 2006.

  15. De Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, et al. The prognostic value of B-type natriuretic peptides in patients with acute coronary syndromes. New Engl J Med. 2001;345:1014–21.

    Article  PubMed  Google Scholar 

  16. Lever M, Sizeland PC, Bason LM, Hayman CM, Chambers ST. Glycine betaine and proline betaine in human blood and urine. Biochim Biophys Acta. 1994;1200:259–64.

    CAS  PubMed  Google Scholar 

  17. Lever M, Atkinson W, Slow S, Chambers ST, George PM. Plasma and urine betaine and dimethylglycine variation in healthy young male subjects. Clin Biochem. 2009;42:706–12.

    Article  CAS  PubMed  Google Scholar 

  18. Storer MK, Lever M. Aracyl triflates for preparing fluorescent and UV absorbing derivatives of unreactive carboxylates, amines and other metabolites. Anal Chim Acta. 2006;558:319–25.

    Article  CAS  Google Scholar 

  19. Storer MK, McEntyre CJ, Lever M. Separation of cationic aracyl derivatives of betaines and related compounds. J Chromatogr A. 2006;1104:263–71.

    Article  CAS  PubMed  Google Scholar 

  20. Lever M, Atkinson W, George PM, Chambers ST. Sex differences in the control of plasma concentrations and urinary excretion of glycine betaine in patients attending a lipid disorders clinic. Clin Biochem. 2007;40:1225–31.

    Article  CAS  PubMed  Google Scholar 

  21. Konstantinova SV, Tell GS, Vollset SE, Nygård O, Bleie Ø, Ueland PM. Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women. J Nutr. 2008;138:914–20.

    CAS  PubMed  Google Scholar 

  22. Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron. 2002;92:536–41.

    Article  CAS  PubMed  Google Scholar 

  23. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.

    Article  Google Scholar 

  24. Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis. 2005;45:485–93.

    Article  CAS  PubMed  Google Scholar 

  25. Lever M, Atkinson W, Chambers ST, George PM. An abnormal urinary excretion of glycine betaine may persist for years. Clin Biochem. 2007;40:798–801.

    Article  CAS  PubMed  Google Scholar 

  26. Watts GF, Dimmitt SB. Fibrates, dyslipoproteinaemia and cardiovascular disease. Curr Opin Lipidol. 1999;10:561–74.

    Article  CAS  PubMed  Google Scholar 

  27. Barter PJ, Rye K-A. Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome? Arterioscler Thromb Vasc Biol. 2008;28:39–46.

    Article  CAS  PubMed  Google Scholar 

  28. Luci S, Geissler S, König B, Koch A, Stangl GI, Hirche F, et al. PPAR-α agonists up-regulate organic cation transporters in rat liver cells. Biochem Biophys Res Comm. 2006;350:704–8.

    Article  CAS  PubMed  Google Scholar 

  29. Ringseis R, Luci S, Spielmann J, Kluge H, Fischer M, Geissler S, et al. Clofibrate treatment up-regulates novel organic cation transporter (OCTN)-2 in tissues of pigs as a model of non-proliferating species. Eur J Pharmacol. 2008;583:11–7.

    Article  CAS  PubMed  Google Scholar 

  30. Wagner CA, Lükewille U, Kaltenbach S, Moschen I, Bröer A, Risler T, et al. Functional and pharmacological characterization of human Na+-carnitine cotransporter hOCTN2. Am J Physiol Renal Physiol. 2000;279:F584–91.

    CAS  PubMed  Google Scholar 

  31. Olthof MR, van Vliet T, Boelsma E, Verhoef P. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J Nutr. 2003;133:4135–8.

    CAS  PubMed  Google Scholar 

  32. Schwab U, Torronen A, Meririnne E, Saarinen M, Alfthan G, Aro A, et al. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. J Nutr. 2006;136:34–8.

    CAS  PubMed  Google Scholar 

  33. Taskinen M-R, Sullivan DR, Ehnholm C, Whiting M, Zannino D, Simes RJ, Keech AC, Barter PJ Relationships of HDL cholesterol, ApoA-I, and ApoA-II with homocysteine and creatinine in patients with type 2 diabetes treated with fenofibrate. Arterioscler Thromb Vasc Biol. 2009;29.

  34. Atkinson W, Elmslie J, Lever M, Chambers ST, George PM. Dietary and supplementary betaine: acute effects on plasma betaine and homocysteine concentrations under standard and post methionine load conditions in healthy male subjects. Am J Clin Nutr. 2008;87:577–85.

    CAS  PubMed  Google Scholar 

  35. Atkinson A, Slow S, Elmslie J, Lever M, Chambers ST, George PM. Dietary and supplementary betaine: effects on betaine and homocysteine concentrations in males. Nutr Metab Cardiovasc Dis. 2009.

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Acknowledgements

Support from the National Heart Foundation of New Zealand, the Neurological Foundation of New Zealand, the Health Research Council of New Zealand, the Canterbury Medical Research Foundation and the Paykel Trust is acknowledged.

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Authors and Affiliations

  1. Biochemistry Unit, Canterbury Health Laboratories, P.O. Box 151, Christchurch, 8140, New Zealand

    Michael Lever, Peter M. George, Sandy Slow & Jane L. Elmslie

  2. Lipid and Diabetes Research Group, Christchurch Hospital, Christchurch, New Zealand

    Russell S. Scott

  3. Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand

    A. Mark Richards

  4. Neurology Department, Christchurch Hospital, Christchurch, New Zealand

    John N. Fink

  5. Pathology Department, University of Otago Christchurch, Christchurch, New Zealand

    Stephen T. Chambers

Authors
  1. Michael Lever
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  2. Peter M. George
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  3. Sandy Slow
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  4. Jane L. Elmslie
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Correspondence to Michael Lever.

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Lever, M., George, P.M., Slow, S. et al. Fibrates may Cause an Abnormal Urinary Betaine Loss Which is Associated with Elevations in Plasma Homocysteine. Cardiovasc Drugs Ther 23, 395–401 (2009). https://doi.org/10.1007/s10557-009-6188-1

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  • DOI: https://doi.org/10.1007/s10557-009-6188-1

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