Shimazawa Rumiko, Ikeda Masayuki
1Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193 Japan.
2Department of Medical Informatics, Kagawa University Hospital, Miki-cho, Kagawa 761-0793 Japan.
J Pharm Policy Pract. 2019 Nov 18;12:30. doi: 10.1186/s40545-019-0193-y. eCollection 2019.
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.
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.
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.
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.
糖化血红蛋白（HbA1c）被公认为评估慢性血糖水平最可靠的指标。本研究旨在调查制药赞助商应美国食品药品监督管理局（FDA）要求开展的心血管结局试验（CVOT）中的血糖控制情况，以确保新型降糖药物不会增加2型糖尿病患者的心血管风险。
我们选择ClinicalTrials.gov作为数据源，以识别新型降糖药物的随机、双盲、安慰剂对照非劣效性试验，FDA 2008年指南要求此类试验需纳入2型糖尿病患者并开展CVOT。
我们识别出12项CVOT，所有试验均按照FDA指南进行，且截至2018年12月已发表。参与者在接受现有治疗的基础上，要么接受活性治疗，要么接受安慰剂治疗。假设安慰剂组的HbA1c浓度会高于治疗组，根据要求鼓励使用开放标签的降糖药物，以帮助所有患者根据当地指南达到适当的HbA1c目标。结果，在10项CVOT中，试验期间接受额外降糖药物治疗的患者数量在安慰剂组多于治疗组。尽管CVOT旨在避免两组之间血糖控制出现任何不平衡，但在整个观察期内，所有CVOT中安慰剂组的HbA１c浓度均显著高于治疗组。在分析任何一项CVOT的结果时，均未考虑安慰剂组较差的血糖控制情况。
新型降糖药物的安全性和有效性可能被高估，因为与治疗组的结果相比，安慰剂组的参与者在整个试验中意外地表现出较差的血糖控制。这种不平衡可能会扭曲数据解读，并掩盖药物的潜在风险。对HbA1c浓度进行调整后重新分析，将确定这些CVOT的结果是否因治疗组和安慰剂组之间血糖控制的差异而产生偏差，并揭示受试药物独立于血糖控制的潜在效果。
