title: Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data.
abstract: Patients with type 2 diabetes have increased cardiovascular risk. PCSK9 monoclonal antibodies have been shown to reduce LDL cholesterol and other lipids, but specific efficacy for patients with diabetes is unknown. We compared the effect of the PCSK9 inhibitor evolocumab on lipid parameters in patients with and without type 2 diabetes.
  
  
  
  We did a random-effects meta-analysis of randomised clinical trials comparing the efficacy of evolocumab, placebo, and ezetimibe to improve lipid parameters in adult patients (age 18-80 years) with or without type 2 diabetes. We searched MEDLINE and Embase to identify eligible 12-week, phase 3 trials published between Jan 1, 2012, and Feb 28, 2015. We excluded trials that included patients who had homozygous familial hypercholesterolaemia. All analyses were based on individual participant data. We used DerSimonian and Laird random-effects meta-analyses to compare the mean changes from baseline in concentrations of LDL cholesterol, non-HDL cholesterol, total cholesterol, triglycerides, lipoprotein(a), and HDL cholesterol at 12 weeks for evolocumab, placebo, and ezetimibe. We also assessed the effect of evolocumab therapy compared with placebo across subgroups of patients based on glycaemia, insulin use, renal function, and cardiovascular disease status at baseline.
  
  
  
  Three trials met our inclusion criteria, and included 413 patients with type 2 diabetes and 2119 patients without type 2 diabetes. In patients with type 2 diabetes evolocumab caused mean reductions in LDL cholesterol concentration that were 60% (95% CI 51-69) versus placebo and 39% (32-47) versus ezetimibe. In patients without type 2 diabetes, evolocumab caused mean reductions in LDL cholesterol that were 66% (62-70) versus placebo and 40% (36-45) versus ezetimibe. In patients with type 2 diabetes, evolocumab was associated with reductions in non-HDL cholesterol (55% [47-63] vs placebo and 34% [26-41] vs ezetimibe), total cholesterol (38% [32-44] vs placebo and 24% [16-31] vs ezetimibe), and lipoprotein(a) (31% [25-37] vs placebo and 26% [16-35] vs ezetimibe), and an increase in HDL cholesterol (7% [4-11] vs placebo and 8% [4-13] vs ezetimibe). Findings were similar across diabetes subgroups based on glycaemia, insulin use, renal function, and cardiovascular disease status.
  
  
  
  Evolocumab markedly reduces atherogenic lipoproteins in patients with type 2 diabetes, an effect that is consistent across subgroups and similar to that seen in patients without type 2 diabetes. Results from ongoing cardiovascular outcome trials of PCSK9 inhibitors will provide additional data to inform the use of these drugs in patients with type 2 diabetes.
  
  
  
  Amgen.
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. Electronic address: naveed.sattar@glasgow.ac.uk.
authors: Naveed
authors: N
authors: Sattar
authors: Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors: David
authors: D
authors: Preiss
authors: Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City, IA, USA.
authors: Jennifer G
authors: JG
authors: Robinson
authors: Amgen, Thousand Oaks, CA, USA.
authors: C Stephen
authors: CS
authors: Djedjos
authors: Amgen, Cambridge, UK.
authors: Mary
authors: M
authors: Elliott
authors: Amgen, Thousand Oaks, CA, USA.
authors: Ransi
authors: R
authors: Somaratne
authors: Amgen, Thousand Oaks, CA, USA.
authors: Scott M
authors: SM
authors: Wasserman
authors: Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.
authors: Frederick J
authors: FJ
authors: Raal
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C577155:evolocumab