Avandia, ApoE & Heart Disease
by Robert A. Morrison, Ph.D.
Bioinvension
It is often said that when opportunity knocks, pessimists call the police to report a disturbance of the peace. Opportunity may be knocking at the door of Glaxosmithkline (GSK), the FDA and all those concerned with safety and effectiveness of drugs such as rosiglitazone. The drug, trade named Avandia by GSK, is in the midst of a swirl of controversy among scientists, regulators and politicians due to recent information indicating an association with increased probability of myocardial infarction (MI) among patients taking rosiglitazone for Type2 diabetes. In a previous report (www.bioinvension.com) we described the GSK rosiglitazone XR clinical program for adjunctive therapy in ApoE4-stratified subjects with mild to moderate Alzheimer’s disease (AD). The opportunity knocking relative to Avandia involves the ApoE genotyping.
ApoE encodes apolipoprotein E which plays a basic role in the binding and transport of lipids through the bloodstream and their delivery to the appropriate organs and tissues for processing and use. This function includes the removal of excess cholesterol from the blood. Maintaining normal levels of cholesterol is essential for the prevention of cardiovascular diseases (CVD) including heart attack and stroke. There are at least three versions (alleles) of the ApoE gene designated E2, E3, and E4. The most common allele is E3, which is found in more than half of the population. Several studies have shown that people who carry at least one copy of the ApoE4 allele are at increased risk for heart attack and stroke due the presence of a defective protein with reduced efficacy in binding and transporting lipids. While ApoE genotyping is occasionally used in follow-up testing if high cholesterol and triglyceride levels are found (to help diagnose a genetic component to a lipid abnormality), more routine testing may identify those at greater risk for CVD for more effective decisions by physicians and patients.
There is precedence for such testing such as liver enzyme assays for some cholesterol-lowering statin drugs. In addition, these drugs are not sufficient therapy in certain individuals due to a wide variability in lipid-lowering drug response including ApoE genotype influence. Though responsive to a low fat diet, research indicates that ApoE4 individuals are less likely to respond to statin drugs with a commensurate low density lipid-cholesterol lowering effect compared to ApoE2 individuals who have a better therapeutic response. Thus, detecting genetic variation affecting plasma lipoprotein levels can help predict therapeutic response and adverse events. It seems obvious that ApoE genotyping can drive a personalized drug-responsive therapeutic decision tree, especially when prescribing drugs with potential links to CVD. The GSK clinical studies of rosiglitazone XR for AD utilized ApoE genotyping to eliminate patients with ApoE4, presumably since these patients did not respond to the therapy compared to patients with the other genotypes. If GSK can use ApoE genotyping to eliminate patients that do not respond to rosiglitazone relative to symptoms of AD, it can use the same test to determine which Type2 diabetes patients taking Avandia should be more vigilant relative to other CVD risk factors. The opportunity knocking at the door involves further research or analyses with existing data to determine the incidence of MI among patients taking Avandia and their ApoE genotype (along with other markers and CVD risk factors). Considering the regulatory and political implications of the Avandia controversy (Congress is considering legislation with provisions including limits on drug advertisements and symbols to alert patients), genotyping should be considered as an integral component in determining and monitoring drug safety.
Source: Bioinvension.com
RELATED READING:
- Compare and Contrast: EMEA and FDA on Avandia
- Networks Dramatize Diabetes Drug Dangers
- Congressional Hearing on FDA's Handling of Avandia
BioHealth Investor.com
_______________________
Bioinvension
It is often said that when opportunity knocks, pessimists call the police to report a disturbance of the peace. Opportunity may be knocking at the door of Glaxosmithkline (GSK), the FDA and all those concerned with safety and effectiveness of drugs such as rosiglitazone. The drug, trade named Avandia by GSK, is in the midst of a swirl of controversy among scientists, regulators and politicians due to recent information indicating an association with increased probability of myocardial infarction (MI) among patients taking rosiglitazone for Type2 diabetes. In a previous report (www.bioinvension.com) we described the GSK rosiglitazone XR clinical program for adjunctive therapy in ApoE4-stratified subjects with mild to moderate Alzheimer’s disease (AD). The opportunity knocking relative to Avandia involves the ApoE genotyping.
ApoE encodes apolipoprotein E which plays a basic role in the binding and transport of lipids through the bloodstream and their delivery to the appropriate organs and tissues for processing and use. This function includes the removal of excess cholesterol from the blood. Maintaining normal levels of cholesterol is essential for the prevention of cardiovascular diseases (CVD) including heart attack and stroke. There are at least three versions (alleles) of the ApoE gene designated E2, E3, and E4. The most common allele is E3, which is found in more than half of the population. Several studies have shown that people who carry at least one copy of the ApoE4 allele are at increased risk for heart attack and stroke due the presence of a defective protein with reduced efficacy in binding and transporting lipids. While ApoE genotyping is occasionally used in follow-up testing if high cholesterol and triglyceride levels are found (to help diagnose a genetic component to a lipid abnormality), more routine testing may identify those at greater risk for CVD for more effective decisions by physicians and patients.
There is precedence for such testing such as liver enzyme assays for some cholesterol-lowering statin drugs. In addition, these drugs are not sufficient therapy in certain individuals due to a wide variability in lipid-lowering drug response including ApoE genotype influence. Though responsive to a low fat diet, research indicates that ApoE4 individuals are less likely to respond to statin drugs with a commensurate low density lipid-cholesterol lowering effect compared to ApoE2 individuals who have a better therapeutic response. Thus, detecting genetic variation affecting plasma lipoprotein levels can help predict therapeutic response and adverse events. It seems obvious that ApoE genotyping can drive a personalized drug-responsive therapeutic decision tree, especially when prescribing drugs with potential links to CVD. The GSK clinical studies of rosiglitazone XR for AD utilized ApoE genotyping to eliminate patients with ApoE4, presumably since these patients did not respond to the therapy compared to patients with the other genotypes. If GSK can use ApoE genotyping to eliminate patients that do not respond to rosiglitazone relative to symptoms of AD, it can use the same test to determine which Type2 diabetes patients taking Avandia should be more vigilant relative to other CVD risk factors. The opportunity knocking at the door involves further research or analyses with existing data to determine the incidence of MI among patients taking Avandia and their ApoE genotype (along with other markers and CVD risk factors). Considering the regulatory and political implications of the Avandia controversy (Congress is considering legislation with provisions including limits on drug advertisements and symbols to alert patients), genotyping should be considered as an integral component in determining and monitoring drug safety.
Source: Bioinvension.com
RELATED READING:
- Compare and Contrast: EMEA and FDA on Avandia
- Networks Dramatize Diabetes Drug Dangers
- Congressional Hearing on FDA's Handling of Avandia
BioHealth Investor.com
_______________________
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