HDL cholesterol response to bezafibrate influences long-term mortality risk

Analysis of 16-year mortality data from the Bezafibrate Infarction Prevention (BIP) study showed that the extent of high-density lipoprotein (HDL) cholesterol raising associated with bezafibrate treatment influenced long-term survival benefits after discontinuation of therapy. The study was reviewed by HDL Forum Editor Professor Philip Barter.

 Goldenberg I, Boyko V, Tennenbaum A et al. Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate. Arch Intern Med 2009;169:508-14.

 The BIP study involved 3090 patients with previous myocardial infarction (MI) and/or angina and a lipid profile characterised by elevated low-density lipoprotein (LDL) cholesterol (<180 mg/dL), HDL cholesterol <45 mg/dL and triglycerides <300 mg/dL. Patients were randomised to treatment with bezafibrate 400 mg/day or placebo. The primary endpoint was a composite of fatal or nonfatal MI or sudden death (1).  After a median of 6.2 years, there was no significant difference in primary endpoint event rates between bezafibrate and placebo groups (13.6% vs. 15.0%). This was largely a result of similar mortality rates in the two groups at the end of treatment. However, post hoc analyses showed an enhanced benefit associated with bezafibrate therapy 2 years after study closure, especially among patients who exhibited the greatest HDL cholesterol raising response with bezafibrate therapy (increase >8 mg/dL) (2,3).

 The aim of the current report was to evaluate whether the magnitude of the increase in HDL cholesterol associated with bezafibrate treatment during the trial was independently predictive of long-term survival. Survival data were obtained from 16-year mortality records for 3026 patients in the trial. Lipid changes were categorised by tertiles for HDL cholesterol (increase of >8 mg/dL, >3-8 mg/dL, and <3 mg/dL) and triglycerides (decrease of >43 mg/dL, 10-43 mg/dL and <10 mg/dL).

 Baseline characteristics of the three groups were generally similar. Baseline triglycerides for patients in the bezafibrate group with >8 mg/dL increase in HDL cholesterol were higher compared with either placebo patients or bezafibrate-treated patients with lower increases in HDL cholesterol (mean values 150 mg/dL versus 145 mg/dL for placebo and 142 mg/dL for bezafibrate-treated patients in the two lower tertiles for HDL cholesterol response).

 When evaluated on the basis of the on-treatment HDL cholesterol response, cumulative mortality rates were significantly lower among patients with an increase of >8 mg/dL (32.1% vs. 37.9% with placebo, p=0.02). These patients had a 22% reduction in risk of death versus placebo, p=0.008 (see slide 1). This difference appeared after about 2 years, persisted for 10 years after discontinuation of study therapy and was independent of baseline lipid levels. There was no difference in mortality rates between placebo and bezafibrate-treated patients with a lower HDL cholesterol response. 

Additionally, patients with greater on-treatment reduction in triglycerides (>43 mg/dL decrease) had significantly improved mortality rates (18% reduction in risk of death versus placebo, p=0.03) (see slide 2).

 These findings are consistent with evidence from other trials that indicates that the magnitude of treatment-associated HDL cholesterol raising is inversely associated with adverse cardiovascular outcome, even among patients who achieve low LDL cholesterol with statin therapy (4).

 The authors concluded that monitoring the short-term lipid response to fibrate therapy may be important in identifying those patients most likely to obtain a long-term survival benefit, even after discontinuation of therapy.

 References

1. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000;102:21-7.

2. Goldenberg I, Goldbourt U, Boyco V et al. Relationship between on-treatment increments in serum HDL levels and cardiac events in patients with coronary heart disease: an extended follow-up of the Bezafibrate Infarction Prevention trial. Am J Cardiol 2006;97:466-71.

3. Goldenberg I, Benderly M, Goldbourt U, BIP Study Group. Secondary prevention with bezafibrate therapy for the treatment of dyslipidemia: an extended follow-up of the BIP trial. J Am Coll Cardiol 2008;51:459-65.

4. Barter P, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.  N Engl J Med. 2007;357:1301-10.

 

 

 


Download Attachment