title: Perspectives on Some Controversies in Cardiovascular Disease Risk Assessment in the Pharmaceutical Development of Glucose-Lowering Medications.
abstract: The U.S. Food and Drug Administration (FDA) issued guidance on requirements to assess cardiovascular disease (CVD) risk with drugs being developed for approval for clinical use. The guidance was triggered by a meta-analysis published by Nissen and Wolski that suggested an increased risk for myocardial infarction with the use of rosiglitazone. This article discusses controversies around CVD trials in diabetes beginning with the University Group Diabetes Program. This is followed by a brief description of the FDA guidance for evaluating CVD risk with glucose-lowering medications. Limitations of meta-analyses of data from phase 2 and 3 (phase 2/3) trials to inform CVD risk are highlighted. These include the differences between patient characteristics in phase 2/3 trials and those in cardiovascular outcome trials (CVOTs) and the relatively short exposure time in phase 2/3 trials. The differences may partly explain the observed disparity between phase 2/3 meta-analyses and the results of completed CVOTs. Approaches to understanding CVD risk with a new medication should get to the answer about risk as efficiently as possible to minimize any potential harm to patients. In that context, we discuss options for clinical trial design and an alternative approach for statistical analyses.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN hoogwerf_byron_james@lilly.com.
authors.forename: Byron J
authors.initials: BJ
authors.lastname: Hoogwerf
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: David H
authors.initials: DH
authors.lastname: Manner
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Haoda
authors.initials: H
authors.lastname: Fu
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Elena
authors.initials: E
authors.lastname: Moscarelli
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Gaydos
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heine
mesh_terms: D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology; D003920:Diabetes Mellitus / Q000188:drug therapy*; D055808:Drug Discovery / Q000379:methods / Q000592:standards; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards; D004345:Drug Industry / Q000639:trends; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000139:chemically induced; D018570:Risk Assessment; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone