The Effects of Pomegranate Extract (POMx), Simvastatin, or Metformin Therapies in Hypercholesterolemic or in Diabetic Patients on Daily Rhythms of Serum Lipids and of Oxidative Stress: A Pilot Study

Abstract

Background: There are no data regarding the effects of conventional therapies or of dietary antioxidants in hypercholesterolemic or diabetic patients, on their lipid and oxidative stress-related daily rhythms. Objective: To investigate the effects of Pomegranate Extract (POMx), simvastatin or metformin in hypercholesterolemic or diabetic patients on daily rhythms of serum lipids and oxidative stress, and their effects on macrophage atherogenicity. Methods: Three healthy subjects, three hypercholesterolemic or two diabetic patients, participated in the current pilot study. Blood samples were collected around the clock from the same patient (every 4 h during a 24 h cycle), before and after two weeks treatment with POMx (1 pill/day), with simvastatin (20 mg/day), or with metformin (850 mgx2/day). Results: In healthy subjects, but not in hypercholesterolemic patients, HDL-cholesterol levels showed daily changes with a maximal level in the afternoon. In both groups, serum Paraoxonase 1 (PON1) arylesterase activity increased during the day between 08:00 to noon, followed by a decrement between 16:00 to 04:00. In patients treated with POMx or simvastatin, serum oxidative stress decreased at each time point vs. results obtained before therapy. In contrast to the reduction in PON1 activity from noon to evening that was observed in serum before therapy, after simvastatin therapy, there was no such a reduction. In diabetics, serum LDL-cholesterol levels showed daily changes, which were completely abolished after POMx or after metformin treatment. Diabetic serum samples before therapy increased macrophage cholesterol accumulation and oxidative stress, and this atherogenic pattern was beneficially changed after metformin therapy. Serum cortisol levels showed similar daily patterns in healthy subjects and in diabetic patients (maximum level at 08:00) whereas in hypercholesterolemic patients the highest cortisol levels were noted at 04:00. The various treatments resulted in a daily rhythm similar to that of the healthy subjects. Conclusion: In the present study we have shown, for the first time, that nutritional antioxidant such as Pomegranate Extract (POMx), as well as simvastatin or metformin therapies in hypercholesterolemic or in diabetic patients, respectively, significantly affect their daily rhythms of serum lipids and of serum oxidative stress, as well as their serum-mediated effects on macrophage atherogenicity. These results could contribute to our understanding of how to use the appropriate therapy along the appropriate time of the day for hypercholesterolemic or diabetic patients' therapy.