Summary: The combination of a fibrate with a statin such as Lipitor does NOT produce a lowering of total cholesterol that is statistically greater than that achieved with statin. Secondarily, we evaluated whether this change in total cholesterol was demonstrated to be clinically meaningful by way of evaluation of clinical outcomes. The primary clinical outcome (ie., “first incidence of a major cardiovascular event” ) and annual rate of death were not improved when adding a fibrate to a statin (ACCORD Study Group, NEJM, 2010).

METHOD: A question is asked whether treatment with a fibrate drug in combination with a statin drug is better than a statin alone with regard to a lowering of total cholesterol. The peer-reviewed literature was searched for English language papers that describe randomized controlled trials that compare the use of a statin alone vs. a statin combined with a fibrate. The studies included comorbidities such as type 2 diabetes mellitus and dyslipidemia in their patient populations. Any studies that reported clinical outcomes, ie. that included blood or plasma cholesterol and lipid results only, were identified.

Literature search results: A total of 6 prospectively designed, randomized controlled trial looked at total cholesterol levels in patients who were given either statin monotherapy or a statin combined with a fibrate (fenofibrate). Only one of these studies followed patients for corresponding clinical outcomes, ie. for ischemic events such as fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke. (ACCORD, NEJM, 2010) This study included patients with type 2 diabetes mellitus who were on a program of glycemic control.

1) Lowering of total cholesterol.

A total of 5 studies were identified that looked at total cholesterol outcomes in a randomized control trials with patients assigned to either a statin alone or a statin combined with a fibrate. Patient populations included those with type 2 diabetes mellitus and with mixed dyslipidemia. Only 2 of these studies demonstrated a statistically significant improvement in total cholesterol when adding a fibrate. (Roth, 2010; ACCORD, 2010). Only one of these 2 studies demonstrated an improvement (lowering) in total cholesterol levels with the combination.

In conclusion, the preponderance of evidence suggests a high level of evidence for a negative predictive value of improved lowering of total cholesterol when adding a fibrate to a statin. When accounting for studies that explored corresponding clinical outcomes, the level of evidence is weakened further. Of note, the studies identified aimed to also explore lipid profiles, ie. LDL, HDL, and tryglycerides. In the ACCORD Lipid trial, the authors concluded a possible benefit in clinical outcomes in patients considered to have dyslipidemia (ie. high triglycerides and low HDL cholesterol), but the outcome was not statistically significant. (P = 0.057).

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FIBRATE + STATIN COMBINATION VS. STATIN MONOTHERAPY

Studies Favorable: Total 2

Level I: 2 Studies

1. Efficacy and safety of rosuvastatin 5 mg in combination with fenofibric acid 135 mg in patients with mixed dyslipidemia – a phase 3 study.
Roth EM, Rosenson RS, Carlson DM, Fukumoto SM, Setze CM, Blasetto JW, Khurmi NS, Stolzenbach JC, Williams LA.
Cardiovasc Drugs Ther. 2010 Dec;24(5-6):421-8.
PMID:
20953684 [PubMed - indexed for MEDLINE]
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2. Effects of combination lipid therapy in type 2 diabetes mellitus.
ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP.
N Engl J Med. 2010 Apr 29;362(17):1563-74. Epub 2010 Mar 14. Erratum in: N Engl J Med. 2010 May 6;362(18):1748.
PMID: 20228404 [PubMed - indexed for MEDLINE]
Free PMC Article
Free full text Related citations

FIBRATE + STATIN COMBINATION VS. STATIN MONOTHERAPY

Studies Unfavorable: Total 3

Level I: 3 Studies

1. Fenofibrate, simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients.
Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Gravina A, Mereu R, Palumbo I, D’Angelo A, Cicero AF.
Curr Med Res Opin. 2009 Aug;25(8):1973-83.
PMID: 19555253 [PubMed - indexed for MEDLINE]
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2. Efficacy and safety of ABT-335 (fenofibric acid) in combination with atorvastatin in patients with mixed dyslipidemia.
Goldberg AC, Bays HE, Ballantyne CM, Kelly MT, Buttler SM, Setze CM, Sleep DJ, Stolzenbach JC.
Am J Cardiol. 2009 Feb 15;103(4):515-22. Epub 2008 Dec 26.
PMID: 19195513 [PubMed - indexed for MEDLINE]
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3. Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial.
Derosa G, Cicero AE, Bertone G, Piccinni MN, Ciccarelli L, Roggeri DE.
Clin Ther. 2004 Oct;26(10):1599-607.
PMID: 15598476 [PubMed - indexed for MEDLINE]

LEVEL I

Randomized, controlled clinical trials. Researchers would use a computer program to randomly assign patients with back pain into two groups of 20. The first group (placebo group known as the control) would drink water (that only tasted like pomegranate juice but was not) for 10 days. The second group would drink real pomegranate juice for 10 days. None of the patients would know if they were drinking the real pomegranate juice or not. (This is called a blinded study). Then a researcher who does not know which person drank what (which now makes this a what’s called a “double blinded” study) would interview the patients to determine if their back pain was reduced, worsened or stayed the same. After this was all done, the information about which patients drank what would then be revealed. One could then see if those who drank the real pomegranate juice were better or not than the water drinking group.

LEVEL II

Non-randomized, prospective comparative study. A researcher looks at 40 patients medical records to select 20 patients for the pomegranate drinking group and 20 patients for the control group who will drink water. This is called a “cohort,” namely a control and experimental patient make a cohort. Here the researcher may introduce his own bias whether he intends to or not. If he believes pomegranate is a safe, effective treatment for back pain then whether he means to or not he may put the healthier patients with less back pain in the pomegranate group and patients complaining of more back pain in the water-drinking group. (This particular bias is called “selection bias.” See section on types of research bias.)

LEVEL III

Retrospective (already occurred) comparative study or case controlled study (each “experimental“ patient is matched to a patient that never had the experimental). This is not a reliable standard for determining one treatment over another, though it can be helpful to, say, see how many complications a certain treatment has. Researchers do a retrospective study for example reviewing 20 patient records of patients who reported they have been drinking pomegranate juice in the past and then 20 patients who have not reported drinking pomegranate juice. Then the researchers review the patients’ medical records determine if the back pain was reported better, worse or stayed the same. Here again, the selection process may introduce bias intentionally or not. In this case it may not only be selection bias, but could involve “recall” bias, or “expectation bias” or “attention bias.” (See Bias in Research section).

LEVEL IV

Case series do not determine success or failure of a treatment compared to other treatments or no treatment at all. Researchers or a physician does a case study on 20 patients who drink pomegranate juice for 10 days and then report the results. In this case there is no control group or comparison to patients who are not drinking pomegranate juice. It does not take into consideration that back pain could get better in 10 days if the patient takes nothing at all for the pain. These studies are easier and cheaper. They can be of value to determine better methods of doing a particular treatment, or what the complications of a certain treatment are, but NOT for determining if one treatment is better than another.

LEVEL V

Expert opinion. One physician expert’s opinion on if pomegranate juice helps reduce back pain. No original research is conducted. Instead, just a written opinion or editorial that may talk about other research and give opinions, but no clinical study is conducted. AME considers this to be one step above hearsay for determining one treatment over another, though it may be valuable for stimulating discussion and ideas on a particular topic.

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