Impact of L-carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials

Maria-Corina Serban, Amirhossein Sahebkar, Dimitri P Mikhailidis, Peter P Toth, Steven R Jones, Paul Muntner, Michael J Blaha, Florina Andrica, Seth S Martin, Claudia Borza, Gregory Y H Lip, Kausik K Ray, Jacek Rysz, Stanley L Hazen, Maciej Banach, Maria-Corina Serban, Amirhossein Sahebkar, Dimitri P Mikhailidis, Peter P Toth, Steven R Jones, Paul Muntner, Michael J Blaha, Florina Andrica, Seth S Martin, Claudia Borza, Gregory Y H Lip, Kausik K Ray, Jacek Rysz, Stanley L Hazen, Maciej Banach

Abstract

We aimed to assess the impact of L-carnitine on plasma Lp(a) concentrations through systematic review and meta-analysis of available RCTs. The literature search included selected databases up to 31(st) January 2015. Meta-analysis was performed using fixed-effects or random-effect model according to I(2) statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The meta-analysis showed a significant reduction of Lp(a) levels following L-carnitine supplementation (WMD: -8.82 mg/dL, 95% CI: -10.09, -7.55, p < 0.001). When the studies were categorized according to the route of administration, a significant reduction in plasma Lp(a) concentration was observed with oral (WMD: -9.00 mg/dL, 95% CI: -10.29, -7.72, p < 0.001) but not intravenous L-carnitine (WMD: -2.91 mg/dL, 95% CI: -10.22, 4.41, p = 0.436). The results of the meta-regression analysis showed that the pooled estimate is independent of L-carnitine dose (slope: -0.30; 95% CI: -4.19, 3.59; p = 0.878) and duration of therapy (slope: 0.18; 95% CI: -0.22, 0.59; p = 0.374). In conclusion, the meta-analysis suggests a significant Lp(a) lowering by oral L-carnitine supplementation. Taking into account the limited number of available Lp(a)-targeted drugs, L-carnitine might be an effective alternative to effectively reduce Lp(a). Prospective outcome trials will be required to fully elucidate the clinical value and safety of oral L-carnitine supplementation.

Figures

Figure 1. Flow chart of the number…
Figure 1. Flow chart of the number of studies identified and included into the meta-analysis.
Figure 2. Forest plot detailing weighted mean…
Figure 2. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of L-carnitine on plasma Lp(a) concentrations.
Lower plot shows leave-one-out sensitivity analysis.
Figure 3. Forest plot detailing weighted mean…
Figure 3. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of oral L-carnitine on plasma L(a) concentrations.
Lower plot shows leave-one-out sensitivity analysis.
Figure 4. Forest plot detailing weighted mean…
Figure 4. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of intravenous L-carnitine on plasma Lp (a) concentrations.
Lower plot shows leave-one-out sensitivity analysis.
Figure 5. Forest plot detailing weighted mean…
Figure 5. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of L-carnitine on plasma lipids.
Figure 6. Meta-regression plots of the association…
Figure 6. Meta-regression plots of the association between mean changes in plasma Lp(a) concentrations after L-carnitine treatment with dose and duration of treatment.
Figure 7. Funnel plot detailing publication bias…
Figure 7. Funnel plot detailing publication bias in the studies reporting the impact of L-carnitine on plasma Lp(a) concentrations.
Open diamond represents observed effect size; closed diamond represents imputed effect size.

References

    1. Marcovina S. M., Koschinsky M. L., Albers J. J. & Skarlatos S. Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein (a) and Cardiovascular Disease: recent advances and future directions. Clinical chemistry 49, 1785–1796 (2003).
    1. Ramasamy I. Recent advances in physiological lipoprotein metabolism. Clinical Chemistry and Laboratory Medicine (CCLM) 52, 1695–1727 (2014).
    1. Clarke R. et al. Genetic variants associated with Lp (a) lipoprotein level and coronary disease. New England Journal of Medicine 361, 2518–2528 (2009).
    1. Berglund L. & Ramakrishnan R. Lipoprotein (a) an elusive cardiovascular risk factor. Arteriosclerosis, thrombosis, and vascular biology 24, 2219–2226 (2004).
    1. Lippi G. & Guidi G. Biochemical risk factors and patient’s outcome: the case of lipoprotein (a). Clinica chimica acta 280, 59–71 (1999).
    1. Lippi G., Braga V., Adami S. & Guidi G. Modification of serum apolipoprotein AI, apolipoprotein B and lipoprotein (a) levels after bisphosphonates-induced acute phase response. Clinica chimica acta 271, 79–87 (1998).
    1. Mellwig K. et al. [Lipoprotein (a): influence on cardiovascular manifestation.]. Clinical research in cardiology supplements 10, 33–8 (2015).
    1. Bennet A. et al. Lipoprotein (a) levels and risk of future coronary heart disease: large-scale prospective data. Archives of internal medicine 168, 598–608 (2008).
    1. Gurdasani D. et al. Lipoprotein (a) and Risk of Coronary, Cerebrovascular, and Peripheral Artery Disease The EPIC-Norfolk Prospective Population Study. Arteriosclerosis, thrombosis, and vascular biology 32, 3058–3065 (2012).
    1. Collaboration, E. R. F. Lipoprotein (a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA: the journal of the American Medical Association 302, 412 (2009).
    1. Vongpromek R. et al. Lipoprotein (a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia. Journal of internal medicine 278, 166–73 (2015).
    1. Lippi G., Franchini M. & Targher G. Screening and therapeutic management of lipoprotein (a) excess: review of the epidemiological evidence, guidelines and recommendations. Clinica Chimica Acta 412, 797–801 (2011).
    1. Nicholls S. J. et al. Lipoprotein (a) levels and long-term cardiovascular risk in the contemporary era of statin therapy. Journal of lipid research 51, 3055–3061 (2010).
    1. Allen S. et al. Expression of adhesion molecules by Lp (a): a potential novel mechanism for its atherogenicity. The FASEB journal 12, 1765–1776 (1998).
    1. Kang C. et al. Lp (a) Particles Mold Fibrin-Binding Properties of Apo (a) in Size-Dependent Manner A Study With Different-Length Recombinant Apo (a), Native Lp (a), and Monoclonal Antibody. Arteriosclerosis, thrombosis, and vascular biology 22, 1232–1238 (2002).
    1. Tsimikas S., Tsironis L. D. & Tselepis A. D. New insights into the role of lipoprotein (a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arteriosclerosis, thrombosis, and vascular biology 27, 2094–2099 (2007).
    1. Nielsen L. B. Atherogenecity of lipoprotein (a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis 143, 229–243 (1999).
    1. Nordestgaard B. G. et al. Lipoprotein (a) as a cardiovascular risk factor: current status. European heart journal 31, 2844–2853 (2010).
    1. Goldstein L. B. et al. Guidelines for the primary prevention of stroke a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke; a journal of cerebral circulation 42, 517–584 (2011).
    1. Banach M. et al. Lipids, blood pressure and kidney update 2014. Pharmacological Research 95, 111-125 (2015).
    1. Lippi G. & Targher G. Optimal therapy for reduction of lipoprotein (a). Journal of clinical pharmacy and therapeutics 37, 1–3 (2012).
    1. Kotani K. et al. Tibolone can decrease lipoprotein(a) concentrations in postmenopausal women: a systematic review and meta-analysis of controlled trials. Eur Heart J 26(Suppl. 1), 286 (2015).
    1. Kotani K. et al. Tibolone decreases Lipoprotein (a) levels in postmenopausal women: A systematic review and meta-analysis of 12 studies with 1009 patients. Atherosclerosis 242, 87–96 (2015).
    1. Banach M. et al. PCSK9 inhibition-a novel mechanism to treat lipid disorders? Current pharmaceutical design 19, 3869–3877 (2013).
    1. Dragan S., Serban M. C. & Banach M. Proprotein convertase subtilisin/kexin 9 inhibitors: an emerging lipid-lowering therapy ? J Cardiovasc Pharmacol Ther, 20, 157–168 (2015).
    1. Raal F. J. et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. The Lancet 375, 998–1006 (2010).
    1. Ladenson P. W. et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. New England Journal of Medicine 362, 906–916 (2010).
    1. Samaha F. F., McKenney J., Bloedon L. T., Sasiela W. J. & Rader D. J. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nature Clinical Practice Cardiovascular Medicine 5, 497–505 (2008).
    1. Merki E. et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. Journal of the American College of Cardiology 57, 1611–1621 (2011).
    1. Tsimikas S. et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–83 (2015).
    1. Banach M. et al. Lipid, blood pressure and kidney update 2013. International urology and nephrology 46, 947–961 (2014).
    1. Sahebkar A., Serban C., Ursoniu S. & Banach M. Effect of garlic on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled clinical trials. Nutrition. 32, 33–40 (2016).
    1. Broderick T. L. ATP production and TCA activity are stimulated by propionyl-L-carnitine in the diabetic rat heart. Drugs in R & D 9, 83–91 (2008).
    1. Sanchez-Niño M. D. & Ortiz A. Differential effects of oral and intravenous l-carnitine on serum lipids: is the microbiota the answer? Clinical Kidney Journal 7, 437–441 (2014).
    1. Koeth R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature medicine 19, 576–585 (2013).
    1. Koeth R. A. et al. γ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO. Cell metabolism 20, 799–812 (2014).
    1. Moher D., Liberati A., Tetzlaff J., Altman D. G. & Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339, b2535, 10.1136/bmj.b2535 (2009).
    1. Higgins J. (Chichester, UK, John Wiley and Sons Ltd. Ref Type: Report, 2010).
    1. Borenstein M., Hedges L., Higgins J. & Rothstein H. Comprehensive meta-analysis version 2. Englewood, NJ: Biostat 104, (2005).
    1. Hozo S. P., Djulbegovic B. & Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC medical research methodology 5, 13 (2005).
    1. Duval S. & Tweedie R. Trim and fill: a simple funnel‐plot–based method of testing and adjusting for publication bias in meta‐analysis. Biometrics 56, 455–463 (2000).
    1. Green S. Cochrane handbook for systematic reviews of interventions version 5.1. 0 [updated March 2011]. The Cochrane Collaboration (2011).
    1. Rajasekar P. & Anuradha C. L-Carnitine inhibits protein glycation in vitro and in vivo: evidence for a role in diabetic management. Acta diabetologica 44, 83–90 (2007).
    1. Fukami K. et al. Oral L-carnitine supplementation increases trimethylamine-N-oxide, but reduces markers of vascular injury in hemodialysis patients. Journal of cardiovascular pharmacology 65, 289–295 (2015).
    1. Rysz J. et al. Increased levels of soluble TNF-alpha receptors and cellular adhesion molecules in patients undergoing bioincompatible hemodialysis. Am J Nephrol 26, 437–44 (2006).
    1. Wang Z. et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. European heart journal 35, 904–10 (2014).
    1. Wang Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
    1. Tang W. H. et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116, 448–455 (2015).
    1. Bennett B. J. et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell metabolism 17, 49–60 (2013).
    1. Tang W. & Hazen S. L. The contributory role of gut microbiota in cardiovascular disease. The Journal of clinical investigation 124, 4204–4211 (2014).
    1. Shih D. M. et al. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. Journal of lipid research 56, 22–37 (2015).
    1. Warrier M. et al. The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance. Cell reports. 10.1016/j.celrep.2014.12.036.
    1. Miao J. et al. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nature communications 6, 6498 (2015).
    1. DiNicolantonio J. J., Lavie C. J., Fares H., Menezes A. R. & O’Keefe J. H. L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis. Mayo Clinic Proceedings 88, 544–551 (2013).
    1. Sahebkar A. Effect of L-Carnitine Supplementation on Circulating C-Reactive Protein Levels: A Systematic Review and Meta-Analysis. Journal of Medical Biochemistry 34, Pages 151–159, ISSN (Online) (2015).
    1. Shang R., Sun Z. & Li H. Effective dosing of L-carnitine in the secondary prevention of cardiovascular disease: a systematic review and meta-analysis. BMC cardiovascular disorders 14, 88 (2014).
    1. Vidal-Casariego A. et al. Metabolic effects of L-carnitine on type 2 diabetes mellitus: systematic review and meta-analysis. Experimental and clinical endocrinology & diabetes 121, 234–238 (2013).
    1. Huang H., Song L., Zhang H., Zhang J. & Zhao W. Influence of L-Carnitine Supplementation on Serum Lipid Profile in Hemodialysis Patients: A Systematic Review and Meta-Analysis. Kidney & blood pressure research 38, 31–41 (2014).
    1. Chen Y. et al. L-Carnitine supplementation for adults with end-stage kidney disease requiring maintenance hemodialysis: a systematic review and meta-analysis. The American journal of clinical nutrition 99, 408–422 (2014).
    1. Yang S.-k. et al. Effect of L-carnitine therapy on patients in maintenance hemodialysis: a systematic review and meta-analysis. Journal of nephrology 27, 317–329 (2014).
    1. Vacha G. M., Giorcelli G., Siliprandi N. & Corsi M. Favorable effects of L-carnitine treatment on hypertriglyceridemia in hemodialysis patients: decisive role of low levels of high-density lipoprotein-cholesterol. The American journal of clinical nutrition 38, 532–540 (1983).
    1. Golper T. A. et al. Multicenter trial of L-carnitine in maintenance hemodialysis patients. I. Carnitine concentrations and lipid effects. Kidney Int 38, 904–911 (1990).
    1. Derosa G. et al. The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. Clinical therapeutics 25, 1429–1439 (2003).
    1. Galvano F. et al. Effects of simvastatin and carnitine versus simvastatin on lipoprotein(a) and apoprotein(a) in type 2 diabetes mellitus. Expert opinion on pharmacotherapy 10, 1875–1882 (2009).
    1. Shakeri A., Tabibi H. & Hedayati M. Effects of L-carnitine supplement on serum inflammatory cytokines, C-reactive protein, lipoprotein (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia. Hemodialysis international 14, 498–504, (2010).
    1. Shojaei M., Djalali M., Khatami M., Siassi F. & Eshraghian M. Effects of carnitine and coenzyme Q10 on lipid profile and serum levels of lipoprotein(a) in maintenance hemodialysis patients on statin therapy. Iranian journal of kidney diseases 5, 114–118 (2011).
    1. Sirtori C. et al. L-carnitine reduces plasma lipoprotein (a) levels in patients with hyper Lp (a). Nutrition, metabolism, and cardiovascular diseases 10, 247–251 (2000).
    1. Solfrizzi V. et al. Efficacy and tolerability of combined treatment with L-carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus. Atherosclerosis 188, 455–461 (2006).
    1. Zhang J. J. et al. L-carnitine ameliorated fasting-induced fatigue, hunger, and metabolic abnormalities in patients with metabolic syndrome: a randomized controlled study. Nutrition journal 13, 110 (2014).

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