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Oral hypoglycemic use and the SANDS trial.

To the Editor: Dr Howard and colleagues reported a 0.012-mm reduction in carotid intimal media thickness (IMT) among participants randomized to aggressive blood pressure/low-density lipid cholesterol–lowering treatment and a 0.038-mm increase in carotid IMT among participants randomized to standard treatment after 36 months in the Stop Atherosclerosis in Native Diabetics Study (SANDS). Randomization is assumed to equally distribute all known and unknown confounders between experimental groups. However, potential confounders may be unevenly distributed between groups in small trials or within strata of large trials and subsequently induce bias despite randomization. Such accidental bias is possible in SANDS because at baseline 82% of participants in the aggressive treatment group concomitantly received oral hypoglycemic medications compared with 73% in the standard treatment group (P=.02). Oral hypoglycemic medications such as metformin and pioglitazone have demonstrated beneficial effects on carotid IMT independent of glycemic control, and both medications are common components of oral hypoglycemic regimens. Therefore, the observed effect for the aggressive therapy group, in which a higher proportion of participants used oral hypoglycemic medications, may be susceptible to a positive bias away from the null. Furthermore, prevalent use of oral hypoglycemic medication may account for the lower than expected progression of subclinical disease within the standard treatment group. Confounding by use of oral hypoglycemic medications might not account for the total difference between groups, but it might overestimate the magnitude of effect. In the study by Howard et al, clinical significance was defined as a difference of 0.05 mm in carotid IMT between groups, which was precisely the observed result. Therefore, even minor overestimation of treatment effect raises uncertainty regarding the clinical significance of aggressive treatment. We recommend controlling for confounding by oral hypoglycemic medications in the analysis to derive an adjusted effect estimate for short-term aggressive treatment among Native Americans with diabetes.