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|Objectives||To determine the efficacy and safety of fibrate therapy in patients with CKD.|
|Study design||Systematic review and and meta-analysis|
|Study population||Ten articles based on eight randomized controlled trials in 16,869 patients were included in the analysis. Two trials assessed the effects of gemfibrozil, two assessed bezafibrate and four trials assessed fenofibrate. The sample size of the individual trials ranged from 24 to 9,795 patients. Mean age ranged from 51-67 years, and the majority of patients in each trial were male (63-100%). Six trials included patients with diabetes at baseline (28-100% of the study population). Baseline cholesterol ranged from 4.35 mmol/L to 7.3 mmol/L.|
Prospective, randomized placebo-controlled trials assessing the effects of fibrate therapy in patients with CKD or renal-related outcomes were identified following systematic review of searches of MEDLINE, EMBASE and the Cochrane Library using relevant text words and medical subject headings, over the period 1950-January 2012.The effects of fibrate therapy were investigated in patients with mild to moderate CKD (estimated glomerular filtration rate [eGFR] £60 mL/min/1.73 m2). Relative risks and 95% confidence intervals (CI) were calculated for the individual trials before data pooling. A random effects model was used to estimate relative risk ratios. For continuous data, weighted mean differences were determined using end-of-trial mean values. The significance level was p<0.05.
In patients with mild to moderate CKD, these improvements in lipid profiles with fibrate therapy were associated with:
There was also a 40% (95% CI 4-62%) reduction in CV death (p=0.032) in patients with moderate CKD, but a non-significant 14% decrease in all-cause death (RR 0.86; p 0.355).
While serum creatinine was increased and eGFR decreased on fibrate therapy, there were no clear effects on ESRD in patients with CKD.
Fibrates could be used more broadly to prevent CVD in patients with mild to moderate CKD.
CKD is regarded as a coronary risk equivalent, with LDL-C reduction usually with a statin recommended as the primary target of therapy to reduce CV risk.1 Statins have also been shown to have beneficial effects on renal outcomes in high-risk patients, especially those with diabetes.2 Despite this, there remains a high post-statin residual CV risk in these patients: in patients with mild to moderate CKD, about 20% experience a CV event over 5 years despite statin therapy, and event rates are even higher in patients with both diabetes and CKD.3
Atherogenic dyslipidemia, characterized by elevated triglycerides and low plasma concentrations of HDL-C, is a feature of CKD and might be an important modifiable contributor to this residual CV risk. Therefore, targeting this non-LDL dyslipidemia with a fibrate may confer additional clinical benefits. This strategy is supported by evidence from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study, in which adding fenofibrate in simvastatin-treated patients with type 2 diabetes and atherogenic dyslipidemia reduced CV events by 30% compared with no benefit in patients without this dyslipidemia.4
However, there has been clinical concern about the use of fibrates in patients with CKD, particularly those with diabetes, given evidence that fibrates also increase serum creatinine,4,5 which is associated with increased risk for ESRD.6.7 This might be expected to translate to increased specialist referral and hospitalisation, particularly among the elderly, thereby conferring greater burden of disease.8
The findings from this meta-analysis confirm that targeting atherogenic dyslipidemia in mild to moderate CKD reduces residual CV risk in these high-risk patients. Reduction in major CV events with fibrate therapy was about 2-fold greater in moderate than mild CKD (relative risk reduction 30% versus 14%). There was also a 40% reduction in CV death in moderate CKD. In patients with diabetes, fibrate treatment (specifically fenofibrate) reduced the progression of albuminuria. While there was an increase in serum creatinine and decrease in eGFR with fibrate therapy, these changes did not significantly impact risk for ESRD.
In ancillary studies of ACCORD Lipid and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD), the increase in serum creatinine with fenofibrate was shown to be fully reversible 6-8 weeks after stopping treatment, and was not associated with increased risk for ESRD.9-10 Indeed, fenofibrate treatment was associated with net preservation of renal function in the longer-term in type 2 diabetes patients. Additionally, patients with moderate CKD derived the greatest CV benefit from fenofibrate treatment, with a 32% reduction in CV events and 49% reduction in CV death, compared with no significant effects in patients with mild CKD.11 -
In conclusion, the results of this meta-analysis allay clinical concerns about the use of a fibrate in patients with mild to moderate CKD (with or without diabetes). Thus, adding a fibrate would be expected to reduce the high residual CV risk, as well as reduce progression of albuminuria, that persists in these high-risk patients and is not sufficiently addressed by statin therapy.
1. 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.