Major Finding: Treating patients with sibutramine for an average of 4 years led to a significant, 1.4% increased rate of cardiovascular disease end points compared with patients on placebo.
Data Source: SCOUT, a multicenter study with 9,804 patients randomized; 76% of study patients had a history of cardiovascular disease.
Disclosures: Abbott sponsored the trial. Dr. W. Philip T. James, has been a consultant to and served on an advisory board for Abbott, Sanofi-Aventis, and GlaxoSmithKline and has been a speaker for Roche and Sanofi-Aventis. Dr. van Gaal and Dr. Caterson had no disclosures; Dr. Rössner has received research and travel support from numerous companies, including Abbott; and Dr. Sharma has served as a consultant to GlaxoSmithKline.
STOCKHOLM — When European drug regulators called for a study to push the safety profile of the sympatho-mimetic weight-loss drug sibutramine to its limit, sibutramine failed the test.
In a randomized, placebo-controlled trial with nearly 10,000 patients, most of whom had a history of cardiovascular disease, an average of nearly 4 years of treatment with 10-15 mg sibutramine daily produced a 1.4% absolute increased rate of cardiovascular events, especially nonfatal myocardial infarction and stroke, compared with placebo patients—a 16% relative increased risk that was statistically significant, Dr. Luc van Gaal, a professor of medicine at Antwerp University Hospital, Belgium, said at the meeting. This excess risk from sibutramine seemed linked to a consistent rise in recipient's blood pressure of 1.5-2.0 mm Hg, and heart rate by 2-4 beats per minute.
Results from the Sibutramine Cardiovascular Outcome Trial (SCOUT) also showed that the drug effectively aided weight loss, producing a significant loss of at least 5% of baseline weight in 42% of treated patients, and these bigger losers had their risk for a cardiovascular event substantially blunted.
Preliminary results of SCOUT were given to the Food and Drug Administration and the European Medicines Agency (EMA) last fall, and in January both regulators took action: FDA contraindicated sibutramine in people with a history of cardiovascular disease, and EMA withdrew its marketing approval. The drug remains available in several other countries including Australia and Brazil.
This inconsistent approach to the new data appeared to rankle European physicians who treat obesity and heard the SCOUT results reported for the first time at the meeting. They seemed especially puzzled by SCOUT's design, with its enrollment largely including patients with cardiovascular disease history or risk even though these are label contraindications, and by continuing patients on chronic sibutramine even when they lacked a weight-loss response.
“Some of us feel we could use sibutramine in a responsible way to benefit patients” despite the safety problem that SCOUT revealed, said Dr. Stephen Rössner, an obesity specialist and professor of health-related behavioral science at the Karolinska Institute in Stockholm, who spoke as a discussant of SCOUT and was not involved in the study. “For many patients, on an individual basis, sibutramine would be very beneficial. We had desperate patients calling when they found out that they would not be able to get the drug anymore.” Currently, The European Union gives marketing approval to just one drug for obesity treatment, orlistat (Xenical), he noted.
“Everyone agrees that sibutramine has cardiologic effects that you need to control for. But many patients without cardiology problems need weight-loss maintenance for treating sleep apnea or osteoarthritis. Sibutramine could be very helpful provided you can control the risks, but I think that can be done by a responsible physician,” Dr. Rössner said in an interview.
SCOUT was sponsored by Abbott, which markets sibutramine (Meridia), to address questions about the drug's safety from the EMA. An independent steering committee formed to run the study, led by Dr. W. Philip T. James, of the London School of Hygiene and Tropical Health and president of the International Association for the Study of Obesity, the meeting organizer.
The trial ran at 297 sites in 16 countries, including Australia, Brazil, and Mexico, as well as several European countries. The first patient randomized in February 2003, the last patient in December 2005, and the follow-up database closed in November 2009.
When SCOUT began, it enrolled three types of patients in equal numbers: patients with type 2 diabetes and at least one cardiovascular risk factor—controlled hypertension, dyslipidemia, smoking, or diabetic nephropathy with microalbuminuria; patients only with diagnosed coronary artery disease or peripheral arterial disease; and patients who fulfilled both of these two criteria. Less than a year into the study, the steering committee decided to boost the event rate in the trial by narrowing enrollment to only patients with a history of cardiovascular disease, either alone or with type 2 diabetes. The consequence was that of the 9,996 patients randomized in SCOUT 76% had a history of cardiovascular disease, and 84% had type 2 diabetes; 60% had both. Their average age was 63, older than is typical in a weight-loss study, and 58% were men, more than is typical in a weight-loss trial. Their average baseline body mass index was 34 kg/m