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
- 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.
- Run-in period: 4-10 weeks
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,
Outcomes
- 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 was defines as time to the first occurrence of a primary outcome. Time to death regardless of the etiology, change from baseline LDL and HDL levels.
- Outcomes were based on 1,3,6,9, and 12 months scheduled visits.[1]
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:
- Increase of HDL (72.1%)
- Decrease of LDL (24.9%)
- 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 mmHg 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.[1]
- 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 important 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).[1]
Additional Publications from ILLUMINATE Trial
Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerosis events (ILLUMINATE) trial
Objective
To evaluate the effect of torcetrapib on glucose homeostasis in 6661 diabetic patients receiving atorvastatin alone or torcetrapib and atorvastatin therapy
Results
Antidiabetic therapy was not stopped in any patient. On the contrary, insulin was added to approximatley 5% and other oral antidiabetics were added to approximately 12-13% of patients in both groups by the end of the trial.
Plasma glucose levels, however, differed significantly between both groups. In patients receiving only atorvastatin, plasma glucose levels increased after 1 month of treatment, whereas they decreased in patients receiving atorvastatin and torcetrapib by the same time frame; the significant net difference of plasma glucose between the two was approximately 0.25 mmol/L (p<0.0001). The difference was further accentuated when measured during 3, 6, and 12 months of therapy; where net difference was 0.34 mmol/L (p<0.0001), 0.22 mmol/L (p<0.0001), and 0.26 mmol/L (p<0.0001), respectively.
Combination therapy with torcetrapib and atorvastatin was believed to improve insulin sensitivity. Serum insulin concentrations were significantly altered with both treatment arms. Patients receiving only atorvastatin had an increase in fasting serum insulin after 3 months of treatment (p=0.02). On the other hand, patients receiving a combination therapy had a significant decrease in serum insulin (p<0.0001). The net difference insulin concentration between the two arms of the study was 11.7 micro-units/mL (p<0.0001). Hemoglobina A1c (HbA1c) levels were significantly lower in patients receiving combination therapy after 1, 6, and 12 months of treatment (p<0.0001 at all times).
Similar to initial observation from tha total ILLUMINATE cohort, there was a significant increase of 66.8% in HDL in patients using a combination therapy vs. minimal change in patients receiving atorvastatin alone (p<0.001).
It is notable, however, to note that when changes in glucose, insulin, ad HbA1c were adjusted for HDL changes, statistical significance of these changes was eventually attenuated.
Conclusion
Treatment with torcetrapib improved glycemic control in diabetic patients. The exact association between the increase in HDL and the diabetic control requires validation.
Conclusion
- There was an increased rate of death and morbidity in torcetrapib group due to an unknown mechanism.
- Study was terminated prematurely due to results of torcetrapib pertaining to increased cardiovascular morbidity and mortality.[1]
References
- ↑ 1.0 1.1 1.2 1.3 Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M; et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events". N Engl J Med. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165.