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 -- .
A Milwaukee Journal Sentinel/乌鸦传媒 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 "" -- 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 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, and Saxenda. 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/乌鸦传媒 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 , a cardiologist with Cedars-Sinai Medical Center in Los Angeles, who also has served on FDA weight-loss drug advisory panels.
, 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.
Sometimes those can be summed up with a calculation known as number-needed-to-harm (NNH), which, as the term implies, is the number of people who experience a harmful side effect for each one who is treated.
In the case of Saxenda, the NNH for vomiting it is eight, according to an analysis done for this story by Rodrigo Kong, MD, an emergency medicine physician in New York City and an editor of . For headache, the NNH is 103.
Conversely, the benefit of a drug can be expressed in its number-needed-to-treat. That's how many need to be treated before a desired benefit is found. The lower the NNT, the better.
One benefit of Saxenda is its ability to produce weight loss of 5% or more after 12 months of treatment. For that benefit, the NNT was 3 or 4, depending on the clinical trial that was analyzed.
But that comes with an important caveat.
Weight loss -- which the FDA focused on when approving Saxenda and three other obesity drugs -- is considered to be a surrogate measure of benefit, not a proven clinical endpoint such as a reduction in strokes of cardiovascular deaths.
"If you want to make weight loss the endgame, that's fine," said , a professor of emergency medicine and toxicology at NYU School of Medicine.
"But the reason to lose weight for most people is to improve their health," said Nelson, a physician who sat on a 2012 FDA advisory panel reviewing weight-loss drugs. "It is not known that losing weight through a pill improves health and, to the contrary, it may be worsen health."
Sharon Corbitt, a spokesperson for Novo Nordisk, the maker of Saxenda and Victoza, said the rate of cardiovascular events was low in the weight-loss study, which included more than 5,000 people.
Data presented by the company showed the rates of cardiovascular problems in the weight-loss trial were 0.2% for Saxenda and 0.5% for a comparison drug, though the trial was not designed to fully assess cardiovascular risk.
Results of another cardiovascular safety trial of liraglutide involving 9,340 people will provide robust data on cardiovascular risk, she said. However, that trial, which is expected to be completed in 2016, involves the lower, 1.8 mg dose, not the 3 mg dose used in Saxenda.
The wait-and-hope approach by the FDA mirrors what Journal Sentinel/乌鸦传媒 investigations found about cancer and diabetes drugs.
Last October, the news organizations found that 74% of the cancer drugs approved over the previous decade were based on surrogate measures such as improvements in blood tests or CT scans, but not hard endpoints.
A story in December found that none of the 30 diabetes drugs approved by the FDA in the last decade were proven to improve key health outcomes such as heart attacks or blindness. Rather, they were approved because they lowered the surrogate measure of blood-sugar levels.
In an email, FDA spokesman Eric Pahon said the four diet drugs were approved because the benefits were determined to outweigh the risks. The agency, he said, continues to monitor the safety of the drugs.
Pahon noted obesity is a significant public health issue and added that studies have shown that losing 5% of body weight is associated with favorable changes in various biomarkers of cardiovascular risk such as blood glucose, blood pressure, and blood lipids.
"All drugs carry risks of potential side effects," Pahon said. "Each drug is evaluated individually, and the decision whether to approve a drug must consider the balance of its benefits and the known risks for its intended use."
Nevertheless, the agency hedged its bets.
It ordered the drug companies to do long-term postmarketing studies on cardiovascular safety. For Saxenda, the agency also required cancer risk to be studied.
Postmarketing studies can take 4 or 5 years to complete -- years during which hundreds of thousands are exposed to the drugs.
Measuring Benefit
Critics argue the standard the FDA uses for approval of a new weight-loss pill -- 5% of body weight compared with placebo -- is based on old research.
That research suggested that losing 5% to 10% of body weight through diet and exercise can lead to beneficial improvements in cholesterol, blood pressure, and blood sugar -- which, in turn, can reduce the risk of heart attacks, strokes, and cardiovascular death.
Therefore, using a weight-loss pill to lose 5% of body weight is presumed to be good for one's heart health.
A on the history of diet drugs called that belief "a small leap of faith."
, an assistant professor of medicine at Harvard Medical School, thinks the FDA has set the bar too low for diet drugs, arguing that long-term cardiovascular studies should be done before, not after, a drug gets on the market.
"Why do we need to wait until postmarketing to see harm?" Cohen said. "Why do we accept any harm?"
Concerns about GLP-1 drugs -- the class that includes liraglutide -- date to at least 2010. That's when a warned that preliminary evidence linked such drugs to pancreatitis and pancreatic cancer.
"History has taught us that enthusiasm for new classes of drugs, heavily promoted by the pharmaceutical companies that market them, can obscure the caution that should be exercised when the long-term consequences are unknown," the authors wrote.
The paper concluded that patients prescribed the drugs should be warned of pancreatic cancer risks.
The FDA, for its part, said it had not found a cause-and-effect connection between drugs in the class that liraglutide belongs to and pancreatitis and pancreatic cancer, but has noted a disproportionate number of reported thyroid and pancreatic cancers with the drug.
, lead author of the 2010 Diabetes Care paper, said that although pancreatitis and pancreatic cancer are not common among patients using GLP-1 drugs such as liraglutide, they remain a legitimate concern.
He noted that patients likely will be taking the drugs for many years, not just the temporary duration of a drug's clinical trial period, and that may increase the risk.
"I don't prescribe Victoza and I won't be prescribing Saxenda," said Butler, chief of endocrinology, hypertension, and diabetes at UCLA School of Medicine. "Most patients, if they thought there was any risk of pancreatic cancer, might not be enthusiastic to take a drug, even if it was a small risk."
Worst Case Scenario
With the approval of higher-dose Saxenda, the FDA doubled down on its confidence in the drug's safety. It has a 3-mg daily dose, compared with 1.2 mg or 1.8 mg for Victoza.
The labels for both drugs also warn patients to stop using the drugs promptly if pancreatitis is suspected.
That's what Tom LaRosa did last August when a blood test showed possible inflammation of his pancreas, said his wife, Sandy. The test was done because he had been having stomach problems, which can be a warning sign of pancreatic cancer.
LaRosa, 72, had been using the 1.8 mg dose of Victoza since 2010 to control his blood sugar with the hope it would also help him lose weight.
LaRosa had been plagued by obesity and diabetes for years.
The galley kitchen of the couple's neat Milwaukee home still has a canopy of LaRosa's favorite pots and pans hanging from the ceiling and large bottles of olive oil on the counter.
"He was a great cook," she said. "He could do Chinese, French, Italian."
Especially Italian. One year, he baked and gave away 67 pounds of Italian Christmas cookies.
Cooking remained a passion even in retirement from his job as an administrative assistant in the county's mental health services department.
Despite stopping the use of Victoza in August, LaRosa's stomach problems got worse.
On Thanksgiving Day, the stomach pain was so severe that he went to the hospital. After a CT scan, he was diagnosed with pancreatic cancer.
He died in January.
Sandy LaRosa said her husband was never told that Victoza might increase his risk of pancreatic cancer. His doctor, , said he did tell LaRosa about the risks of pancreatitis and pancreatic cancer risk.
"I have that discussion with everybody," said Javorsky, an endocrinology and diabetes specialist and assistant professor with the Medical College of Wisconsin.
In a January financial filing, Novo Nordisk said 121 people have filed product liability lawsuits. Most of the claims are for pancreatic cancer allegedly caused by Victoza and other products.
A Novo Nordisk spokesperson declined to comment on the lawsuits or LaRosa's case.
Sandy LaRosa, who is considering her own lawsuit, said patients have to be their own advocates.
"They have to dig into this stuff," she said. "Read all the labels carefully. People have to know what they are getting into."
John Fauber is a reporter with the Milwaukee Journal Sentinel. Coulter Jones and Kristina Fiore are reporters with 乌鸦传媒. This story was reported as a joint project of the Journal Sentinel and 乌鸦传媒, which provides a clinical perspective for physicians on breaking medical news at medpagetoday.com.