BackgroundStatins are the most widely prescribed medication to lower low-density lipoprotein cholesterol (LDL-c). However, a significant portion of patients are unable to tolerate them due to side effects, most commonly muscle related. Nutraceuticals, natural plant derivatives with lipid-lowering properties, may provide an alternative to lower LDL-c in these patients.AimsTo investigate whether a nutraceutical regimen, either alone or in combination with ezetimibe, can lower LDL-c in patients with hypercholesterolemia who are intolerant to statins.MethodsParticipants were recruited into a double-blind, randomized, placebo-controlled intervention study. Treatments were (i) placebo, (ii) nutraceutical (500 mg berberine, 200 mg red yeast rice (RYR), 2 g plant sterols)/daily, (iii) ezetimibe (10 mg)/daily, or (iv) the combination of nutraceutical and ezetimibe/daily. At baseline and week 8, all participants provide a fasting blood sample for assessment of lipid profile and safety bloods.ResultsFifty participants were randomized, with 44 completing the treatment period. Following adjustment for baseline levels and compared with placebo, LDL-c was significantly reduced (all p < 0.0001) with ezetimibe (−1.02 mmol/L), nutraceutical (−1.15 mmol/L) and the nutraceutical and ezetimibe combination (−1.92 mmol/L). Non-HDL cholesterol was significantly reduced (all p < 0.0001) with ezetimibe (−1.29 mmol/L), nutraceutical (−1.37 mmol/L) and the nutraceutical and ezetimibe combination (−2.18 mmol/L). Remnant cholesterol and triglycerides was significantly reduced with the nutraceutical and ezetimibe combination (p = 0.018).ConclusionA nutraceutical regimen (berberine, RYR and plant sterols) and ezetimibe independently and additively lower LDL-c in patients with hypercholesterolemia who are intolerant to statins.