Lower Baseline Glycemia Reduces Apparent Oral Agent Glucose-Lowering Efficacy

Abstract

Perusal of advertisements for oral hypoglycemic agents in this and many other medical journals shows an emphasis on the absolute reduction in HbA1c (A1C). Evidence linking reduction in A1C in diabetic patients to prevention of macrovascular events is weak. However, epidemiological evidence suggests that the risk for cardiovascular disease in this group may actually begin at A1C concentrations well within the normal range (1). This association has led a number of professional organizations to recommend that A1C levels be brought to levels <6.5% (2). An important question to be asked is whether the reduction in A1C differs at lower versus higher baseline levels of A1C. Expectations for the degree of reduction to be attained with a given agent may be excessively optimistic when a person’s initial A1C is already <7.5–8.0%. Some of the deliberations of policy advisory groups are available. The European Agency for the Evaluation of Medicinal Products has published guidelines for diabetes product evaluation suggesting that the change in A1C be utilized as “primary analysis” of drug efficacy, although allowing the baseline A1C to be included as a covariate (3). A meeting of the Center for Drug Evaluation and Research Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration concluded that A1C should be the primary outcome variable for diabetes drugs and suggested an absolute decrease of 0.7% as the minimal acceptable level for approval (4). This may prevent acceptance of agents that are as effective as existing treatments at A1C levels …