All patients began on 10 mg sibutramine daily for a 6-week run-in to screen out patients whose blood pressure rose too high. Most patients also lost weight during this phase, an average of 2.2 kg.
After 6 weeks, randomization assigned patients to either 10 mg sibutramine or placebo. Those in the active-treatment arm could have their dosage raised to 15 mg/day, which happened for a third of the sibutramine patients.
The intention-to-treat primary end–point analysis included 4,906 patients treated with sibutramine and 4,898 who received placebo followed for an average of 3.8 years on treatment. In addition to the primary end point, the combined rate of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, and cardiovascular death (see table), the SCOUT investigators reported several other important outcomes.
In the 24% of patients with diabetes and one risk factor, the primary end–point rate ran 6.5% in both the sibutramine and placebo groups. In contrast, in patients with cardiovascular disease history and diabetes sibutramine added 2% to the placebo risk, and in those with cardiovascular disease history only sibutramine produced an added 1.8% of event rates over placebo.
The results also documented sibutramine's efficacy for weight loss. Forty-two percent of patients in the sibutramine group lost at least 5% of their baseline weight, compared with 24% of the placebo patients. The percent of patients who gained weight on the regimen was 24% on sibutramine and 38% on placebo. Patients who responded to sibutramine by losing weight also had an improved prognosis. For each 1 kg lost during the 6-week sibutramine-treatment phase for all patients, patients had a 0.8% reduction in their incidence of a primary outcome event during follow-up, said Dr. Ian Caterson, professor of human nutrition at the University of Sydney and another collaborator on the study.
In addition, patients who lost weight had a significant reduction in their blood pressure. The average blood pressure of patients who lost at least 5% of their baseline weight closely tracked with the placebo level throughout the 5 years of the study. Only patients on sibutramine who failed to lose at least 5% had significantly increased blood pressure, compared with the placebo group, reported Dr. Arya M. Sharma, professor of medicine and chairman of obesity research and management at the University of Alberta, Edmonton, and another member of the SCOUT steering committee.
Despite the positive weight-loss results, the known action of sibutramine as a serotonin-noradrenalin reuptake inhibitor, its discernable blood pressure effect, and the excess of cardiovascular events it caused in SCOUT together create a “causal train” between the drug and clinically meaningful adverse events, said Dr. Steven B. Heymsfield. “Drug companies will stay away from this,” said Dr. Heymsfield, who spoke as the session's second invited discussant and is executive director of clinical sciences and head of obesity drug development at Merck in Rahway, N.J.
“The question is risk benefit, and they haven't shown the benefit of [sibutramine.] It's critical to show a medical benefit” from sibutramine, Dr. Heymsfield said.
Despite Dr. Heymsfield's skepticism about regulators accepting a future role for sibutramine in routine practice, one member of the steering committee voiced his support of countries that have kept sibutramine available.
“In Brazil sibutramine is still on the market and widely used, with a million prescriptions per year,” said Dr. Walmir Coutinho, an endocrinologist at Catholic University in Rio de Janeiro, and a member of the SCOUT steering committee. “Brazilian physicians believe it should remain on the market,” he said, citing a recent statement from the society of Brazilian endocrinologists. “The event rates in patients without cardiovascular disease were very low.”
Aside from Dr. Coutinho's statement of support for the Brazilian approach to regulating sibutramine, the SCOUT steering committee members who presented the study's data deliberately avoided commenting on the EMA's action. The closest anyone came was when Dr. James, in response to a question, referred back to what Dr. Coutinho had said. He “said effectively that [the EMA's decision] wasn't appropriate,” Dr. James said.
Elsevier Global Medical News