Recently I reviewed a paper published in the New England Journal of Medicine by Steven Nissen which raised concerns about diabetes drugs and the resulting cardiovascular events which I think you might find interesting. I cannot say I totally agree with the method used; however, it does provide sufficient supportive information to merit significant attention which, in effect, caused the FDA to respond. The study involved the drug rosiglitazone focusing on adverse cardiovascular events. Even though Nissen’s choice of Meta-analysis may not have been the appropriate study design the emerging findings raised an important question on the regulatory pathways for development of diabetic drugs. 1 After a brief overview of the antidiabetics drug pathway and actions presented in the paper, the following points of concern will be addressed in greater detail:
1. Was Meta-Analysis appropriate to answer the hypothesis on cardiovascular effects?
2. Were the methods appropriate?
3. Was the interpretation of the data justified?
4. Post-marketing recommendation?
5. FDA Response?
A sustained reduction of blood glucose levels with appropriate safety levels has been adequate for FDA approval of diabetic drugs. Type 2 Diabetes causes heart problems including death by cardiovascular causes, so this is a potential concern for this drug.
The product diaglitazone along with rosiglitazone and pioglitazone are the currently approved agents from the thiazolidinedione class of antidiabetic medication which are widely used to lower blood glucose levels. Successful therapies for Type 2 Diabetes should result in the reduction of complications from diabetes in addition to its primary focus of reduction of serum glucose levels. The thiazolidinediones drugs are agonist for the PPAR (Peroxisome Proliferator-Activated Receptors) receptors which modulate gene expression lowering blood glucose and enhance the action of insulin in muscle, liver, and adipose tissue. Peroxisome effects cellular morphology and enzymatic activity affecting hepatic lipid metabolism and kidney.2 No definitive studies have been done on rosiglitazone to determine the effect on cardiac injury and mortality, hence the reason for this study. Pioglitazone was studied in a prospective trial investigating cardiac outcome.
Rosiglitazone was approved by the FDA for marketing in 1999. Rosiglitazone in trial studies looked at the effectiveness on the control of blood glucose levels not at cardiovascular events. Rosiglitazone is a member of the thiazolidinediones class of medication which works by modulating the PPAR receptor. Barak reported in animal experiments that thiazolidinediones affect the cardiovascular system through the PPAR receptor, so it is apparent that it is important to investigate cardiac issues with any drug affecting this receptor.3
Meta-Analysis may not have been the appropriate study design to address the hypothesis that rosiglitazone was possibly associated...