title: Nonstatin Low-Density Lipoprotein-Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council.
abstract: Pharmacological reduction of low-density lipoprotein (LDL) cholesterol using statin drugs is foundational therapy to reduce cardiovascular disease (CVD) risk. Here, we consider the place of nonstatin therapies that also reduce LDL cholesterol in prevention of CVD. Among conventional nonstatins, placebo-controlled randomized clinical trials showed that bile acid sequestrants, niacin, and fibrates given as monotherapy each reduce CVD end points. From trials in which patients' LDL cholesterol was already well controlled on a statin, adding ezetimibe incrementally reduced CVD end points, whereas adding a fibrate or niacin showed no incremental benefit. Among emerging nonstatins, monoclonal antibodies against proprotein convertase subtilisin kexin type 9 added to a statin and given for ≤78 weeks showed preliminary evidence of reductions in CVD outcomes. Although these promising early findings contributed to the recent approval of these agents in Europe and in North America, much larger and longer duration outcomes studies are ongoing for definitive proof of CVD benefits. Other nonstatin agents recently approved in the United States include lomitapide and mipomersen, which both act via distinctive LDL receptor independent mechanisms to substantially reduce LDL cholesterol in homozygous familial hypercholesterolemia. We also address some unanswered questions, including measuring alternative biochemical variables to LDL cholesterol, evidence for treating children with monitoring of subclinical atherosclerosis, and potential risks of extremely low LDL cholesterol. As evidence for benefit in CVD prevention accumulates, we anticipate that clinical practice will shift toward more assertive LDL-lowering treatment, using both statins and nonstatins initiated earlier in appropriately selected patients.
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.). hegele@robarts.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.).
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Gidding
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.).
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.).
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.).
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Raal
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.).
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Robinson
authors.affiliation: From the Department of Medicine, Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada (R.A.H.); Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, DE (S.S.G.); Irving Institute for Clinical and Translational Research, Department of Medicine, Columbia University, New York, NY (H.N.G.); Department of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R); Department of Genetics (D.J.R.) and Division of Translational Medicine and Human Genetics, Department of Medicine (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Epidemiology and Medicine, University of Iowa, Iowa City (J.G.R.); and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.K.W.).
authors.forename: Francine K
authors.initials: FK
authors.lastname: Welty
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000517:prevention & control*; D008078:Cholesterol, LDL / Q000097:blood*; D015536:Down-Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D017410:Practice Guidelines as Topic; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D008078:Cholesterol, LDL
keywords: LDL; atherosclerosis; cardiovascular diseases; cholesterol; guideline; lipids; lipoproteins; therapeutics