July 18th, 2011

Study Suggests Possibility That CETP Inhibitors May Improve Glycemic Control

A new analysis of the ILLUMINATE trial raises the possibility that CETP inhibitors like torcetrapib might have the unexpected beneficial effect of improving glycemic control in addition to their intended effect of raising HDL cholesterol. Development of torcetrapib was halted several years ago following the early termination of the large ILLUMINATE trial due to an excess of deaths and cardiovascular events in patients treated with the drug. Other CETP inhibitors (anacetrapib from Merck and dalcetrapib from Roche) are under active development, however, as many researchers believe that the adverse effects of torcetrapib were due to off-target effects of the drug that may not be found with other drugs in the class.

In a post-hoc analysis published in Circulation, Philip Barter and colleagues studied the 6,661 diabetic patients enrolled in ILLUMINATE. At baseline there were no differences in glycemic parameters. At 3 months, however, compared to patients receiving atorvastatin alone, patients receiving torcetrapib in addition to atorvastatin had:

  • plasma glucose levels 0.34 mmol/L lower (P<0.0001)
  • insulin levels 11.7 µU/mL lower (P<0.0001)

At 6 months, mean hemoglobin A1c levels were 7.29% in the atorvastatin arm versus 7.06% in the combination therapy arm (P<0.0001). A similar pattern was observed in ILLUMINATE patients who did not have diabetes, but these differences did not achieve statistical significance.

The authors raise “an obvious question” and ask whether the effects they observed are “secondary to CETP inhibition, or did they reflect an off-target effect of the drug unrelated to inhibition of CETP?”

In an accompanying editorial, Stephen Wiviott writes that although the differences are small, the consistency of the findings across multiple subgroups, measures, and time points “suggests that these findings may indeed be real.” He writes that dalcetrapib and anacetrapib “are clean CETP inhibitors” that “do not seem to share the hyperalderosteronism/hypertension off-target effects of torcetrapib.” Large phase III clinical outcomes trials with these drugs “will be of substantial interest to determine . . . whether the glycemic effects of torcetrapib are a class effect of CETP inhibitors, or unique to this agent.”

5 Responses to “Study Suggests Possibility That CETP Inhibitors May Improve Glycemic Control”

  1. The spin the authors place on this new result seems to be that other CETP inhibitors may be of benefit if they safely improve glycaemic control. However, there is another interpretation of this result, and it is that torcetrapib is once again a reminder to us of the hazards of relying on intermediate endpoints, rather than clinically meaningful endpoints. We already knew torcetrapib killed people despite “improving” lipids. Now we know it also killed people despite “improving” glycaemic control. It’s a great example of an important principle in the assessment of new medications.

  2. Louis Krut, MB.ChB. MD says:

    Brett Montgomery: You have put things with absolute clarity. Hard to understand why our “thought leaders” can’t see the obvious. Perhaps its not so hard to see why.

    Competing interests pertaining specifically to this post, comment, or both:

  3. I do not know how anyone can say that dalcetrapib and anacetrapib are ‘clean CETP inhibitors – they need to prove their worth in the outcomes studies – all these drugs have many unmeasured effects – and we cannot even be sure that the aldosterone issue was the reason that torcetrapib failed. And Brett is right…hard to know what this property means given the effect on mortality that the drug had.

  4. Leon Hyman, Ms M.D. says:

    If the second generation CETP inhibitors ever are FDA approved and hit the market, The Medical Letter on Drugs and therapeutics will say “The long term side effects of these drugs are unknown.” It takes at least 10 years after a drug hits the Rx market before a really good appreciation of the problems and also unexpected benefits are appreciated.

    Competing interests pertaining specifically to this post, comment, or both:

  5. Umar Shakur, D.O. says:

    Excellent analysis by Dr. Montgomery! We have other drugs that can drop A1c and do nice things for lipids, but end up having some bad outcomes (TZDs). I don’t hold much hope for the CETP inhibitors, no matter how “clean” they get.