Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Canadian Cardiovascular Congress 2007

Quebec City, Quebec / October 20-24, 2007

Lifestyle modification is widely considered the cornerstone of obesity management but is frequently ineffective. Several pharmacologic therapies have been developed to augment lifestyle interventions, but many clinicians do not aggressively treat obesity because of concern that the time investment is not adequately compensated by likelihood of a successful outcome. However, the definition of a successful outcome may be poorly understood. Only modest reductions in weight loss are sufficient to achieve substantial reductions in cardiovascular (CV) risk and many other health problems associated with excess weight. According to experts participating in a symposium on treatment of obesity, physicians who fail to treat obesity forego a major opportunity for risk control.

“Obesity is associated with numerous CV comorbidities such as stroke, congestive heart failure, myocardial infarction and sleep apnea,” reported Dr. Paul Poirier, Director of the Prevention/Rehabilitation Program, Quebec Heart Institute, Quebec City. While its pathogenic role in a number of modifiable risk factors explains why weight loss is included in treatment guidelines for hypertension, diabetes and other CV risk factors, Dr. Poirier noted that an ideal body weight need not be the goal. Rather, “for the clinician involved in the management of obese patients, long-term weight loss of 5% to 10% should be considered efficient therapeutic treatment.”

Voluntary weight loss by a combination of calorie restriction and increased calorie expenditure, although effective, is often difficult to achieve because of food craving mediated by hormonal signalling. Comprehensive treatment plans typically require lifestyle changes that include diet, exercise, and behaviour modification. However, pharmacological therapy can play a critical adjunctive role. There are two therapies currently approved for treatment. These are sibutramine, which is a serotonin and norepinephrine inhibitor that promotes satiety, and orlistat, which inhibits gastrointestinal absorption of fat. According to a summary of clinical trials, Dr. David C.W. Lau, Professor, Departments of Medicine/Biochemistry and Molecular Biology, University of Calgary, Alberta, reported that the average weight loss with sibutramine is approximately 4.3 kg, while the average weight loss with orlistat is approximately 2.7 kg.

“As recommended by the evidence-based Canadian obesity clinical practice guidelines, pharmacological therapy is an acceptable adjunct when lifestyle modification fails to achieve the desired weight loss,” reported Dr. Lau, citing recently published recommendations (Lau et al. CMAJ 2007; 176:1103-6). He noted that both sibutramine and orlistat are “approved for long-term therapy, decreased waist circumference values, lower serum triglyceride values, and increased HDL-C levels.”

SCOUT

Although treatments that yield improvements in CV risk factors, such as dyslipidemias, are by definition appropriate for CV disease prevention, a major study specifically testing the effect of sibutramine on CV outcomes will be completed in 2008. In SCOUT (Sibutramine Cardiovascular Outcomes), 10,765 patients at high risk for a CV event were placed on lifestyle modification and randomized to receive sibutramine or placebo. At the end of a mean follow-up of three years, the two randomized groups will be compared for the composite primary end point of myocardial infarction, stroke, resuscitated cardiac arrest, and CV death.

“I am very optimistic that we will see benefit,” affirmed SCOUT senior investigator Dr. Christian Torp-Pedersen, Professor of Medicine, Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark. Accepting an invitation to provide findings from the SCOUT run-in treatment experience here at the CCC, Dr. Torp-Pedersen reported that there have been no safety issues associated with sibutramine but favourable effects on a number of risk factors, including reductions in systolic blood pressure.

In SCOUT, which involves 300 treatment centres in 16 countries, entry was restricted to individuals 55 years of age or older with a body mass index (BMI) of ³27 and £45 kg/m2 or ³25 and <27 kg/m2 with a waist circumference of ³102 cm in men or ³88 cm in women. Patients were also required to have had a previous CV event or have type 2 diabetes and another CV risk factor. The design called for a two-week screening phase prior to a six-week, single-blind run-in treatment with 10 mg daily of sibutramine. All patients participated in the active treatment run-in before being randomized to remain on active treatment or switch to placebo. Although recruitment of more than 10,000 patients was planned in anticipation of a 7% dropout rate in the run-in period, the drop-out rate was only 2.7%, reinforcing the relative safety of this agent, which has been approved for use in many countries for at least a decade.

During the single-blind run-in, “body weight decreased by a median of 2.2 kg, waist circumference was reduced by a median 2.0 cm, systolic blood pressure fell by an average of 3.0 mm Hg, and diastolic blood pressure fell by an average of 1.0 mm Hg,” reported Dr. Torp-Pedersen who recently published these results (Torp-Pedersen et al. Eur Heart J 2007;June 26; Epub ahead of print). Although sibutramine has a relative contraindication in hypertensive patients because of past reports of an increase in pulse pressure, 88% of patients recruited in SCOUT had hypertension at entry. During the run-in, two consecutive increases in blood pressure or pulse rate of >10 mm Hg/10 bpm were observed in only 4.7% and 3.5% of patients, respectively.

According to Dr. Torp-Pedersen, “There have been no safety issues so far. The Data Safety Monitoring Committee has met seven times over the course of the trial and has always recommended continuing.”

Changing the Weight Loss Dynamic

One of the reasons that treatment of obesity deserves to be a priority in CV risk management is that it underlies a range of other risk factors. Adipose cells release a variety of hormones implicated in the development of diabetes, hypertension and dyslipidemia. The interrelationship of the pathophysiology of modifiable risk factors has been the basis for the term metabolic syndrome, for which central adiposity is a key clinical factor. According to Dr. Jean-Pierre Després, Director of Research, Quebec Heart Institute, the importance of adiposity in mediating CV risk will allow the obesity epidemic to reverse the reductions in CV mortality documented in some industrialized countries.

“There is still debate about the key factor responsible for the increased prevalence of obesity, but it is likely that increased consumption of energy-dense refined food and the reduced energy requirements of daily activities have both contributed to the obesity-diabetes epidemic,” Dr. Després reported. He suggested that more aggressive and innovative efforts are needed to increase the proportion of obese patients who successfully achieve weight loss.

A similar perspective was offered by Dr. Sonia Anand, Associate Professor of Medicine, McMaster University, Hamilton, Ontario. She suggested that 5% of clinical efforts in CV risk management go into prevention while 95% are directed to treatment. She confirmed, “We need to shift these proportions around.” Although she emphasized that rates of CV disease can be reduced by treating patients to goal for all modifiable risk factors, she suggested that controlling obesity is one of the major challenges to improving outcomes.

Summary

Many physicians do not consistently or effectively treat obesity because of the difficulty of achieving sustained and meaningful weight reductions. However, the amount of weight loss required for CV risk reductions is relatively modest. Although lifestyle changes are difficult to implement, pharmacologic therapies in the context of diet and exercise can increase the likelihood of success. While the SCOUT trial will evaluate whether treatment of obesity with sibutramine leads directly to a reduction in CV events, there is already abundant evidence that weight control favourably affects almost all of the modifiable risk factors, including hypertension, dyslipidemia and abnormal glucose metabolism.

Based on the CCS/CCC-sanctioned session:

“Managing Obese Patients at Risk of Cardiovascular Disease.” Tuesday, October 23, 18:30-21:30, Room 200B, Level 2.

This symposium is accredited and co-developed as an Accredited Group Learning Activity under Section 1 of the framework of Continuing Professional Development options as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC).