Novel PPAR-alpha agonist shows no advantage over fenofibrate and raises safety concerns
March 25, 2007 Michael O'Riordan
New Orleans, LA - The evaluation of a potent and selective new peroxisome proliferator-activated receptor- (PPAR-) agonist in patients with atherogenic dyslipidemia and hypercholesterolemia failed to impress today here at the American College of Cardiology (ACC) 2007 Scientific Sessions.
In patients with dyslipidemia, the new agent, known as LY518674 (Eli Lilly and Co), lowered triglyceride levels and raised HDL cholesterol in a manner similar to fenofibrate, a weak PPAR- agonist; whereas hypercholesterolemic patients treated with LY518674 in addition to atorvastatin experienced a modest incremental reduction in triglyceride levels and a modest 10% increase in HDL cholesterol. Important to the discussion, say investigators, is the finding that the potent PPAR- agonist and fenofibrate both raise creatinine levels, and about 38% of those treated with these agents had elevations above the upper limits of normal.
"From everything we knew, this drug had great potential and we were excited to study it," Dr Steven Nissen (Cleveland Clinic, OH), lead study investigator, told heartwire. "Now everybody knows that this PPAR-, a very potent agent, about 10 000 times more potent than the weaker agonists, is unlikely to produce superior results compared with fenofibrate."
The study has been published in the Journal of the American Medical Association to coincide with the ACC presentation. [1]
Two studies, both negative results
The PPARs are a class of drugs in development to promote reverse cholesterol transport. These drugs are nuclear receptors that activate ABCA1, which in turn stimulates the first step of reverse cholesterol transport, the efflux of cholesterol out of cells onto HDL-cholesterol particles. There are three types of PPARs—alpha, gamma, and delta—and all are targets for agonists as drugs. Fibrates, for example, work by binding to PPAR-, causing both an increase in HDL cholesterol and a decrease in triglycerides. PPAR- agonists, including the glitazones, drugs used primarily in diabetes, raise HDL cholesterol only modestly, and their major effect seems to be a reduction in insulin resistance. PPAR- seems to have all three effects.
"Fenofibrates have been around since 1974, and gemfibrozil more recently," said Nissen. "They are widely used. We didn't know back then that they [would] work as a PPAR- agonist, a nuclear receptor, turning on certain genes and turning off others. We knew that these drugs lowered triglycerides and raised HDL cholesterol modestly. This new drug is a pure, selective, powerful PPAR, and the hypothesis was that it would lower triglycerides more, raise HDL cholesterol more, and also be safer."
To test the safety and efficacy of PPAR- agonist, investigators designed separate clinical-trial protocols in two patient populations, one with atherogenic dyslipidemia and the other hypercholesterolemia. Both were multicenter, randomized, double-blind, placebo-controlled studies, and they were conducted at the same time.
In the atherogenic dyslipidemia study, 309 patients were randomized to a four-week placebo lead-in period to evaluate the effect of the National Cholesterol Education Program (NCEP) lifestyle-changes diet, followed by a 12-week active-treatment period in which they were randomized to receive placebo, LY518674 (10 g, 25 g, 50 g, or 100 g), or fenofibrate 200 mg. In the hypercholesterolemia study, 304 patients entered a four-week active-treatment period in which they were randomized to placebo or atorvastatin 10 mg or 40 mg. Patients subsequently entered a 12-week treatment period during which each of these treatment groups were randomized to placebo or LY518674 10 g or 50 g.
In the atherogenic study population, the novel PPAR- agonist lowered triglycerides approximately 35% and increased HDL cholesterol 15%, although this was not different from fenofibrate. The agent demonstrated an unusual dose-response curve, with smaller increases at the highest doses. The agent also raised LDL-cholesterol levels 20% in a dose-dependent fashion and to a much greater extent than fenofibrate. Both drugs were generally well tolerated but raised serum creatinine levels above the upper limits of normal in 35% to 38% of patients.
Atherogenic dyslipidemia study: Percent change in laboratory parameters from baseline until follow-up visit
Parameter
Placebo (n=51)
LY518674 10 g (n=51)
LY518674 25 g (n=53)
LY518674 50 g (n=51)
LY518674 100 g (n=52)
Fenofibrate 200 mg (n=51)
Total cholesterol (mg/dL)
-1.4
-7.3
-4.4
0.8
-2.4
-6.0
LDL cholesterol (mg/dL)
-0.3
2.1
11.9
18.3
19.5
2.3
HDL cholesterol (mg/dL)
-1.1
9.6
15.8
11.1
2.1
14.4
Triglycerides (mg/dL)
1.3
-36.1
-40.9
-41.7
-34.9
-32.8
Apolipoprotein A1 (mg/dL)
2.3
4.0
10.3
7.6
-4.2
8.7
To download table as a slide, click on slide logo below
In the hypercholesterolemia study, LY518674 in combination with atorvastatin lowered triglycerides, reduced LDL cholesterol, and increased HDL cholesterol. In patients previously treated with atorvastatin, the incremental effect of adding LY518674 resulted in a 20% to 43% additional reduction in triglyceride levels, a 1% to 12% increase in HDL cholesterol, and a further small reduction in LDL cholesterol. Serum creatinine increases were observed in about 20% of patients.
Regarding the negative findings, Nissen told heartwire: "The company says there is an increased production of creatinine, but there is also some evidence that it might be directly renotoxic. The bottom line is that this is a disappointing result. A new drug, with great potency, didn't produce superior results in terms of lipid effects."
Overall, Nissen emphasized, there is still residual risk for patients treated with statins, and because of this, investigators continue to seek out new drugs to raise HDL cholesterol. However, with the collapse of torcetrapib in the ILLUSTRATE study, which showed an increased risk of mortality and cardiovascular events with the experimental HDL-cholesterol-raising drug, there is pressure on industry to develop new agents.
"This is the worst period I can remember in terms of industry's inability to come [up] with innovative new approaches," said Nissen. "We haven't had a new class of antiatherosclerotic drugs since 1987, when the statins were introduced. It is really important to understand that we are in a very tough period."
Publish your findings (even the negative results)!
When you do a trial in a promising new class, and you have done the trial well, it belongs in the public domain.
Despite the results, Nissen commended Eli Lilly, the makers of LY518674, for publishing the results, something that has not occurred in recent years, despite the more than 50 investigational new-drug applications for PPAR agonists by pharmaceutical companies.
"Most development of these agents has been terminated due to toxicity, but there have been virtually no publications detailing what happened," Nissen told heartwire. "I am making a statement here. When you do a trial in a promising new class, and you have done the trial well, it belongs in the public domain. The fact that we don't have documentation as to why these many trials failed is wrong. It is extremely important when you do a study like this to publish the results because it tells people what works, what doesn't work, and lets us focus our energies on other strategies."
Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA), who chaired the late-breaking clinical-trials session, agreed with Nissen about the publication of negative results. Instead of praising Eli Lilly, Ridker told the audience that publication, regardless of the findings, should be an academic requirement. Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX), who chaired the session with Ridker, noted that clinicians using low-dose fenofibrate have improved their lipid profiles, suggesting that investigators might want to go in the other direction to determine whether weaker PPAR- agonists are more beneficial. |
