Today, the New England Journal of Medicine publishes the results of the Sibutramine Cardiovascular OUTcome (SCOUT) trial - a study in over 10,000 high-risk individuals with excess weight.
Over the past eight years, I have had the privilege of being on the Executive Steering Committee of this largest ever randomised controlled trial of obesity treatment.
The SCOUT trial examined the effect of the serotonin and norepinephrine reuptake inhibitor sibutramine plus lifestyle intervention versus placebo and lifestyle intervention alone in 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both, who successfully completed a six-week run-in phase on sibutramine.
The primary end point was the time from randomisation to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death).
Unfortunately, individuals, randomised to the sibutramine arm of the study, despite signifiicantly greater weight loss, had a 16% higher relative risk (11.4% vs. 10.0%) for a primary endpoint. This was largely accounted for by higher rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group.
Fortunately, there was no increased risk of fatal events.
Given that the SCOUT participants were essentially an “off-label” high-risk population (in fact largely patients, in whom the current label specifically does not recommend the use of this agent) , one needs to be careful in extrapolating these findings to “on-label” patients, who tend to generally have much lower risk profiles.
In fact, as a colleague once aptly put it, prescribing sibutramine, may perhaps not be unlike prescribing vigorous exercise, which can potential kill someone with pre-existing heart disease, but may well be quite beneficial and well-tolerated in younger low-risk individuals.
Apart from the subjects in the SCOUT trial being an essentially “off-label” populations, it is perhaps also worth noting that in this trial, patients were advised to continue on sibutramine irrespective of wether or not they actually lost any weight.
While this was feature of the study design was meant to test for potential, non-weight loss related benefits of sibutramine, this is certainly very different from clinical practice, where it is most unlikely that anyone taking a weight-loss drug would continue taking it without at least some discernible weight loss.
Obviously, without the benefits of weight loss, simply taking a drug that can (in the same manner as other SNRIs) increase heart rate and blood pressure, certainly may ultimately cause more harm than benefit.
However, before concluding that sibutramine itself (as suggested by an accompanying editorial) is a “flawed” drug, it would be important to consider the alternatives - which for most patients in reality means continuing weight gain with the eventual prospect of facing bariatric surgery (currently widely seen as the only effective treatment for obesity).
While “hard” endpoints are clearly relevant and important in the long-term, my clinic is full of patients who desperately need help in the short term, especially given their failure, despite best efforts, to control their weight with diet and lifestyle alone. They are clearly more concerned about their back pain, their sleep apnea and their poor quality of life than they are of dying of heart disease somewhere in the remote future.
Fortunately, in clinical practice it is relatively easy to predict both weight loss response as well as any unacceptable increases in blood pressure or heart rate within the first weeks of starting treatment with sibutramine. Indeed, the SCOUT trial did not reveal any unexpected or irreversible “side effects” of this compound - both the increase in heart rate and any increase in blood pressure is quickly reversed after stopping the drug.
As blogged recently, given the heterogeneity of obesity, I neither expect to see 100% of my patients respond to any given drug, not do I expect everyone to tolerate a given substance. Even if a new treatment for obesity turns out to be safe and effective for only 15% of obese patients, we are still talking about millions who would stand to benefit from such a treatment.
Yes, there is always a potential for “misuse” in that people who should not be taking a given drug may chose to do so. Unfortunately, I doubt that there will ever be an anti-obesity drug that will be safe enough to be widely misused or abused.
As much as we may have a responsibility to prevent the wrong people from using treatments that may potentially harm them, we have a far greater responsibility of making treatments that work accessible to those for whom they may clearly have a favourable risk-benefit ratio.
Let us not forget that for many patients battling obesity, the current choices are either drowning in a mire of essentially ineffective and unregulated “weight loss” products or ultimately opting for the far riskier path of obesity surgery.
AMS
Chicago, IL
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Disclosure: I have received consulting and speaking honoraria from Abbott Laboratories, the makers of sibutramine.
James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL, & SCOUT Investigators (2010). Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. The New England journal of medicine, 363 (10), 905-17 PMID: 20818901
In The News
September 2nd, 2010 at 9:43 am
Taking Sibutramine for a year resulted in a decrease of 1.7 Kg (3.7 lbs) in weight vs an increase of weight of 0.7 Kg (1.5 lbs) in the placebo group. This is a net difference of only 2.4 kg (5.3 lbs) and it may not be enough of a benefit to outweigh the possible side effect risk. The journal article also says the medication should not be used for longer than two years. Therefore this medication can’t have a long term impact on weight. People lost 2.6 Kg in the six week lifestyle intervention, if they had continued the lifestyle intervention along with the medication it would have been interesting to see if an average weight loss of 5-10% could have been achieved.
September 2nd, 2010 at 10:15 am
@anonymous: You make a good point regarding the lead-in period, which is where most of the “placebo” group lost most of their weight. Thus,this study does not have a true placebo group, which would have been very unlikely to have lost much weight without the active lead-in.
September 5th, 2010 at 6:04 pm
Your point about the off-label use of sibutramine in this study is very well taken. The manufacturer has told us for years NOT to prescribe it for people with cardiovascular disease. Most of the people in the NEJM study had cardiovascular disease.
An FDA advisory panel reviews sibutramine later this month. They should leave it on the market.
Prior studies established that if users didn’t lose at least 4-5 pounds (2 kg) in the first four weeks, then ongoing use is likely a waste of time. Stop the drug in those folks.
-Steve
September 6th, 2010 at 9:58 am
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