Close Concerns: Obesity and CV Outcome Trials

Last week, the influential healthcare information firm Close Concerns published a rather lengthy interview regarding my take on a wide range of issues related to the future of obesity management. The interviews were conducted by Joseph Shivers, Vincent Wu, Lisa Vance, and Kelly Close, who certainly challenged and stimulated my thinking with their well-informed questions.

The following is the final excerpt from this interview published in their newsletter Closer Look:

JOSEPH: Back on the regulatory theme, what were your thoughts going into the FDA’s March advisory panel on CV outcomes studies for weight-loss drugs?

DR. SHARMA: It’s a tough one, because I understand why there is such a focus on cardiovascular outcomes when people think about obesity. But I think that probably one of the big differences between obesity and other indications like diabetes or heart disease is that, first of all, the people who get the problem are much younger than with those with the other conditions. And obesity causes so many other health problems, cardiometabolic issues are actually not the main reason why you would even need an obesity drug.

JOSEPH: That’s very interesting – it would be great if you could expand on that for us.

DR. SHARMA: I tell this to a lot of people, and especially to companies. When I have a patient in front of me, my problem is not “how do I manage their blood pressure?” or “how do I manage their cholesterol?” or “how do I manage their diabetes?” I’ve got plenty of drugs for all of those indications, and those drugs are generic, they’re cheap, and they’ve been proven efficacious. I can do all of that. That is not my problem. My problems with managing obesity are chronic pain, osteoarthritis, fatty liver disease, sleep apnea, or urinary incontinence. Those are the problems that patients actually have for which I do not have good medical treatments.

So it’s interesting to say, “Well, yes, this is the cardiometabolic risk of obesity.” But from my perspective, especially in the patients that I see who are 40 or 45 years old, nobody comes to me because they’re worried about their diabetes. They come to me because of all of these other indications for which we do not have good medical treatments, but which will benefit substantially from weight loss.

So all I really care about is that the drug is not dangerous, that it’s not killing people, that it’s right in the center in terms of hazard ratio. But if it can lead to improvements of any of these other conditions for which I do not have good treatment, I’m actually pretty happy.

JOSEPH: We focus mostly on diabetes therapies, and we often think of obesity as a sort of precursor or a risk factor for these other cardiometabolic diseases. How does that fit in with addressing these other problems?

DR. SHARMA: I give you that. But I’m not saying that that’s not an important benefit. Of course, if I can treat someone’s obesity and that reduces the risk of diabetes, or high blood pressure, whatever it is, well, that’s all a bonus. But if I don’t have the obesity drugs to do that, I can still somehow manage the diabetes and their heart disease. But for all of these other problems that I’ve mentioned that are also related to obesity, I don’t have good medical treatments.

KELLY CLOSE: Arguably, the diabetes is not necessarily being well-managed, since 44% of patients in the US alone are not at their glycemic target, according to Diabetes Care (Volume 31, Number 1, January 2008)… but we see what you mean that there are more therapies to address this, even if doctors find them hard to prescribe or patients find them challenging to adhere to.

VINCENT WU: Do you see a convergence in cardiometabolic and weight-management therapies down the road?

DR. SHARMA: Obviously, once we have an effective obesity drug that also improves cardiometabolic health in a manner comparable to the benefits we see with current antihypertensive or anti diabetic treatments, that would be great – but that could be putting up a high bar for an obesity drug. On the other hand, if the obesity drug helps get my patient off their CPAP machine or reduces their pain without lowering their blood pressure, I’d still be happy because there are other ways I can manage their blood pressure.

VINCENT: Bringing it back to the present, how would you have voted – and explained your vote – if you had been a member of the Qnexa AdCom?

DR. SHARMA: I would have voted ‘yes’ for all of the reasons I stated – acute unmet medical need, discourage use of generics, better control of prescriptions and access, manageable risk, and perhaps most importantly, chances of having a long-term outcome trial.

VINCENT: And what did you think about the outcome of the CVOT AdCom at the end of March? How would you have voted?

DR. SHARMA: I see no reason other than weight-bias and discrimination to require pre-approval CV outcome trials for anti-obesity drugs without even a theoretical (let alone a likely) risk of cardiovascular harm.

Imagine there were no effective drugs for depression, which itself is clearly associated with CV disease. Indeed, an article in Molecular Psychiatry a decade ago summed up that depression is recognized as an independent CV risk factor (Licinio et al., Mol Psychiatry 2002). In patients with a recent myocardial infarction, depression has similar implications on mortality as left ventricular dysfunction (Frasure-Smith et al., JAMA 1994). Then imagine that because of this relationship between depression and CVD, the FDA would make it fiscally impossible for drug companies to develop anti-depression drugs – leaving patients with no option but to eventually opt for electroconvulsive shock treatment. I can only imagine the families of depression and suicide victims taking to the streets and writing strong letter of protest to their representatives in Congress.

But of course not the people suffering from obesity (or their family members). After all, isn’t obesity self-inflicted? Don’t obese people simply lack self-control? Don’t they just want to look better? Aren’t they simply too dumb to heed package inserts, and don’t they need the ‘nanny state’ to look out for them? (Funnily enough, the ‘nanny state’ has popular appeal only when it comes to medications for obesity, not when it comes to the many societal factors that drive it).

As someone who is well aware of the history and potential misuse of anti-obesity drugs, I do fully agree that to date, most of the patients enrolled in the phase 2 and 3 clinical trials for investigational obesity drugs have very low short-term risk for major adverse cardiovascular events (MACE) (e.g., <0.5% per year). I agree that there should be a requirement to enrich the phase 2 and 3 clinical trials with overweight and obese individuals at higher risk for cardiovascular events (e.g., history of myocardial infarction, stroke, multiple risk factors) and to perform a meta-analysis of prospectively adjudicated events. In fact, I would limit all anti-obesity drug trials to individuals with EOSS Stage 2 obesity or higher.

Frankfurt, Germany