Plant Stanol Esters Enhance Rx Cholesterol Drugs - McNeil Petition

Foods and dietary supplements containing plant stanol esters augment the cholesterol-lowering effects of several Rx drugs, McNeil Consumer Healthcare states in a health claim petition recently made available by FDA.

The Benecol marketer cites several trials in which plant stanol ester products were given to patients taking pravastatin (Bristol-Myers Squibb's Pravachol), simvastatin (Merck's Zocor) or neomycin, an antibiotic found in Rx and OTC products such as Warner-Lambert's Neosporin. Each of the trials showed the addition of plant stanol esters to the subjects' diets enhanced the reduction of total and low-density lipoprotein (LDL) cholesterol compared to the drug alone, McNeil notes.

The studies are part of McNeil's effort to obtain agency approval of a heart disease risk reduction health claim for its line of Benecol products made with plant stanol esters. The company recently altered the line's offerings, having dropped its salad dressings (¹ (Also see "Salad dressings discontinued" - Pink Sheet, 1 May, 2000.)).

The petition, filed with FDA Feb. 10, was submitted just three days after the firm filed a citizen petition protesting FDA's restrictive view regarding cholesterol claims voiced in the structure/function claim final rule (² (Also see "Cholesterol-Lowering Claim Disease Status Protested By McNeil" - Pink Sheet, 14 Feb, 2000.)).

If plant stanol esters are granted a health claim, the ingredient would join oat bran, psyllium and soy protein as substances with approved heart disease risk reduction claims.

The study results cited by McNeil vary considerably. A 1994 study showed taking 2.6 g per day plant stanol esters along with 40 mg/d or 80 mg/d pravastatin lowered cholesterol levels more than taking the statin drug alone, but the effect was not significant. Another study found an 11% reduction in total cholesterol and a 14% drop of LDL cholesterol from 5.1 g/d plant stanol esters alone and a total reduction of 35% and 44%, respectively, when taken with 40 mg/d pravastatin.

Another trial showed 1.5 g/d neomycin reduced total and LDL cholesterol levels by 26% and 29%, respectively; taking 5.1 g/d plant stanol esters in combination with neomycin enhanced the effects by an additional 12%.

A fourth study revealed, "combined with [10 mg/d -20 mg/d] simvastatin, [5.1 g/d] plant stanol esters reduced serum total cholesterol and LDL-cholesterol by an additional 11.3% and 16.5%, respectively," in postmenopausal heart attack survivors who had taken the Rx drug for one year.

Novartis Consumer Health has said the effects of its cholesterol-lowering Phytrol phytosterol plateaus when exceeding 1.8 g/d, making it "impossible to overdose" on the substance, an issue that could be of concern if cholesterol-lowering spreads are taken in conjunction with Rx medications. Novartis' GRAS notification for Phytrol was cleared by FDA April 24 (³ (Also see "Phytrol Lowers Total Cholesterol Up To 19%, Novartis Research Shows" - Pink Sheet, 15 May, 2000.)).

In total, McNeil submitted 23 published trials and 11 unpublished studies to support its petition. "'Significant scientific agreement' has been established through multiple, peer-reviewed, published clinical studies demonstrating the cholesterol lowering effects of the regular dietary use of plant stanol ester," the firm maintains. "The most compelling clinical data are derived from double-blind, placebo-controlled studies."

The various studies involve adults with normal and high cholesterol, adults with coronary heart disease and non-insulin-dependent diabetes mellitus, and children with normal and high cholesterol.

McNeil states .85 g plant stanol esters should be consumed per serving, since "this level is derived by dividing the recommended intake of 3.4 g plant stanol esters by four daily servings." However, the firm asserts "the most effective benefit can be achieved by ingesting 5.1 g per day plant stanol esters."

FDA approval of a heart disease claim for plant stanol ester-containing products would require exempting them from criteria involving acceptable levels of fat and necessary levels of certain nutrients.

"In a limited number of situations involving the use of stanol esters in foods consumed in small quantities...it is important to waive the 'per 50 gram' criteria for the disqualifying level of fat for these small servings," McNeil maintains.

"FDA may permit a health claim despite...a disqualifying level of a nutrient...on finding that such a claim will assist consumers in maintaining healthy dietary practices," the company asserts.

To justify its request, McNeil points out such products "would be small servings only and would continue to comply with the fat levels...on a 'per serving' and 'per [reference amount customarily consumed]' basis." In addition, since the health claim would instruct consumers on the appropriate number of servings to consume, "the substantial benefit outweighs any possible negative dietary consequences," McNeil says.

"Benecol foods are promoted as foods to be used in place of similar foods...and, therefore, will not increase the overall level of fat in the diet," the firm states.

McNeil also asks for an exemption from the minimum nutrient content requirement of 10% of the daily reference intakes for vitamins A and C, iron, calcium, protein or fiber. "Individual foods containing plant stanol esters make up a relatively small portion of the diet" and their benefit "outweighs the need of these foods to contribute certain nutrient levels," the company says.

Take Control marketer Lipton asked for similar exemptions in its petition for a heart disease claim on its competing line of plant sterol-containing products (⁴ (Also see "Vegetable Oil Sterol Esters Heart Disease Claim Sought By Lipton" - Pink Sheet, 22 May, 2000.)). The firm submitted its petition nine days before McNeil.

However, unlike the Unilever division's proposed claims, McNeil's do not include language referring to a diet low in saturated fat and cholesterol. The company said plant stanol esters are more efficacious than plant sterol esters or other ingredients, and therefore no such stipulation is necessary. McNeil notes, however, that its promotions for Benecol will stress "foods containing plant stanol esters should be eaten along with a diet low in saturated fat and cholesterol."

One of the three claims McNeil suggests reads: "A diet with at least 3.4 g plant stanol esters per day reduces cholesterol and may reduce the risk of heart disease. 5 g of plant stanol esters per day is more effective in reducing cholesterol and may further reduce the risk of heart disease. This product contains ___ g plant stanol esters per serving."

Another states: "3.4 g plant stanol esters per day may reduce the risk of heart disease. 5 g plant stanol esters may be more beneficial in reducing the risk of heart disease. This product contains ___ g of plant stanol esters per serving."

The third says: "3.4 g plant stanol esters per day has been demonstrated to lower LDL (bad) cholesterol and may reduce the risk of heart disease. 5 g plant stanol esters per day has been shown to further lower LDL (bad) cholesterol and may further reduce the risk of heart disease. This product contains ___ g of plant stanol esters per serving."