ILLUMINATE - Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events

ILLUMINATE - Rationale A novel mechanism for raising HDL levels is to inhibit a protein known as cholesteryl ester transfer protein (CETP). This protein transfers cholesterol from the protective HDL fraction to the harmful LDL fraction. Thus, inhibiting CETP retains cholesterol in the protective HDL. Torcetrapib is a drug that inhibits CETP and has been shown in humans to raise the level of HDL cholesterol and lower that of LDL cholesterol. The ILLUMINATE trial was designed to test the hypothesis that inhibiting CETP with torcetrapib would also protect against cardiovascular disease in humans. CETP (cholesteryl ester transfer protein) in human plasma promotes the transfer of cholesterol from high density lipoproteins (HDL) to low density lipoproteins (LDL) and triglyceride-rich lipoproteins such as very low density lipoproteins (VLDLs) and chylomicrons. Consequently, inhibition of CETP has the potential to shift the balance of plasma cholesterol in favour of the protective HDL fraction. Thus, the development of the CETP inhibitors potentially represents a novel class of drug for raising circulating HDL cholesterol levels. In a rabbit model of atherosclerosis, inhibiting CETP by treatment with torcetrapib led to a marked increase in HDL cholesterol and reduction in susceptibility to development of atherosclerosis (1). In human subjects, treatment with torcetrapib increase the concentration of HDL cholesterol and decreased that of LDL cholesterol and apoB (2). These data provide the background to testing the hypothesis that inhibiting CETP with torcetrapib would also protect against cardiovascular disease in humans. References 1. Morehouse LA, Sugarman ED, Bourassa PA, et al. J Lipid Res. 2007;48:1263-1272. 2. Davidson MH, McKenney JM, Shear CL, Revkin JH. J Am Coll Cardiol. 2006;48:1774-1781 Barter P et al. N Engl J Med 2007;357:2109-22.

ILLUMINATE - Study Design Patients with CHD or CHD risk equivalents (planned 4.5 years of treatment) Atorvastatin run-in to LDL-C <100 mg/dL (2.6 mmol/L) 4-10 weeks. Torcetrapib + titrated atorvastatin dose. Titrated atorvastatin dose. Patient Population Subjects Primary End Point Men or postmenopausal women Statin eligible Any HDL-C level CHD or risk equivalent (type 2 DM) 15,000 7 countries Major cardiovascular events (MCE) ILLUMINATE (1) was a multicenter, double-blind, parallel-group outcomes study in patients with CHD or CHD risk equivalents. The primary end point was major cardiovascular events (MCE), a composite of CHD death, nonfatal MI, or stroke. Subjects initially entered an atorvastatin run-in period during which atorvastatin treatment was initiated. Subjects previously treated with other statins were switched to an equivalent dose of atorvastatin. The atorvastatin dose was then titrated to a target LDL-C level of <100 mg/dL (2.6 mmol/L). Following attainment of the LDL-C goal, patients were randomized to either torcetrapib/atorvastatin or atorvastatin alone. In both treatment arms, the dose of atorvastatin is that established during the atorvastatin run-in phase. Patients were randomized to treatment irrespective of their baseline HDL-C levels. Follow-up was to be driven by end points (984 events) and estimated to last approximately 4.5 years. Reference 1. Barter P, Caulfield M, Eriksson M et al. New Eng J Med 2007;357:2109-22. Barter P et al. N Engl J Med 2007;357:2109-22.

ILLUMINATE: Terminated on Dec 02, 2006 due to excess mortality and MCE Atorvastatin Group=A (n=7534) Torcetrapib/Atorvastatin Group=T/A (n=7533) T/A increased HDL-C by 72% and reduced LDL-C by 25% A T/A Major cardiovascular events 373 464 (P=0.001) Deaths 59 93 (P=0.006) ILLUMINATE was prematurely terminated due to an excess of major cardiovascular events (464 vs. 373, hazard ratio 1.25; 95%CI 1.09 to 1.44, p=0.001) and deaths (93 vs. 59, hazard ratio 1.58; 95%CI 1.14 to 2.19, p=0.006) in the torcetrapib-treated group. The excess of deaths included both cardiovascular and non-cardiovascular causes (1). Reference 1. Barter P, Caulfield M, Eriksson M et al. New Eng J Med 2007;357:2109-22. Barter P et al. N Engl J Med 2007;357:2109-22.

ILLUMINATE - Causes Of Death Atorvastatin (n=59) Torcetrapic/Atorvastatin (n=93) ANY CARDIOVASCULAR 35 49 Sudden cardiac death 25 26 Fatal MI – not procedure related 6 8 Fatal stroke Other cardiac death 1 4 Fatal heart failure 2 Other vascular death/procedure related MI 3 ANY NON-CARDIOVASCULAR 20 40 Cancer 14 24 Infection 9 Other non-cardiovascular Trauma/suicide/homicide REASON UNKNOWN Reference 1. Barter P, Caulfield M, Eriksson M et al. New Eng J Med 2007;357:2109-22. Barter P et al. N Engl J Med 2007;357:2109-22.

Off-target pharmacological effects of torcetrapib unrelated to CETP inhibition In patients receiving torcetrapib/atorvastatin (but not in those receiving atorvastatin alone) there was a significant: Increase: in blood pressure, serum bicarbonate, sodium and aldosterone. Decrease: In serum potassium. These changes are consistent with activation of the renin-angiotensin-aldosterone system. Mortality rates were higher in torcetrapib-treated patients who had a decrease in potassium ≥1.0 mmol/L (the median change): 54 deaths (1.5%) vs. 35 deaths (1.0%) in patients with a decrease in potassium <1.0 mmol/L. There were also more deaths in patients who had an increase in bicarbonate >0.7 mmol/L (median change): 54 deaths (1.47%) vs. 35 deaths (0.9%) in patients with increases in bicarbonate ≤ 0.7 mmo/L The relationship between events and changes in blood pressure was confusing, as analysis showed that the patients who had the greatest increase in blood pressure also had the lowest level of blood pressure at baseline, making it difficult to interpret the relationship without further analysis. Increases in blood pressure in torcetrapib-treated patients were also associated with a decrease in serum potassium and increases in serum sodium, bicarbonate and aldosterone. This suggests that torcetrapib may have activated the renin-angiotensinaldosterone system (RAAS). Thus, the data suggest that off-target effects of torcetrapib contributed to the increased rate of major cardiovascular events and death. Reference 1. Barter P, Caulfield M, Eriksson M et al. New Eng J Med 2007;357:2109-22. Barter P et al. N Engl J Med 2007;357:2109-22.

ILLUMINATE - Conclusions The adverse clinical outcome associated with the use of torcetrapib may have been the consequence of an off-target pharmacology. However, the possibility of an adverse effect of CETP inhibition cannot be excluded by the results of this randomized trial. Barter P et al. N Engl J Med 2007;357:2109-22.

Effects of torcetrapib and CETP genotypea on lipids and lipoproteins Torcetrapib trials Genetic studies B1B2 vs. B1B1a B2B2 vs. B1B1a HDL-C, mmol/L 0.78 (0.68-0.87)* 0.06 (0.05-0.07)* 0.13 (0.11-0.14)* ApoA-I, g/L 0.30 (0.30-0.31)* 0.03 (0.02-0.04)* 0.06 (0.05-0.08)* Total C, mmol/L 0.18 (0.10-0.25)* 0.01 (-0.01-0.02) 0.05 (0.03-0.07)* LDL-C, mmol/L -0.54 (-0.64, -0.43)* -0.01 (-0.03, 0) -0.03 (-0.05, 0.01)* TG, mmol/L -0.12 (-0.18, -0.07)* -0.04 (-0.06, -0.02)* -0.06 (-0.10, -0.02)* ApoB, g/L -0.11 (-0.11, -0.10)* -0.01 (-0.02, 0) -0.02 (-0.03, 0.01)* In this large-scale collaborative analysis, the authors used an alternative approach to investigate the effects of torcetrapib and carriage of common CETP single nucleotide polymorphisms SNPs in the CETP gene to investigate effects on lipids, lipoproteins, blood pressure and other markers of cardiovascular risk. This analysis included data from up to 67,687 individuals from genetic studies and 17,911 individuals from randomized trials of torcetrapib. Both CETP SNPs and torcetrapib treatment reduced CETP activity, and this had a concordant effect on eight lipid and lipoprotein traits: total, LDL and HDL cholesterol, HDL2, HDL3, apolipoproteins A-I and B, and triglycerides. The genetic effect on HDL cholesterol (increase by 0.13 mmol/L, 95% CI 0.11-0.14) was consistent with that expected with a 10 mg dose of torcetrapib. However, the CETP genotype was not associated with changes in blood pressure, serum sodium, potassium, creatinine concentration or with urinary sodium or potassium concentration. These findings support the interpretation that the blood pressure-raising effect of torcetrapib (as well as effects on electrolytes) was not related mechanistically to CETP inhibition. Reference Sofat R, Hingorani AD, Smeeth L et al. Circulation published on-line 21 December 2009. DOI: 10.1161/CIRCULATIONAHA.109.865444 a Variants of the TaqIB allele, either heterozygous (B1B2) or homozygous (B2B2); * statistically significant Sofat R et al. Circulation published on-line Dec 21, 2009.