In our June 25, 2010 article on the Biopharmconsortium Blog, we discussed the “contrarian” views of Dr. Katherine M. Flegal and her colleagues at the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC) on the epidemiology of obesity.
According to Dr. Flegal, based on epidemiological data from the National Health and Nutrition Examination Survey (NHANES), people in the overweight class have a lower risk of death than those in either the normal weight or the obese class. These weight classes are determined on the basis of the body mass index (BMI), with underweight at <18.5, normal weight at 18.5-24.9, overweight at 25-29.9, and obesity at >30.
Dr. Flegal’s conclusions–as summarized in our 2010 article–were mainly based on work published in the 2005-207 period, as well as other analyses of her results published between 2005 and 2010. In January 2013, Dr. Flegal and her colleagues published a report in the Journal of the American Medical Association. This report was based on an analysis of a wide variety of published reports indexed in PubMed and EMBASE that reported all-cause mortality for weight categories based on standard BMI categories.
In this study, the researchers compared all-cause mortality in the normal weight class (BMI 18.5-24.9) with that in the overweight (BMI 25-<30), grade 1 obese (BMI of 30-<35) and grade 2 and 3 obese (BMI of ≥35) classes. They came to similar conclusions as in their earlier studies. Specifically, both obesity (all grades) and grades 2 and 3 obesity were associated with significantly higher all-cause mortality as compare to normal weight. Grade 1 obesity was not associated with higher all-cause mortality, and overweight was associated with significantly lower all-cause mortality.
Reactions to Dr. Flegal’s 2013 study
As usually happens when one of Dr. Flegal’s “contrarian” studies is published, other leaders of the obesity epidemiology and nutrition community who hold the “majority” view react strongly against it. This was detailed, for example, in a feature article in the 23 May issue of Nature written by science writer Virginia Hughes. On 20 February 2013, a meeting was held at the Harvard School of Public Health “to explain why [Dr. Flegal’s new study] was absolutely wrong”. The organizer of the meeting, Dr. Walter Willett, said in an earlier radio interview, “This study is really a pile of rubbish, and no one should waste their time reading it.” At the meeting, speaker after speaker got up to criticize the Flegal study.
The major concern of Dr. Willett and the other speakers was that Dr. Flegal’s study (and the commentary on that study in the popular press) would serve as a license for the general public and for doctors to let up on weight loss programs, and to undermine public policies aimed at curbing the rate of obesity. Dr. Willett was also concerned that the Flegal studies might be “hijacked by powerful special-interest groups, such as the soft-drink and food lobbies, to influence policy-makers”.
Nevertheless, as also detailed in Ms. Hughes’ article, other researchers accept Dr. Flegal’s results, and see them as part of the evidence for what they call “the obesity paradox”. Although for the general population overweight increases one’s risk of type 2 diabetes, cardiovascular disease, and cancer, overweight in some populations may not be harmful and may even lower the risk of death. These populations especially include people over 50 and especially those over 60 or 70, as well as patients with cardiovascular disease or cancer. We also discussed the decreased association of mortality with weight in older people in our June 25, 2010 article.
Explaining the “obesity paradox”, and the need for better metrics than BMI
In the 23 August issue of Science, Rexford S. Ahima, M.D., Ph.D. and Mitchell A. Lazar, MD., Ph.D. (both metabolic disease researchers at the Perelman School of Medicine, University of Pennsylvania, Philadelphia PA) published a Perspective entitled “The Health Risk of Obesity—Better Metrics Imperative”. The goal of this essay was to enable researchers to find better means to study and to explain the “obesity paradox”, and to use the results of their studies to improve the health of patents with metabolic diseases and their complications (e.g., cardiovascular disease).
These researchers noted that although it is easily measured and widely used, BMI does not adequately measure body composition (especially the proportion of muscle and fat) and the distribution of fat in the body. These factors may be especially important for such health outcomes as development of insulin resistance and type 2 diabetes, and cardiovascular risk. Other researchers, notably Dr. José Viña and his colleagues at the University of Valencia in Spain, who wrote a critical response to Dr. Flegal’s 2013 article, came to similar conclusions. The Spanish researchers criticized Flegal’s studies because they were based on BMI. However, unlike Dr. Willett, they accept the validity of the “obesity paradox”.
Notably, the Ahima and Lazar article includes a figure that shows metabolically healthy people with normal and obese BMIs, and contrasts them with metabolically unhealthy people with normal and obese BMIs. The main difference between metabolically healthy versus unhealthy people (whatever their BMI) is muscle mass and fitness. The unhealthy subjects exhibit muscle loss, or sarcopenia, and reduced fitness.
The authors note that skeletal muscle accounts for the majority of glucose disposal. Thus loss of muscle mass, or sarcopenia, due to aging and/or physical inactivity, can result in reduced insulin sensitivity, development of diabetes, and poor cardiovascular health. This applies people with poor metabolic health, whether they have apparently normal BMIs or are obese. Metabolically unhealthy individuals–whether of normal BMI or obese–also have excess visceral fat. Excess visceral fat is associated with the metabolic syndrome and development of type 2 diabetes and cardiovascular disease.
Drs. Ahima and Lazar call for better metrics than BMI, in order to assess a patient’s risk of metabolic disease. They cite the “body shape index”, which quantifies abdominal adiposity (and thus visceral adiposity) relative to BMI and height as potentially a better predictor of mortality than BMI. The body shape index is based on measuring waist circumference, and adjusting it for height and weight. They further call for the development of “accurate, practical, and affordable tools to assess body composition, adipose hormones, myokines, cytokines, and other biomarkers” to use in assessing obesity and other metabolic disorders in order to determine the risk of developing diabetes and cardiovascular disease, and the risk of mortality.
Appreciating the role of muscle mass in health and disease
The analysis of Ahimsa and Lazar also suggests the hypothesis that loss of muscle mass–sarcopenia–due to aging and/or lack of exercise may be a key factor in the development of obesity-related diseases.
There are at least two other recent reports that focus on sarcopenic obesity. The first, a 2012 paper in Nutrition Reviews entitled “Sarcopenic obesity in the elderly and strategies for weight management” is authored by Zhaoping Li, M.D., Ph.D. and David Heber, M.D., Ph.D. of the Center for Human Nutrition, David Geffen School of Medicine, University of California at Los Angeles. The second paper, entitled “Sarcopenic obesity: strategies for management”, by Melissa J. Benton, PhD, MSN and her colleagues (Valdosta State University College of Nursing, Valdosta, GA) was published in 2011 in the American Journal of Nursing. The first of these reports is a scientific review article, while the second is a practically-oriented report for nurses (carrying continuing education credits); the lead author is a nurse with advanced training in education, sports medicine, and gerontology.
The Li and Heber paper covers much of the same ground as the Ahimsa and Lazar Science Perspective, with respect to the inadequacy of BMI as a metric for obesity, and the need to have better measures of body composition (especially with respect to fat versus skeletal muscle). However, it goes beyond this concern for metrics, by focusing on “sarcopenic obesity”, its relationship with a sedentary lifestyle and with aging, and how sarcopenic obesity might be treated.
Loss of muscle mass as a function of aging in sedentary individuals results in age-associated decreases in resting metabolic rate and muscle strength, and is also a major factor in decreases in activity levels. These factors result in the decreased energy requirement in aging individuals. If (as is usual) calorie intake does not decrease to match the decreased energy requirements, obesity (i.e., accumulation of excess body fat) results. Sarcopenic obesity in aging individuals is associated not only with type 2 diabetes and other metabolic and cardiovascular diseases, but also with loss of independence and increased risk of mortality. It is a major public health challenge in the over-65 population.
Li and Heber discuss various means to measure body composition, and thus to diagnose sarcopenia and sarcopenic obesity. They then go on to discuss ways to treat this condition, via emphasizing resistance training and increased intake of protein, in order to increase muscle mass and the resting metabolic rate. The authors cite resistance training as “the most effective intervention for reversing sarcopenia in the elderly”. Based on evidence in the field, the authors also hypothesize that increased dietary protein (especially the use of protein supplements or meal replacements) is also important in building muscle mass and as a result reducing fat mass.
It is known that increased dietary protein results in maintenance of muscle mass during calorie-restricted diets, as compared to diets with “normal” or inadequate intakes of protein. However, the authors see the need for more research to determine whether a high-protein diet (up to 35% of caloric intake) will be beneficial in improving muscle anabolic responses to resistance exercise in older adults.
The Benton et al. paper also emphasizes the role of resistance training and a high-protein diet in treatment of sarcopenic obesity. However, being a practically-oriented nursing article, it gives specific recommendations for exercise, as well as sources of high-quality protein in the diet. (This article focuses on high-protein foods, not protein supplements.)
This article also states that nurses should be knowledgeable about sarcopenic obesity and its management. They should also educate older patients on utilizing resistance training and dietary protein to prevent or reverse sarcopenia and sarcopenic obesity. This education should also apply to educating now-healthy aging adults on the need to prevent these conditions, since prevention is easier than reversing sarcopenic obesity once it has developed.
It would seem that not only nurses, but also primary care physicians and other doctors need to be aware of these issues as well.
The Benton et al. paper also wisely counsels that patients contemplating diet and exercise programs such as recommended in their article should first consult with their primary care physician. We agree with this recommendation. We also once again emphasize that this blog does not exist to give diet or exercise advice, or to receive comments or guest posts that purport to give such advice.
However, you are welcome to use this article, or better yet the publications we have cited herein, to help your primarily care provider to be aware of issues involving sarcopenic obesity. Some medical facilities also include physical therapists and/or access to gyms with trainers who can help patients with exercise programs, once one’s primary care physician has been consulted.
1. Currently marketed drugs for obesity–and for such conditions as type 2 diabetes, dyslipidemia, and other metabolic diseases that are usually found in obese individuals and metabolically unhealthy individuals with normal BMI–are generally prescribed as adjuncts to diet and exercise. “Diet and exercise” generally means the types of hypocaloric diets and aerobic exercise conventionally prescribed for weight loss. Researchers and physicians may need to take sarcopenic obesity into account when prescribing these drugs for patients with this condition, and in designing and conducting clinical trials. Diet and especially exercise recommendations may be different for patients with sarcopenic obesity than the current recommendations.
2. We have discussed “alternative” (i.e., non-CNS or gut targeting) antiobesity therapies now in development in several articles on this blog. Unlike CNS-targeting drugs [e.g., lorcaserin (Arena’s Belviq) and phentermine/topiramate (Vivus’ Qsymia)], which are aimed at curbing appetite, these novel therapeutics are designed to increase energy expenditure or to inhibit the biosynthesis of fat. These drugs, if and when they are approved, will be indicated for patients with extreme obesity, such as those who may currently be candidates for bariatric surgery.
Similarly, we have discussed Novartis’ bimagrumab, an anti-muscle wasting drug now entering Phase 3 clinical trials in patients with the rare muscle wasting disease sporadic inclusion body myositis (sIBM). Bimagrumab is also in Phase 2 clinical trials in sarcopenic older adults with mobility limitations. If and when this drug is approved, it will be at least initially indicated for patients with sIBM, and perhaps eventually for older adults with severe sarcopenia (with or without obesity) that has resulted in mobility limitations.
It will be an extremely long time–if ever–before such drugs are approved for the broader obese and obese-sarcopenic population (or those at risk for these conditions). The diet and resistance exercise approaches discussed in this article may be appropriate for many in this broader group of individuals, and are free of drug-related adverse effects. They may also prevent the development of extreme obesity and its complications, as well as loss of independence due to sarcopenia or obese sarcopenia.
3. We have also discussed the development of anti-aging therapies in various articles in this blog. This field has generated a lot of interest in the news lately, because of Google’s launch of the anti-aging company Calico. As we discussed, for example, in our August 15, 2013 aging article, no pharmaceutical company can run a clinical trial with longevity as an endpoint. Companies must test their drugs against a particular aging-related disease. Many such companies test their agents (e.g., drugs that target sirtuins) against type 2 diabetes.
Why develop an “anti-aging” drug for type 2 diabetes rather than a specific antidiabetic drug? The hope is that an “anti-aging” drug approved for treatment of, for example, type 2 diabetes, will have pleiotropic effects on multiple diseases of aging, and will ultimately be found to increase lifespan or “healthspan” (the length of a person’s life in which he/she is generally healthy and not debilitated by chronic diseases).
Given the major role of sarcopenia and sarcopenic obesity in aging-related disability and mortality, those involved in research and development of anti-aging therapeutics need to take preservation and restoration of muscle mass into account, as they study and/or target pathways involved in aging and longevity.
As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.