In this report, we demonstrate the beneficial effects of an intensive lifestyle intervention on concentrations of CRP and fibrinogen in adults with IGT. Previous studies of lifestyle interventions and CRP involved less than 50 participants (principally women) (17
). In the current report, we show an ~30% reduction in CRP levels in both sexes. This reduction in CRP occurred despite only a 7% decline in weight achieved at 6 months and is comparable to the 25% reduction in CRP levels reported with starting doses of statins (pravastatin 40 mg, simvastatin 20 mg, and atorvastatin 10 mg) (30
). The current study shows very high CRP levels compared with previous studies (12
), which probably reflects the nearly universal overweight and insulin resistance in the DPP cohort.
Baseline waist and BMI were strongly correlated with HOMA-IR, CRP, and fibrinogen (). However at baseline, physical activity was only modestly inversely correlated with HOMA-IR, CRP, and fibrinogen (although significant at P < 0.01). The analysis based on change between baseline and 1 year presented in and also suggests that the reduction in CRP is more closely related to weight loss than to increases in physical activity. However, this result needs to be interpreted with caution because the DPP intensive lifestyle intervention combined both weight loss and increased physical activity and because weight loss is more easily and precisely measured than the amount of exercise (which was based on self-report from three questionnaires).
Although baseline HOMA-IR (a surrogate for insulin resistance) and CRP levels were moderately correlated (r
= 0.19) (), a change in HOMA-IR was only modestly correlated with a change in CRP (r
= 0.11, P
< 0.001) in and . Previous cross-sectional analyses have suggested that high levels of CRP are strongly related to insulin concentrations (15
) and insulin resistance (12
). Indeed, a recent article from the IRAS in prediabetic participants (the majority of whom have IGT) reported that elevated levels of CRP were more closely related to insulin resistance than to obesity (32
). The IRAS used the frequently sampled intravenous glucose tolerance test, a direct measure of insulin resistance, not the HOMA-IR, to distinguish high and low insulin sensitivity. It has been reported that insulin sensitizers such as thiazolidinedione may lower CRP by 20–60% (21
) despite no weight change or perhaps even a small weight increase. Therefore, it is not clear why changes in insulin resistance did not strongly predict changes in CRP in the DPP study, but it may be partially a measurement issue related to the use of the HOMA-IR or perhaps to the severity of obesity in the DPP population; thus, a truncated distribution of obesity and insulin resistance may be responsible for the attenuation in the relation of CRP with insulin resistance and obesity.
In this report, we showed a larger reduction in CRP levels with lifestyle change than with metformin. In fact, the reduction in CRP levels at 1 year with metformin (−7%) was statistically significant compared with placebo (+5%) in men (P
= 0.006). No previous trials have compared the effect of metformin versus intensive lifestyle. The suggestion from this report is that metformin may have only a modest effect on CRP reductions. In a small report that compared metformin and troglitazone in type 2 diabetic patients, the reduction in CRP was greater with troglitazone than with metformin (23
Consistent with earlier reports, we also observed reductions in fibrinogen with intensive lifestyle interventions (19
). The reduction in fibrinogen with lifestyle was modest. The correlation of baseline HOMA-IR and fibrinogen was moderate (r
= 0.18, P
< 0.001). Additionally, the change in HOMA-IR was only modestly correlated with change in fibrinogen (r
= 0.05) ().
The role of subclinical inflammation as a predictor of cardiovascular disease has been widely accepted (11
). However, it is not clear whether CRP represents a risk factor for cardiovascular disease or is a risk marker. Several lines of evidence suggest that CRP may be etiologically involved in the development of cardiovascular disease, including inhibition of nitric oxide synthesis (33
), increases in monocyte chemoattractant protein 1 (34
), impairment in endothelial dysfunction (35
), and increases in plasminogen activator inhibitor 1 expression in human aortic endothelial cells (36
). If the reduction in CRP precedes reductions in cardiovascular disease, over the long term, lifestyle intervention may be associated with a significant reduction in cardiovascular disease as appears to be the case with other interventions such as hydroxym-ethylglutaryl-CoA reductase inhibitors. Over the 2.8 years of the DPP active intervention, participants had too few cardiovascular events to test this hypothesis (25
). A 5-year follow up of the DPP study is currently underway.
In conclusion, intensive lifestyle intervention reduced levels of nontraditional cardiovascular risk factors both relative to placebo and to a lesser degree relative to metformin. These significant reductions were achieved despite a relatively modest weight loss of ~6–7% over the 1st year with most participants still being obese at the end of 1 year. The DPP study suggests that not only does intensive lifestyle intervention reduce the risk of developing type 2 diabetes but also it has effects on risk markers that may eventually reduce the risk of cardiovascular disease.