Nutraceutical pill containing berberine versus ezetimibe on plasma lipid pattern in hypercholesterolemic subjects and its additive effect in patients with familial hypercholesterolemia on stable cholesterol-lowering treatment

Background: Although statins (STs) are drugs of first choice in hypercholesterolemic patients, especially in those at high cardiovascular risk, some of them are intolerant to STs or refuse treatment with these drugs. In view of this, we have evaluated the lipid-lowering effect of a nutraceutical pill containing berberine (BBR) and of ezetimibe, as alternative treatments, in monotherapy or in combination, in 228 subjects with primary hypercholesterolemia (HCH), with history of STs intolerance or refusing STs treatment. In addition, since PCSK9 was found up-regulated by STs dampening their effect through an LDL receptors (LDLRs) degradation, and BBR suppressed PCSK9 expression in cellular studies, we supplemented the stable lipid-lowering therapy of 30 genotype-confirmed Familial Hypercholesterolemia heterozygotes (HeFH) with BBR, searching for a further plasma cholesterol reduction. Plasma lipid pattern was evaluated at baseline and during treatments. Results: In HCH subjects the nutraceutical pill resulted more effective than EZE in lowering LDL cholesterol (-31.7% vs -25.4%, P < 0.001) and better tolerated. On treatment, LDL-C level below 3.36 mmol/L (<= 130 mg/dl) was observed in 28.9% of subjects treated with the nutraceutical pill and 11.8% of those treated with EZE (P < 0.007). In the group treated with EZE the subjects carrying the G allele of the g. 1679 C > G silent polymorphism of NPC1L1 gene showed a higher response to EZE than homozygous for the common allele (GG + CG: LDL-C -29.4 +/- 5.0%, CC -23.6 +/- 6.5%, P < 0.001). Combined treatment with these drugs was as effective as STs in moderate doses (LDL cholesterol -37%, triglycerides -23%). In HeFH patients the addition of BBR resulted in LDL cholesterol reductions inversely related to those induced by the stable therapy (r = -0.617, P < 0.0001), with mean 10.5% further decrease. Conclusions: The alternative treatments tested in our HCH subjects were rather effective and safe. The findings in HeFH patients suggest that BBR might act in vivo increasing expression and stability of LDLRs and/or suppressing PCSK9 expression.