Dietary Supplement Safety

By Sanford H. Levy, MD, FACP, ABIHM

Many individuals assume that natural equates to safe – this is not always the case (consider the coca leaf, to which Sigmund Freud reportedly became addicted). A published report and accompanying editorial in the most recent issue of the Annals of Internal Medicine, (Ann Intern Med. 2012. 156. 857-860 and editorial 894-895) piqued my interest. This particular report focused on Limbrel® (flavocoxid), a proprietary mixture (>90% standardized blend) of two specific flavonoids (baicalcin and catechin) shown to have COX-1, COX-2, and 5-LOX inhibitory effects. Limbrel is medical food, and thus requires a prescription. Limbrel became available in US in 2004, and is available in 250 and 500 mg tablets.

In the DILIN consortium of 8 clinical centers, a network established in 2004 to conduct a prospective observational study of individuals suspected to have liver injury due to prescription agents or herbal supplements, 877 patients with suspected liver injury were enrolled between 2004 and 2010. Amongst these 877 patients with liver injury were 4 adults who developed signs and symptoms of severe liver injury within 1-3 months of initiation of flavocoxid. Manifestations included marked elevations of ALT (mean peak 1268 U/L), alkaline phosphatase (mean peak 510 U/L) and bilirubin (mean peak 9.4 mg/dl). These values returned to normal range within 3-12 weeks of discontinuation of flavocoxid. All patients recovered clinically, without experiencing acute liver failure or chronic liver disease. Causality was judged as highly likely in 3 patients and possible in 1 patient.

In addition to this report of acute liver injury, mild elevations of liver function tests (LFTs) have been reported too (J Med Food. 2009. 12. 143-148; Adv Ther. 2010. 27. 31-42). Based on a postmarketing surveillance study in 1067 patients (GOAL trial), the estimated incidence of liver injury is 0.1% (Curr Med Res Opin. 2010. 26. 1055-1063).

This published report and accompanying editorial reminded me that I must not assume that a newly marketed dietary supplement is inherently safe simply because it is natural. Of course, in our clinical care of patients, one must balance risk versus efficacy, consider cost, and consider the safety of the alternatives. A couple of RCTs (albeit with methodologic limitations) report that the efficacy of flavocoxid is similar to naproxen, and the safety profile of flavocoxid is likely superior to the safety profile of naproxen.