Pterostilbene and Grape Extract in Hypercholesterolemia

This trial was a prospective, randomized, double-blind placebo-controlled intervention trial. This trial was approved by the University of Mississippi Medical Center Institutional Review Board. The target population was patients with hypercholesterolemia, defined as a baseline total cholesterol ≥200 mg/dL and/or, baseline low-density lipoprotein cholesterol ≥100 mg/dL. Patients were included if they were ≥18 years of age and on either no cholesterol therapy or cholesterol medication at a stable dose for at least 2 months prior to baseline laboratory. Patients were excluded if they had significant hepatic, renal, or gastrointestinal tract disease, were receiving thiazolidinediones or fibric acid derivatives, had current overt cardiovascular disease, were women of reproductive potential not receiving birth control, or were pregnant/nursing women.
The trial planned for an enrollment of 80. Subjects were divided equally into one of four groups: pterostilbene 50 mg twice daily (low dose), pterostilbene 125 mg twice daily (high dose), pterostilbene 50 mg/grape extract 100 mg twice daily (low dose + grape extract), or matching placebo twice daily for 6–8 weeks. Ciprofibrate is a peroxisome proliferator-activated receptor-α (PPAR-α) agonist [8 (link)]. Pterostilbene has demonstrated similar PPAR-α activation at approximately equimolar concentrations in animal models [4 (link)]. Since a standard human dose of ciprofibrate is 100 mg/day, this dose was selected for the lowest effective pterostilbene dose in monotherapy and combination. The higher daily dose was evaluated to assess for potential dose-related efficacy or adverse effect. All patients received identical counseling on lifestyle intervention and compliance with currently prescribed medication regimens.
The manufacturer of the pterostilbene and placebo products was deemed in compliance by the FDA current good manufacturing practices prior to the initiation of this trial. The process of pterostilbene synthesis for this trial is described elsewhere [13 ].
The safety markers included biochemical and subjective measures collected at two visits (baseline and final). Donated blood was analyzed for all biochemical measures at the same laboratory values. Primary safety measures included Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), serum creatinine, and blood glucose. Other safety markers include blood electrolytes and symptomatic subjective adverse drug reactions (ADRs) collected during patient interviews at baseline and final visits. Blood pressure, cholesterol, and weight were collected and reported separately as efficacy endpoints. Pill counts were utilized to assess for compliance.
Linear mixed models were used to estimate primary safety measure treatment effects in order to account for intra subject associations arising from the repeated measures before and after longitudinal design. The underlying missing-at-random architecture implicit in mixed models was assumed. Various models were fit to examine potential baseline effects including as appropriate the following:

3-way interaction models of final outcome × treatment group × baseline value;

2-way interaction models including all 2-way terms from (1) but excluding the 3-way term;

models assuming baseline value affected change similarly across treatment groups;

models assuming change in outcome were independent of baseline value.

Each model was examined in unadjusted and adjusted form (adjusting for age, gender and race). Final reported treatment effects were obtained from the simplest appropriate adjusted model for each outcome. For secondary measures compared to baseline and/or placebo, a t-test was performed for continuous data and a Fisher's exact test was performed for dichotomous data.