A Long Term Study of Sibutramine and the Role of Obesity Management in Relation to Cardiovascular Disease in Overweight and Obese Patients

Sibutramine Cardiovascular Morbidity/Mortality Outcomes Study in Overweight or Obese Subjects at Risk of a Cardiovascular Event

The purpose of the study was to determine the long-term effect of sibutramine treatment on cardiovascular outcomes in overweight and obese patients at risk of a cardiovascular event.

The study consisted of 4 periods: 1) a Screening Period of approximately 2 weeks; 2) a 6-week Lead-in Period, during which subjects received single-blind sibutramine and country-specific standard of care for weight management. Subjects who discontinued study drug treatment during the Lead-in Period were not randomized and did not participate in the double-blind Treatment Period or the Follow-up Period; 3) a double-blind Treatment Period in which subjects were randomized to 1 of the 2 treatment groups and were followed until the study ended; and 4) a double-blind Follow-up Period, during which randomized subjects who discontinued study drug were followed until the study ended. The Randomization Phase consisted of the double-blind Treatment Period and the double-blind Follow-up Period. Subjects received country-specific standard of care for weight management during the Randomization Phase.

An independent events adjudication committee evaluated all potential cardiovascular outcome events and confirmed the outcome events and time of onset to be included in the statistical analyses.

Inclusion Criteria:

• Subject's body mass index (BMI) was >= 27 kg/m(2) and <= 45 kg/m(2) or their BMI was >= 25 kg/m(2) and < 27 kg/m(2) with waist circumference of >= 102 cm in males or >= 88 cm in females.

• Medical history positive for:

  • Preexisting cardiovascular disease (i.e., coronary artery disease, cerebrovascular disease, or peripheral arterial occlusive disease) and/or
  • Type 2 diabetes mellitus with at least 1 other risk factor (i.e., dyslipidemia, controlled hypertension, current smoker, or diabetic nephropathy with evidence of microalbuminuria)

Exclusion Criteria:

• History of recent myocardial infarction.

• Heart failure symptoms greater than New York Heart Association Functional Class II.

• Hemodynamically significant valvular or left ventricular (LV) tract obstruction.

• Subjects without a pacemaker and with any of the following:

  • Sinus bradycardia (< 50 bpm)
  • Sick sinus syndrome
  • Atrioventricular block of more than 1st degree

• Mean sitting systolic blood pressure (SBP) > 160 mmHg. Mean sitting diastolic blood pressure (DBP) > 100 mmHg. Mean sitting heart rate (HR) > 100 bpm.

• Syncopal episodes presumed to be due to uncontrolled life-threatening arrhythmias.

• Planned cardiac surgery or coronary angioplasty within 6 months of screening.

• History of recent non-hemorrhagic stroke or transient ischemic attack (TIA), history of hemorrhagic stroke.

• Hyperthyroidism.

• Known chronic liver disease or endstage renal disease.

• Severe, symptomatic benign prostatic hyperplasia which may require surgery.

• Known pheochromocytoma, history of narrow angle glaucoma, Gilles de la Tourette syndrome, history of seizures, history of bariatric or abdominal obesity surgery (excluding liposuction).

• Concomitant use of monoamine oxidase inhibitors or drugs that increase levels of serotonin in the brain.

• Treated hypertension stabilized for less than 3 months.

• Inability to perform regular physical activity.