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R3i EDITORIAL

5 January 2013

Addressing the residual burden of CVD in renal impairment: do PPARa agonists provide an answer?

Prof. JC Fruchart, Prof. J. Davignon, Prof. M Hermans

An Editorial from the R3i Trustees
Prof. JC Fruchart, Prof. J. Davignon, Prof. M Hermans Chronic kidney disease (CKD) represents a growing challenge. In the US, one in 10 individuals has some degree of renal impairment, with even higher prevalence among those aged 65 years or more.(1) Data from Europe, although less comprehensive, indicate a similar scenario.(2) CKD is an important determinant of the burden of the major non-communicable diseases, being a risk multiplier in cardiovascular disease (CVD), diabetes and hypertension.(3) Indeed, CKD is acknowledged as a coronary artery disease risk equivalent in recent guidelines, with reduction in low-density lipoprotein cholesterol (LDL-C) the primary focus of therapy.(4) As shown by recent meta-analyses, treatment with a statin confers clinical benefit across the spectrum of CKD.(5,6) However, it is acknowledged that there remains a high residual risk of CV events in CKD patients despite best treatment. Moreover, as shown in the latest meta-analysis of statin therapy in CKD, statin treatment had no benefit on renal events.(5)

Triglyceride-rich lipoproteins as a mediator of CVD in CKD

This month’s Focus article highlights new evidence from the Multi-Ethnic Study of Atherosclerosis (MESA),(7) implying that part of the association between CVD and CKD is mediated via elevations in triglyceride-rich lipoproteins, a key component of atherogenic dyslipidemia. While statins are undoubtedly effective in lowering LDL-C, their effects on atherogenic dyslipidemia, characterised by an increase in triglyceride-rich lipoproteins and low high-density lipoprotein (HDL), are more modest. It is therefore plausible that additional therapy targeting this non-LDL dyslipidemia may help to reduce the residual burden of CVD in CKD patients.

In this context, a case can be made for the peroxisome proliferator-activated receptor alpha (PPARα) agonists, fibrates. These agents are efficacious in reducing elevated triglycerides, a marker of triglyceride-rich lipoproteins. In post hoc analyses, fibrates have been shown to be effective in reducing CV risk in individuals with marked atherogenic dyslipidemia, the combination of elevated triglycerides (≥204 mg/dL or 2.3 mmol/L) and low HDL cholesterol (≤34 mg/dL or 0.88 mmol/L).(8) A recent meta-analysis showed that fibrate therapy (predominantly fenofibrate) improves lipid profiles and reduces CV risk in individuals with CKD, to a similar extent as in those with normal renal function.(9)

However, clinicians may regard the use of fibrates in this population with caution due to safety concerns related to elevation in serum creatinine. Recent findings contribute to allay such concerns. Reports from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study have confirmed that the fenofibrate-related increases in creatinine are reversible.(10,11) Furthermore, the increase in serum creatinine associated with fenofibrate treatment did not appear to carry the same risk of decline in renal function and was reversible following drug wash-out. An analysis from the FIELD study showed no increase in risk of end-stage renal disease or additional safety issues compared with patients with no or mild renal impairment.(12) Indeed, there was evidence of potential renoprotection with fenofibrate, including reduction in secular loss of estimated glomerular filtration rate (eGFR) and albuminuria.(10) Taken together, despite the acute changes in creatinine associated with fenofibrate therapy, the available data indicate long-term clinical benefits. These data merit consideration in guideline review.

The Residual Risk Reduction Initiative (R3i) believes that the addition of a PPARα agonist, which is efficacious in lowering elevated triglyceride-rich lipoproteins, may offer the potential to reduce the residual burden of CVD in patients with CKD. The R3i strongly believes that such evidence should be considered in guidelines for the management of dyslipidemia in CKD. Whether improving the selectivity and potency of agents targeting PPARα may provide further benefit is very much a focus of ongoing research.

References

1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). Kidney Disease Statistics for the United States. http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/#1. Accessed 22 April 2013.
2. Zoccali C, Kramer A, Jager KJ. Epidemiology of CKD in Europe: an uncertain scenario. Nephrol Dial Transplant 2010;25: 1731-3.
3. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int 2011;80:1258-70.
4. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
5. Hou W, Lv J, Perkovic V et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart 2013;Epub ahead of print March 6, 2013.
6. Upadhyay A, Earley A, Lamont JL, Haynes S, Wanner C, Balk EM. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;157:251-62.
7. Lamprea-Montealegre JA, McClelland RL, Astor BC, Matsushita K, Shlipak M, de Boer IH, Szklo M. Chronic kidney disease, plasma lipoproteins, and coronary artery calcium incidence: the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol 2013;33:652-8.
8. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
9. Jun M, Zhu B, Tonelli M, Jardine MJ, Patel A, Neal B, Liyanage T, Keech A, Cass A, Perkovic V. Effects of fibrates in kidney disease: a systematic review and meta-analysis. J Am Coll Cardiol;60:2061-71.
10. Davis TME, Ting R, Best JD et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 2011;54:280–90.
11. Mychaleckyj JC, Craven T, Nayak U et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care 2012;35:1008 –14
12. Ting RD, Keech AC, Drury PL et al. Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care 2012;35:218-25.