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Abstract: 1064 SEPARTATING MECHANISM-BASED & OFF-TARGET ACTIONS OF CETP-INHIBITORS USING CETP GENE POLYMORPHISMS: MENDELIAN RANDOMISATION FOR DRUG TARGET VALIDATION
Workshop VI-2 - Pharmacology and Novel Therapies: Transfer Protein Inhibition Abstract: 1064 Citation: Atherosclerosis Supplement 2009, Vol. 10, Issue 2
SEPARTATING MECHANISM-BASED & OFF-TARGET ACTIONS OF CETP-INHIBITORS USING CETP GENE POLYMORPHISMS: MENDELIAN RANDOMISATION FOR DRUG TARGET VALIDATION R Sofat, Torcetrapib/CETP Genetics Collaboration Centre for Clinical Pharmacology, UCL, London Objectives:To assess if the unexpected hypertensive effect of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, developed to raise HDL-cholesterol is mechanism based or an off-target effect, and so to assess if CETP inhibition continues to be a valid therapeutic goal for cardiovascular disease prevention. Methods:We compared the effect of CETP SNPs and torcetrapib treatment on lipids and blood pressure in up to 67,687 individuals from genetic studies and randomised trials. Results:CETP SNPs and torcetrapib treatment reduced CETP activity having concordant effects on 8 lipid traits (total-, LDL- and HDL cholesterol, HDL2, HDL3, apolipoproteins AI, -B & triglycerides). The genetic effect on HDL-cholesterol (0.13 mmol/L;95% CI 0.11,0.14) was consistent with that expected of torcetrapib 10mg (0.13 mmol/L;0.10, 0.15). At 60mg, torcetrapib elevated systolic and diastolic blood pressure by 4.47mmHg (4.10,4.84) and 2.08mmHg (1.84,2.31) respectively. However, the genetic effect on systolic and diastolic blood pressure of 0.16mmHg (-0.28,0.60) and -0.04mmHg (-0.36,0.28) was null and significantly different from that expected of torcetrapib 10mg. Conclusions:Discordance in the effect of CETP SNPs and torcetrapib treatment on blood pressure, despite concordant effects on lipids & lipoproteins indicates the hypertensive effect of torcetrapib is unlikely to be due to CETP-inhibition. These findings support CETP inhibition as a valid therapeutic goal and the continued development of chemically dissimilar drugs of the same class. Genetic studies could be incorporated into drug development programmes at earlier stages as a new source of randomised evidence for drug target validation in man.
SEPARTATING MECHANISM-BASED & OFF-TARGET ACTIONS OF CETP-INHIBITORS USING CETP GENE POLYMORPHISMS: MENDELIAN RANDOMISATION FOR DRUG TARGET VALIDATION R Sofat, Torcetrapib/CETP Genetics Collaboration Centre for Clinical Pharmacology, UCL, London Objectives:To assess if the unexpected hypertensive effect of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, developed to raise HDL-cholesterol is mechanism based or an off-target effect, and so to assess if CETP inhibition continues to be a valid therapeutic goal for cardiovascular disease prevention. Methods:We compared the effect of CETP SNPs and torcetrapib treatment on lipids and blood pressure in up to 67,687 individuals from genetic studies and randomised trials. Results:CETP SNPs and torcetrapib treatment reduced CETP activity having concordant effects on 8 lipid traits (total-, LDL- and HDL cholesterol, HDL2, HDL3, apolipoproteins AI, -B & triglycerides). The genetic effect on HDL-cholesterol (0.13 mmol/L;95% CI 0.11,0.14) was consistent with that expected of torcetrapib 10mg (0.13 mmol/L;0.10, 0.15). At 60mg, torcetrapib elevated systolic and diastolic blood pressure by 4.47mmHg (4.10,4.84) and 2.08mmHg (1.84,2.31) respectively. However, the genetic effect on systolic and diastolic blood pressure of 0.16mmHg (-0.28,0.60) and -0.04mmHg (-0.36,0.28) was null and significantly different from that expected of torcetrapib 10mg. Conclusions:Discordance in the effect of CETP SNPs and torcetrapib treatment on blood pressure, despite concordant effects on lipids & lipoproteins indicates the hypertensive effect of torcetrapib is unlikely to be due to CETP-inhibition. These findings support CETP inhibition as a valid therapeutic goal and the continued development of chemically dissimilar drugs of the same class. Genetic studies could be incorporated into drug development programmes at earlier stages as a new source of randomised evidence for drug target validation in man.