"The body really defends body mass very rigorously. Whenever there's a little bit of weight loss, systems are activated to protect the body against starvation," said Niswender.
"Some diseases, like obesity, are severe and we need to use multiple medications to get control of them," said Kushner.
While its fen-phen counterpart was pulled from the market, doctors still prescribe phentermine, which works as an appetite suppressant.
It was originally approved for only short-term use, but today, doctors use it for long-term weight loss.
"Obesity is now thought of as a long-term disease. When it was first approved, obesity wasn't well understood, so it was approved only for a short period of time," said Kushner.
Others say it should only be used for short-term weight loss.
"It's pretty good for rapid weight loss, but when you stop it, the weight comes right back," said Niswender.
It's also widely used because it's safe and cheap.
"It's generic, so it's the cheapest," said Dr. Priscilla Hollander, an endocrinologist at Baylor University Medical Center. Hollander is a clinical trials investigator for Orexigen, the manufacturer of Contrave. "It also has a good safety record."
The next drug, Meridia (sibutramine), hit the market in 1997. It's still available for use. Meridia increases the levels of serotonin, norepinephrine and dopamine, which makes people feel full.
Doctors say it's only "modestly effective," and does have a potentially dangerous side effect.
"Because it works on norepinephrine and epinephrine, there's a lot of risk for increasing blood pressure," said Dr. Lisa Ganjhu, a gastroenterologist at St. Luke's-Roosevelt Hospital, who was not involved in the Contrave trial.
"People that are overweight or obese have a much higher prevalence of hypertension," said Niswender.
An FDA panel is scheduled to review Meridia's safety in December.
After Meridia came orlistat, also known as Xenical. A lower-dose, over-the-counter version called Alli was approved in 2007.
Orlistat is a fat blocker, and while doctors say it's only mildly effective for weight loss, it's very safe.
"It stays in the gastrointestinal tract," said Kushner.
It has unpleasant side effects, such as loose stools and diarrhea, but doctors say those side effects are what help people lose weight.
"It teaches people to eat properly. They won't eat fatty foods because of the side effects," said Ganjhu.
"The mechanism is much more about bring about behavior changes, such as decreasing fat intake," said Niswender.
While all the other drugs that have ever been used only contain one medication, there's a batch of new drugs that combine two of them. Contrave is one, and the others are Qnexa and Lorcascerin.
An FDA panel recently voted against recommending Qnexa for approval. Doctors speculated it had to do with potential side effects. Qnexa is a combination of phentermine and topiramate, a drug commonly used to treat epileptic seizures. Trial participants experienced double-digit weight loss with Qnexa.
"I think it had to do more with the topiramate," said Hollander, who has led clinical trials with Qnexa. "There's concern it can cause fatigue, loss of concentration, numbness and tingling."
Since Qnexa targets mood-related physiological systems, side effects can be mood-related.