Background—Von Willebrand factor (vWF) is inconsistently associated with cardiovascular disease (CVD). This might be explained by associations of vWF with type 2 diabetes mellitus and insulin resistance.

Methods and Results—We tested whether vWF predicted incident CVD in 3799 Framingham Offspring Study participants, and in particular, among those with type 2 diabetes mellitus or insulin resistance. During 11 years of follow-up, 351 participants developed CVD. In proportional hazards models (with adjustment for age, sex, blood pressure, smoking, body mass index, total and high-density lipoprotein cholesterol, and treatment with aspirin, insulin, antihypertensives, and lipid-lowering medications) with the lowest quartile of the vWF distribution as the referent, the hazard ratio (HR) for CVD was 0.94 in the second quartile, 0.98 in the third, and 1.32 in the highest (P=0.04 for trend). Additional adjustment for type 2 diabetes mellitus or insulin resistance (homeostasis model) partially attenuated the association (multivariable HRs for top quartile 1.28 and 1.21, respectively). We then stratified the models by diabetes status or the homeostasis model of insulin resistance distribution (top quartile versus lower 3 quartiles). vWF was associated with CVD among participants with diabetes mellitus (HR for top quartile relative to bottom 1.47, P=0.04 for trend) but not among nondiabetic participants (HR 1.15, P=0.5) and similarly among insulin-resistant (HR 1.50, P=0.01) but not insulin-sensitive (HR 1.02, P=0.9) participants.

Conclusions—Higher levels of vWF were associated with risk of CVD in people with type 2 diabetes mellitus or insulin resistance, which suggests that vWF may be a risk factor unique to these populations.