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- May 17, 2008 |
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"The case for rosiglitazone therapy : putting theory into practice"Dr. Kathleen Wyne (biography)
English - 2003-08-26 - 30 minutes
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 | (32 slides) |
Summary :
Historically, the aim of physicians treating type 2 diabetes has been to reduce hyperglycaemia through diet and exercise supplemented with oral anti-diabetic agents and/or insulin. Even with intensive use of these therapies, however, many of our patients fail to reduce HbA1c to the ADA target level of < 7%, and we are seeing increasing numbers of individuals with cardiovascular disease (CVD). Importantly, 75% of mortality in type 2 diabetes is attributable to CVD. One possible explanation for the failure of many current treatment regimens may be because they do not address both of the underlying causes of type 2 diabetes: insulin resistance and beta-cell dysfuntion.
The thiazolidinediones (TZDs; PPAR-gamma agonists) are insulin sensitizers, which have several benefits that extend beyond their effects on glycaemic control. For example, rosiglitazone has been shown to affect a number of components of the Insulin Resistance Syndrome, including lowering microalbuminuria, reducing visceral fat and decreasing diastolic blood pressure. The TZDs also improve the dyslipidaemic profile through increases in HDL-cholesterol levels (primarily the more cardioprotective HDL2 subfraction), and a reduction in the relative proportion of atherogenic, small dense LDL particles.
However, the effects of TZDs are not restricted to these traditional components of the Insulin Resistance Syndrome. Increases in the inflammatory marker, C-reactive protein (CRP), have been associated with the development of atherosclerosis and cardiovascular disease, while there is a positive correlation between the concentration of PAI-1 and insulin resistance. Rosiglitazone has beneficial effects on both of these factors, reducing CRP by almost 30% and PAI-1 levels by nearly 35%. Rosiglitazone also improves vascular reactivity and myocardial blood flow, indicating an improvement in endothelial function. Further beneficial effects on other markers of the development and progression of atherosclerosis support these potential anti-atherogenic properties.
Long-term treatment with metformin improves cardiovascular outcomes, possibly mediated by insulin-sensitization and accompanying decreases in PAI-1 levels. Promising results have also been observed with TZDs added to metformin. In short-term studies, addition of rosiglitazone to sub-maximal dose metformin significantly decreases insulin resistance versus maximal dose metformin alone, with reductions also seen in CRP and PAI-1.
Overall, the TZDs have many potential benefits compared with conventional therapies, either as monotherapy or in combination with other oral agents, such as metformin. In particular, their beneficial effects on inflammatory markers are exciting given the increasing numbers of patients with cardiovascular disease. Whether these benefits beyond glycaemic control observed in preliminary studies translate into long-term improvements in clinical outcomes is currently being investigated.
More information is available about C-Reactive Protein.
Learning objectives :
The participant will review data supporting the use of rosiglitazone.
Conclusions:
- A1c target is now below 6.5%
- Most patients will require combination therapy to attain this target A1c
- Combination therapy needs to be oriented toward the disease process
- It’s not just about sugar which is the end result of the process
Bibliographic references :
Wyne KL, Drexler AJ, Miller JL, Bell DS, Braunstein S, Nuckolls JG. Constructing an algorithm for managing type 2 diabetes. Focus on role of the thiazolidinediones. Postgrad Med. 2003 May;Spec No:63-72.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
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