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12 January 2012
Meta-analysis: Targeting atherogenic dyslipidemia with a fibrate can reduce residual vascular risk in chronic kidney disease

Atherogenic dyslipidemia is a risk factor for cardiovascular disease in patients with chronic kidney disease (CKD). While statins have modest beneficial effects in mild to moderate (stages 2-3) CKD, patients still remain at high residual vascular risk. Findings from this meta-analysis in nearly 17,000 CKD patients indicate that fibrates, which specifically target atherogenic dyslipidemia, can help to reduce the high residual CV risk that persists in patients with mild to moderate CKD.

Jun M, Zhu B, Tonelli M et al
Effects of fibrates in kidney disease. J Am Coll Cardiol 2012;60:2061-71.
Summary
Comments & References
STUDY SUMMARY
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. 
Primary variable
  •  Major clinical outcomes, defined as cardiovascular (CV) events, CV death, stroke and all-cause mortality
Secondary variables
  • Lipids: total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)
  • Serum creatinine
  • Renal outcomes: albuminuria, renal function changes and end-stage renal disease (ESRD)
  • Adverse events
Methods

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.
Main results
  • Fibrate therapy improved lipid profiles, with significant decreases in total cholesterol and triglycerides, and a significant increase in HDL-C

Lipid

Change from baseline (mmol/L)

Total cholesterol

¯ 0.32 (12 mg/dL), p=0.05

Triglycerides

¯ 0.56, (50 mg/dL), p=0.03

HDL-C

­ 0.06 (2.3 mg/dL), p=0.001

In patients with mild to moderate CKD, these improvements in lipid profiles with fibrate therapy were associated with:

  • Reduction in the risk of CV events according to renal function:

eGFR (mL/min/1.73 m2)

Risk ratio for fibrate vs. placebo (95% CI), p-value

³60 (i.e. mild CKD)

0.86 (0.77-0.96), p=0.009

30-59.9 (i.e. moderate CKD)

0.70 (0.54-0.89), p=0.004

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).

  • There was a 14% reduction in the risk of albuminuria progression and a 19% regression of albuminuria in patients with CKD and diabetes; RR 0.86 (0.76-0.98), p=0.02, and RR 1.19 (1.08-1.31); p 0.0005, respectively.

While serum creatinine was increased and eGFR decreased on fibrate therapy, there were no clear effects on ESRD in patients with CKD.

Author's conclusion

Fibrates could be used more broadly to prevent CVD in patients with mild to moderate CKD.

 

COMMENT

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. 

References

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.
2. Shepherd J, Kastelein JJ, Bittner V et al, Treating to New Targets Investigators. Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study. Clin J Am Soc Nephrol 2007; 2 :1131-9
3. 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.
4. Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
5. FIELD study investigators.  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.
6. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR; UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 2006;55:1832-9.
7. Afghahi H, Cederholm J, Eliasson B et al. Risk factors for the development of albuminuria and renal impairment in type 2 diabetes--the Swedish National Diabetes Register (NDR). Nephrol Dial Transplant 2011;26:1236-43.
8. Zhao YY, Weir MA, Manno M et al. New fibrate use and acute renal outcomes in elderly adults: a population-based study. Ann Intern Med 2012;156:560-9.
9. 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.
10. 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.
11. 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.