ORLANDO (EGMN) – The multiplicity of reactions to a new drug-treatment concept has helped put “poly” in the polypill.

The idea of broadly administering a single, daily capsule containing five drugs proven to cut cardiovascular risk finally had its first field test on more than 2,000 people at 50 centers throughout India. The results proved the principle that three different antihypertensive drugs, a statin, and aspirin could safely and effectively coexist in a single pill, although the treatment effects were modest.

But the study also triggered an outpouring of opinions from physicians on exactly what principles are involved. What is the potential role for a polypill, and who are the people who should take it?

According to the study’s leader, Dr. Salim Yusuf, the underlying premise is that average risk-factor levels are abnormal in all individuals in most urban settings around the world, and so a polypill that reduces cardiovascular disease (CVD) risk could potentially be targeted to most or even all people older than 50 in countries spanning the globe.

The Indian Polycap Study (TIPS) enrolled people aged 45-80 years with a single CVD risk factor: type 2 diabetes, moderately elevated blood pressure (more than 140/90 mm Hg but less than 160/100 mm Hg, smoking within the prior 5 years, a serum LDL cholesterol of more than 3.1 mmol/L (121 mg/dL), an HDL cholesterol of less than 1.04 mmol/L (40 mg/dL), or an elevated waist/hip ratio.

“The big question is whether you treat the whole world at large at a certain age. That’s been proposed, and it’s a possibility. I really don’t know the answer right now,” Dr. Yusuf said during a press briefing before he reported his findings on March 30 at the annual meeting of the American College of Cardiology. Accumulating evidence suggests that the threshold for diagnosing a level of blood pressure or serum LDL that poses a CVD risk should move lower than it is today. “What is normal will be substantially revised [downward] in the next 2 decades,” predicted Dr. Yusuf, professor of medicine and director of the Population Health Research Institute at McMaster University, Hamilton, Ont.

But others saw the polypill in a different role: a way to simplify treatment and boost compliance in the more conventional drug-treatment setting of secondary prevention.

“I would use it to treat people with some elevations of both blood pressure and lipids,” said Dr. Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic. “I wouldn’t use a one-size-fits-all pill for many people who are not at a whole lot of risk. I would use it for people with [a few] risk factors and make it easy for them by giving a single pill once a day.”

Simplicity and the potential for improved compliance were features that attracted Dr. Sidney C. Smith Jr., professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina in Chapel Hill. “We’re looking at this [simplified dosing with single pills] in the United States,” said Dr. Smith, who serves on committees involved in setting American treatment guidelines. He also agreed that “the first approach is for secondary prevention, people who need treatment.”

Others saw as too global and facile the development of a single pill aimed at quickly and easily damping down blood pressure and serum lipids in people who might not have elevations in several risk factors.

The polypill “is compelling to a certain extent, but it has gaps,” said Dr. Daniel W. Jones, vice chancellor for health affairs at the University of Mississippi in Jackson. “If you’re committed to using pills, it simplifies treatment and moves you away from marketing, but people who don’t need [every drug in] the pill will be exposed to its risk. It moves you away from the individualized approach, added Dr. Jones, an internal medicine physician and hypertension specialist.

“It takes effort to educate the public about hypertension and obesity. If something like [the polypill] becomes prevalent, it takes away from that focus,” said Dr. Clyde Yancy, medical director of the Baylor Heart Institute in Dallas. “There is nothing more effective than modifying lifestyle, but people may tend to dismiss that concept if they believe a pill is lowering their risk of heart disease.”

Dr. Yusuf himself stressed that no matter where the polypill may lead, “lifestyle modification is the crux of CVD prevention.”

The 2,053 people participating in TIPS were recruited during March 2007–August 2008. Their average age was 54, their average blood pressure was 134/85 mm Hg, their average LDL level was 117 mg/dL, and 13% were recent smokers. Of them, 412 were randomized to receive the once-daily polypill, a capsule cocktail with three half-doses of blood pressure–lowering medications (5 mg ramipril, 50 mg atenolol, and 12.5 mg hydrochlorothiazide), 100 mg aspirin, and 20 mg simvastatin. Eight additional groups of about 200 people each were randomized into various treatment arms that received one, two, three, or four of these drugs in different combinations to compare the safety and efficacy of the five-drug polypill formulation against its component parts. Treatment was delivered for 12 weeks. Halving the usual antihypertensive dosages helped ensure safety in this initial study, said Dr. Yusuf,

The study was sponsored by Cadila Pharmaceuticals, an Indian company that makes the polypill (Polycap). Dr. Yusuf reported receiving lecture fees and research grants from Cadila.

The polypill lowered blood pressure by an average of 7.4/5.6 mm Hg; LDL levels fell by an average of about 23%. These reductions tracked what was seen in the comparator groups. About 18% of participants discontinued the polypill arm of the study, and similar proportions dropped out of each of the other arms. Fewer than 5% of people in the polypill group dropped out because of drug-specific reasons, a rate similar to that seen in the other treatment groups. Concurrent with Dr. Yusuf’s report at the meeting, the results were released in a paper published online (Lancet 2009 March 30 [doi:10.1016/S0140-6736(09)60611-5]).

Based on the risk factor reductions seen, polypill treatment was estimated to cut the average risk for coronary heart disease by 62%, and for stroke by 48%, Dr. Yusuf said.

Further testing of the polypill is underway in India, and the manufacturer is arranging collaborations with North American drug companies to launch U.S. tests, Dr. Yusuf said in an interview. Asked if the target population for the polypill is the western world or third world, Dr. Yusuf said his target is “the sensible world.”