ILLUMINATE Trial

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Objective

Raising HDL levels by a combination of torcetrapib, a CETP inhibitor, and atorvastatin, an HGM-CoA reductase inhibitor.

Timeline

Start Date

August 23, 2004

End Date

Premature Termination on December 2, 2006. Data collection continued till July 15, 2007.

Methods

• Phase III trial
• Prospective, randomized, multicenter, double-blind clinical trial that recuited 15,067 patients.
• Inclusion criteria: Patients aged 45-75 years who have a history of cardiovascular disease 30 days to 5 years before screening; patients who have type 2 diabetes mellitus that meet criteria of the American Diabetes Association or receive anti-diabetic agents, even without previous cardiovascular disease.
• Exclusion criteria: Unstable medical condition, life expectancy less than 5 years, LDL-C levels < 100 mg/dL, those not receiving anti-lipidemic medications, if LDL-C target level not achieved at termination of run-in period, and those who have cardiovascular event during run-in period or uncontrolled hypertension: SBP>140 mmHg or DBP>90 mmHg,
• Run-in period: 4-10 weeks
• Cardiovascular disease was defined as myocardial infarction, stroke, acute coronary syndrome, unstable angina, peripheral vascular disease, and cardiac revascularization.
• Two arms of the study: Atorvastatin alone or atorvastatin plus torcetrapib 60 mg. Dosage of atorvastatin was determined while achieving of target LDL-C levels during run-in period and can be changed during the study period according to LDL-C levels.
• Primary Outcome was defined as the time to first “cardiovascular event”.
• “Cardiovascular event” defined as death from coronary artery disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Procedure-related deaths and events were excluded.
• Secondary outcome: time to the first occurrence of a primary outcome. Time to death regardless of the etiology, change from baseline LDL and HDL levels.
• Outcomes based on 1,3,6,9, and 12 months scheduled visits.

Results

• Median follow-up: 550 days
• Follow-up completion: 99.7% of patients
• Early discontinuation: 11% in atorvastatin group and 13.4% in torcetrapib group.
• One year follow-up showed increase of HDL (72.1%), a decrease of LDL (24.9%), and a decrease of 9% of triglycerides among patients on torcetrapib vs. minimal change in lipid profile in atorvastatin group (p<0.001).
• After 3 months follow-up, there was a small, but significant, change in CRP levels (p=0.01)
• After 12 months follow-up, blood pressure decrease was 0.9% in atorvastatin group vs. 5.4 mmHg in torcetrapib group (p<0.001). Torcetrapib group also have a 0.08 mmol/L decrease in potassium, a 1.39 mmol/L increase in sodium, and a 2.28 mmol/L increase in bicarbonate vs. an increase in all 3 among the atorvastatin group with electrolyte values increasing 0.06 mmol/L, 0.78 mmol/L, and 1.93 mmol/L, respectively (p<0.001)..
• In contrast, estimated glomerular filtration rate (eGFR) increased 0.8 ml/min/1.73m2 in torcetrapib group, but decreased 0.3 ml/min/1.73m2 in the atorvastatin group (p<0.001)
• QT interval changes after 12 months were 3.3 msec and 0.3 msec in torcetrapib and atorvastatin groups, respectively (p<0.001)
• Measurements of aldosterone showed that after 3 months, there was a significant increase in aldosterone measurements in the torcetrapib group among 85th, 90th, and 95th percentile values.

Study Outcomes

• Hazard ratio for death was 1.58 in torcetrapib group at the end of the study (p=0.006).
• Torcetrapib group had a 1.25 hazard ratio for primary outcomes (p=0.001), most notably significant for unstable angina (p=0.001) and least importanta for stroke (0.74).
• Significant increase in adverse events in torcetrapib group was reported: hypertension, peripheral edema, angina pectoris, dyspnea, and headache (p<0.001 – p=0.02).

Conclusion

• T There was an increased rate of death and morbidity in torcetrapib group due to unknown mechanism.
• Study terminated prematurely due to results of torcetrapib pertaining to increased cardiovascular morbidity and mortality.