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      Type 2 diabetes mellitus development programs in the new regulatory environment with cardiovascular safety requirements

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          Abstract

          For type 2 diabetes mellitus treatment and clinical development, proper evaluation of cardiovascular risk has been required by regulatory agencies (eg, the US Food and Drug Administration) since cardiovascular safety is very important in this patient population. The US Food and Drug Administration issued general guidelines for cardiovascular safety evaluation that outlined the requirements considered adequate for cardiovascular safety evaluation. However, there are multiple options to obtain the data and fulfill these requirements. In this paper, we outline the potential pathways and challenges in various aspects of cardiovascular safety evaluation in type 2 diabetes clinical development, including study design, populations, and endpoints. Specifically, we discuss some challenges in statistical analysis which have implications for the design, implementation, and interpretation of these outcome studies.

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          Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

          Robert Bresalier, Robert Sandler, Hui Quan … (2005)
          Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk. Copyright 2005 Massachusetts Medical Society.
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            A randomized trial of therapies for type 2 diabetes and coronary artery disease.

            Jesse Goldberg, Saul M. Genuth, B Sobel … (2009)
            Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established. We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention. At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003). Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.) 2009 Massachusetts Medical Society
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              Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation

              WHO/IDF, W IDF (2006)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Metab Syndr Obes
                Journal ID (iso-abbrev): Diabetes Metab Syndr Obes
                Journal ID (publisher-id): Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Title: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Publisher: Dove Medical Press
                ISSN (Electronic): 1178-7007
                Publication date Collection: 2015
                Publication date (Electronic): 20 July 2015
                Volume: 8
                Pages: 315-325
                Affiliations
                [1 ]AstraZeneca, Gaithersburg, MD, USA
                [2 ]GlaxoSmithKline, Upper Merion, PA, USA
                [3 ]Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, WI, USA
                Author notes
                Correspondence: Fred Yang, AstraZeneca, One Medimmune Way, Building 200, Gaithersburg, MD 20878, USA, Tel +1 267 980 9451, Email fredyyang@ 123456yahoo.com
                Article
                Publisher ID: dmso-8-315
                DOI: 10.2147/DMSO.S84005
                PMC ID: 4516202
                SO-VID: 81996c98-db9e-4d23-84a3-1d8c5cc45bcb
                Copyright © © 2015 Yang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License
                License:

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Subject: Review

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: t2dm,cardiovascular outcome,cv risk,noninferiority,superiority,major adverse cardiac event
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: t2dm, cardiovascular outcome, cv risk, noninferiority, superiority, major adverse cardiac event

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