Differential effects of heart rate reduction by atenolol or ivabradine on peripheral endothelial function in type 2 diabetic patients

Objective To assess whether reduction of heart rate (HR) has beneficial effects on endothelial function in patients with type 2 diabetes mellitus (T2DM). Design Randomised, double-blind, placebo-controlled study. Setting University hospital. Patients 66 T2DM patients without overt cardiovascular disease. Interventions Patients were randomised to receive for 4 weeks, in addition to their standard therapy, one of the following treatments: atenolol (25 mg twice daily), ivabradine (5 mg twice daily) or placebo (1 tablet twice daily). Main outcome measures Systemic endothelial function, assessed by flow-mediated dilation (FMD); endothelium-independent vasodilation, assessed by nitrate-mediated dilation (NMD); cardiac autonomic function, assessed by HR variability (HRV). Results 61 patients completed the study (19, 22 and 20 patients in atenolol, ivabradine and placebo groups, respectively). Compared with baseline, HR was similarly reduced by atenolol (87±13 vs 69±9 bpm) and ivabradine (86±12 to 71±9 bpm), but not by placebo (82±10 vs 81±9 bpm) (p<0.001). FMD improved at follow-up in the atenolol group (4.8±1.7 vs 6.4±1.9%), but not in the ivabradine group (5.2±2.5 vs 4.9±2.2%) and in the placebo group (4.8±1.5 vs 4.7±1.7%) (p<0.01). NMD did not change significantly in any group. HRV parameters did not change in the placebo group; they, instead, consistently increased in the atenolol, whereas a mild increase in SDNNi was only observed in the ivabradine group. A significant correlation was found in the atenolol group between HR and FMD changes (r=−0.48; p=0.04). Conclusions Despite a comparable reduction in HR, atenolol, but not ivabradine, improved FMD in T2DM patients suggesting that changes in HR are by themselves unlikely to significantly improve endothelial function.