Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes
Background Glycated hemoglobin (HbA1c) is accepted as the most reliable marker for assessing chronic glycemia. The present study aimed to investigate glycemic control in cardiovascular outcome trials (CVOTs) performed by pharmaceutical sponsors, at the request of the United States Food and Drug Admi...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-12-01
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| Series: | Journal of Pharmaceutical Policy and Practice |
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| Online Access: | http://dx.doi.org/10.1186/s40545-019-0193-y |
| _version_ | 1797401339571994624 |
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| author | Rumiko Shimazawa Masayuki Ikeda |
| author_facet | Rumiko Shimazawa Masayuki Ikeda |
| author_sort | Rumiko Shimazawa |
| collection | DOAJ |
| description | Background Glycated hemoglobin (HbA1c) is accepted as the most reliable marker for assessing chronic glycemia. The present study aimed to investigate glycemic control in cardiovascular outcome trials (CVOTs) performed by pharmaceutical sponsors, at the request of the United States Food and Drug Administration (FDA) to ensure that newer hypoglycemic agents do not increase cardiovascular risk for patients with type 2 diabetes. Methods We chose ClinicalTrials.gov as a data source to identify randomized, double-blind, placebo-controlled non-inferiority trials of newer hypoglycemic agents for which the FDA 2008 guidance required a CVOT involving patients with type 2 diabetes. Results We identified 12 CVOTs, all of which were performed in accordance with the FDA guidance and published as of December 2018. Participants received either active treatment or placebo in addition to their existing therapy. On the assumption that HbA1c concentrations would be higher in the placebo group than in the treatment group, the use of open-label glucose lowering agents was encouraged as required to help all patients reach appropriate HbA1c targets according to local guidelines. As a result, the number of patients who received additional hypoglycemic agents during the trial was greater in the placebo group than in the treatment group in 10 of the CVOTs. Although the CVOTs were designed to avoid any imbalance in glycemic control between the groups, HbA1c concentrations were substantially higher in the placebo group than in the treatment group in all CVOTs throughout the observational period. The inferior glycemic control in the placebo groups was not considered in analyzing the outcomes in any of the CVOTs. Conclusions The safety and efficacy of new hypoglycemic agents are potentially inflated because the participants in the placebo groups unexpectedly exhibited inferior glycemic control throughout the trial compared with the outcomes in the treatment groups. This imbalance may distort data interpretation and mask potential risks of the drugs. Re-analysis with adjustment for HbA1c concentrations would determine whether the results of these CVOTs were biased by the difference in glycemic control between the treatment and placebo groups and reveal potential effects of the test drugs independent of glycemic control. |
| first_indexed | 2024-03-09T02:07:30Z |
| format | Article |
| id | doaj.art-430f4d303ccc4bbebf80fe1fef59bb2d |
| institution | Directory Open Access Journal |
| issn | 2052-3211 |
| language | English |
| last_indexed | 2024-03-09T02:07:30Z |
| publishDate | 2019-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Pharmaceutical Policy and Practice |
| spelling | doaj.art-430f4d303ccc4bbebf80fe1fef59bb2d2023-12-07T15:28:02ZengTaylor & Francis GroupJournal of Pharmaceutical Policy and Practice2052-32112019-12-0112110.1186/s40545-019-0193-y12315119Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetesRumiko Shimazawa0Masayuki Ikeda1Department of Clinical Pharmacology,Department of Medical Informatics,Background Glycated hemoglobin (HbA1c) is accepted as the most reliable marker for assessing chronic glycemia. The present study aimed to investigate glycemic control in cardiovascular outcome trials (CVOTs) performed by pharmaceutical sponsors, at the request of the United States Food and Drug Administration (FDA) to ensure that newer hypoglycemic agents do not increase cardiovascular risk for patients with type 2 diabetes. Methods We chose ClinicalTrials.gov as a data source to identify randomized, double-blind, placebo-controlled non-inferiority trials of newer hypoglycemic agents for which the FDA 2008 guidance required a CVOT involving patients with type 2 diabetes. Results We identified 12 CVOTs, all of which were performed in accordance with the FDA guidance and published as of December 2018. Participants received either active treatment or placebo in addition to their existing therapy. On the assumption that HbA1c concentrations would be higher in the placebo group than in the treatment group, the use of open-label glucose lowering agents was encouraged as required to help all patients reach appropriate HbA1c targets according to local guidelines. As a result, the number of patients who received additional hypoglycemic agents during the trial was greater in the placebo group than in the treatment group in 10 of the CVOTs. Although the CVOTs were designed to avoid any imbalance in glycemic control between the groups, HbA1c concentrations were substantially higher in the placebo group than in the treatment group in all CVOTs throughout the observational period. The inferior glycemic control in the placebo groups was not considered in analyzing the outcomes in any of the CVOTs. Conclusions The safety and efficacy of new hypoglycemic agents are potentially inflated because the participants in the placebo groups unexpectedly exhibited inferior glycemic control throughout the trial compared with the outcomes in the treatment groups. This imbalance may distort data interpretation and mask potential risks of the drugs. Re-analysis with adjustment for HbA1c concentrations would determine whether the results of these CVOTs were biased by the difference in glycemic control between the treatment and placebo groups and reveal potential effects of the test drugs independent of glycemic control.http://dx.doi.org/10.1186/s40545-019-0193-ybiascardiovascular diseasesclinical trialsdrug approvalglycated hemoglobinhypoglycemic agentstype 2 diabetes mellitus |
| spellingShingle | Rumiko Shimazawa Masayuki Ikeda Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes Journal of Pharmaceutical Policy and Practice bias cardiovascular diseases clinical trials drug approval glycated hemoglobin hypoglycemic agents type 2 diabetes mellitus |
| title | Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes |
| title_full | Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes |
| title_fullStr | Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes |
| title_full_unstemmed | Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes |
| title_short | Imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes |
| title_sort | imbalance in glycemic control between the treatment and placebo groups in cardiovascular outcome trials in type 2 diabetes |
| topic | bias cardiovascular diseases clinical trials drug approval glycated hemoglobin hypoglycemic agents type 2 diabetes mellitus |
| url | http://dx.doi.org/10.1186/s40545-019-0193-y |
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