Role of Genetic Data Emerges in Antismoking Effort

Abstract

Genetics’ influence on quit-smoking drugs.

The field of pharmacogenetics “is very complex and involves interactions of many different genes,” says Penn’s Caryn Lerman, PhD.

Smoking may be the leading cause of preventable death in the United States, but there aren’t many new smoking cessation products available. Smokers who want to quit can choose from nicotine replacement therapies that have been around for decades —patches, gums, lozenges, nasal sprays, and inhalers — and two non-nicotine prescription drugs, bupropion (Wellbutrin or Zyban) or varenicline (Chantix).

With 45 million U.S. smokers and hundreds of millions more in foreign markets, nicotine dependence looks like a good market for new treatments, but more efficient methods than trial-and-error will be needed to learn which drug is going to work best for an individual smoker who wants to quit. Researchers are already finding answers to that question.

VERY HOT TOPIC

According to a study published in Biological Psychiatry, smokers with the CYP2B6*6 genotype appear to be good candidates for bupropion treatment for smoking cessation (Lee 2007). The CY2B6 gene codes for the primary enzyme that metabolizes bupropion.

Smokers with one or two copies of the CYP2B6*6 variant had a harder time quitting, but were 3 times more likely to quit and stay off cigarettes at six months when treated with bupropion than smokers in the placebo group. Conversely, smokers with the CYP2B6*1 variant did not benefit from bupropion treatment in quitting. About 30 percent of smokers in this group quit regardless of whether they were given bupropion or a placebo.

“Pharmacogenetics and nicotine dependence treatment is a very hot topic because there is tremendous variability in response to different treatments for smoking cessation,” says Caryn Lerman, PhD, deputy director of the Abramson Cancer Center at the University of Pennsylvania, and a coauthor of this study. “If we can appropriately personalize therapy based on genotype, then we will have increased efficacy of our treatment.”

Bupropion increases the levels of dopamine and nor-epinephrine, brain chemicals involved in the pleasurable effects of smoking, and also may block nicotinic receptors in the brain. Varenicline, which was approved in 2006, also blocks certain nicotinic receptors, thereby reducing withdrawal and craving, and increases dopamine levels, albeit less than smoking itself does.

So far, researchers have identified several genetic markers that predict response to treatment for smoking cessation.

“The field of pharmacogenetics and nicotine dependence treatment is still in its infancy,” says Lerman. “Before [its] findings can be translated into clinical practice, we need independent validation trials, and these validation studies are just starting to come out.”

The pharmacogenetics of smoking cessation treatments will grow out of infancy as more smoking cessation drugs come to market. But these drugs will be pricey, and genotyping tests will add even more cost. That brings up the question of whether it will make sense for employers to pay for the tests and the drugs.

WHERE THE MONEY IS

For years, employers have been shifting healthcare costs to workers. But that trend may have peaked — at least, for larger companies.

“We work with large, self-insured companies with employee bases of 2,000 and up, and our clients feel that they’ve done about as much shifting of costs to employees as they can do,” says Michael Cryer, MD, senior consultant and a medical director with Hewitt Associates, the human resources consulting company. “At this point, they feel that the biggest potential financial return is in keeping people healthy and on the job, because then you can reduce total costs over the time they’re with you.”

A recent survey seems to corroborate Cryer’s experience. Released in June, the survey of member companies of the National Association of Manufacturers and the ERISA Industry Committee found that 71 percent use incentives to drive employee participation in health management programs — compared to 62 percent last year (see next page).

A positive return on investment is certainly needed when you start $3,800 in the hole. That’s about how much more a smoker costs a company than a nonsmoker, according to the Centers for Disease Control and Prevention. The additional cost is attributed to lost productivity due to sick days and absences, and costs associated with a higher prevalence of hypertension and respiratory conditions.

An effective smoking cessation program can eliminate that extra cost in two to three years, Cryer claims. He estimates that the return for most clients is 1.5 to 2 times their investment.

“The biggest potential financial return is in keeping people healthy and on the job,” says Hewitt’s Michael Cryer, MD.

“It’s still a hard road, and you win in small increments,” says Cryer, but those increments tend to get bigger as the investment in smoking cessation gets bigger. For example, the one-year quit rate for a smoking cessation program that includes online and telephone counseling, nicotine replacement therapy, and such smoking cessation drugs as varenicline, is about 7.5 percent, compared to about 4 percent for a program without counseling or drug coverage.

“My message to employers is to go where the money is,” says Cryer. “The key is to get the right vendors, set up a stop-smoking program that’s got the highest probability for good outcomes, and [develop a] strong measurement program to monitor the process and the results. If you do those things, then you’ll generate enough savings to cover your costs.”

Like Lerman, Cryer expects pharmacogenetic testing to make smoking cessation therapy more efficient through the avoidance of drugs that don’t work for a given person.

“Our clients say if it becomes a standard of care and it’s supported by clinical evidence, they’ll support it, but it will primarily be administered through the physicians and the networks that provide the care,” Cryer adds.

PRIMARY CARE’S ROLE

But what if physicians aren’t prepared to order these genotyping tests for their patients? And what if consumers are leery about the potential misuse of these test results?

“Just the word ‘genetic’ actually posed a barrier to adoption by primary care physicians, regardless of the characteristics of the test,” says Alexandra Shields, PhD, referring to the conclusions of two recent studies she coauthored (Shields 2008, Shields 2005). “If primary care physicians don’t buy into genetically tailored smoking cessation treatment, then it won’t be offered to patients.”

Shields is director of the Harvard/MGH Center on Genomics, Vulnerable Population, and Health Disparities, and principal investigator on a five-year grant from the Robert Wood Johnson Foundation to study clinical and ethical issues related to tailoring smoking cessation treatment by genotype.

Primary care physicians are among those with the least experience with clinical genetics, according to Shields. The short duration of office visits and lack of practice guidelines contribute to their disinclination to get into genetic testing and counseling.

Moreover, it’s not just a matter of ordering a test that matches a patient with the most effective smoking cessation treatment. Some of the genetic variants that would be useful for tailoring smoking cessation treatments also are associated with increased risk for other addictions and psychiatric illnesses, such as attention deficit hyperactivity disorder, depression, and compulsive disorders. These pleiotropic associations would need to be explained to obtain a patient’s informed consent for testing.

“An individual may not want that additional information generated about them or have it end up in their health record,” Shields notes. “It might not be an issue now, but as new research comes to light, that information could be potentially harmful in the hands of the wrong people. Now is the time to address the challenges associated with translating pharmacogenetic treatment strategies into practice. Only if we understand these challenges will we be able to reap the benefits of new, more effective treatments.”

Smoking cessation tops in health and wellness measures

In a survey by the National Association of Manufacturers and the ERISA Industry Committee, smoking cessation was most often listed as the most successful of members’ health and wellness programs. It ranked ahead of programs designed to encourage weight loss, regular exercise, and reductions in blood pressure.

Smoking cessation also offers the biggest cash incentives to employees, ranging from $5 to $600, with weight management closest behind. Overall, the average annual per-employee incentive was $192.

The full report of the survey, “2008 Employee Health and Productivity Management Programs: The Use of Incentives,” is available at «www.incentone.com/surveyresults».