Diet drug dilemma: If CVD drops tomorrow are risks justified today?

Shelley Wood

October 20, 2010

San Diego, CA - Obesity experts say physicians and drug regulators need to sit up and take notice: people seeking a medicine to boost their chances of losing weight will find the pharmacy shelves all but bare. What's more, they say, if cardiologists accept that obesity is now the most pervasive risk factor for cardiovascular disease, they also must acknowledge that a small increase in adverse events early on may be a worthwhile trade-off if it prevents a larger number of people from actually developing diabetes or full-blown cardiovascular disease.

Others counter, however, that with no hard outcomes data for any of the obesity drugs on or approaching the marketplace, approving drugs with potentially serious side effects would be a health experiment on a colossal scale: there are 93 million obese Americans in the US alone. Moreover, risks of any drugs become more acceptable if efficacy is substantial, something hotly debated for the drugs currently in the pipeline.

Dr Louis Aronne

On everyone's mind at Obesity 2010 last week was the FDA's request that the manufacturer withdraw sibutramine (Meridia, Abbott Laboratories) from the market on the basis of the SCOUT trial. In SCOUT, study subjects with preexisting cardiovascular conditions experienced a 16% rise in serious cardiovascular events while taking the weight-loss drug. But physicians who had hoped the drug would remain on the market point out that sibutramine was an effective drug in people with no cardiovascular risk factors and that SCOUT studied people in whom the drug was already contraindicated.

"The FDA's position was . . . if this drug isn't good for people with CVD, then it can't be good for anybody," a frustrated Dr Louis Aronne (Weill Cornell Medical College, New York, NY) complained to heartwire . "My position is, if that's the case, then we should outlaw running. Running kills people. If you are 75 years old and you have CVD, you could die from running."

Dr Michael EJ Lean

And Dr Michael EJ Lean (University of Glasgow, Scotland), also attending Obesity 2010, called the FDA's decision "a mistake," blaming those on the agency's advisory panel who fixated on the increased blood pressure and heart rate seen in SCOUT.

"The problem with cardiologists is that they see obesity as some kind of adjunct to cardiology," he groused. Sibutramine "was a valuable drug, a drug that turned around lives. I had patients who lost 20 to 30 kg. . . . [The FDA's decision] all hinged on this one stupid trial, in patients who we already don't give the drug to. But the patients who do get the drug did very well."

Dr Hubbard's cupboard

Now the only drug remaining on the US market and others as a long-term treatment for obesity is the notoriously side-effect-plagued orlistat (GlaxoSmithKline)—available over the counter at a lower dose (Alli) and by prescription for a higher dose (Xenical). As a result, off-label long-term use of drugs approved only for short-term use—phentermine and diethylpropion—is on the rise. One of the most eagerly awaited drugs for obesity—rimonabant—was briefly marketed in Europe but never in the US: in November 2008, drug-maker Sanofi-Aventis announced the discontinuation of the full clinical-trial program for rimonabant.

The FDA's position was, if this drug isn't good for people with CVD,then it can't be good for anybody. My position is, if that's the case, then we should outlaw running.

That's left doctors who treat obesity pinning their hopes on three up-and-comers: not a rosy picture here, either, following negative decisions for two drugs this past summer by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee. Lorcaserin (Arena Pharmaceuticals) was voted down 9 to 5 due to concerns about a cancer signal seen in animal studies and the potential for valvular heart disease. Later, the panel voted 10 to 6 against recommending a combination of phentermine and controlled-release topiramate (proposed name: Qnexa, Vivus), citing wide-ranging potential adverse events: birth defects, psychological and cognitive disorders, increased heart rate, and more. The third drug, and the only other novel obesity agent close to market consideration, is a combination of naltrexone HCl/bupropion HCl (proposed name: Contrave, Orexigen), slated to go before the FDA's advisory committee December 7, 2010.

Dr Steven Smith

Dr Steven Smith (Translational Research Institute for Metabolism and Diabetes, Winter Park, FL) believes discussions of obesity treatments are "lopsided," since the focus is always on side effects and not on long-term benefits of weight loss. He says the public, as well as physicians generally, tend to think of obesity as something that "otherwise-healthy" individuals can tackle by exercising a little "willpower"—thus any potential harms of drug therapy are deemed intolerable.

He points out that topiramate has long been approved as an anticonvulsant and, more widely, as a migraine drug. At the recent FDA advisory hearing for Qnexa, however, one of the reasons panel members rejected the drug was because of signs it increased birth defects, and if approved, would be widely used by women of child-bearing age.

Yet women in this age group also make up the bulk of migraine sufferers, he notes.

"It comes down to this: how do we evaluate the risk/benefit ratio in a way that matches what we do in other therapeutic areas?" Smith asks. "If you look at migraine drugs or seizure drugs, the discussion of risks and benefits is a different discussion from what we have here [with obesity]. We have drugs that are being developed in the obesity space that carry with them all the baggage from their use in other therapeutic areas . . . yet we can tolerate a certain uncertainty in those areas."

Tarnished by the past


The obesity drug approval process has been scarred by high-profile drug withdrawals dating back to d initrophenol in the 1930s, continuing through the fen-phen debacle of the 1990s, and most recently rimonabant, where concerns about suicidality and depression ultimately torpedoed the drug.

"We have had not just one but a whole series of disasters, so I appreciate the need for caution, but again, that's a one-sided conversation," Smith says. But in the case of rimonabant, the decision to discontinue the drug may have been "premature," he says, alluding to recently published CRESCENDO data. "There are those that would argue that, ultimately, if you look at the truncated study with rimonabant, which showed no harm in terms of hard outcomes, [there's] some evidence that, okay, we really weren't killing people with rimonabant."  

Aronne, likewise, points to a subset analysis of SCOUT that was considered by the FDA panel but ultimately dismissed, showing that the people taking sibutramine whose blood pressure went in the wrong direction were the ones not losing weight on the drug. By contrast, study participants at the lowest baseline risk of CV events, particularly those who had diabetes but no other CV risk factors, not only had reduced CV events, they also had reduced mortality, Aronne says.

"This drug was targeting younger, healthier, overweight people who haven't developed complications yet but who could in the future get diabetes and CVD, and you are preventing them from getting to that point [by bringing down their weight]," he says. "In my mind, you have potentially a very valuable tool that you are now not able to utilize."

A lack of tools in the toolbox

Last week, the Obesity Action Coalition (OAC), which is partly funded by drug-makers, paid for advertising space in the Washington Post and Politico (the newspaper delivered to US legislative offices) to publish an open letter to the FDA. Noting that the agency is weighing or soon to weigh the fates of three new obesity drugs, the OAC letter pleads with regulators to make a "fair and balanced decision on these medical treatments . . . to help the millions of Americans affected by obesity." It also warns: "Should the FDA fail to approve any of these three new obesity medications, we believe that will clearly indicate that the FDA has chosen a double standard for evaluating and approving treatment options for this disease."

If there were a medication . . . that was really spectacular in terms of efficacy but had some safety concerns . . . I think the response from the panel would have been different.

According to OAC president and CEO Joe Nadglowski, the organization has 20 000 members, of whom 93% are "somewhere on the journey of struggling with weight loss." The remaining 7% are made up of healthcare professionals interested in obesity, and "less than 1% are corporate members." Most of the society's money comes from membership and the annual walk for obesity, he said. "We do accept some corporate contributions for educational products, and two of the three new obesity drug manufacturers [Vivus and Orexigen] have committed support, but very small amounts," Nadglowski said.

The point of the open letter, he says, was to convey to the FDA that "there are not enough tools in the toolbox.

"The simple reality is people do need options. If you've finally got up the courage to say 'Doc, I need to do something about my weight,' and then there aren't tools to help you, we are likely missing an opportunity. Right now, the common belief in the public and among some of our healthcare providers is that diet and exercise alone will solve the obesity epidemic. That's not working."

A chafing point for Aronne and others is the sheer size and follow-up of the studies the FDA is asking of diet drugs, prior to market approval; many of the companies developing new drugs are small. "They can't afford to do $125-million outcomes studies," Aronne says.

He acknowledges the FDA is in a tough position, facing criticism on its safety record at the same time it is being pressured to approve drugs faster. But Aronne believes the desperate situation being faced by obese patients and their physicians calls for special concessions—even, he hints, postmarketing outcomes studies.

Safety issues more prominent, when efficacy is questionable

Dr Abraham Thomas


Dr Abraham Thomas (Henry Ford Hospital, Detroit, MI), a member of the FDA advisory panel that has been reviewing these new diet drugs, rejects the argument that their thinking is "lopsided" in any way and says panel members are not averse to postmarketing studies, particularly since the rare adverse events, like cancer or birth defects, would never be picked up by prospective trials.

"I think people on the FDA committees do appreciate the issues of obesity and all its complications—that's never been an issue," Thomas says. "But the FDA mandate is one, to make sure that medications are safe initially, and two, that they have efficacy." For the drugs that have recently gone before the advisory panel, he says, one or both of these have not been met.

"If there were a medication that had come forward that was really spectacular in terms of efficacy but had some safety concerns that could be addressed either postapproval or with additional trials, I think the response from the panel would have been different. I got the impression being part of these meetings that many people weren't very impressed with the degree of weight loss with one of the medications and were very concerned about the side effects for the other."

Aronne, however, insists that diet drugs are being held to a higher bar than is realistic, given the utter lack of treatment options.

"In hypertension, we have a hundred drugs in nine categories; in diabetes, we have dozens; in lipids, dozens. In obesity, we have nothing. Almost everything we are using now, we are using off-label. . . . Are we supposed to just sit there? That's not what doctors are inclined to do. People come to my office, and I want to help them."

Nadglowski at the OAC agrees. "My belief is that the FDA says, we know the risk of people being obese currently, and we're afraid of any risks that would come forward from treating their obesity and exposing them to a new drug that might change those risks. I would argue that most people are willing to accept some risk. We have many patients in our coalition who have undergone bariatric surgery, so they've taken on a different set of risks, and most people can be educated enough about the pros and cons of any therapy and are able with the guidance of their physicians to make a choice that's right for them."

The long road to hard outcomes

But in fact, bariatric surgery remains the only intervention in obesity research that actually has any outcomes data to support it (not including SCOUT, which enrolled higher-risk subjects in order to amplify any signal of risk). Aronne, for one, believes that one can extrapolate from the surgery data sets to other interventions that yield weight loss, saying, "The evidence that losing weight reduces risk is, in my opinion, becoming incontrovertible."

Dr Robert Eckel

But that intuitive leap is just that, a leap. Dr Robert Eckel (University of Colorado Denver School of Medicine), who also spoke with heart wire at Obesity 2010, points out that it's not just diet drugs that are lacking hard outcomes data.

"We don't know that losing weight long term can be done, much less [that it can] reduce cardiovascular events or death from heart disease. So I think we need to pause and just be careful."

The Look AHEAD study is trying to answer this question in patients with type 2 diabetes, he notes. "But despite all the enthusiasm about Look AHEAD, I think we're seeing really this waning of beneficial effect over a four- to five-year period of observation. That study needs to be extended because of the more limited number of events than expected, but as of right now, we don't even know that lifestyle-induced weight loss has a benefit! I expect it does, but we need to prove it."

Eckel acknowledges the hurdles faced by diet drug manufacturers, but he insists side effects matter. "There's no question that a drug that modifies risk unfavorably despite modest weight reduction could be associated with unfavorable outcomes," he says, referring to the SCOUT trial, "but that doesn't mean that there can't be obesity compounds developed that are not associated with undue risk."

Eckel, along with most of the people interviewed by heart wire for this story, predicts that, as with blood pressure and diabetes, two or more drugs in combination may be needed to "get the job done" in obesity, too. And he agrees: "For these patients with obesity, they need to get their weight down earlier. If a drug can do that, let's not wait until they have a much higher risk of heart disease and then give them a drug that could potentially have an adverse effect."

Aronne has disclosed receiving research support from Amylin, Arena, Hoffman-La Roche, Novo Nordisk, Orexigen, Pfizer, Tran sTech, Schering-Plough, Merck, Vivus, and Sanofi-Aventis; serving as a s cientific a dvisor to Amylin, GI Dynamics, Johnson & Johnson, NeuroSearch, Novo Nordisk, Orexigen, Pfizer, Merck, Vivus, and Sanofi-Aventis; and having an ownership i nterest in CardioMetabolic Support Network. Eckel had no disclosures. Lean has disclosed receiving research funding from Novo Nordisk. Smith disclosed receiving funds for consulting, advisory boards, and/or research funding from Amgen, Amylin, Arena, B ristol- M yers S quibb , G laxoSmithKline , Jenrin Discovery, Novartis, Takeda, and Zafgen. Thomas has received g rant funding from the National Institutes of Health , the Centers for Disease Control and Prevention , Roche, Amylin, Eli Lilly, and Abbott and speaker's fees from Novo Nordisk, Takeda, and Sanofi-Aventis. He is a pas t consultant for EMD Pharmaceuticals and Inamed.


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