The FIRST study: Does fenofibric acid reduce subclinical atherosclerosis in high-risk, statin-treated patients with atherogenic dyslipidemia?

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Macrovascular Residual Risk Studies

10 May 2012

Study design, rationale, and baseline characteristics: evaluation of fenofibric acid on carotid intima-media thickness in patients with type IIb dyslipidemia with residual risk in addition to atorvastatin therapy (FIRST) trial. Cardiovasc Drugs Ther 2012;26:249-5.

Davidson M, Rosenson RS, Maki KC et al.

STUDY SUMMARY

Objective:

Test the hypothesis that treatment with fenofibric acid will result in CIMT benefits in statin-treated high-risk patients with controlled LDL-C levels but persistent atherogenic dyslipidemia.

Study population:

682 patients (68% male, 88% white, 29% obese, mean age 60.8 years). About 50% of patients had type 2 diabetes, 79% had hypertension, and 22% had coronary artery disease.

Primary outcome:

The rate of change from baseline to 104 weeks in mean posterior-wall common CIMT (composite of both sides).

Secondary outcomes:

Include rates of change from baseline to 104 weeks in other CIMT variables, cardiovascular events and changes in lipids over this period.

Study design & method

Multicentre, double-blind randomised study.

COMMENT

The FIRST trial aims to address this important question.

While reduction of low-density lipoprotein cholesterol (LDL-C) with statin therapy is clearly effective in lowering cardiovascular risk, about two-thirds of patients remain at high residual risk of cardiovascular events or progression of pre-existing macroangiopathy.(1)
Even when LDL-C levels are reduced to optimal levels (or below), patients remain at high risk of incident cardiovascular events. Evidence from population and case-control studies indicates that atherogenic dyslipidemia, the combination of low high-density lipoprotein cholesterol (HDL-C) and elevated fasting triglycerides, is an important contributor to this residual risk.(2,3)
Indeed, the European Atherosclerosis Society Consensus Panel highlights the importance of atherogenic dyslipidemia as a driver of cardiovascular risk, especially among individuals with cardiometabolic disease.(4)

REALIST: Atherogenic Dyslipidemia is a Contributor to Residual Coronary Risk (3)

Elevated TG and low HDL-C act synergistically to increase coronary risk

This provides a rationale for targeting atherogenic dyslipidemia as emerging modifiable cardiovascular risk factor in statin-treated patients to reduce this residual vascular risk. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study, fenofibrate treatment was shown to reduce cardiovascular risk by about 70% in statin-treated type 2 diabetes patients with baseline triglycerides >=204 mg/dL (2.3 mmol/L) and HDL-C <=34 mg/dL (0.88 mmol/L) and mean LDL-C already at target at baseline.(5) This effect was subsequently confirmed in a meta-analysis investigating the effect of fibrate treatment in patients with atherogenic dyslipidemia, as defined by the ACCORD Lipid criteria. The odds of experiencing a cardiovascular event were reduced by 35% in this subgroup compared with 6% in a matched cohort without this dyslipidemic profile.(6)

These data reinforce the importance of targeting atherogenic dyslipidemia to reduce residual cardiovascular risk, a key priority of the Residual Risk Reduction Initiative (R3i).

However, targeting subclinical atherosclerosis may provide further benefit. Carotid intima-media thickness (CIMT) is an established measure of subclinical atherosclerosis and a surrogate of cardiovascular disease. A previous study(7) showed that treatment with fenofibrate plus antihypertensive treatment either stabilized or regressed atherosclerosis (as measured by CIMT) in patients with hypertension and high triglycerides. In contrast, patients receiving antihypertensive therapy alone had significant progression of CIMT.

These data provide a rationale for the FIRST trial.(8) This study aims to test the hypothesis that treatment with fenofibric acid will result in CIMT benefits in statin-treated high-risk patients with controlled LDL-C levels but persistent atherogenic dyslipidemia.

The R3i look forward to the results of this exciting trial.

References

1. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diab Vasc Dis Res 2008;5:319-35.

2. Assmann G, Cullen P, Schulte H. Non-LDL-related dyslipidaemia and coronary risk: a case-control study. Diab Vasc Dis Res 2010l;7:204-12.

3. Carey VJ, Bishop L, Laranjo N, Harshfield BJ, Kwiat C, Sacks FM. Contribution of high plasma triglycerides and low high-density lipoprotein cholesterol to residual risk of coronary heart disease after establishment of low-density lipoprotein cholesterol control. Am J Cardiol 2010;106:757-63.

4. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.

5. ACCORD Study Group, 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.

6. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.

7. Zhu S, Su G, Meng QH. Inhibitory effects of micronized fenofibrate on carotid atherosclerosis in patients with essential hypertension. Clin Chem 2006;52:2036-42.

8. Davidson M, Rosenson RS, Maki KC et al. Study design, rationale, and baseline characteristics: evaluation of fenofibric acid on carotid intima-media thickness in patients with type IIb dyslipidemia with residual risk in addition to atorvastatin therapy (FIRST) trial. Cardiovasc Drugs Ther 2012;26:249-58.