Statin-fibrate combination for mixed dyslipidaemia: a limited option?

Abstract

A growing body of evidence suggests that targeting low-density lipoprotein cholesterol is not enough and that a substantial residual risk remains despite aggressive statin treatment, particularly in patients with mixed dyslipidemia. Statin plus fibrate combination results in a more effective control of several lipid parameters than either monotherapy with a safety profile similar to both monotherapies. Therefore, this combination might represent a therapeutic option for selected patients with mixed dyslipidemia. However, the clinical benefit of statin/fibrate combination has only been observed in small subgroup analyses and more data are needed before a wider implementation is recommended in everyday clinical practice.

Key words::

• Clinical outcome
• Efficacy
• Fibrate
• Mixed dyslipidaemia
• Safety
• Statin

Mixed dyslipidaemia (MD) is the commonest lipid disorder among patients who suffer myocardial infarction (MI) before the age of 601. In MD, a cluster of lipid disorders and thrombogenic abnormalities significantly increase the risk for cardiovascular disease (CVD)1. In addition to the increased low-density lipoprotein cholesterol (LDL-C) levels, which have been proven to play a role in atherogenesis, the high levels of triglycerides (TGs), decreased concentration of high-density lipoprotein cholesterol (HDL-C) and the predominance of small, dense, prone to oxidation LDL particles2,3, constitutes the atherogenic phenotype B in patients with MD. This phenotype is associated with a three-fold increase in CVD incidence4 and more advanced coronary atherosclerosis5, independently of LDL-C levels. Moreover, high plasma fibrinogen levels, which are present in most cases of MD, also appear to be associated with greater risk for MI6,7.

The combination of statins and fibrates has the potential to improve all the lipid abnormalities that characterize MD. However, early reports of myopathy and rhabdomyolysis mainly involving gemfibrozil, originally with lovastatin, and later, with cerivastatin limited the use of this regimen in clinical practice8,9. Nevertheless, several studies suggested that statins could be safely combined with fibrates. In an early study from our group in patients with familial combined hyperlipidaemia and coronary artery disease (CAD), a simvastatin–ciprofibrate combination was more beneficial than either monotherapy on all lipid parameters, on LDL particle structure and distribution as well as on plasma fibrinogen levels10. There were no safety issues but the number of patients was small10. Later we reported a favourable safety and efficacy profile of three different statin–fibrate combinations in patients with MD totalling 940 person years of follow up11. More recently, we showed the safety and efficacy of four different statin–fibrate combinations in nearly 500 patients followed up for a mean of 5 years (2625 person years)12. More importantly, in the latter report, treatment with statin + fibrate combination resulted in very low CVD event rates that were similar to the general population. However, the lack of a control group (for obvious ethical reasons) was a limitation of this study. Nevertheless, when we used as a control group patients given atorvastatin alone, all statin + fibrate combinations were superior in efficacy and similar in safety13. We also reported that atorvastatin plus micronized fenofibrate combination is safe in patients with type 2 diabetes mellitus (a CAD equivalent) and combined hyperlipidaemia and reduces CVD risk factors more than either drug alone14. Moreover, the same combination was safe and effective in patients with metabolic syndrome but without diabetes and reduced the prevalence of non-alcoholic fatty liver disease15. Thus, in patients with MD of varying aetiology (i.e. with or without type 2 diabetes mellitus or metabolic syndrome) the statin fibrate combination was safe and very effective.

The paper by Wierzbicki et al. in this issue of the journal16 reports safety, efficacy and survival data in 318 patients with MD who were treated with fibrate–statin combination for a mean of 7.5 years (i.e. 2400 patient-years). The study population was at high vascular risk; their mean age was 62 years, 68% had previous CVD, 17% were smokers, 41% were hypertensive and 32% had diabetes mellitus. The fibrate–statin combination reduced total cholesterol (TC) levels by 27%, TGs by 42% and increased HDL-C by 21%; side-effects were rare. Major adverse coronary events (MACE) occurred in 25% of the patients and logistic regression analysis showed that patients with MACE had higher initial TC (p = 0.002), greater prevalence of established CVD (65 vs 57%; p = 0.05), and a lower atherogenic index response (31 vs 38%; p = 0.008). Cox regression analysis showed that the degree of reduction in TG (p = 0.009) and TC levels (p = 0.04) and the extent of increase in HDL-C levels (p = 0.05) were associated with better prognosis16. Thus, the lipid-modifying effects of statin + fibrate combination appear to reduce vascular risk. This study adds to the evidence that combining statins with fibrates improves clinical outcomes17. This is an important issue because aggressive statin treatment reduces vascular risk more than ‘moderate’ statin doses but does not eliminate risk18,19. Indeed, in the Treating to New Targets (TNT) trial18, intensive lipid-lowering therapy with atorvastatin 80 mg/day in patients with stable CAD reduced vascular risk 22% more than atorvastatin 10 mg/day (p < 0.0001). However, 8.7% of patients treated with atorvastatin 80 mg/day had a vascular event or died. This percentage represents the residual CVD risk after maximum dose of an effective statin and reaching low LDL-C levels (77 mg/dl [2.0 mmol/l]). Similarly, in the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial19, intensive lipid-lowering therapy with atorvastatin 80 mg/day in patients with acute coronary syndromes (ACS) reduced vascular risk by 16% more than pravastatin 40 mg/day. However, 22.4% of patients treated with atorvastatin 80 mg/day had a CVD event or died despite achieving very low LDL-C levels (62 mg/dl [1.6 mmol/l]). Several experts suggest that this residual risk of dyslipidaemic patients who are treated according to current standards of care needs to be addressed with lifestyle and/or pharmacotherapy20. In other words, if we aspire to achieve further vascular risk reduction, we should probably also aim at reducing TG and increasing HDL-C levels20.

In the Wierzbicki et al. study there was a 21% increase in HDL-C levels and a 42% reduction in TG levels. These benefits are difficult to achieve with statin monotherapy. Moreover, the multivariate analysis suggested that these changes in TG and HDL-C levels independently contributed to the reduction in mortality16. This is in accordance with the findings of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (n = 9795)21,22. In FIELD, treatment with fenofibrate had a non-significant effect on the primary endpoint (nonfatal MI, CAD death; −11%, p = 0.11)21. However, by study closure 36% of subjects of the placebo group and 19% of the fenofibrate 19% was on other hypolipidaemics (>90% statins). This may have masked some of the beneficial effects of fenofibrate therapy21. Thus, when the primary endpoint was adjusted for the initiation of statin treatment in study participants, CHD events reduction by fenofibrate was found to be −19% (p = 0.01)21,22. About two-thirds of the change in effect due to adjustment for other medicines can be explained by statin use alone22. Therefore, FIELD suggests that statin–fibrate combination might further reduce vascular risk22.

The recently published Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial provides further insight on the effects of statin + fibrate combination on clinical outcomes23. In the entire ACCORD population (5518 patients with type 2 diabetes mellitus), the combination of fenofibrate and simvastatin did not reduce the rate of fatal CVD events, nonfatal MI or nonfatal stroke compared with simvastatin alone23. However, a trend toward benefit of fibrate plus simvastatin treatment was recorded in a prespecified subgroup analysis of patients with TG levels in the highest third (≥204 mg/dl; ≥2.30 mmol/l) and HDL-C levels in the lowest third (≤34 mg/dl; ≤0.88 mmol/l). In these patients, the primary outcome rate was 12.4% in those taking fenofibrate + simvastatin vs 17.3% in the simvastatin plus placebo arm (i.e. a significant 31% risk reduction). In this subgroup of patients only 20 study participants had to be treated for 5 years to prevent one CVD event23. These results are similar to those of post hoc subgroup analyses of other fibrate trials24,25 and suggest a benefit from adding a fibrate to a statin in diabetic patients with MD. Another important finding of the ACCORD trial is that adding fenofibrate to simvastatin was safe and did not result in any excess risk of myopathy, venous thrombosis or pancreatitis23. There was a greater increase in serum creatinine levels in patients treated with fenofibrate but renal function remained relatively stable after the first year of the trial23. In addition, fenofibrate reduced the incidence of both micro- and macroalbuminuria, consistent with results from FIELD21,22. However, further analysis of the effect of statin + fibrate combinations on the primary outcome across prespecified baseline subgroups showed the incidence of the primary outcome for men was 11.2% in the fenofibrate group vs 13.3% in the placebo group, whereas the rate for women was 9.1% in the fenofibrate group vs 6.6% in the placebo group (p = 0.01 for interaction)23, suggesting a possible harmful effect for women.

Conclusions

Current treatment guidelines for dyslipidaemia focus on reducing LDL-C, with HDL-C and TGs considered as secondary targets26. Available data suggest that simply increasing the amount of circulating HDL-C does not reduce the risk of CHD events, CHD deaths, or total deaths27. Furthermore, in some trials like the Veterans Affairs High-Density Lipoprotein Intervention Trial that selected a low HDL-C population, the benefit (in terms of vascular event reduction) has not been solely attributed to raising HDL-C levels28. In contrast, there is evidence from a meta-analysis that TG levels predict vascular risk29.

There is a growing body of evidence suggests that targeting LDL-C is not enough and that a substantial residual risk remains despite aggressive statin treatment and in some patients with MD, statin + fibrate combination might be an alternative. This might result in a more effective control of several lipid parameters than either monotherapy, with a safety profile similar to both monotherapies. Other ‘non-lipid’ effects such as lowering plasma fibrinogen levels may be useful when using statin + fibrate combination therapy30. Therefore, this regimen might represent a therapeutic option for selected patients with MD. However, the clinical benefit of statin + fibrate combinations has only been observed in small subgroup analyses and more data are needed before a wider implementation is recommended in everyday clinical practice. Whether such data will ever be available is not clear.

Transparency

Declaration of funding

This editorial was written independently. The authors did not receive financial or professional help with the preparation of the editorial.

Declaration of financial/other relationships

D.P.M. has disclosed that he is the recipient of sponsorship funding to attend meetings on behalf of Merck, Sharpe & Dohme and Astra-Zeneca; is a consultant for Merck, Sharpe & Dohme; and is a member of the speakers bureaux for Merck, Sharpe & Dohme, Solvay and Astra-Zeneca. V.A.G. has disclosed that he has no relevant financial relationships.

Peer reviewers may receive honoraria from CMRO for their review work. The peer reviewers disclosed no relevant financial relationships.