Results from the 2 studies reveal a close association between insulin sensitivity and nearly all of the key thrombotic and inflammatory factors thought to modulate CVD risk. This relationship was apparent in different ethnic groups and was independent of the presence of diabetes. More important, targeted pharmacological improvement of insulin sensitivity significantly improved nearly all of the thrombotic and inflammatory biomarkers without lowering blood pressure or weight or altering body composition. Although fasting glucose levels improved with treatment, all treatment-related improvements in PAI-1, CRP, TNF-α, adiponectin, triglycerides, HDL-C, and non–HDL-C remained significant after adjustment for interim changes in HbA1c and fasting glucose concentrations. This finding reinforces the hypothesis that hyperglycemia, hypertension, and adiposity do not account for the entirety of thrombotic and inflammatory dysregulation present in individuals with impaired fasting glucose and type 2 diabetes.
Study 2 clearly demonstrated that therapeutic doses of metformin and pioglitazone have a favorable effect on many important CVD risk factors. Although on the basis of these data one cannot conclude definitively that improvement in insulin sensitivity alone caused all of the favorable changes in thrombotic and inflammatory factors, these changes occurred with improved insulin sensitivity and independent of glycemia, blood pressure, and body composition. The parallel, double-blind, randomized controlled study design minimized potential confounders of dietary and physical activity modifications.
Insulin resistance is a key feature of metabolic syndrome and has been proposed to be the unifying abnormality underlying atherothrombotic risk among individuals with both diabetes and metabolic syndrome.2,29
The ability of insulin sensitizer therapy to improve CVD biomarkers while improving insulin sensitivity but without altering blood pressure, weight, adiposity, or glycemic control further supports the importance of insulin resistance in driving CVD risk. It may similarly explain how in addition to improving insulin sensitivity, exercise30,31
and caloric restriction32
also significantly lower inflammatory cytokine levels.
Longer-term studies are needed to determine whether insulin sensitizer therapy in insulin-resistant individuals without diabetes will lower atherothrombotic event rates and/or mortality rates. Nonetheless, the observed improvements in inflammatory and thrombotic factors strongly support the theory that insulin-sensitizing agents can translate directly into improved clinical outcomes. Indeed, metformin-pioglitazone therapy increased HDL-C levels by 10% and adiponectin by 149.7% while lowering concentrations of triglycerides by 11.9% and CRP by 45.2%, all of which have been linked to decreased rates of fatal and nonfatal CVD events.33,34
Insulin sensitizer therapy was previously found to improve these molecular risk factors in individuals with known CVD,35
but no prior prospective studies specifically assessed the association between insulin sensitization and molecular CVD risk factors. Indeed, pioglitazone has been shown to reduce the risk of fatal and nonfatal stroke, as well as fatal and nonfatal myocardial infarction, in patients with type 2 diabetes with and without a history of stroke.22
Likewise, intensive medical therapy, which included insulin sensitization or insulin provision therapy, resulted in similar CVD outcomes during a 5-year period as did a more invasive revascularization strategy among patients with type 2 diabetes and angiographically confirmed CVD.25
Yet the study presented here represents the first prospective trial of insulin sensitizer therapy in individuals without known CVD.
These results also offer a potential mechanistic explanation for earlier observations that metformin and pioglitazone therapies lower CVD event rates in patients with type 2 diabetes.18,20,21,36
It remains to be determined whether insulin sensitizer therapy can similarly improve thrombotic and/or inflammatory profiles in individuals with other diseases characterized by insulin resistance, such as chronic kidney disease, polycystic ovarian syndrome, autoimmune disorders, and hypertension.
The significantly lower insulin sensitivity, along with the concomitantly higher concentrations of inflammatory and thrombotic factors, in Asian Indians without diabetes compared with Northern European Americans without diabetes observed in the current study may explain the disproportionately higher incidence of CVD among Asian groups.37,38
Consistent with previously published studies, Asian Indians without diabetes have greater insulin resistance and higher circulating levels of inflammatory markers than Northern European Americans without diabetes.26,39,40
We have also shown that prothrombotic factors are increased in Asian Indians without diabetes compared with Northern European Americans without diabetes, potentially contributing to CVD risk.
A potential limitation of the study 1 design is that a cohort of Northern European Americans with diabetes was not included in the study. Because Northern European Americans with type 2 diabetes tend to have significantly higher BMI than age-matched Asian Indians with diabetes, the marked discrepancies in BMI between the 2 groups would confound any conclusions drawn from the effect of insulin sensitivity itself. Indeed, the 9 participants of study 2 who met the criteria for diagnosis of diabetes on enrollment (fasting glucose level ≥126 mg/dL) had a mean BMI of 33±6.08 compared with 26.6±3.5 in Asian Indians with diabetes. Body mass index is known to be associated with the inflammatory and thrombotic factors under investigation, and the goal of our studies was to determine the potential contribution of insulin sensitivity to this relationship. The increase in CVD risk factors and insulin resistance despite significantly lower BMI are consistent with clinical data showing that Asian Indians develop diabetes and CVD at much lower BMI than Northern Europeans.