Hindsight: Sympatholytic Action of Sibutramine
One of the widely accepted notions about the now defunct anti-obesity drug, which was well known to increase heart rate and blood pressure, was that it was a sympathomimetic drug. However, as we showed in a study published in CIRCULATION back in 2002, this story was not really that simple. In this study, we carefully characterized the effect of sibutramine relative to placebo on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. in 11 young healthy volunteers, who were given sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) in a double-blind and crossover fashion. As expected, sibutramine increased both blood pressure and heart rate, an effect that was completely blocked by co-administration of metoprolol. On the other hand, sibutramine also (paradoxically?) attenuated the blood pressure response to cold pressor and handgrip testing, two powerful tests of sympathetic activity. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position. From these studies we concluded that the cardiovascular effect of sibutramine resulted from a complex interaction of peripheral and central nervous system effects. We postulated that a inhibitory ‘clonidine-like’ sympatholytic action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Based on these findings we proposed that sibutramine may well increase blood pressure and heart rate through its peripheral sympathomimetic effects in people with low sympathetic activity (like in people with normal blood pressure) but may actually lower blood pressure in individuals with increased sympathetic activity (like in people with high blood pressure). Interestingly enough, this hypothesis was later borne out by other investigators, who demonstrated that sibutramine did indeed lower blood pressure in hypertensive individuals while modestly raising it in those with normal blood pressure. According to Google Scholar, this paper has been cited 71 times. AMS Edmonton, Alberta
Metabolically ‘Healthy’ Obesity is Not Associated With Higher Mortality Risk
Technically, this is not ‘news’ but it is always good to see other investigators more or less ‘reproduce’ your findings, so here goes… In a study by Mark Hamer and Emmanuel Stamatakis from University College London, published in the Journal of Clinical Epidemiology, the researchers show that ‘metabolically’ healthy obese individuals have minimally (if at all) increased risk of cardiovascular mortality. Their study looked at mortality records in 22,203 men and women community-dwelling adults from the general population in Scotland and England without known history of cardiovascular disease (CVD) at baseline. Based on blood pressure, high-density lipoprotein-cholesterol, diabetes diagnosis, waist circumference, and low-grade inflammation (C-reactive protein ≥ 3 mg/liter), participants were classified as either metabolically healthy (0 or 1 metabolic abnormality) or unhealthy (two or more metabolic abnormalities). Compared with metabolically healthy nonobese participants, metabolically ‘healthy’ obese individuals were not at elevated risk of CVD over the seven year observation period. In contrast both metabolically ‘unhealthy’ nonobese and obese participants were were at a significantly elevated risk for heart disease. In addition, metabolically ‘unhealthy’ obese participants were also at elevated risk of all-cause mortality compared with their metabolically healthy obese counterparts. Regular readers of these pages will recall our findings that obesity individuals without metabolic risk factors or other comorbidities or functional limitations, which we would classify as EOSS Stage 0 obesity, do not have an increased mortality risk, but that this markedly increase for Stage 2 and 3 patients. Although, the present study used the rather arbitrary definition of 0 or 1 metabolic risk factor as ‘healthy’, they certainly are in line with our findings that neither obesity based on BMI or waist circumference alone is a reliable marker of risk. Rather, it is essential that clinicians consider other risk factors and comorbidities in determining the risk of their obese patients, and remember that nonobese individuals with these same risk factors may be at as much risk as their obese counterparts. Clearly treatment recommendations based on BMI alone should be now considered obsolete and perhaps best relegated to history books. AMS Edmonton, Alberta Hamer M, & Stamatakis E (2012). Metabolically Healthy Obesity and Risk of All-Cause and Cardiovascular Disease Mortality. The Journal of clinical endocrinology and metabolism PMID: 22508708 .
Calorie Restricted Diet Decreases Breast Cancer Biomarkers in Post-Menopausal Women
Although, much of the discussion around the health risks of obesity tends to focus around diabetes and heart disease, it is important not to forget that in women, excess weight is closely linked to the risk for post-menopausal breast cancer (by far the most common form of breast cancer). Now, a team of researchers led by Kristin Campbell from the University of British Columbia, Vancouver, in a paper published in the Journal of Clinical Oncology, shows that weight loss achieved by calorie restriction and exercise can significantly reduce circulating levels of the sex-hormones implicated in the development of post-menopausal breast cancer. The single-blind, 12-month, randomized controlled trial was conducted in 50 to 75 year-old women with a BMI greater than 25, who were assigned to one of three intervention groups: (1) reduced-calorie weight loss diet (“diet”; n = 118), (2) moderate- to vigorous-intensity aerobic exercise (“exercise”; n = 117), (3) combined reduced-calorie weight loss diet and moderate- to vigorous-intensity aerobic exercise (“diet + exercise”; n = 117), or (4) control (n = 87). The weight loss diet intervention was a modification of the dietary component of the Diabetes Prevention Program36 and the Look AHEAD (Action for Health in Diabetes) lifestyle intervention programs, with a goal of daily energy intake of 1200 to 2000 kcal/d based on baseline weight, less than 30% daily energy intake from fat, and a 10% reduction in body weight by 6 months with maintenance to 12 months. The exercise intervention goal was 45 minutes of moderate- to vigorous-intensity aerobic exercise, 5 days per week (225 minutes/wk). Each week, participants attended three monitored exercise sessions at the study facility and two at home. The program progressed to the maintenance target of 70% to 85% maximal heart rate for 45 minutes by week. Activities with four or more metabolic equivalents,38 such as brisk walking, were counted toward the prescribed exercise target. These interventions resulted in significant weight loss at 12 months: diet alone and diet + exercise resulted in about 11-12 Kg weight loss, exercise alone resulted in about 3.5 Kg weight loss, the control group lost no weight. Compared with controls, estrone decreased 9.6% with diet, 5.5% with exercise, and 11.1% with diet + exercise. Estradiol decreased 16.2% with diet, 4.9% with exercise, and 20.3% with diet + exercise. Sex hormone-binding globulin (SHBG) increased 22.4% with diet and 25.8% with diet + exercise. Free estradiol decreased… Read More »
Battle of the bulge: Does treating obesity as a disease help?
Sharma: “… any discussion about weight must begin with the doctor first asking the patient’s permission. It’s one of the cornerstones of a new roadmap for doctors the network is launching Tuesday. Called the “5 A’s of obesity management” — ask, assess, advise, agree, assist — the checklist is designed to help doctors and other health care workers broach the subject in a sensitive and non-judgmental manner.”
The 5As of Obesity Management™
Yesterday, I posted on the 5 core principles of obesity management that evolved out of extensive work with patients, primary care practitioners and obesity experts. In order to operationalise these principles, they have been integrated into a modification of the well-known 5A framework that has been used to address smoking cessation, improving physical activity and a wide range of other health interventions. To be applicable to obesity management, the 5As (Ask, Advise, Assess, Assist, Arrange) had to be significantly modified, but the principles remain. In short, the 5As of Obesity Management™ are: Ask for permission to discuss weight and explore readiness for change. Assess obesity related health risk and potential “root causes” of weight gain. Advise on obesity risks, discuss benefits treatment options. Agree on realistic weight-loss expectations and on a SMART plan to achieve behavioral goals. Assist in addressing drivers and barriers, offer education and resources, refer to provider, and arrange follow-up. More information for health professionals and ordering information on the 5As of Obesity Management™ can be found here. AMS Philadelphia, PA
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