Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study
BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l5125 (Published 27 September 2019) Cite this as: BMJ 2019;366:l5125
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This study showed that, in statin-treated patients, addition of fenofibrate to statin decreased a composite endpoint but had no effect on individual outcomes (new coronary heart disease, stroke or cardiovascular death). There is a need for clarity in how best to use fibrates, both for primary prevention and to decrease residual risk in statin-treated patients.
Very little substantial new evidence has accumulated in the past decade. It seems clear from early trials with fibrates that they can decrease the incidence of adverse cardiovascular outcomes. However, the balance of evidence is influenced by trials with the drugs clofibrate and bezafibrate. 1 The former is no longer available, and the latter is only available in some countries. Fenofibrate and gemfibrozil are now the only two widely available fibrates, and there are important differences between the two drugs. Two trials, the Helsinki Heart Study and the Veterans Affairs HDL Intervention Trial (VA-HIT) showed a clear benefit of gemfibrozil in preventing cardiovascular outcomes in primary and secondary prevention cohorts respectively. 1 By contrast, the major trials with fenofibrate in high-risk diabetic cohorts – FIELD (statin-naive) and ACCORD-LIPID (with statin) – showed no clear benefit of the fibrate. 1 Gemfibrozil is less likely to increase plasma homocysteine and creatinine than other fibrates and also has favourable effects on LDL and HDL subclasses that may contribute to its benefit.
A recent study of 2 million US veterans with chronic kidney disease (CKD) leaves no doubt that elevated triglycerides is a risk factor for premature cardiovascular mortality and all-cause mortality. 2 Atherogenic dyslipidaemia (high triglycerides and low HDL-cholesterol) is a major contributor to residual risk in statin-treated patients. A very recent meta-regression analysis confirms that lowering triglycerides decreases cardiovascular risk. 3 This analysis was, however, heavily influenced by the REDUCE-IT study published earlier this year. 4 REDUCE-IT demonstrated that treatment with eicosapentaenoic acid ethyl lowered triglycerides and decreased risk of cardiovascular death and ischaemic events. By contrast, recent data suggest that standard marine omega-3 fatty acids, widely used to lower triglycerides, probably do not decrease risk from cardiovascular disease. 5
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists fenofibrate and gemfibrozil both favourably alter triglycerides and HDL-cholesterol and thus decrease cardiovascular risk and should certainly be considered for patients with atherogenic dyslipidaemia, including diabetic patients. Curiously the major benefit of fenofibrate in diabetic patients may be to prevent microvascular, rather than macrovascular, disease. This benefit may not be through altering circulating lipids. Future developments will include more potent PPAR-alpha agonists and agents that activate multiple peroxisome proliferator-activated receptors. Fish oil (omega-3 fatty acids) is one of the most widely used nutritional supplements but does not reliably prevent ischaemic events. Modified marine fatty acids in high doses appear to be much more effective but, again, more evidence is needed.
References
1. Jun M, Foote C, Lu J, et al. Effects of fibrates on cardiovascular outcomes: a systemic review and meta-analysis. Lancet 2010:375;1875-84.
2. Soohoo M, Moradi H, Obi Y, et al. Serum triglycerides and mortality risk across stages of chronic kidney disease in 2 million US veterans. Journal of Clinical Lipidology Published online August 4, 2019.
3. Marston NA, Giugliano RP, Ah Im K, et al. Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering classes: A systematic review and meta-regression analysis of randomized controlled trials. Circulation Published online September 18, 2019.
4. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with Icosapent Ethyl for hypertriglyceridemia. New England J Med 2019:380;11-22.
5. Manson JE, Cook NR, Lee I-M, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. New England J Med 2019:380;23-32.
Competing interests: No competing interests
Where’s the Beef?
In the mid-1980s, Wendy’s had a commercial where an older women asked the question “Where’s the Beef?” We should all be asking ourselves a similar question today – “Where’s the evidence?”
The recent publication by Kim, et al [1] states that fenofibrate has a beneficial effect for individuals already taking a statin medication by lowering their risk of a cardiovascular event. The proof of this is based upon ICD-10 codes. It appears that the publication of manuscripts in medical journals no longer requires diagnostic proof but merely the referral to a billing code. I see this all to often myself as a reviewer for medical journals. There is nothing so convincing, as a retrospective analysis of CPT and ICD codes – not!
As most of us know, once a diagnosis is placed on a patient, it follows them for life – hence the term preexisting condition. Patients with elevated lipids, as in this case, will automatically be assigned the applicable CPT and ICD code(s) since this is how payment for medical care is determined – no matching ICD or CPT code equals no payment for services – and no payment for service interferes with reimbursement and provision of medical care – and that is of course, unacceptable.
Coronary artery disease (CAD) is an inflammatory process associated with a variety of mediators, which have different impacts on different people, determined by the genetics of the individual involved [2]. These mediators are measured via blood tests and include lipids (LDL, HDL, TG), homocysteine, lipoprotein (a), fibrinogen, c-reactive protein, interleukin-6, potential infectious agents, et cetera [2]. However, the measured changes in these blood tests do not correlate with the actually measured changes in CAD [3]. If you want to know if CAD changes, you actually need to measure it [4].
In reviewing the medical literature, it is clear that the primary methods for assessing the benefit of lipid lowering and dietary regimens, has been (A) the retrospective review of ICD and CPT codes - which fails as discussed, (B) blood tests - which do not correlate with changes in CAD [3] and (C) coronary arteriography - which is severely flawed as already established in the literature [5].
So once again, I ask, “Where’s the proof?” Where is the scientific evidence that statins or the fibric acid derivatives actually reverse or stabilize CAD and do more than merely change a blood test?
Acknowledgment: FMTVDM issued to author.
References:
1. Kim NH, Han KH, Choi J, Lee J, Kim SG. Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study. BMJ 2019;366:l5125.
2. Fleming RM. Chapter 64. The Pathogenesis of Vascular Disease. Textbook of Angiology. John C. Chang Editor, Springer-Verlag New York, NY. 1999, pp. 787-798.
3. Fleming RM, Harrington GM. "What is the Relationship between Myocardial Perfusion Imaging and Coronary Artery Disease Risk Factors and Markers of Inflammation?" Angiology 2008;59:16-25.
4. Fleming RM, Fleming MR, Chaudhuri TK. The Need to Actually Measure What We’re Talking about before We Put it All Together. Int J Nuclear Med Radioactive Subs 2019;2(1):000114.
5. Fleming RM., Kirkeeide RL, Smalling RW, Gould KL. Patterns in Visual Interpretation of Coronary Arteriograms as Detected by Quantitative Coronary Arteriography. J Am Coll. Cardiol. 1991;18:945- 951.
Competing interests: FMTVDM issued to author.
A recent systematic review and meta-analysis of 31 randomized controlled trials (RCTs) on 154,601 patients with a follow-up of 6 months or more and a sample size of 100 or more patients, concluded that "high-density lipoprotein cholesterol modifying treatments (like fibrates) had no significant effect on cardiovascular mortality, stroke or all-cause mortality. The beneficial effect on myocardial infarction was lost when drugs were used with statin therapy."
Reference
https://journals.sagepub.com/doi/abs/10.1177/2047487318816495
Competing interests: No competing interests
The authors describe a composite, primary outcome of cardiovascular events and secondary outcomes of lipid profiles and transaminases but do not report overall mortality.
I would like to see the figures for both total deaths and other serious non-cardovascular events published.
Competing interests: No competing interests
Re: Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study
Dear Editor,
I read with interest the article entitled Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome. I would like to set forth the following points for consideration regarding the authors study design, conclusions and limitations.
Although the study includes participants with Metabolic syndrome per Adult Treatment panel III guidelines, the mean BMI was only 25.8, so most participants tend to meet the criteria for Hypertriglyceridemia for metabolic syndrome that can cause over-estimation of the effect of fibrates
When looking at the Kaplan-Meier survival curves for composite cardiovascular outcomes, Significant proportion of participants dropped out at the end of 6 year period from both statin only group and combined treatment group in an unequal amount. This raises concern about lack of adequate data to support the end points of the study.
Although the propensity score matching method was used in selecting the study group and control group, possible bias still exists as some of the confounding variables (β blocker use, diuretic use, and triglyceride concentrations) were not balanced at baseline even after matching. The number of patients with β blocker use and diuretic use in the combined treatment group was higher than the statin only group. The β blocker use or diuretic use could have lowered the risk of major cardiovascular events. Although the study stated these variables were adjusted in further analyses, it is hard to ignore their effects on outcomes.
The Study shows a difference in composite cardiovascular events between statin only group and combined treatment group, but was not able to establish the objective of reduction in persistent cardiovascular risk.
The cut off points for HDL and triglyceride concentration were derived from subgroups who benefited from fenofibrate treatment on cardiovascular outcomes in previous randomized controlled trials instead of using ATP criteria for metabolic syndrome. This may cause overestimation of fenofibrate efficacy.
The objectives of study seem to change when comparing outcomes, as comparison was also done among high TG/low HDL and low TG/High HDL subgroups, which showed a statistically significant difference among high TG/low HDL which might be due to the population selected.
Competing interests: No competing interests