Association of insulin resistance and inflammation with peripheral arterial disease: the National Health and Nutrition Examination Survey, 1999 to 2004

Abstract

Background: Although the role of inflammation in the pathophysiology of peripheral arterial disease (PAD) is well established, the contribution of insulin resistance (IR) to PAD is less clear. We hypothesized that IR is associated with PAD and that the presence of IR would influence the association between C-reactive protein (CRP) and PAD, an association established predominantly in healthy individuals.

Methods and results: We analyzed data from 3242 adults in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 who underwent measurement of ankle brachial index, CRP, and fasting glucose and insulin, enabling calculation of homeostasis model of IR (HOMA-IR). Odds ratios (ORs) and 95% CIs were estimated by logistic regression. The mean prevalence of PAD (defined as an ankle brachial index </=0.9) was 5.5% (SE, 0.47%). HOMA-IR was independently associated with PAD (OR, 2.06; 95% CI, 1.1 to 4.0; P=0.03 for quartile 4, P for trend across quartiles=0.047) after adjustment for age, gender, race/ethnicity, hypertension, hyperlipidemia, smoking, body mass index, chronic kidney disease, and CRP. Elevated CRP (>3 mg/L) also was strongly associated with PAD (OR, 2.2; 95% CI, 1.3 to 3.6; P=0.003 versus CRP <1 mg/L). Stratifying subjects on the basis of median HOMA-IR, we found that CRP >3 mg/L was no longer significantly associated with PAD in subjects with IR (OR, 1.3; 95% CI, 0.8 to 2.1; P=0.3, P for interaction=0.08).

Conclusions: These findings demonstrate that IR is strongly and independently associated with PAD. Furthermore, IR modifies the association of inflammation with PAD. These data establish a role of IR in PAD and highlight the relative importance of inflammation in patients with and without IR.

Figure 1

Age- and gender- standardized PAD prevalence (%) in increasing HOMA-IR quartiles. There is a graded increase in PAD prevalence in increasing HOMA-IR quartiles (p=0.037 by chi-square test). PAD=peripheral arterial disease, HOMA-IR=homeostasis model of insulin resistance.

Figure 2

Unadjusted PAD prevalence (%) in increasing CRP categories (<1, 1–3, and >3mg/L) in groups stratified by absence or presence of insulin resistance (defined as having a HOMA-IR below or above the median value of 1.86, respectively). In the absence of insulin resistance, there is a robust relationship between increasing CRP category and prevalence of PAD, with a PAD prevalence of 2.2%, 4.4% and 6.7% in increasing CRP categories (p=0.007). However, in the presence of insulin resistance, the relationship between CRP and PAD is significantly blunted with PAD prevalence rates of 5.5%, 6.5% and 6.9% (p=0.56). IR=insulin resistance; CRP=C-reactive protein. P-values are generated by chi-square test.