Metabolic & Atherosclerosis Research Center
Metabolic & Atherosclerosis Research Center
PubMed | University Hospitals Leuven, University of Oslo, McMaster University, University of British Columbia and 5 more.
Type: Clinical Trial | Journal: Journal of clinical lipidology | Year: 2015
Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Guidelines recommend initiating statins early to reduce low-density lipoprotein cholesterol (LDL-C). Studies have evaluated rosuvastatin in children aged 10 years, but its efficacy and safety in younger children is unknown.Children with HeFH and fasting LDL-C >4.92 mmol/L (190 mg/dL) or >4.10 mmol/L (>158 mg/dL) with other cardiovascular risk factors received rosuvastatin 5 mg daily. Based on LDL-C targets (<2.85 mmol/L [<110 mg/dL]), rosuvastatin could be uptitrated to 10 mg (aged 6-9 years) or 20 mg (aged 10-17 years). Treatment lasted 2 years. Changes in lipid values, growth, sexual maturation, and adverse events (AEs) were assessed.The intention-to-treat analysis included 197 patients. At 24 months, LDL-C was reduced by 43, 45, and 35% vs baseline in patients aged 6-9, 10-13, and 14-17 years, respectively (P < .001 for all groups). Most AEs were mild. Intermittent myalgia was reported in 11 (6%) patients and did not lead to discontinuation of rosuvastatin treatment. Serious AEs were reported by 9 (5%) patients, all considered unrelated to treatment by the investigators. No clinically important changes in hepatic biochemistry were reported. Rosuvastatin treatment did not appear to adversely affect height, weight, or sexual maturation.In HeFH patients aged 6-17 years, rosuvastatin 5-20 mg over 2 years significantly reduced LDL-C compared with baseline. Treatment was well tolerated, with no adverse effects on growth or sexual maturation.
PubMed | Metabolic & Atherosclerosis Research Center, Gemphire Therapeutics, Jacksonville Center for Clinical Research and Louisville Metabolic & Atherosclerotic Research Center
Type: Journal Article | Journal: Journal of clinical lipidology | Year: 2016
Ezetimibe added to statin therapy further reduces LDL-C and clinical atherosclerotic cardiovascular disease compared to statin alone. However, the number of effective and safe oral agents for patients not at LDL-C goal is limited. In prior clinical trials, gemcabene reduced LDL-C and was generally well-tolerated in nearly 900 patients treated for up to 12weeks.To evaluate the LDL-C lowering and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients.This was an 8-week, double-blind, placebo-controlled, randomized, phase 2 study in men and postmenopausal women 18 and 65 years of age with LDL-C 130mg/dL (3.4mmol/L) while on low-intensity to high-intensity stable statin (the majority on moderate intensity) therapy. Sixty-six patients were randomized 1:1:1 to gemcabene 300mg, 900mg, or placebo QD.Gemcabene 300mg and 900mg produced a mean percent change in LDL-C of -23.44.7% (P=.005) and -27.7 4.3% (P<.001), respectively, vs -6.2 4.3% for placebo. The median percent change in CRP was -26.1% (P=.196) and -53.9% (P<.001) for gemcabene 300mg and 900mg, respectively, vs -11.1% for placebo. Gemcabene 300mg and 900mg were well-tolerated with no significant difference in AEs compared to placebo.Gemcabene as add-on to stable statin therapy demonstrated additional dose-dependent and statistically significant reductions in LDL-C of >20% and CRP >40% compared to placebo. The results support gemcabene-continued development for patients requiring LDL-C lowering beyond that provided by background statin therapy.
PubMed | Metabolic & Atherosclerosis Research Center
Type: Journal Article | Journal: Clinical therapeutics | Year: 2015
Over the past 3 decades reducing LDL-C has proven to be the most reliable and easily achievable modifiable risk factor to decrease the rate of cardiovascular morbidity and mortality. Statins are effective, but problems with their side effects, adherence, or LDL-C efficacy in some patient groups remain. Most currently available alternative lipid-modifying therapies have limited efficacy or tolerability, and additional effective pharmacologic modalities to reduce LDL-C are needed.Recent literature on new and evolving LDL-C-lowering modalities in preclinical and clinical development was reviewed.Several new therapies targeting LDL-C are in development. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a recently elucidated key regulator of plasma LDL-C, is the most promising and effective, with a number of approaches aimed at this target. The most advanced are monoclonal antibodies, which have demonstrated LDL-C reductions of ~60%, whether given alone or added to statins. Other PCSK9-targeted therapies in clinical development include adnectins and gene silencing techniques. Preclinical approaches involve vaccines, whereas a search remains for small molecule inhibitors. Other new pharmacologic approaches in Phase III clinical trials include a refocusing of cholesterol ester transfer protein inhibitors from primarily agents to increase HDL-C to their off-target effect on LDL-C and adenosine triphosphate citrate lyase inhibition. In earlier clinical development is new delivery of nicotinic acid-containing compounds. Additional agents are being developed as orphan indications expressly for patients with homozygous familial hypercholesterolemia, including peroxisome proliferator activated receptor- agonists, angiopoietin-like protein 3 inhibitors, and gene therapy.Monoclonal antibodies that inhibit PCSK9 were shown to be very effective reducers of LDL-C and well tolerated despite subcutaneous administration, and no significant safety issues have yet emerged during large Phase II and III trials. They have the potential to substantially impact further the risk of cardiovascular disease. A number of additional new, but less effective, oral LDL-C-lowering agents are also in various stages of development, including some which are targeted only to patients with homozygous familial hypercholesterolemia.