Torcetrapib Improves Glycemic Control in Diabetes

July 18, 2011

July 18, 2011 (Sydney, Australia) — New data from a post-hoc analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial indicate the cholesterol ester transfer protein (CETP) inhibitor torcetrapib (Pfizer)--no longer in clinical development due to an increased risk of death and cardiovascular disease associated with the drug--may improve glycemic control [1].

Investigators say the findings are important given that two other CETP inhibitors, dalcetrapib (Roche) and anacetrapib (Merck), are currently being tested in large-scale clinical trials, and these agents are not believed to have the same toxicity as torcetrapib.

"Given that results with torcetrapib may not be generalizable to other CETP inhibitors, it will be of great interest to see whether dalcetrapib and anacetrapib also improve diabetic control," write Dr Philip Barter (University of Sydney, Australia) and colleagues in the July 19, 2011 issue of Circulation.

Off-Target Toxicity

The end for torcetrapib came in December 2006, when Pfizer announced an increased risk of death and cardiovascular events among patients treated with the CETP inhibitor. The signal emerged in ILLUMINATE, a randomized, double-blind study of the effect of torcetrapib plus atorvastatin (Lipitor, Pfizer) vs atorvastatin alone on the occurrence of major cardiovascular events in 15 000 patients with coronary heart disease or risk equivalents. As reported by heartwire , concerns were raised about the off-target blood-pressure effects of torcetrapib, and later analyses showed that torcetrapib stimulates aldosterone, which possibly accounted for its adverse outcomes.

In this latest study, Barter and colleagues investigated the effects of torcetrapib on glycemic control in 6661 patients with diabetes included in ILLUMINATE. They point out that HDL cholesterol--which torcetrapib is designed to raise, and has effectively done so in various studies--has also been shown to have antidiabetic properties.

After three months of treatment with torcetrapib and atorvastatin, plasma glucose levels were 0.34 mmol/L lower and insulin levels 11.7 µU/mL lower than in patients treated with torcetrapib alone--both reductions were statistically significant. Insulin resistance, measured using homeostasis model assessment, was also significantly reduced in the torcetrapib plus atorvastatin arm. At six months, mean HbA1c was 7.29% in patients who received atorvastatin alone compared with 7.06% in patients treated with the CETP inhibitor and atorvastatin. The benefits of treatment with torcetrapib were maintained until 12 months, and while such metabolic improvements were observed in ILLUMINATE patients without diabetes, the magnitude of change was largest in patients with diabetes.

Barter and colleagues point out that it is unknown whether the beneficial effects of torcetrapib on glucose homeostasis is the consequence of changes in plasma lipids secondary to CETP inhibition, or if they reflected yet another off-target effect of the drug.

Barter has received research grant support from Merck, Pfizer, and Roche, and honoraria for lectures or serving on scientific advisory boards from Abbott, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Pfizer, and Roche. ILLUMINATE is sponsored by Pfizer.