Rosiglitazone symposium abstract WCC - Dr Richard Nesto

A number of metabolic and hemodynamic abnormalities, all associated with insulin resistance, tend to cluster in the same individual. These factors include hyperglycemia, dyslipidemia, hypertension, and also other associated factors including endothelial dysfunction, microalbuminuria, elevated levels of plasminogen activator inhibitor-1 (PAI-1), and increased levels of C-reactive protein (CRP). Up to 75% of mortality in type 2 diabetes is due to cardiovascular disease, and the insulin resistance is an independent predictor. Small, dense LDL particle patterns are associated with a higher degree of insulin resistance. Despite of maximal dose of statin in patients with Coronary Heart Disease (CHD), substantial risk persists (Deedwanina et al., 2006). There is a correlation between levels of CRP and the number of metabolic disorders present. A linear correlation was observed between CRP levels and the number of components present, suggesting that chronic, sub-clinical inflammation is part of the Insulin Resistance Syndrome.

Rosiglitazone (RSG) demonstrated a rapid effect on endothelial function and inflammatory biomarkers when used in 10 healthy non-diabetic subjects without dyslipidemia, hypertension, smoking and obesity (Hetzel et al., 2005). Moreover, RSG decreases plaque inflammation and increases collagen content. In diabetic patients, RSG was able to increase the content of interstitial collagen, as well as decrease MMP-9, proteasome 20S and ubiquitin, when compared to placebo (Marfella et al., 2006).

Despite all preliminary data demonstrating a favourable profile of RSG on cardiovascular (CV) systems, a recent metanalysis, published by Nissen et al (2007), demonstrated a sign of increase in CV risk, raising many controversies. This was a retrospective analysis of short term trials not designed to evaluate CV events. Moreover, the events were not adjudicated and the absolute risk was very small.

However, only prospective clinical trials designed for the specific purpose of establishing the CV benefit or risk of RSG will resolve the controversy about its safety. Under this perspective, large, long-term randomized trials, such as DREAM, ADOPT and RECORD, comparing RSG to other OAD or placebo showed no increased risk of major CV events or death. A safety monitoring long-term independent trial (ACCORD) offers further reassurance on CV safety profile. In RECORD, a 12-month substudy evaluating changes in ambulatory blood pressure with RSG combined with metformin (MET) or sulphonylurea (SU) compared with MET + SU in combination, showed reductions from baseline in systolic and diastolic blood pressure, significantly greater in patients treated with RSG + MET compared with MET + SU. In ACCORD, 19,202 patient years of exposure to RSG was not associated with any increased risk to death.

In order to address some questions and concerns in diabetes management and impact on CV risk, different studies were designed: (i) Does lowering HbA1c reduce CV events? ACCORD, ADVANCE, VADT, ORIGIN studies; (ii) Does it matter which drug is used? PERISCOPE, APPROACH, BARI-2D, RECORD studies; (iii) Is there a threshold HBA1c at which the risk outweigh the benefits? ACCORD, ADVANCE, VADT, ORIGIN studies.

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