Larger-than-anticipated increases in systolic blood pressure with torcetrapib

New York, NY - The imaging studies are closer to completion, but the early buzz on torcetrapib is starting to shift from initial excitement to concerns that the novel cholesteryl-ester-transfer-protein (CETP) inhibitor might carry a risk of hypertensive side effects that could offset the benefit of raising HDL-cholesterol levels. Preliminary data released this week show that the drug increases systolic blood-pressure levels more than previously suspected, which is possibly bad news for the drug being heralded as Pfizer's next blockbuster.

As previously reported by heart wire , an early dose-ranging study found that patients with elevated LDL-cholesterol levels but without overt cardiovascular disease taking 60 mg of torcetrapib had an increase in systolic blood pressure of approximately 2 to 3 mm Hg. The newest data show the average increase to be higher, in the 3- to 4-mm-Hg range.

Commenting on the findings for heart wire , Dr Franz Messerli (St Luke's-Roosevelt Hospital, NY) said that while it might be argued that a 3- to 4-mm-Hg increase is not significant, the recent one-million-patient meta-analysis by DrSarah Lewington (Oxford University, UK) and colleagues suggest that an increase of 3- to 4-mm-Hg systolic blood pressure would translate, populationwise, into a 20% higher stroke mortality and a 12% higher mortality from ischemic heart disease ^[1]. Equally important, he said, is that not all increases in blood pressure are created equal.

"Target organs and patients differ in their responsiveness to small blood-pressure changes," he said. "For instance, the diabetic patient is more susceptible than the nondiabetic patient to small blood-pressure changes. Cerebrovascular disease and diabetic renal disease are distinctly more blood-pressure dependent than is coronary artery disease. Conceivably, therefore, a drug like torcetrapib that elevates HDL cholesterol and blood pressure may still be very useful in the 'uncomplicated' patient with coronary artery disease. However, its usefulness may be more limited or necessitate additional antihypertensive therapy in diabetic hypertensive patients and in patients at risk for cerebrovascular disease."

The preliminary blood-pressure findings emerged from the phase 3 studies being conducted with the drug. The largest of those trials is ILLUMINATE, a randomized, double-blind evaluation of the effect of torcetrapib/atorvastatin (Lipitor, Pfizer) vs atorvastatin alone on the occurrence of major cardiovascular events in 15 000 subjects with coronary heart disease or risk equivalents. The blood-pressure findings emerged from preliminary results of approximately 4000 patients already enrolled in Pfizer's phase 3 clinical trials.

Despite the increase in blood pressure, Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) told heart wire that he is not too concerned about the increase and thinks the drug will be a much-needed addition to his clinical toolbox.

"Previously, what we had been told was that the drug increased blood pressure about 2 to 3 mm Hg, but based on what was presented previously, most people have no or minimal change in blood pressure," said Blumenthal. "There is a small subset of people who might have a larger 10- to 15-mm-Hg increase, but generally those are people who start off with real low blood pressures, those in the 100- to 110-mm-Hg range. I personally think the drug will still be a blockbuster, but what is needed, of course, is to see exactly what the drug does to atherosclerosis."

Just exactly what the drug does to atherosclerosis will be known sooner rather than later. In March 2007, Dr Steven Nissen (Cleveland Clinic, OH) is expected to present the results of the ILLUSTRATE study, one of three vascular imaging studies to be presented at American College of Cardiology Scientific Sessions. ILLUSTRATE is a multicenter, randomized, 1200-person study comparing atorvastatin/torcetrapib combination therapy with atorvastatin alone in preventing progression of coronary atherosclerosis as measured by IVUS in coronary heart disease patients.

The effects of the blood-pressure increase on IVUS-derived end points should be evident when the results from this study are in, Nissen previously told heart wire . In the CAMELOT trial, for example, a 5-mm-Hg difference in blood pressure resulted in a significant difference in plaque progression between treatment arms, he said.

"If indeed we see a significant decrease in atherosclerosis over a relatively short period of time, we'll know that at least in the short run, a modest increase in blood pressure is completely overwhelmed by the marked improvement in lipids," said Blumenthal. The long-term effects of the 3- to 4-mm-Hg increase in systolic blood pressure likely won't be known until the results of the large ILLUMINATE study are presented, he said, but added that the modest increase should not pose a problem for clinicians.

"What we expect to see with torcetrapib are HDL-cholesterol increases in the 40% range, maybe as high as 50%," he said. "If we have a drug that significantly decreases plaque volume, then as a cardiologist I know how to treat a modest increase in blood pressure. That's not a problem. There are clearly going to be some people, one in 10 or one in 20, who have rather large increases in blood pressure, although these are predominantly people in the low-normal range. If they go from 140 mm Hg to 160 mm Hg, that would clearly change the need for more medication."

As far as approval, Blumenthal said the increase in blood pressure might cause the FDA and other regulatory agencies to wait for the clinical-outcome studies, but he personally does not believe such a delay will be necessary if the IVUS study shows a significant affect on atherosclerosis. "We have so many people with severe atherosclerosis, claudication, and angina that I'd like to have that drug on the market if the short-term studies look safe," he said.

Messerli told heart wire that only a comprehensive outcome study would allow experts to quantify the risk/benefit ratio of torcetrapib and identify its place in the cardiovascular arsenal. He noted that it should be remembered that the increased risk of cardiovascular morbidity and mortality associated with some COX-2 inhibitors could also be caused, at least to some extent, by an increase in blood pressure.

Heartwire from Medscape © 2006 

Cite this: Larger-than-anticipated increases in systolic blood pressure with torcetrapib - Medscape - Nov 03, 2006.