Sibutramine Cardiovascular Outcomes - SCOUT

Description:

The goal of the trial was to evaluate treatment with the weight loss agent sibutramine (Meridia) compared with placebo among obese individuals.

Sibutramine is a norepinephrine and serotonin reuptake inhibitor; therefore, it has sympathomimetic effects.

Hypothesis:

Sibutramine will reduce cardiovascular events.

Study Design

  • Blinded
  • Parallel
  • Randomized
  • Placebo Controlled

Patient Populations:

  • Obese patients at least 55 years of age with:
    • Body mass index between 27 kg/m2 to 45 kg/m2, or
    • Body mass index between 25 kg/m2 to 27 kg/m2 with waist circumference >102 cm for men or 88 cm for women
  • Patients were also required to have a history of cardiovascular disease (coronary artery disease, stroke, or peripheral arterial disease), type 2 diabetes (with hypertension, hyperlipidemia, current smoking, or diabetic nephropathy), or both

Number of screened applicants: 10,744
Number of enrollees: 9,804
Duration of follow-up: mean 3.4 years
Age range: mean 63 years
Percentage female: 43%

Exclusions:

  • Heart failure symptoms: New York Heart Association class III or IV
  • Blood pressure >160/100 mm Hg
  • Pulse >100 bpm
  • Scheduled cardiac surgery or percutaneous coronary intervention
  • Weight loss >3 kg in the last 3 months

Primary Endpoints:

  • Time to first occurrence of a primary outcome event: cardiovascular death, myocardial infarction, stroke, or resuscitated cardiac arrest

Secondary Endpoints:

  • All-cause mortality

Drug/Procedures Used:

Eligible obese patients underwent a 6-week lead-in period with sibutramine 10 mg daily to exclude those with an exaggerated blood pressure or heart rate response. Patients were then randomized to sibutramine 10 mg daily (n = 4,906) versus placebo (n = 4,898).

Sibutramine could be up-titrated to 15 mg daily if weight loss was inadequate. All patients underwent individualized weight loss and exercise programs.

Concomitant Medications:

At baseline in the sibutramine group, the use of aspirin was 78%, beta-blocker was 61%, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker was 78%, and statin was 67%.

Principal Findings:

Overall, 9,804 patients were randomized. The mean treatment duration was 3.4 years. In the sibutramine group, the mean age was 63 years, 43% were women, mean body mass was 96 kg, mean body mass index was 34 kg/m2 for men and 36 kg/m2 for women, mean blood pressure was 138/78 mm Hg, mean pulse was 71 bpm, mean glycated hemoglobin in diabetics was 7.5%, mean total cholesterol was 195 mg/dl, and mean low-density lipoprotein cholesterol was 110 mg/dl.

During the lead-in period, there was a 2.6 kg weight loss, followed by a further 1.7 kg loss at 12 months in the sibutramine group versus a 0.7 kg gain at 12 months in the placebo group. Systolic blood pressure was higher in the sibutramine group compared with placebo, with a mean difference ranging from -0.3 to 1.2 mm Hg. Pulse was also higher in the sibutramine group compared with placebo, with a mean difference ranging from 2.2 to 3.7 bpm.

The primary outcome of death, myocardial infarction, stroke, or resuscitated cardiac arrest occurred in 11.4% of the sibutramine group versus 10% of the placebo group (p = 0.02). All-cause death occurred in 8.5% versus 8.2% (p = 0.54), cardiovascular death occurred in 4.5% versus 4.7% (p = 0.90), nonfatal myocardial infarction occurred in 4.1% versus 3.2% (p = 0.02), and nonfatal stroke occurred in 2.6% versus 1.9% (p = 0.03), respectively.

In the cohort of diabetics with cardiovascular disease, the primary outcome occurred in 13.9% versus 11.9% (p = 0.02), all-cause mortality occurred in 10.1% versus 9.7% (p = 0.54), cardiovascular mortality occurred in 5.5% versus 5.5% (p = 0.83), nonfatal myocardial infarction occurred in 4.9% versus 4.1% (p = 0.09), and nonfatal stroke occurred in 3.1% versus 2.2% (p = 0.02), respectively.

Study drug discontinuation occurred in 40.2% of the sibutramine group versus 42.3% of the placebo group.

Interpretation:

Among obese patients with pre-existing cardiovascular disease or diabetes, sibutramine was associated with increased adverse cardiovascular events. This was mainly due to an excess of nonfatal myocardial infarction and stroke. Despite more weight loss in the sibutramine group, blood pressure and pulse were slightly, but significantly elevated compared with placebo. The prognostic importance of small elevations in blood pressure and pulse cannot be understated.

Product labeling for this medication has been modified to state that sibutramine should be avoided in individuals with a history of cardiovascular disease.

References:

James WP, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese Subjects. N Engl J Med 2010;363:905-17.

U.S. Food and Drug Administration. Postmarket Drug Safety Information for Patients and Providers.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Hypertension, Smoking

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Follow-Up Studies, Serotonin Uptake Inhibitors, Hyperlipidemias, Cholesterol, LDL, Weight Loss, Diabetes Mellitus, Type 2, Peripheral Arterial Disease, Diabetic Nephropathies, Heart Arrest, Cyclobutanes, Smoking, Sympathomimetics, Hemoglobin A, Glycosylated, Waist Circumference, Cholesterol, Obesity, Anti-Obesity Agents, Hypertension


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