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1 September 2013
Fibrates and adiponectin: pleiotropic effects on residual cardiovascular risk?

A recent meta-analysis suggests that treatment with a fibrate increases circulating levels of adiponectin, an adipokine which plays a key role in the maintenance of energy balance and homeostasis. Whether this contributes to the reduction in residual cardiovascular risk in dyslipidaemic subjects treated with a fibrate merits further study.

Sahebkar A, Watts GF. Fibrate therapy and circulating adiponectin concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials. Atherosclerosis 2013 doi: 10.1016/j.atherosclerosis.2013.06.026 [Epub ahead of print].
Summary
Comments & References
STUDY SUMMARY
Objective Based on evidence of an inverse association between plasma adiponectin levels and development of cardiovascular outcomes, this study investigated available clinical trial evidence relating to the impact of fibrate therapy on circulating adiponectin levels
Study design Systematic review and meta-analysis of randomized placebo-controlled trials of fibrate therapy including adiponectin measurement
Study population

769 subjects (with dyslipidaemia, type 2 diabetes, coronary artery disease, metabolic syndrome, obesity and/or human immunodeficiency infection) in 12 randomized placebo-controlled studies (10 with fenofibrate, dose range 145-200 mg/day and 2 with bezafibrate 400 mg/day).

Primary variable • Plasma or serum adiponectin measurement
Methods

A MEDLINE search was conducted using the terms “fibrate” OR “fibric acid” OR “fenofibrate” OR “bezafibrate” OR “ciprofibrate” OR “clofibrate” OR “gemfibrozil” OR “procetofen” OR "clofibric acid", and all of the above terms were combined with “adiponectin. Studies were included if they satisfied the following criteria: placebo-controlled, case-control or case-cross-over design, (ii) investigated the effect of fibrate monotherapy on circulating levels of adiponectin, (iii) baseline and post-trial concentrations of adiponectin and iv) published in a peer-reviewed journal.

Meta-analysis was performed using a random-effects model. Quality assessment, sensitivity analysis and publication bias evaluations were conducted using standard methods.

Main results

Fibrate treatment had a significant effect in increasing circulating plasma/serum adiponectin levels (weighed mean difference: 0.38 μg/mL; 95% confidence interval: 0.13-0.63 μg/mL; p = 0.003). This effect remained significant when only fenofibrate trials were analysed (0.31 (95% CI 0.21-0.42) μg/mL; p <0.00001). Sensitivity analyses showed that this effect was robust and independent of fibrate dose.

Author's conclusion This meta-analysis suggests that fibrate therapy increases circulating levels of adiponectin. Whether the increase in adiponectin levels contributes to reduction of cardiovascular effects in subjects with dyslipidaemia treated with fibrates merits further investigation.
 

COMMENT

Adiponectin is considered to be a beneficial adipokine given evidence of anti-inflammatory, anti-atherogenic, anti-diabetic and cardioprotective effects and favourable effects on endothelial function.(1,2) Low circulating plasma levels of adiponectin, often observed in overweighted or obese subjects with central fat distribution, are associated with an increased prevalence of cardiometabolic abnormalities, including atherogenic dyslipidaemia, the combination of elevated triglycerides and a low plasma level of high-density lipoprotein cholesterol (HDL-C),(3) itself an important contributor to residual cardiovascular risk.(4,5) Thus, up-regulation of adiponectin and/or its receptors may confer clinical benefits, particularly in the settings of metabolic syndrome and type 2 diabetes.

Fibrates, peroxisome proliferator-activated receptorα (PPARα) agonists have been shown in recent meta-analyses to reduce cardiovascular outcomes, particularly in individuals with atherogenic dyslipidaemia.(6,7) In addition to favourable lipid-modifying activities, including lowering triglyceride-rich lipoproteins, fibrates also exhibit a range of pleiotropic effects which may contribute to the observed cardioprotective effects. Experimental studies suggest – albeit not consistently - that fibrates may increase circulating levels of adiponectin,(8.9) potentially involving PPARα activation, mediated by a downstream effect on the AMP-activated protein kinase (AMPK) pathway, although other mechanisms, including those involving fibroblast growth factor 21, have also been implicated.(10-12)

The results of this meta-analysis show that fibrate monotherapy raises circulating plasma levels of adiponectin, an effect which is independent of triglyceride-lowering effects. Consequently, these data implicate non-lipid, pleiotropic activities of fibrates in the observed reduction in residual cardiovascular risk. Furthermore, taking into consideration the profile of protective effects of adiponectin on vasoreactivity and endothelial function, which include attenuation of vascular inflammation and oxidative stress, inhibition of endothelial cell activation and leukocyte interaction, stimulation of endothelial nitric oxide and suppression of endothelial cell apoptosis,(13) it is possible that increases in adiponectin levels may also contribute to the beneficial effects of fibrates in reducing the residual risk of diabetic microvascular complications, notably diabetic retinopathy and nephropathy, irrespective of baseline triglycerides.(14-16)

While recognising the limitations of sample size and trial heterogeneity of this meta-analysis, the Residual Risk Reduction Initiative suggests that the beneficial effects of fibrates on residual vascular risk in individuals with atherogenic dyslipidemia may also involve non-lipid, pleiotropic activities associated with PPARα activation. The findings from this meta-analysis merit further study to i) explore whether adiponectin is a contributing modifiable factor associated with reduction in residual vascular risk, and ii) whether the effects of adiponectin are also observed following combination lipid-lowering therapy, especially those involving statins.

References

1.  Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005;96:939-49.
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14. Keech AC, Mitchell P, Summanen PA et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97.
15. Keech A, Simes RJ, Barter P et al. 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.
16. Chew EY, Ambrosius WT, Davis MD et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-44.