Administering torcetrapib to type 2 diabetes mellitus patients who are also treated with atorvastatin improves glycemic control, according to a study published July 18 in Circulation. The data regarding torcetrapib, a cholesterol ester transfer protein (CETP) inhibitor (Pfizer), which can increase levels of HDL, was taken from the ILLUMINATE trial, which was halted five years ago due to cardiovascular problems among patients that could have been associated with drug administration.
The ILLUMINATE trial joins a long list of other disappointing trials and therapies that have attempted to explore HDL-raising treatments. For example, fenofibrate recently showed poor results during the ACCORD trial after it proved unsuccessful in reducing the rate of cardiovascular events in diabetic patients within the ACCORD-Lipid trial, despite the fact that it lowered triglyceride levels.
However, the current analysis of the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) trial, performed by Philip J. Barter, MBBS, PhD, of the University of Sydney in Australia, and colleagues found that the drug may be useful to improve glycemic control when administered with statins in type 2 diabetes patients.
The trial was conducted to evaluate the effects of glycemic control on the 6,661 diabetic patients enrolled in the trial. At baseline, the researchers found no difference between the two treatment arms in terms of plasma glucose, insulin, hemoglobin A1c or the homeostasis model assessment of insulin resistance.
The researchers reported that after three months of taking the drug combination (torcetrapib plus atorvastatin) patients had plasma glucose levels that were 0.34 mmol/L lower and insulin levels 11.7 µ U/mL lower than those receiving atorvastatin alone. Homeostasis model assessment of insulin resistance values decreased from 49.1 to 47.3 in the patients who received torcetrapib/atorvastatin compared with an increase in homeostasis model assessment of insulin resistance in the atorvastatin arm.
At six months, mean HbA1c levels in the atorvastatin arm were 7.29 percent compared with 7.06 percent in the torcetrapib/atorvastatin arm.
Additionally, Barter and colleagues reported that the addition of torcetrapid also lowered both glucose and insulin levels in nondiabetic patients; however, the effects were not as great.
While the results seem promising, Barter et al stated that it remains to be seen whether the effect is the consequence of torcetrapib.
The authors wrote that the results bring forth an important question: “Were these beneficial effects of torcetrapib on glucose homeostasis the consequence of changes in plasma lipid levels secondary to CETP inhibition, or did they reflect an off-target effect of the drug unrelated to inhibition of CETP?”
Barter and colleagues noted that torcetrapib has a multitude of adverse effects including the synthesis and release of aldosterone and cortisol from adrenal cortical cells, an increase in blood pressure and increase in serum sodium and bicarbonate and a decrease in serum potassium. “There is mounting circumstantial evidence that these off-target effects accounted for the harm caused by torcetrapib in the ILLUMINATE trial,” the authors wrote. “It is therefore possible that the effects of torcetrapib on glucose homeostasis observed in the present analysis represented an additional off-target effect of the drug that, in this case, was beneficial rather than adverse.
“The possibility that CETP inhibitor drugs may not only reduce the risk of heart attack 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,” Barter, the study’s lead author, concluded.
However, the authors cautioned that the present analysis provided little insight of the mechanism by which torcetrapib improved diabetic control and said that the analysis was post hoc and data driven.
While the effects of torcetrapib may not be generalizable to other CETP inhibitors, the authors said it will be of great interest to better understand whether dalcetrapib and anacetrapib also improve diabetic control.