New data from ILLUMINATE
According to HDL Forum Editor and author Professor Philip Barter, exploratory post hoc analyses of the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact on Atherosclerotic Events) trial failed to identify a contributing role of lipid effects and/or off-target pharmacology of torcetrapib and its clinical harm. The findings were reported at the American Heart Association Scientific Sessions 2008.
Shear C, Beltangady M, Ports W et al. Torcetrapib: predictors of increased clinical risk in the ILLUMINATE study. Circulation 2008;118:S_370-S_371. [Abstract 1694].
Multiple regression using the Cox proportional hazards model was used to investigate potential baseline predictors of risk from among the following variables:
- Demographics: age, gender, BMI, smoking status, weight;
- Medical history: congestive heart failure (CHF), hypertension, MI, stroke, type 2 diabetes;
- Lipids: apolipoprotein (apo)A-I, apoB, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol or triglycerides
- Systolic blood pressure
- Other markers: serum bicarbonate, potassium, sodium, C-reactive protein (CRP)
On-trial predictors of risk were evaluated using biomarkers values at 3-months with an analysis of covariance (ANCOVA) model.
Evidence of risk was limited to the torcetrapib/atorvastatin 10 mg vs. atorvastatin 10 mg group for both all-cause mortality (hazard ratio 2.68, p<0.0001) (Figure 1) and major cardiovascular events (hazard ratio 1.41, p=0.002) (Figure 2). Of the 34 excess deaths with torcetrapib, 31 occurred in the torcetrapib/atorvastatin 10 mg subgroup.
The multivariate Cox proportional hazards model showed that, in addition to torcetrapib, increasing age, prior CHF or stroke and high CRP were significantly associated with all-cause mortality risk, and lower apoA-I levels, and history of smoking, hypertension, CHF, MI or stroke were significantly associated with risk of major cardiovascular events.
There was no evidence to support the hypothesis that lipids, blood pressure or the RAAS played a role. Exploratory analyses of on-trial biomarkers at 3 months showed a lack of meaningful association between atorvastatin dose and lipid levels, including HDL cholesterol (Figures 3, 4). Similarly, there was no association between atorvastatin dose and the change in blood pressure, electrolytes or aldosterone values.
The results of these analyses were intriguing as they suggest that atorvastatin at higher doses (>10 mg) may mitigate the risk of harm with torcetrapib. However, this lack of evidence should be interpreted with caution, given experimental findings of off-target pharmacology with
torcetrapib.1-3
Background to the ILLUMINATE trial
The ILLUMINATE trial was a double-blind randomised trial that included 15,067 patients at high cardiovascular risk (clinical evidence of cardiovascular disease or with type 2 diabetes). The trial tested the clinical benefit of torcetrapib against a background of atorvastatin. The primary end point was the time to first occurrence of a major cardiovascular event, defined as coronary heart disease (CHD) death, nonfatal myocardial infarction, stroke or hospitalisation for unstable angina.
All patients were treated with atorvastatin at a dose necessary to reduce the level of low-density lipoprotein (LDL) cholesterol level to less than 100 mg/dL (2.6 mmol/L) before being allocated treatment with torcetrapib 60 mg daily or matching placebo. The follow-up was estimated to be 4.5 years in order to achieve enough events to test the hypothesis that treatment with torcetrapib was cardioprotective.
ILLUMINATE trial was terminated on December 2, 2006 after a median follow up of only 18 months due to a statistically significant excess of all-cause mortality (93 vs. 59, hazard ratio 1.58; 95%CI 1.14 to 2.19, p=0.006d) and major cardiovascular events ((464 vs. 373, hazard ratio 1.25; 95%CI 1.09 to 1.44, p=0.001) in the group treated with torcetrapib. This was despite increases in HDL cholesterol by 72% and decreases in LDL cholesterol by 25% over and above values achieved by treatment with atorvastatin alone. The findings and effects of torcetrapib on blood pressure (increase by 5.4 mmHg), and potassium, sodium, bicarbonate and aldosterone have been previously reported.4
Reference
1. DePasquale et al. Presented at American Heart Association Scientific Sessions, 2007
2. Forrest MJ, Bloomfield D, Briscoe RJ et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008; 154(7):1465-73.
3. Hu et al. International Aldosterone Conference, 2008-11-12
4. Barter P, Caulfield M, Eriksson M et al. Effects of torcetrapib on morbidity and mortality in patients at high risk for coronary events. New Eng J Med 2007;357:2109-22.
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