- Click here for explanation of classification scheme.

To evaluate the safety and tolerability of three levels of plant sterol-esters administered in reduced-fat spread and salad dressing vs. control products.

TC less than 7.8mmol per L (300mg per dL) and TG levels less than 4.0mmol per L (350mg per dL).

BMI higher than 35, medically unstable conditions, pregnancy or lactation. Women of childbearing potential required to use contraception. Persons using hypolipidemic medications or therapies within four weeks prior, as well as drugs for hemostasis, systemic corticosteroids, androgens, phenytoin, erythromycin or thyroid hormones.

• Six weeks (screening): Required to abstain from all dietary supplements for four weeks prior, eligibility further assessed by medical history review and fasting lipid profile, vital signs, body weight, serum chemistry, hematology, urinalysis, physical exam, ECG
• Randomization to four groups: Control (0g phytosterols per day), average daily (3.0g per day), high but still reasonable (6.0g per day), high unlikely (9.0g per day)
• One week: Vital signs, body weight, serum chemistry, hematology, urinalysis, vitamin, carotenoid and sterol profiles, serum lipid profile, three-day diet record instruction
• Zero weeks: Vital signs, body weight, serum chemistry, hematology, urinalysis, vitamin, carotenoid and sterol profiles, serum lipid profile, three-day diet record
• Two weeks: Vital signs, body weight, serum chemistry, hematology, urinalysis, lipid profiles, vitamins, carotenoids, sterols
• Four weeks: Vital signs, body weight, serum chemistry, hematology, urinalysis, lipid profiles, vitamins, carotenoids, sterols, three-day diet record
• Six weeks: Vital signs, body weight
• Eight weeks: Vital signs, body weight, serum chemistry, hematology, urinalysis, lipid profiles, vitamins, carotenoids, sterols, physical exam, three-day diet record.

Fat-soluble vitamins (a- and ?-tocopherol, 25-hydroxyvitamin D, phylloquinone), carotenoids (a- and trans-ß-carotene, trans-lycopene, lutein, zeaxanthin, cryptoxanthin), sterols (total sterols including cholesterol, total plant sterols, campesterol, ß-sitosterol), serum TC, HDL-C and TG. LDL-C calculated using Friedewald equation. Double blind.

• 124 subjects were screened to identify the 84 subjects who were randomized. Seven dropped out prior to completion.
• There were no significant differences among groups in baseline characteristics with the exception of race (P=0.013). Subjects in the control, 3g per day and 9g per day were predominantly Caucasian (65% to 86%), whereas those in the 6g per day group were predominantly black and Hispanic (53%). 
• The ratio of male to female subjects was approximately evenly distributed ranging from 48% to 61% male across groups.

• 62% of randomized subjects experienced adverse effects during the treatment period, but they did not differ among the groups during the study, and there were no study product-related serious adverse effects.
• There were no changes in clinical laboratory values in response to phytosterol intake, with the exception of alanine aminotransferase (P=0.05) and creatine kinase (P=0.017). 
• Blood concentrations of all fat-soluble vitamins remained within normal reference ranges, and there were no differences in serum vitamin responses among the four groups. 
• Alpha- and trans-ß-carotene levels were reduced in the 9.0g per day group vs. control (P<0.05), but all carotenoid values remained within normal ranges throughout the study. 
• After correction for TC concentration, the significance of the reduction in the 9.0g per day group persisted for trans-ß-carotene vs. control (-16.6% vs. 18.6%, P<0.05). 
• All groups receiving phytosterols had significant increases in serum campesterol vs. control (P<0.001), but ß-sitosterol responses did not differ from control. 
• TC, LDL-C and HDL-C responses did not differ significantly among the groups.  The total:HDL-C response in the 9.0g per day group was significantly different from the control group response (-9.6% vs. 2.6%, P<0.05).  A median increase of 7.8% in serum TG was observed in the control group, which differed significantly from the response in the 3.0g per day arm (-13.3%, P<0.05). 

In this double-blind, randomized, controlled clinical trial, eight-week administration of phytosterol esters at levels ranging from those expected to be consumed during daily use by the average consumer (3.0g per day phytosterols) to levels unlikely to be achieved with normal daily consumption (9.0g per day phytosterols) were found to be safe and well tolerated. The results of this study indicate that phytosterol esters are well tolerated and show no evidence of adverse effects at a daily intake of up to 9.0g of phytosterols for eight weeks.

Government:	Boston VA Medical Center
University/Hospital:	Chicago Center for Clinical Research, Tuffs University

Large study. Some of the unexpected results in the 3g per day group may relate to the racial differences between groups.

• After eight weeks of 3.0g sterols:
  • TC baseline: 5.29 ±108mmol per L (204.5±41.7mg per dL) 
  • TC ending: 5.17±1.02mmol per L (200.1±39.5 mg per dL) 
    • Percent change: 5.1%±7.4% lower, not significant 
  • LDL-C baseline: 3.40±0.93mmol per L (131.3±35.9mg per dL)  
  • LDL-C ending: 3.31±0.80mmol per L (128.1±31.0mg per dL)  
    • Percent change: 5.0%±10.5% lower, not significant 
  • HDL-C and TG: No statistically significant changes
• After eight weeks of 6.0g sterols:
  • TC baseline: 5.37±0.78mmol per L (207.8±30.2mg per dL)
  • TC ending: 5.07±0.82mmol per L (196.1±31.8 mg per dL) 
    • Percent change: 2.1%±6.8% lower, not significant 
  • LDL-C baseline: 3.36±0.66mmol per L (129.9±25.4mg per dL) 
  • LDL-C ending: 3.10±0.66mmol per L (120.0±25.4mg per dL)
    • Per change: 2.8%±8.1% lower, not significant 
  • HDL-C and TG: No statistically significant changes
• After 8 weeks of 9.0g sterols:
  • TC baseline: 5.27±1.07mmol per L (203.8±41.5mg per dL) 
  • TC ending:  5.03±0.90 mmol per L (194.4mg per dL)    
    • Percent change: 5.8%±8.6% lower, not significant 
  • LDL-C baseline: 3.37±0.87mmol per  (130.2±33.8mg per dL)  
  • LDL-C ending: 3.13±0.76mmol per L (121.0±29.6mg per dL)      
    • Percent change: 9.0%±12.3% lower, not significant
  • HDL-C and TG: No statistically significant changes.