View Article PDF

In a 2007 viewpoint article in this Journal, Benatar and Stewart1 posed the question "Is it time to stop treating dyslipidaemia with fibrates?". Their main points were that the success of statin therapy for dyslipidaemia made fibrates redundant, and that there was only equivocal evidence for decreased mortality with fibrate therapy. Although they did not question the safety of fibrates, others have; this safety has been reviewed and affirmed2,3 and the case made for the use of fibrates in conjunction with statins, especially for the treatment of combined dyslipidaemia in patients with the metabolic syndrome or Type 2 diabetes, elevated plasma triglycerides and low HDL-cholesterol.4-8 Statins are well-known to be highly effective, but despite optimal treatment with statins and while achieving LDL-cholesterol treatment goals, 65-75% of the cardiovascular disease risk persists.8,9 It is now accepted that fibrates reduce the risk in patients with persistent elevated triglyceride and low HDL-cholesterol which persist even with high doses of statins.4,6,9 Prospective studies to quantify the clinical value of these agents are still in progress. One of the concerns raised about fibrate therapy is the apparent effect on renal function, and in particular the elevation of plasma homocysteine. The commonly observed rise in plasma creatinine and homocysteine has been interpreted to indicate the apparent impairment of renal function, although these changes may not be associated with a change in the glomerular filtration rate.10 In the FIELD study (on patients with Type 2 diabetes) fenofibrate was found to reduce the incidence of renal complications,11 and fibrates decrease microalbuminuria.12Nevertheless the elevation in homocysteine has been suggested as a limitation on the effectiveness of fibrates13 although the implied causal connection has been questioned.14 We have shown that the elevation of homocysteine by bezafibrate is associated with a greatly increased excretion of betaine in the urine.15 A probable primary renal effect of fibrates is to increase betaine excretion. The fractional clearance of betaine in these patients is often in excess of 100%, implying an active process, and this contrasts with normal betaine excretion which is minimal even after a betaine load (< 2% of dose).16 It is likely that the effect on betaine excretion is particularly pronounced in patients with dyslipidaemia or other features of the metabolic syndrome, many of whom may lose excessive betaine without drug treatment,17 and since this population is the one that is most likely to be prescribed fibrates, it is not surprising that New Zealand patients being treated with bezafibrate are losing so much betaine. Although betaine loss from fibrates is variable the daily loss through the urine exceeds the normal dietary intake of betaine in some patients; the median intake of the New Zealand population is about 220 mg/day.18 Betaine is probably the most important osmolyte used by tissues for cell volume regulation, and additionally it functions as a store of methyl groups which are needed for the synthesis of creatine phosphate, phospholipids and for the epigenetic control of gene expression.16,19 Excessive betaine loss means that more choline must be oxidized to betaine to correct the betaine deficit, thus placing stress on the supply of choline, which in itself is an essential nutrient with many important biological functions. Betaine can be easily replaced by supplementation.20 It is a natural by-product of the sugar beet industry, and long-term betaine supplementation is safe and socially acceptable. Health food shops often market betaine, also called "trimethylglycine" (TMG), as a nutritional supplement with extravagant claims for its benefits in a wide range of diseases and although most of these have not been substantiated by controlled trials, there are good grounds for believing that the supply of betaine is relevant to health.16,19 Betaine is widely used in the animal industries as a long-term additive to animal feeds because this decreases body fat and increases the proportion of lean meat.21,22Comparable long-term supplementation data is not available for any human population, but there is cross-sectional evidence that plasma betaine negatively correlates with important lipid cardiovascular risk factors such as plasma triglycerides, percent body fat and especially non-HDL cholesterol.23 Betaine appears to affect the partitioning of lipids between tissues and blood, and limitations in the supply of betaine are probably a feature of the metabolic syndrome.16It is also well-established that modest betaine supplementation lowers plasma homocysteine in humans.24-27 The betaine supply is the main determinant of non-fasting homocysteine,16 and we believe that the loss caused by fibrates is the main reason why fibrate therapy is associated with elevations in plasma homocysteine. The interaction between betaine and lipids means that the loss of betaine induces a betaine deficiency which will also compromise the effectiveness of the fibrate in improving the lipid profile. Therefore, we conclude that fibrate therapy combined with betaine supplementation should be an attractive therapeutic option. The level of supplementation that is added to pig and poultry feed corresponds to about 2 gm betaine a day in a human population, or about ten times the median daily New Zealand intake. Although the dietary betaine intake can be raised by increasing the consumption of whole wheat products and high betaine vegetables of the beet family, long-term intakes of more than about 850 mg/day cannot be achieved by dietary modification alone (Elmslie, unpublished data). Large increases in dietary betaine intake are likely to be associated with substantial increases in total energy intakes, but we have shown that dietary betaine and betaine supplied in the form of supplements have similar effects.20 Much higher levels of supplementation than those proposed have been used in human populations without ill effects.16,19 Such modest supplementation would be easy to achieve, and is close to that which has been shown recently to improve athletic performance.28,29 The cost of supplementation would be less than $NZ0.50 per day. This level of supplementation may be beneficial by itself, but if combined with fibrate it would be expected to completely compensate for the increased betaine loss. A predicted marker of compensation should be lowered plasma homocysteine, which in many of these patients is presumed to be a marker of betaine deficiency. This should remove one of the concerns about using fibrates, and could be recommended on the basis of present evidence, however there will still be a need for prospective studies to see if the combination of fibrate and betaine delivers the long-term health outcomes that fibrate treatment would be expected to achieve, but without the equivocation in the results of previous trials. The combination should offer benefits that are complementary to those of statins, and answer the question posed in 2007 by Benatar and Stewart.1 Competing interests: None. Author information: Michael Lever, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Peter M George, Clinical Director, Canterbury Health Laboratories, Christchurch; Sandy Slow, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Jane L Elmslie, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Brett I Shand, Scientific Officer, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Russell S Scott, Director, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Stephen T Chambers, Professor, Department of Pathology, University of Otago, Christchurch

Summary

Abstract

Because most of the cardiac risk remains despite successful statin therapy there has been renewed interest in fibrate therapy for persisting hyperlipidaemia. Fibrate therapy lowers triglycerides but causes the urinary loss of betaine, which is an essential metabolite that is involved in osmoregulation, in methyl group metabolism, and which also affects lipid partitioning in the body. Loss of betaine is associated with an elevation of homocysteine and may compromise the potential benefits of fibrate therapy. However, betaine deficiency could be easily and inexpensively corrected by concurrent betaine supplementation. Clinical trials of combinations of betaine and fibrate, to complement statin therapy, are needed to determine the value of these agents in reducing the residual cardiovascular disease risk.

Aim

Method

Results

Conclusion

Author Information

Michael Lever, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Peter M George, Clinical Director, Canterbury Health Laboratories, Christchurch; Sandy Slow, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Jane L Elmslie, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Brett I Shand, Scientific Officer, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Russell S Scott, Director, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Stephen T Chambers, Professor, Department of Pathology, University of Otago, Christchurch

Acknowledgements

We have received support from the National Heart Foundation of New Zealand and from the Paykel Trust.

Correspondence

Dr Michael Lever, Scientific Officer, Canterbury Health Laboratories, PO Box 151, Christchurch 8140, New Zealand.

Correspondence Email

michael.lever@otago.ac.nz

Competing Interests

None.

- Benatar JR, Stewart RA. Is it time to stop treating dyslipidaemia with fibrates? N Z Med J. 2007;120(1261).http://www.nzma.org.nz/journal/120-1261/2706/content.pdf-- Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99[suppl]:3C-18C.-- Brown WV. Expert Commentary: The safety of fibrates in lipid-lowering therapy. Am J Cardiol. 2007;99[suppl]:19C-21C.-- Brinton EA. Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio? Curr Atheroscler Rep. 2008;10:25-32.-- 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.-- Tziomalos K, Atyhros VG, Karagiannis A, et al. Triglycerides and vascular risk: Insights from epidemiological data and interventional studies. Current Drug Targets. 2009;10:320-7.-- Rosenson RS. Management of non-high-density lipoprotein abnormalities. Atherosclerosis. 2009;207:328-35.-- Reiner 017d. Combined therapy in the treatment of dyslipidemia. Fundament Clin Pharmacol. 2010;24:19-28.-- Fruchart JC, Sacks FM, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diab Vasc Dis Res. 2008;5:319-35.-- Hottelart C, El Esper N, Archard JM, et al. Fenofibrate increases blood creatinine, but dies not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie. 1999;20:41-4.-- 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.-- Ansquer JC, Foucher C, Rattier S, et al. 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.-- Taskinen M-R, Sullivan DR, Ehnholm C, et al. 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;29:950-5.-- Lacut K, Le Gal G, Abalain J-H, et al. Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: Role of drug induced homocysteinemia? Thrombosis Res. 2008;122:314-9.-- Lever M, George PM, Slow S, Elmslie JL, Scott RS, Richards AM, Fink JN, Chambers ST. Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine. Cardiovasc Drugs Ther. 2009;23:395-401.-- Lever M, Slow S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem. 2010;43:732-744.-- 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.-- Slow S, Donnaggio M, Cressey PJ, Lever M, George PM, Chambers ST. The betaine content of New Zealand foods and estimated intake in the New Zealand diet. J Food Comp Anal. 2005;18:473-85.-- Craig SAS, Betaine in human nutrition. Am J Clin Nutr. 2004;80:539-49.-- 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;19:767-73.-- Eklund M, Bauer E, Wamatu J, Mosenthin R. Potential nutritional and physiological functions of betaine in livestock. Nutr Res Rev. 2005;18:31-48.-- Ratriyanto A, Mosenthin R, Bauer E, Eklund M. Metabolic, osmoregulatory and nutritional functions of betaine in monogastric animals. Asian-Austral J Animal Sci 2009;22:1461-76.-- Konstantinova SV, Tell GS, Vollset SE, et al. 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.-- Schwab U, T 00f6rr 00f6nen A, Toppinen L, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr. 2002;76:961-7.-- 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.-- Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr. 2003;133:1291-5.-- Olthof MR, Verhoef P. Effect of betaine intake on plasma homocysteine concentrations and consequences for health. Current Drug Metab. 2005;6:15-22.-- Armstrong LE, Casa DJ, Roti MW, et al. Influence of betaine consumption on strenuous running and sprinting in a hot environment. J Strength Cond Res. 2008;22:851-60.-- Hoffman J, Ratamess N, Kang J, et al. Effect of betaine supplementation on power performance and fatigue. J Internat Soc Sports Nutr. 2009;6:7.-

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

In a 2007 viewpoint article in this Journal, Benatar and Stewart1 posed the question "Is it time to stop treating dyslipidaemia with fibrates?". Their main points were that the success of statin therapy for dyslipidaemia made fibrates redundant, and that there was only equivocal evidence for decreased mortality with fibrate therapy. Although they did not question the safety of fibrates, others have; this safety has been reviewed and affirmed2,3 and the case made for the use of fibrates in conjunction with statins, especially for the treatment of combined dyslipidaemia in patients with the metabolic syndrome or Type 2 diabetes, elevated plasma triglycerides and low HDL-cholesterol.4-8 Statins are well-known to be highly effective, but despite optimal treatment with statins and while achieving LDL-cholesterol treatment goals, 65-75% of the cardiovascular disease risk persists.8,9 It is now accepted that fibrates reduce the risk in patients with persistent elevated triglyceride and low HDL-cholesterol which persist even with high doses of statins.4,6,9 Prospective studies to quantify the clinical value of these agents are still in progress. One of the concerns raised about fibrate therapy is the apparent effect on renal function, and in particular the elevation of plasma homocysteine. The commonly observed rise in plasma creatinine and homocysteine has been interpreted to indicate the apparent impairment of renal function, although these changes may not be associated with a change in the glomerular filtration rate.10 In the FIELD study (on patients with Type 2 diabetes) fenofibrate was found to reduce the incidence of renal complications,11 and fibrates decrease microalbuminuria.12Nevertheless the elevation in homocysteine has been suggested as a limitation on the effectiveness of fibrates13 although the implied causal connection has been questioned.14 We have shown that the elevation of homocysteine by bezafibrate is associated with a greatly increased excretion of betaine in the urine.15 A probable primary renal effect of fibrates is to increase betaine excretion. The fractional clearance of betaine in these patients is often in excess of 100%, implying an active process, and this contrasts with normal betaine excretion which is minimal even after a betaine load (< 2% of dose).16 It is likely that the effect on betaine excretion is particularly pronounced in patients with dyslipidaemia or other features of the metabolic syndrome, many of whom may lose excessive betaine without drug treatment,17 and since this population is the one that is most likely to be prescribed fibrates, it is not surprising that New Zealand patients being treated with bezafibrate are losing so much betaine. Although betaine loss from fibrates is variable the daily loss through the urine exceeds the normal dietary intake of betaine in some patients; the median intake of the New Zealand population is about 220 mg/day.18 Betaine is probably the most important osmolyte used by tissues for cell volume regulation, and additionally it functions as a store of methyl groups which are needed for the synthesis of creatine phosphate, phospholipids and for the epigenetic control of gene expression.16,19 Excessive betaine loss means that more choline must be oxidized to betaine to correct the betaine deficit, thus placing stress on the supply of choline, which in itself is an essential nutrient with many important biological functions. Betaine can be easily replaced by supplementation.20 It is a natural by-product of the sugar beet industry, and long-term betaine supplementation is safe and socially acceptable. Health food shops often market betaine, also called "trimethylglycine" (TMG), as a nutritional supplement with extravagant claims for its benefits in a wide range of diseases and although most of these have not been substantiated by controlled trials, there are good grounds for believing that the supply of betaine is relevant to health.16,19 Betaine is widely used in the animal industries as a long-term additive to animal feeds because this decreases body fat and increases the proportion of lean meat.21,22Comparable long-term supplementation data is not available for any human population, but there is cross-sectional evidence that plasma betaine negatively correlates with important lipid cardiovascular risk factors such as plasma triglycerides, percent body fat and especially non-HDL cholesterol.23 Betaine appears to affect the partitioning of lipids between tissues and blood, and limitations in the supply of betaine are probably a feature of the metabolic syndrome.16It is also well-established that modest betaine supplementation lowers plasma homocysteine in humans.24-27 The betaine supply is the main determinant of non-fasting homocysteine,16 and we believe that the loss caused by fibrates is the main reason why fibrate therapy is associated with elevations in plasma homocysteine. The interaction between betaine and lipids means that the loss of betaine induces a betaine deficiency which will also compromise the effectiveness of the fibrate in improving the lipid profile. Therefore, we conclude that fibrate therapy combined with betaine supplementation should be an attractive therapeutic option. The level of supplementation that is added to pig and poultry feed corresponds to about 2 gm betaine a day in a human population, or about ten times the median daily New Zealand intake. Although the dietary betaine intake can be raised by increasing the consumption of whole wheat products and high betaine vegetables of the beet family, long-term intakes of more than about 850 mg/day cannot be achieved by dietary modification alone (Elmslie, unpublished data). Large increases in dietary betaine intake are likely to be associated with substantial increases in total energy intakes, but we have shown that dietary betaine and betaine supplied in the form of supplements have similar effects.20 Much higher levels of supplementation than those proposed have been used in human populations without ill effects.16,19 Such modest supplementation would be easy to achieve, and is close to that which has been shown recently to improve athletic performance.28,29 The cost of supplementation would be less than $NZ0.50 per day. This level of supplementation may be beneficial by itself, but if combined with fibrate it would be expected to completely compensate for the increased betaine loss. A predicted marker of compensation should be lowered plasma homocysteine, which in many of these patients is presumed to be a marker of betaine deficiency. This should remove one of the concerns about using fibrates, and could be recommended on the basis of present evidence, however there will still be a need for prospective studies to see if the combination of fibrate and betaine delivers the long-term health outcomes that fibrate treatment would be expected to achieve, but without the equivocation in the results of previous trials. The combination should offer benefits that are complementary to those of statins, and answer the question posed in 2007 by Benatar and Stewart.1 Competing interests: None. Author information: Michael Lever, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Peter M George, Clinical Director, Canterbury Health Laboratories, Christchurch; Sandy Slow, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Jane L Elmslie, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Brett I Shand, Scientific Officer, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Russell S Scott, Director, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Stephen T Chambers, Professor, Department of Pathology, University of Otago, Christchurch

Summary

Abstract

Because most of the cardiac risk remains despite successful statin therapy there has been renewed interest in fibrate therapy for persisting hyperlipidaemia. Fibrate therapy lowers triglycerides but causes the urinary loss of betaine, which is an essential metabolite that is involved in osmoregulation, in methyl group metabolism, and which also affects lipid partitioning in the body. Loss of betaine is associated with an elevation of homocysteine and may compromise the potential benefits of fibrate therapy. However, betaine deficiency could be easily and inexpensively corrected by concurrent betaine supplementation. Clinical trials of combinations of betaine and fibrate, to complement statin therapy, are needed to determine the value of these agents in reducing the residual cardiovascular disease risk.

Aim

Method

Results

Conclusion

Author Information

Michael Lever, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Peter M George, Clinical Director, Canterbury Health Laboratories, Christchurch; Sandy Slow, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Jane L Elmslie, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Brett I Shand, Scientific Officer, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Russell S Scott, Director, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Stephen T Chambers, Professor, Department of Pathology, University of Otago, Christchurch

Acknowledgements

We have received support from the National Heart Foundation of New Zealand and from the Paykel Trust.

Correspondence

Dr Michael Lever, Scientific Officer, Canterbury Health Laboratories, PO Box 151, Christchurch 8140, New Zealand.

Correspondence Email

michael.lever@otago.ac.nz

Competing Interests

None.

- Benatar JR, Stewart RA. Is it time to stop treating dyslipidaemia with fibrates? N Z Med J. 2007;120(1261).http://www.nzma.org.nz/journal/120-1261/2706/content.pdf-- Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99[suppl]:3C-18C.-- Brown WV. Expert Commentary: The safety of fibrates in lipid-lowering therapy. Am J Cardiol. 2007;99[suppl]:19C-21C.-- Brinton EA. Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio? Curr Atheroscler Rep. 2008;10:25-32.-- 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.-- Tziomalos K, Atyhros VG, Karagiannis A, et al. Triglycerides and vascular risk: Insights from epidemiological data and interventional studies. Current Drug Targets. 2009;10:320-7.-- Rosenson RS. Management of non-high-density lipoprotein abnormalities. Atherosclerosis. 2009;207:328-35.-- Reiner 017d. Combined therapy in the treatment of dyslipidemia. Fundament Clin Pharmacol. 2010;24:19-28.-- Fruchart JC, Sacks FM, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diab Vasc Dis Res. 2008;5:319-35.-- Hottelart C, El Esper N, Archard JM, et al. Fenofibrate increases blood creatinine, but dies not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie. 1999;20:41-4.-- 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.-- Ansquer JC, Foucher C, Rattier S, et al. 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.-- Taskinen M-R, Sullivan DR, Ehnholm C, et al. 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;29:950-5.-- Lacut K, Le Gal G, Abalain J-H, et al. Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: Role of drug induced homocysteinemia? Thrombosis Res. 2008;122:314-9.-- Lever M, George PM, Slow S, Elmslie JL, Scott RS, Richards AM, Fink JN, Chambers ST. Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine. Cardiovasc Drugs Ther. 2009;23:395-401.-- Lever M, Slow S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem. 2010;43:732-744.-- 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.-- Slow S, Donnaggio M, Cressey PJ, Lever M, George PM, Chambers ST. The betaine content of New Zealand foods and estimated intake in the New Zealand diet. J Food Comp Anal. 2005;18:473-85.-- Craig SAS, Betaine in human nutrition. Am J Clin Nutr. 2004;80:539-49.-- 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;19:767-73.-- Eklund M, Bauer E, Wamatu J, Mosenthin R. Potential nutritional and physiological functions of betaine in livestock. Nutr Res Rev. 2005;18:31-48.-- Ratriyanto A, Mosenthin R, Bauer E, Eklund M. Metabolic, osmoregulatory and nutritional functions of betaine in monogastric animals. Asian-Austral J Animal Sci 2009;22:1461-76.-- Konstantinova SV, Tell GS, Vollset SE, et al. 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.-- Schwab U, T 00f6rr 00f6nen A, Toppinen L, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr. 2002;76:961-7.-- 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.-- Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr. 2003;133:1291-5.-- Olthof MR, Verhoef P. Effect of betaine intake on plasma homocysteine concentrations and consequences for health. Current Drug Metab. 2005;6:15-22.-- Armstrong LE, Casa DJ, Roti MW, et al. Influence of betaine consumption on strenuous running and sprinting in a hot environment. J Strength Cond Res. 2008;22:851-60.-- Hoffman J, Ratamess N, Kang J, et al. Effect of betaine supplementation on power performance and fatigue. J Internat Soc Sports Nutr. 2009;6:7.-

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

In a 2007 viewpoint article in this Journal, Benatar and Stewart1 posed the question "Is it time to stop treating dyslipidaemia with fibrates?". Their main points were that the success of statin therapy for dyslipidaemia made fibrates redundant, and that there was only equivocal evidence for decreased mortality with fibrate therapy. Although they did not question the safety of fibrates, others have; this safety has been reviewed and affirmed2,3 and the case made for the use of fibrates in conjunction with statins, especially for the treatment of combined dyslipidaemia in patients with the metabolic syndrome or Type 2 diabetes, elevated plasma triglycerides and low HDL-cholesterol.4-8 Statins are well-known to be highly effective, but despite optimal treatment with statins and while achieving LDL-cholesterol treatment goals, 65-75% of the cardiovascular disease risk persists.8,9 It is now accepted that fibrates reduce the risk in patients with persistent elevated triglyceride and low HDL-cholesterol which persist even with high doses of statins.4,6,9 Prospective studies to quantify the clinical value of these agents are still in progress. One of the concerns raised about fibrate therapy is the apparent effect on renal function, and in particular the elevation of plasma homocysteine. The commonly observed rise in plasma creatinine and homocysteine has been interpreted to indicate the apparent impairment of renal function, although these changes may not be associated with a change in the glomerular filtration rate.10 In the FIELD study (on patients with Type 2 diabetes) fenofibrate was found to reduce the incidence of renal complications,11 and fibrates decrease microalbuminuria.12Nevertheless the elevation in homocysteine has been suggested as a limitation on the effectiveness of fibrates13 although the implied causal connection has been questioned.14 We have shown that the elevation of homocysteine by bezafibrate is associated with a greatly increased excretion of betaine in the urine.15 A probable primary renal effect of fibrates is to increase betaine excretion. The fractional clearance of betaine in these patients is often in excess of 100%, implying an active process, and this contrasts with normal betaine excretion which is minimal even after a betaine load (< 2% of dose).16 It is likely that the effect on betaine excretion is particularly pronounced in patients with dyslipidaemia or other features of the metabolic syndrome, many of whom may lose excessive betaine without drug treatment,17 and since this population is the one that is most likely to be prescribed fibrates, it is not surprising that New Zealand patients being treated with bezafibrate are losing so much betaine. Although betaine loss from fibrates is variable the daily loss through the urine exceeds the normal dietary intake of betaine in some patients; the median intake of the New Zealand population is about 220 mg/day.18 Betaine is probably the most important osmolyte used by tissues for cell volume regulation, and additionally it functions as a store of methyl groups which are needed for the synthesis of creatine phosphate, phospholipids and for the epigenetic control of gene expression.16,19 Excessive betaine loss means that more choline must be oxidized to betaine to correct the betaine deficit, thus placing stress on the supply of choline, which in itself is an essential nutrient with many important biological functions. Betaine can be easily replaced by supplementation.20 It is a natural by-product of the sugar beet industry, and long-term betaine supplementation is safe and socially acceptable. Health food shops often market betaine, also called "trimethylglycine" (TMG), as a nutritional supplement with extravagant claims for its benefits in a wide range of diseases and although most of these have not been substantiated by controlled trials, there are good grounds for believing that the supply of betaine is relevant to health.16,19 Betaine is widely used in the animal industries as a long-term additive to animal feeds because this decreases body fat and increases the proportion of lean meat.21,22Comparable long-term supplementation data is not available for any human population, but there is cross-sectional evidence that plasma betaine negatively correlates with important lipid cardiovascular risk factors such as plasma triglycerides, percent body fat and especially non-HDL cholesterol.23 Betaine appears to affect the partitioning of lipids between tissues and blood, and limitations in the supply of betaine are probably a feature of the metabolic syndrome.16It is also well-established that modest betaine supplementation lowers plasma homocysteine in humans.24-27 The betaine supply is the main determinant of non-fasting homocysteine,16 and we believe that the loss caused by fibrates is the main reason why fibrate therapy is associated with elevations in plasma homocysteine. The interaction between betaine and lipids means that the loss of betaine induces a betaine deficiency which will also compromise the effectiveness of the fibrate in improving the lipid profile. Therefore, we conclude that fibrate therapy combined with betaine supplementation should be an attractive therapeutic option. The level of supplementation that is added to pig and poultry feed corresponds to about 2 gm betaine a day in a human population, or about ten times the median daily New Zealand intake. Although the dietary betaine intake can be raised by increasing the consumption of whole wheat products and high betaine vegetables of the beet family, long-term intakes of more than about 850 mg/day cannot be achieved by dietary modification alone (Elmslie, unpublished data). Large increases in dietary betaine intake are likely to be associated with substantial increases in total energy intakes, but we have shown that dietary betaine and betaine supplied in the form of supplements have similar effects.20 Much higher levels of supplementation than those proposed have been used in human populations without ill effects.16,19 Such modest supplementation would be easy to achieve, and is close to that which has been shown recently to improve athletic performance.28,29 The cost of supplementation would be less than $NZ0.50 per day. This level of supplementation may be beneficial by itself, but if combined with fibrate it would be expected to completely compensate for the increased betaine loss. A predicted marker of compensation should be lowered plasma homocysteine, which in many of these patients is presumed to be a marker of betaine deficiency. This should remove one of the concerns about using fibrates, and could be recommended on the basis of present evidence, however there will still be a need for prospective studies to see if the combination of fibrate and betaine delivers the long-term health outcomes that fibrate treatment would be expected to achieve, but without the equivocation in the results of previous trials. The combination should offer benefits that are complementary to those of statins, and answer the question posed in 2007 by Benatar and Stewart.1 Competing interests: None. Author information: Michael Lever, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Peter M George, Clinical Director, Canterbury Health Laboratories, Christchurch; Sandy Slow, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Jane L Elmslie, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Brett I Shand, Scientific Officer, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Russell S Scott, Director, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Stephen T Chambers, Professor, Department of Pathology, University of Otago, Christchurch

Summary

Abstract

Because most of the cardiac risk remains despite successful statin therapy there has been renewed interest in fibrate therapy for persisting hyperlipidaemia. Fibrate therapy lowers triglycerides but causes the urinary loss of betaine, which is an essential metabolite that is involved in osmoregulation, in methyl group metabolism, and which also affects lipid partitioning in the body. Loss of betaine is associated with an elevation of homocysteine and may compromise the potential benefits of fibrate therapy. However, betaine deficiency could be easily and inexpensively corrected by concurrent betaine supplementation. Clinical trials of combinations of betaine and fibrate, to complement statin therapy, are needed to determine the value of these agents in reducing the residual cardiovascular disease risk.

Aim

Method

Results

Conclusion

Author Information

Michael Lever, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Peter M George, Clinical Director, Canterbury Health Laboratories, Christchurch; Sandy Slow, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Jane L Elmslie, Scientific Officer, Biochemistry Unit, Canterbury Health Laboratories, Christchurch; Brett I Shand, Scientific Officer, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Russell S Scott, Director, Lipid and Diabetes Research Group, Canterbury District Health Board, Christchurch; Stephen T Chambers, Professor, Department of Pathology, University of Otago, Christchurch

Acknowledgements

We have received support from the National Heart Foundation of New Zealand and from the Paykel Trust.

Correspondence

Dr Michael Lever, Scientific Officer, Canterbury Health Laboratories, PO Box 151, Christchurch 8140, New Zealand.

Correspondence Email

michael.lever@otago.ac.nz

Competing Interests

None.

- Benatar JR, Stewart RA. Is it time to stop treating dyslipidaemia with fibrates? N Z Med J. 2007;120(1261).http://www.nzma.org.nz/journal/120-1261/2706/content.pdf-- Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99[suppl]:3C-18C.-- Brown WV. Expert Commentary: The safety of fibrates in lipid-lowering therapy. Am J Cardiol. 2007;99[suppl]:19C-21C.-- Brinton EA. Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio? Curr Atheroscler Rep. 2008;10:25-32.-- 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.-- Tziomalos K, Atyhros VG, Karagiannis A, et al. Triglycerides and vascular risk: Insights from epidemiological data and interventional studies. Current Drug Targets. 2009;10:320-7.-- Rosenson RS. Management of non-high-density lipoprotein abnormalities. Atherosclerosis. 2009;207:328-35.-- Reiner 017d. Combined therapy in the treatment of dyslipidemia. Fundament Clin Pharmacol. 2010;24:19-28.-- Fruchart JC, Sacks FM, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diab Vasc Dis Res. 2008;5:319-35.-- Hottelart C, El Esper N, Archard JM, et al. Fenofibrate increases blood creatinine, but dies not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie. 1999;20:41-4.-- 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.-- Ansquer JC, Foucher C, Rattier S, et al. 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.-- Taskinen M-R, Sullivan DR, Ehnholm C, et al. 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;29:950-5.-- Lacut K, Le Gal G, Abalain J-H, et al. Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: Role of drug induced homocysteinemia? Thrombosis Res. 2008;122:314-9.-- Lever M, George PM, Slow S, Elmslie JL, Scott RS, Richards AM, Fink JN, Chambers ST. Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine. Cardiovasc Drugs Ther. 2009;23:395-401.-- Lever M, Slow S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem. 2010;43:732-744.-- 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.-- Slow S, Donnaggio M, Cressey PJ, Lever M, George PM, Chambers ST. The betaine content of New Zealand foods and estimated intake in the New Zealand diet. J Food Comp Anal. 2005;18:473-85.-- Craig SAS, Betaine in human nutrition. Am J Clin Nutr. 2004;80:539-49.-- 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;19:767-73.-- Eklund M, Bauer E, Wamatu J, Mosenthin R. Potential nutritional and physiological functions of betaine in livestock. Nutr Res Rev. 2005;18:31-48.-- Ratriyanto A, Mosenthin R, Bauer E, Eklund M. Metabolic, osmoregulatory and nutritional functions of betaine in monogastric animals. Asian-Austral J Animal Sci 2009;22:1461-76.-- Konstantinova SV, Tell GS, Vollset SE, et al. 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.-- Schwab U, T 00f6rr 00f6nen A, Toppinen L, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr. 2002;76:961-7.-- 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.-- Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr. 2003;133:1291-5.-- Olthof MR, Verhoef P. Effect of betaine intake on plasma homocysteine concentrations and consequences for health. Current Drug Metab. 2005;6:15-22.-- Armstrong LE, Casa DJ, Roti MW, et al. Influence of betaine consumption on strenuous running and sprinting in a hot environment. J Strength Cond Res. 2008;22:851-60.-- Hoffman J, Ratamess N, Kang J, et al. Effect of betaine supplementation on power performance and fatigue. J Internat Soc Sports Nutr. 2009;6:7.-

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