The aim of this study was to investigate the time course of C-reactive protein (CRP) reduction with simvastatin in patients with type 2 diabetes mellitus. Thirty-five subjects (mean +/- SEM body mass index 32.8 +/- 1 kg/m(2), mean +/- SEM glycated hemoglobin 7.3 +/- 0.2%) were studied using a randomized, crossover, double-blind design. Patients were treated with simvastatin 40 mg or placebo for 28 days, with a minimum 28-day intervening washout. On entry, all subjects had low-density lipoprotein cholesterol >100 mg/dl and/or non-high-density lipoprotein cholesterol >130 mg/dl. High-sensitivity CRP (hs-CRP) was measured on days 0, 1, 3, 7, 14, 21, and 28 of each phase; fasting lipids were measured weekly. The mean hs-CRP level was 4.2 +/- 0.6 mg/L at baseline (>3.0 mg/L represents high risk). After simvastatin administration, there was a significant reduction in levels of log(hs-CRP) (p = 0.001). This effect of simvastatin was seen by day 7 (p = 0.008), with maximal reduction seen at day 14 (p = 0.004; hs-CRP in original units 3.1 +/- 0.5 mg/L with simvastatin and 4.1 +/- 0.6 mg/L with placebo). As expected, the change in hs-CRP was not related to low-density lipoprotein cholesterol reduction. By day 28 with simvastatin, hs-CRP had returned to near baseline levels. In conclusion, in patients with type 2 diabetes mellitus, simvastatin reduced hs-CRP within 7 days. However, this potentially beneficial effect was lost within 28 days.