March 23rd, 2011
Fibrate Prescriptions: A Tale Of Two Countries
Larry Husten, PHD
During the past decade, fibrate use more than doubled in the U.S. but remained relatively stable in Canada, according to a study just published in JAMA.
In January 2002, fibrate use was similar in the two countries: 336 prescriptions per 100,000 population in the U.S. versus 402 per 100,000 in Canada. By December 2009, the number in the U.S. had skyrocketed to 730 per 100,000, while the number in Canada hit only 474 per 100,000 . Most of the change in the U.S. was attributed to an increase in the use of branded fenofibrate, whereas in Canada, fibrate use shifted from branded drugs to generic ones.
The study investigators (including senior author Harlan Krumholz, who is editor-in-chief of CardioExchange) concluded that “at a time when a less-is-more approach is being embraced by the medical community, this ever-increasing pattern of prescribing brand-name medications without evidence of clinical benefit warrants attention and close scrutiny to ensure that such medication use is optimized for clinical benefit, while avoiding unwarranted costs.” Here, lead author Cynthia Jackevicius answers questions about the study from CardioExchange editor Susan Cheng.
Q: Accumulating evidence suggests that fibrates have limited clinical utility, yet this study shows that fibrate use is increasing in the U.S. What do you think are some of the main reasons behind that observation?
CJ: We did not specifically study the reasons for the increase in fibrate prescriptions, but prescribing changes are usually a result of changes in evidence, policy, or marketing. During the past decade, there was not any new evidence — or any widespread policy changes — to support fibrate use, so the most likely influential factor was marketing.
Q: Is your group likely to pursue an analysis of outcomes associated with the observed prescribing patterns?
CJ: Whether the increasing use of fibrates in the U.S. over the last decade translates into improved patient outcomes is uncertain, so we would definitely like to explore this more. The main evidence to support clinical outcomes benefit is from placebo-controlled trials with the older fibrates gemfibrozil and clofibrate. These trials exert substantial influence in the meta-analyses that show that fibrates in aggregate significantly reduce cardiac events but not overall mortality. The relevance of this older evidence to contemporary practice is uncertain, particularly given the negative results of the ACCORD study, which is the only trial that has assessed fibrates in a population taking statins.
Q: How would you recommend that clinicians apply the main findings from this study? What about practice groups, health plans, and policy makers?
CJ: Our results should give clinicians pause about what is being accomplished with the increased use of fibrates. From a mechanistic perspective, lowering triglycerides should lower the risk for cardiac events and mortality, but the recent fenofibrate trials do not support this relationship. The increased use of fenofibrate that we observed indicates that the negative clinical outcomes results of these trials have been ignored. Continued caution is warranted in guideline and formulary recommendations for fibrates, particularly fenofibrate, as we await evidence of clinical outcomes benefits.
Questions to Dr. Cohen come from CardioExchange’s Dr. Richard A. Lange and Dr. L. David Hillis.
19 Responses to “Fibrate Prescriptions: A Tale Of Two Countries”
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I generally use fenofibrates for my diabetic patients, because almost all of them have elevated triglyderides, no matter how good there sugar control is. Since they are at such a high risk for ASCVD, unless a study showed that the use of fenofibrates was dangerous, I will continue. I also almost never act on the first study, but wait for a second and confirming study.
I think there is sufficient evidence that after getting LDL to below 70mg% with a statin, high triglycerides are an independent risk factor and need to be tackled aggressively with a statin & fenofibrate combination. ACCORD results did not show benefit because there fibrates were given to patients with normal or slightly raised triglycerides !
Anil: Can you cite a study with patient outcomes that tested the strategy of treating patients to an LDL < 70 mg/dl? Not sure how you can say there is sufficient evidence for that? And Robin: with regard to fibrates... in the statin era, where is the proof? Is plausibility sufficient? Shouldn't the intervention have the burden of proof?
Although successful marketing of fibrates is a possible explanation, another may be the increased incidence of diabetes (and hypertriglyceridemia). In other words, physician prescribing practices haven’t changed, but the number of patients with the condition has increased substantially.
What can Anil and Harlan tell us about this?
Over the period of our study (2002-2009), fibrate use in the US increased ~117%. According to the latest available CDC stats, between 2002-2008 the prevalance of diabetes increased only ~20%, so more diabetes would appear to explain only a portion of the observed increase during this time frame.
Competing interests pertaining specifically to this post, comment, or both:
None.
In the FIELD study http://www.ncbi.nlm.nih.gov/pubmed/16310551 total mortality was greater in the fenofibrate group compared to placebo with a p value of .18. In other words we are 82% certain that fenofibrate kills people. This is not a level that we regard as “proof”, however it raises a red flag and until evidence appears that it saves lives I will continue to not prescribe it.I am using flax oil (omega 3) to lower triglycerides (good evidence that fish oils lower triglycerides but many fish species are being fished into extinction therefore raising ethical considerations regarding prescription of fish oils). Anecdotaly, it seems to be working.
Competing interests pertaining specifically to this post, comment, or both:
none
Part of the reason for increasing fibrate prescriptions may be the relatively new safety data when coprescribing with statins. I am curious if the percent of coprescriptions was determined above. Of course, such” safety”, does not justify use, and coprescribing behavior is certainly promoted by the drug companies…I have often heard the lingo” residual risk”. Its kind of like stenting a stable patient: its nice to” see” good numbers.
Since FIELD, I only coprescribe for trig quite high on potent statin and w- 3. I am more hopeful re niacin-statin combo…but who knows really until AIM- HIGH?
We did not have data available on the percent of coprescriptions of fibrates with statins. Agree that the increased comfort with coprescribing could certainly contribute to increased use, especially in the setting of marketing around this specific issue.
Harlan : Please refer to “The recently published 2008 post-hoc analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE IT: TIMI 22) trial demonstrated the potential importance of therapeutic lowering of high triglyceride levels to less than 150 mg/dL in improving clinical outcomes. Reducing high triglyceride levels conferred additional protection against coronary heart disease (CHD) events, independently of LDL-C and high-sensitivity C-reactive protein (hs-CRP) reduction.” Miller M et al J Am Coll Cardiol 2008;51:724-730
Anil, Harlan certainly doesn’t need me to speak for him but it occurs to me that the key words in your comment are that the “post-hoc analysis” showed “the potential importance” of TG lowering. This is a very shaky evidence base to justify major changes in prescribing patterns!
I agree with Larry. That study in no way justifies the remarkable increase in the use of the medication.
and although the study you cite is in a trial population – this analysis is an observational study of the prognostic importance of TG levels – not of the benefit of an intervention – let alone the benefit of fibrates.
I agree that study does not justify increase in fibrates prescription. But, it does bring up the issue of bringing down the Tg to below 150 mg%, to further cut down the residual risk after statins have brought the LDL to below 70 mg%. And, after using high doses of statin, the only way to bring Tg further down is by adding a fenofibrate. Since, the Tg / HDL axis disorders are more prominent in the Indian subcontinent , I feel use of statin and fenofibrate therapy is quite justified in the Asian Indians.
The SAFARI trial did show significant reductions in the Tg and a rise in HDL, but wheteher this would translate into long-term clinical benefit and mortality reduction is not known. I’m not aware of any long-term outcome study with fibrates as compared to statins. But, the fact that statins alone are not able to eliminate the risks in patients with raised Tg or low HDL, does permit one to try such an intervention theoretically.
Harlan, I agree that plausibility/suspicion alone should not be enough in most cases. But there has been no harm shown in using the present fibrates in diabetic patients (unlike the harm shown with Gemfibrozil and Finnish smokers and heart disease). I should have been clearer: A relative deficiency of insulin in diabetics inhibits the clearance of triglycerides into fat cells and their conversion into fats. So by using fenofibrate, I think I am taking an additional step towards normalizing the many metabolic disarrangements in diabetic patients with AODM. I am not quite so certain with Type I diabetics.
Even if there were a subset of statin-treated patients with high triglycerides who would benefit from the addition of fibrates (and this has not been shown), the choice of a branded formulation is questionable. I believe ACCORD used the generic. But industry not only insinuates that all lipid profiles should be normalized, they also claim exclusive” FDA safety privileges”. Does the FDA indirectly contribute to branded prescription behavior? Should they require a comparison with the generic (maybe adding Federal financial support)?
Anil, Harlan asked a question about outcomes evidence to support lowering LDL < 70mg/dl, are you aware of any such trials? I noticed some of us are treating LDLs to < 70 and tried finding supporting outcome evidence and couldn't find any.
Competing interests pertaining specifically to this post, comment, or both:
None
I have used gemfifrozil for many years as a result of the Helsinki heart study which showed cardiovascular benefit. This drug went generic and statins were released. There is no financial incentive for a company to do a comparative trial demonstrating safety and efficacy regarding combination of gemfibrozil and a statin. I did this for many years, was cautious, and did not have any problems. The only reason fenofibric acid is FDA indicated for combination with a statin is that it had not become generic yet and the company would have a new position to market the drug from. In a sense, the FDA is unknowingly colluding with manufacturers to promote branded products by discouraging research on non branded drugs.
Competing interests pertaining specifically to this post, comment, or both:
none
Fibates are only useful for treating elevated triglycerides. In most cases an elevated triglyceride represents loosely controlled diabetes or prediabetes.The solution is to treat the diabetes more aggressively. This can be done using diabetes drugs that do not cause hypoglycemia when used without sulfonoureas or insulin. The cheapest and simplist is to use metformin. As alternative for patients with and elevated creatinine or intolerance to metformin is pioglitizone.
B.A Kottke M.D., Ph.D., FACC
Emeritus Professor of Medicine
Mayo College of Medicine