Slippery Slope: Diet Drugs No Help for Heart

After 13 years of rejecting applications for new diet drugs, the U.S. Food and Drug Administration in the last 3 years has allowed five potentially harmful products on the market -- including two in the last 4 months.

The agency approved the drugs despite the potential for serious side effects, including suicidal thinking, increased heart rate, and cancer risk, and no proof the drugs improve the main health concern posed by obesity -- cardiovascular harms such as heart attacks.

Critics worry the new products will repeat the diet-drug mistakes of the past, which have led to decades of injuries, deaths, and, in the end, products forced off the market.

The FDA's about-face comes after pressure from the companies that manufacture the drugs, medical societies that get funding from those drug makers, and even the U.S. Senate -- where pharmaceutical money also finds takers -- which in 2011 called on the FDA to approve new obesity treatments.

A Milwaukee Journal Sentinel/MedPage Today investigation found diet-drug manufacturers paid at least $9 million to doctors to promote their products and to medical societies that advocate their use in 2013 alone.

Those same companies also spent $51 million lobbying the U.S. Senate and FDA on a host of issues, including obesity, in the last 5 years, records show.

Despite the longstanding medical quest to reduce waistlines and improve health, no diet or weight-loss drug has been proven to reduce heart attacks, strokes, or cardiovascular deaths.

That includes the concoctions popular in the 1940s through the 1960s known as "rainbow pills" -- a mix of amphetamines, thyroid hormone, laxatives, and tranquilizers that caused dozens of deaths.

It also is true of the combination drug fenfluramine and phentermine -- fen-phen -- that was taken off the market in 1997 after it was found to have caused heart valve damage in thousands of users.

It also includes the drug Meridia, which was in use for 13 years until it was taken off the market in 2010 because it was linked to increased heart attacks and strokes in a large clinical trial initiated only after its U.S. approval in 1997.

Indeed, in the wake of the fen-phen problems, the FDA rejected all drug company efforts to win approval for new weight-loss drugs between 1999 and 2012.

Since then, it has approved four drugs for weight loss -- Belviq, Qsymia, Contrave, andSaxenda. Another, Vyvanse, was approved in January for a condition known as binge-eating disorder

In some cases, the drugs had previously been approved for treating different conditions. Vyvanse, for instance, had been used to treat attention deficit hyperactivity disorder (ADHD). Saxenda, approved in December for weight loss, had been used to treat type 2 diabetes.

The Journal Sentinel/MedPage Today investigation found 3,000 cases in the FDA's own adverse event reporting database where drugs used as components in one of these new diet drugs were the primary suspect in a patient's death.

Another 11,000 hospitalizations were reported with those drugs as the primary suspect.

Generic bupropion, part of the formula for Contrave, was the primary suspect in at least 1,500 patient deaths since 2004, according to the data. Phentermine and topiramate, the drugs used in Qsymia, were linked to a combined 670 deaths.

Belviq is chemically similar to fenfluramine, the fen part of the fen-phen combination that caused heart valve problems. Researchers say the drug targets a slightly different serotonin receptor than fenfluramine -- one that is not found in the heart, and therefore should not cause valve problems. But studies have shown numerically higher rates of valvulopathy with Belviq than with placebo.

In an email, Laurie Ostroff-Landau, a spokesperson for Eisai, which co-markets Belviq, said that the company already had started a long-term cardiovascular safety trial of the drug.

The 12,000-person trial, which was announced in February 2014, will last 5 years.

In an email, Carin Ganz, a spokesperson for Vivus, the maker of Qsymia, said the two drugs that make up Qsymia have been on the market, separately, for many years at higher doses than what is used in Qsymia.

"We are confident in the safety and efficacy profile of Qsymia," she said.

The drug Contrave helps address an unmet need in the treatment of obesity, Lori Rodney, a spokesperson for Takeda Pharmaceuticals, which co-markets the drug, said in an email.

"... We are committed to further exploring the cardiovascular safety of Contrave as part of postmarketing requirements," she said.

Those adverse events, plus many other potential side effects, need to be weighed against the main benefit offered by the drugs, which, in some cases, is modest weight loss.

"If you are 40% overweight and you lose 5% or 7% of your weight, is that really of consequence?" asked Sanjay Kaul, MD, a cardiologist with Cedars-Sinai Medical Center in Los Angeles, who also has served on FDA weight-loss drug advisory panels.

Jeanmarie Perrone, MD, a drug safety expert at the University of Pennsylvania, said the push for the new drugs seems to be driven more by what consumers and drug companies want than by a desire to improve public health.

"There's a great market out there, so let's make a bunch of drugs that try to address it," Perrone, a professor of emergency medicine who has sat on FDA drug advisory panels, said of the thinking.

About 35% of adults -- nearly 80 million Americans -- are obese.

"We certainly have to learn from a lot of history that has gone before us with these drugs," she added.

Weighing True Risk

Amid the hype and promotion, it can be difficult for doctors and patients to assess the true risk and benefit of new drugs. Indeed, this is one of the most important considerations of medicine, but often it gets little discussion.

Consider liraglutide, an injectable drug that works in part by helping the pancreas produce more insulin. The drug also suppresses appetite by fooling the brain into thinking the stomach is full.

Liraglutide is the generic name for Saxenda, which was approved for obesity in December. It is merely a higher dose of Victoza, a drug that has been marketed since 2010 for type 2 diabetes.

As a diabetes drug, Victoza was the primary suspect in 348 deaths and more than 3,100 hospitalizations through June 2014, according to the most recently available FDA data. At least 100 of those reported deaths were linked to pancreatic cancer.

Clinical trials for both Victoza and Saxenda raised concerns -- still unresolved -- that both drugs may increase the risk of pancreatitis, which can increase the risk of pancreatic cancer.

In clinical trials of Victoza, there were 13 cases of pancreatitis reported versus one for a comparator drug. In clinical trials of Saxenda, there were nine cases of acute pancreatitis among 3,291 people who got the drug versus one case in the 1,843 who got a placebo.

Both versions of the drug also carry the FDA's most stringent black box warning because animal research revealed the possibility that both drugs could cause thyroid tumors.

Saxenda and Victoza also have several less serious and more defined side effects such as nausea and constipation.

Read more: http://www.medpagetoday.com/

Makers of diet drugs spent more than $60 million on payments to doctors, organized medicine, and lobbyists to get their drugs approved.

http://www.medpagetoday.com/

Graham