Torcetrapib raised HDL, may help control diabetes

An analysis of the ILLUMINATE trial data revealed new findings: Torcetrapib, a cholesteryl ester transfer protein inhibitor, may improve HDL levels and blood glucose in those with diabetes who are also taking a statin.

Researchers discovered the beneficial effects of torcetrapib while analyzing data from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which was halted in 2006 because patients with diabetes assigned to torcetrapib and atorvastatin (Lipitor, Pfizer) had more cardiovascular problems and a higher mortality rate vs. patients assigned to atorvastatin and a placebo. Researchers later determined that the adverse events were related to other effects of torcetrapib, not its cholesteryl ester transfer protein (CETP) inhibition, according to a press release from the American Heart Association.

Data from ILLUMINATE showed that after 3 months of treatment, more than 6,600 patients with diabetes who were taking torcetrapib and atorvastatin had lower fasting blood glucose levels (0.34 mmol/L) and fasting insulin levels (11.7 mcU/mL) than patients taking statin and placebo. Insulin resistance also improved in the investigational combination therapy group. After 6 months, average blood glucose levels were lower in the torcetrapib and atorvastatin group (7.06%) compared with the statin and placebo group (7.29%). Additionally, HDL levels improved 66.8% after 1 year with torcetrapib and atorvastatin compared with a minimal change with statin and placebo. Researchers said it is unclear whether torcetrapib’s effect on HDL may account, in part, for the improvement in diabetes control. Torcetrapib also improved glucose and insulin measurements in study participants without diabetes, although not as much.

“The possibility that CETP inhibitor drugs may not only reduce the risk of [myocardial infarction] and stroke, but may also improve the control of blood sugar in people with diabetes, is an exciting prospect that may translate into real health benefits for people with diabetes,” Philip Barter, MBBS, PhD, director of the Heart Research Institute at University of Sydney, Australia, said in a press release.

Although torcetrapib’s effect on diabetes was not as effective as other commonly used antidiabetic therapies, “inhibition of CETP has the potential to prevent a worsening of diabetic control that often occurs in people taking statin drugs,” Barter said.

ILLUMINATE included more than 15,000 participants aged 45 to 75 years with a history of MI, stroke, chest pain, peripheral vascular disease or cardiac revascularization, and all were taking antidiabetic therapies.

Although the development of torcetrapib was halted, researchers said two other CETP inhibitors that do not cause the adverse effects — dalcetrapib and anacetrapib — are in the drug approval pipeline.

In an accompanying editorial, Stephen D. Wiviott, MD, a member of the TIMI Study Group and from the CV division at Brigham and Women’s Hospital, Harvard School of Medicine, said “this analysis may provide additional insight into the relationships between two key risk factors for CV disease, lipids (in particular, HDL) and glycemia.”

However, Wiviott said the glycemic findings from ILLUMINATE may be due to chance, as is the case in some post hoc analyses.

“With these important reductions of key surrogate markers of the risk of CV disease, including LDL, HDL, triglycerides and glycemia, this seems like a drug that should be widely prescribed to those at risk for CVD. Of course, it is not now, and will never be, prescribed to our patients for these indications. The reason for this is that, despite the observed benefits on these key surrogates, patients treated with torcetrapib in ILLUMINATE had 25% more CV events, including 58% more total deaths than those treated with placebo,” Wiviott wrote.

For more information:

Barter P. Circulation. 2011;124
Wiviott SD. Circulation. 2011;124

Disclosure: The Heart Research Institute in Sydney funded the study and Pfizer provided statistical assistance. Dr. Wiviott said this research for the editorial was funded by Eli Lilly, Daiichi Sankyo, Merck and Pfizer; he also reported consulting and independent CME speaking for Eli Lilly, Daiichi Sankyo, AstraZeneca, Angelmed, Medco, Bristol-Myers Squibb, Ortho-McNeil and Sanofi-Aventis.

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