R3i Editorial

Across the spectrum of cardiometabolic disease, chronic kidney disease (CKD) is largely overlooked. This is despite a similar epidemiology to diabetes in the general population. By the age of 65 years, 10-35% of the general population have at least moderate CKD, and in line with the increasing prevalence of diabetes, a major cause of CKD, this prevalence is growing.(1,2) Given that CKD is now regarded as a coronary risk equivalent in international guidelines,(3) this has drawn attention to the unmet needs of CKD in clinical management.

Acting early to reduce lifetime risk

An early proactive approach to cardiovascular prevention is one strategy to target this burden of disease. Recent evidence shows that being overweight in adolescence not only impacts cardiovascular risk, but is also linked with a significantly increased risk in adulthood of end-stage renal disease (ESRD), related or not to diabetes.(4,5) In particular, those who were overweight or obese at the age of 17 years had about 6-fold and 19-fold increased risk for diabetic ESRD. Lifestyle intervention is fundamental to reducing the lifetime risk of both cardiovascular disease and CKD.(5)

Atherogenic dyslipidemia: a feature of CKD

In patients with CKD, lowering low-density lipoprotein cholesterol (LDL-C) levels, usually with a statin, is the primary strategy to reducing the high risk of cardiovascular disease.3 However, there remains a high residual risk of cardiorenal events. Data from the Pravastatin Pooling Project showed that about one in five patients with mild to moderate CKD, had a cardiovascular event in the following 5 years despite statin therapy. Furthermore, cardiovascular event rates were even higher in patients with both CKD and diabetes.(6)

Atherogenic dyslipidema – the combination of elevated triglycerides and low HDL-C – is an important driver of non-LDL cardiovascular risk, including in patients with CKD. Thus, treatments which are effective in targeting this dyslipidemic profile have potential for reducing this residual cardiovascular risk. Fibrates have been previously shown to be effective in reducing residual cardiovascular risk in high risk patients with atherogenic dyslipidemia (with or without statin therapy). However, there have also been concerns regarding the potential risk of progression of renal impairment in patients with moderate CKD, due to on-treatment elevation of serum creatinine associated with fibrate. The meta-analysis from Jun and colleagues,(7) featured in this month’s FOCUS ON article, not only reaffirms the substantial cardiovascular benefits of fibrates in patients with mild to moderate CKD, but also shows that there was no effect on risk for ESRD. The results of ancillary studies from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study in patients with type 2 diabetes, also showed that fibrate therapy, in this case fenofibrate, was associated with reduced albuminuria and lesser secular loss of kidney function over time, despite a paradoxical and reversible elevation in serum creatinine.(8-10) Together,these data provide clarity on the role of fibrates to reduce residual vascular risk in high-risk patients with CKD.

Recent non-fibrate studies of treatments with potential for targeting atherogenic dyslipidemia or its components in high-risk patients have been disappointing. AIM-HIGH (with niacin, previously discussed by the R3i) and dal OUTCOMES (with the cholesteryl ester transfer protein [CETP] inhibitor dalcetrapib, discussed in the LANDMARK trial website section) were both terminated early due to futility. While there are interesting, novel agents in development, including dual peroxisome proliferator-activated receptor agonists and other CETP inhibitors which target both apolipoprotein B-containing lipoproteins in addition to HDL-C, these will not be available to the practising clinician for some time.

The R3i believe that this meta-analysis of nearly 17,000 patients with CKD reaffirms the place of fibrate therapy in the management of cardiorenal risk in patients with mild to moderate CKD. Targeting atherogenic dyslipidaemia with a fibrate not only safely reduces residual cardiovascular risk but also prevents albuminuria progression in these high-risk patients.

References

1. Zoccali C, Kramer A, Jager KJ. Epidemiology of CKD in Europe: an uncertain scenario. Nephrol Dial Transplant 2010;25:1731–3.

2. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney Disease Statistics for the United States. Available at http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/. Accessed 22 November 2012.

3. 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.

4. Tirosh A, Shai I, Afek A et al. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N Eng J Med 2011;364:1315-25.

5. Vivante A, Golan E, Tzur D et al. Index in 1.2 million adolescents and risk for end-stage renal disease. Arch Intern Med. Published on-line October 29, 2012. Doi:10.1001/2013.jamainternmed.85

6. Tonelli M, Keech A, Shepherd J et al. Effect of pravastatin in people with diabetes and chronic kidney disease. J Am Soc Nephrol 2005;16:3748–54.

7. Jun M, Zhu B, Tonelli M et al. Effects of fibrates in kidney disease. J Am Coll Cardiol 2012;60:2061-71.

8. Davis TM, 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.

9. 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.

10. 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