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Experts debate the ‘myth’ of metabolically healthy obesity

Though the American Medical Association and American Association of Clinical Endocrinologists have both deemed obesity a disease, experts still debate that classification among themselves. Within that debate lies the question of whether patients should be categorized as metabolically healthy obese, and what this all means for both patient and physician moving forward in promoting effective management and treatment strategies for obesity.

Although the term “metabolically healthy obese” has yet to be defined with universally accepted criteria, it is widely used in the field, and according to two studies conducted in 2013, about one-third of the obese population may not be at increased risk for metabolic complications. As more research is published, this phenomenon of metabolically healthy obese is stirring debate among experts regarding the definition and management of these patients.

James O. Hill, PhD 

James O. Hill, PhD, Anschutz professor of health and wellness and executive director of the Anschutz Health and Wellness Center at the University of Colorado, treats all of his obese patients in the same manner via the implementation of a healthy lifestyle. Photo courtesy of the University of Colorado.

James O. Hill, PhD, Anschutz professor of health and wellness and executive director of the Anschutz Health and Wellness Center at the University of Colorado, told Endocrine Today that someone who is currently metabolically healthy may not remain so over time, and he does not treat these patients differently than other patients with obesity.

“Metabolically healthy obese is not a permanent characteristic of a person. Metabolic health is probably the result of a lifestyle. There are people that we can say are metabolically healthy, but if those people don’t maintain a healthy lifestyle, the chances are they won’t stay metabolically healthy,” Hill said. “I treat every patient the same because I promote a healthy lifestyle.”

Some experts have said there is a need to create a category of metabolically healthy obese to stratify patients in the clinical management of obesity to help optimize risks vs. benefits of treatment for optimal benefit of care. Others said obesity is the disease on which there is a focus, and all patients with obesity should be treated as such, taking into consideration the severity of the disease.

Daniel Bessesen

Daniel Bessesen

“The whole goal here is to, over time, develop a more nuanced view of this that puts into account all of the data. There is a tendency for people to polarize and say, ‘Yes, it is a disease’ and ‘No, it’s not,’” Daniel Bessesen, MD, professor of medicine in the division of endocrinology at the University of Colorado School of Medicine and associate director of the Anschutz Health and Wellness Center in Aurora, Colo., told Endocrine Today. “The truth is, it has many qualities of a disease, but the condition of obesity has some qualities that are unique.”

Disease vs. modifiable risk factor

Tied to ideas surrounding the best ways to manage patients who are metabolically healthy obese is the main question about obesity itself and its status as a disease.

W. Timothy Garvey, MD, co-author of the 2011 American Association of Clinical Endocrinologists position statement that declared obesity a disease supported that statement in an interview with Endocrine Today.

“In that position statement, we outlined a rationale for that based on the American Medical Association’s own definition of what a disease is,” Garvey, Butterworth professor and chair in the department of nutrition sciences at the University of Alabama at Birmingham and director of the UAB Diabetes Research Center in Birmingham, Ala., said Hill, lead author of an editorial titled “The Myth of Healthy Obesity” that recently appeared in the Annals of Internal Medicine, said: “By calling obesity a disease, we actually enhance our ability to treat it. That is why I’m supportive of calling it a disease.

If it is a disease, it will lead to reimbursements for treatments, and it will lead to better treatments in the long run. You certainly can argue that excessive body fat affects almost every body system in a negative way. We can debate about how you get the extra fat, but once someone has the extra fat, it is negatively affecting every system, so I think it is fair to call obesity a disease.”

Caroline M. Apovian, MD, echoed that sentiment in an interview with Endocrine Today.

Caroline M. Apovian

Caroline M. Apovian

“The pathways to appetite and satiety centers in the brain seem to be disrupted due to inflammation. Whether or not the excess adipose tissue causes inflammation and other comorbidities is a separate issue,” Apovian, professor of medicine and pediatrics at Boston University School of Medicine and director of the Center for Nutrition and Weight Management at Boston Medical Center, said.

Bessesen said obesity may be more of a significant but modifiable risk factor, rather than a disease.

“Data suggests that not everybody with a BMI of ≥30 has a problem that is an urgent health problem. There is a spectrum of risk. Not everybody with a BMI of ≥30 has the same risk. There are other metabolic factors — blood pressure, blood sugar, lipid levels and inflammations — that all play into the ultimate health effects of a person’s weight. So, obesity may be more clearly thought of as a significant risk factor and a modifiable risk factor. If we say obesity is a disease, and that people don’t choose to be obese, then a logical response to that is that people have no power at all over their weight. And that is clearly wrong, too,” Bessesen said.

He said he treats all patients with obesity, but using resources to treat patients with obesity who are not going to benefit from therapy is not consistent with a cost-effective approach to treatment.

Definition of metabolically healthy obesity

Despite the lack of a universally accepted definition, the term ‘metabolically healthy obese’ is often defined in relation to cardiovascular risk, whereas obesity, as a whole, is associated with a range of complications other than CV.

According to Norbert Stefan, MD, head of the department of pathophysiology of prediabetes at the Institute for Diabetes Research and Metabolic Diseases in Tübingen, Germany, and colleagues, who wrote a viewpoint article in The Lancet Diabetes & Endocrinology, the term is used to describe patients considered obese (BMI ≥30) but who lack major CV risk factors. The risk for CVD is no higher than that of nonobese individuals, according to the article. Compared with obese individuals with major CV risk factors, metabolically healthy obese also have a lower risk for CV morbidity and mortality. Stefan and colleagues identified other criteria that have been used to define metabolically healthy obesity in literature. These include an absence of abdominal obesity based on waist circumferences; an absence of metabolic syndrome components; insulin sensitivity on the basis of a homeostatic model assessment of insulin resistance (HOMA-IR); and those with a high level of cardiorespiratory fitness.

Norbert Stefan

Apovian said she feels that metabolically healthy obese patients, by definition, do not have a high risk for developing type 2 diabetes. The definition also precludes inflammation, she added.

“There is usually less inflammation in those who are metabolically healthy obese because this would lead to inflammation in the liver, pancreas and endothelium, which would predispose the patients to develop comorbidities,” Apovian said.

“Metabolically healthy obese do exist, at least from the cardiometabolic disease perspective,” Garvey said. “People who say there is no such thing as metabolically healthy obese are making a mistake. The error is that they consider metabolically healthy as people who don’t have the syndrome. In that case, they are missing a lot of risk in people who just have one or two traits.”

Dale A. Schoeller, PhD, professor emeritus of nutritional sciences at the University of Wisconsin-Madison, told Endocrine Today that the term metabolically healthy obese is appropriate, depending on how it is used. Obesity without other metabolic complications does happen, he said.

“A lot of metabolic consequences increase with age. Not everyone who is obese is going to run into a problem with any of the comorbidities. But the percentages of ‘healthy obese’ go down with age,” Schoeller said.

Garvey, conversely, said the metabolically healthy aspect of these obese patients should be considered in relation to their insulin sensitivity, which is a lifetime, not lifestyle, characteristic.

Dale A. Schoeller

“What really defines this pool of obese patients is weight accretion on an insulin-sensitive background. There is a wide variation in insulin sensitivity, a trait that is identifiable early in life. Actually, while insulin sensitivity can be affected by lifestyle, the trait overall is relatively stable,” Garvey said. “People who develop obesity and are relatively insulin sensitive are not at increased risk of cardiovascular disease and are at a much decreased risk for diabetes throughout their lives, compared with people who gain excessive weight and are insulin resistant. This was clearly the case in our cardiometabolic disease staging of subjects in NHANES and the CARDIA study national cohort.”

Long-term risks

Some experts have advised that there is no healthy pattern of obesity, suggesting that despite the term metabolically healthy, these patients are at risk for complications in the long term.

In a systematic review of data and meta-analysis, Caroline K. Kramer, MD, and colleagues conducted a study at Leadership Sinai Centre for Diabetes at Mount Sinai Hospital in Toronto, and concluded: “Compared with metabolically healthy normal-weight individuals, obese persons are at increased risk for adverse long-term outcomes even in the absence of metabolic abnormalities, suggesting that there is no healthy pattern of increased weight.”

Kramer and colleagues evaluated data from studies that examined all-cause mortality or CV events or both in patient groups defined by BMI and metabolic status based on the presence or absence of metabolic syndrome components. The researchers found that metabolically healthy obese did not have increased risk for events compared with metabolically healthy normal-weight individuals when data with less than 10 years of follow-up were included. Elevated risk was found in metabolically healthy obese individuals vs. the normal-weight individuals when the researchers used data with 10 or more years follow-up. Among all metabolically unhealthy individuals, risk was comparable.

The study did not include lifestyle and physical fitness, leading to speculation on the data. “There was no increased risk in the metabolically healthy obese group until the researchers pulled out the 10-year group,” Bessesen said.

Additionally, the Look AHEAD trial was designed to show whether weight loss through a lifestyle intervention resulted in lower mortality among patients with type 2 diabetes. This study was stopped early due to futility because the overall number of endpoints were not significantly different between groups, Bessesen explained.

“The number of people who had CV events in that study was much lower than the researchers thought it was going to be. One interpretation of that is that weight management is just one of many strategies to lower CVD — including taking lipid-lowering medicines, treating BP and lowering blood sugars. And, it may be that if a group of people like the people in that study were physically active and had all of their risk factors managed well, the benefits of weight loss are fairly modest compared to that,” he said.

Another study recently published in the Journal of the American College of Cardiology by Bjørn Mørkedal, MD, PhD, of Norwegian University of Science and Technology in Trondheim, Norway, and colleagues concluded that compared with metabolically healthy normal-weight participants, those who were obese had an elevated risk for heart failure regardless of metabolic status, particularly in patients with long-lasting or severe obesity. The researchers did not find a substantially increased risk for first incidence acute myocardial infarction in metabolically healthy obese patients vs. normal-weight patients considered metabolically healthy.

Apovian concurs: “Metabolically healthy obese have less CV risk because of lower risk of developing type 2 diabetes, hypertension, elevated lipids; however, they may still develop right-sided heart failure from the direct effects of excess adipose tissue on the heart and lungs,” she said.

Garvey said this increased risk often comes from a misclassification as metabolically healthy when risk factors do exist. In theory, truly metabolically healthy person would not have this increased risk, he said.

“Again, the studies that claim that there are no metabolically healthy obese compare people with metabolic syndrome and without metabolic syndrome.Because metabolic syndrome diagnostic criteria have high specificity and low sensitivity for identifying insulin resistance and cardiometabolic disease, many people placed incorrectly in the ‘low-risk’ group may be insulin resistant and have one or two metabolic syndrome risk factors, and will still be at high risk of future diabetes (even though they do not meet diagnostic criteria for the metabolic syndrome),” Garvey explained.

Schoeller said surveillance is important with obesity, even in the absence of metabolic risk factors, because the “risk of developing chronic illness with increasing age is higher than a nonobese patient.”

Treatment, management of metabolically healthy obese

Clinicians face a spectrum of risk factors when managing patients with obesity.

“I treat all forms of obesity with diet and exercise behavioral therapy as well as medications for weight loss and adjust medications that may cause weight gain,” Apovian said.

Hill said considering an obese person metabolically healthy does not address other risk factors.

“Patients who are metabolically healthy because they don’t have a risk for CVD may have risk factors for diabetes, orthopedic conditions or cancers. So, simply saying they are metabolically healthy because they don’t have a CV risk, doesn’t mean they aren’t at increased risk for other things that are associated with obesity,” Hill said.

Bessesen said it is clear that obesity predisposes to a range of illnesses — diabetes, high BP, cancer, joint problems, sleep apnea, reproductive problems — but, it may still be useful to stratify patients as metabolically healthy obese because there is a “gradation of risk.”

“It goes from pretty low if all of those variables are normal to pretty high if all of those variables are all abnormal. And so how does a clinician decide who to treat and how does a patient decide what to think about that?” Bessesen said. “It is useful to be aware of the gradation of risk, and to not treat all obese patients as if they have a single disease that needs a single treatment and will have the same benefits. There will be a range of benefits.”

Garvey said there are other reasons to treat patients aside from metabolic health, but physicians need to decide based on optimal benefit-to-risk ratio of the intervention.

“We will treat metabolically healthy obese if they are not healthy due to the biomechanical complications of obesity,” Garvey said. “If they do not have any complications at all, we are going to be less aggressive with those patients.

“Some patients may be interested in a cosmetic effect for weight loss … and that is valid. But those patients are not the patients who would most benefit from weight-loss therapy. So we would not tend to use more aggressive, extensive, intense or risky interventions in those patients. That wouldn’t be consistent with the optimal benefit-to-risk ratio of the intervention,” Garvey said.

Another tool for physicians to stratify treatments is the Edmonton Obesity Staging System (EOSS), Apovian said.

“It separates comorbidities of obesity into medical, functional and mental. The comorbidities of obesity include functional and mental as well, so that even if you do not develop diabetes and CVD, you could still have depression and physical limitations from obesity and have an increase in mortality. Any mental or physical impairments would require treatment if you consider obesity to be a disease,” Apovian said.

Obesity as an inflammatory process

A recent study published in the Journal of Clinical Endocrinology & Metabolism, by Catherine Phillips, BSc, PhD, of University College Cork in Ireland, and colleagues, showed “lower levels of inflammation may account for better metabolic health in obese and non obese people.”

Research connecting inflammatory markers to the process of obesity is emerging, but some clinicians said they need more data before using it in making clinical decisions in practice.

“I absolutely think that it is great science that is coming together,” Hill said. However, it is not clear that inflammation is the only mediator between obesity and other negative conditions, he added.

“Inflammation is a link between obesity and some of these metabolic diseases, but obesity is probably linked to negative outcomes through other mechanisms as well,” Hill said.

W. Timothy Garvey

W. Timothy Garvey

“In terms of how we rigorously use inflammatory markers to make clinical decisions, we just need a lot more data,” Garvey said.

Metabolic health and overweight children

Children who are overweight or obese have different considerations compared with adults because children are generally healthier overall, clinicians said.

“Children are more resilient. They are healthier, in general. Problems happen at higher weights than they do in adults. But there clearly are some children who have health problems for their weight. A lot of younger people are heavy, but they don’t have a lot of metabolic health problems, yet. So, there is some interaction between weight and health over time,” Bessesen said.

Metabolic syndrome traits may be found in children, but considerations may be different than in adults, Garvey said.

“In children, generalized obesity carries some importance that is not as readily apparent in adults, and that is both insulin resistance (high insulin levels) and general adiposity (BMI values that are above 95% in that age group) confer increased risk of metabolic syndrome in adulthood,” Garvey said.

Lifestyle interventions may be difficult but are the key to counteract that risk in children, Hill said.

“We know that overweight and obese children are not going to grow out of it. They are going to grow up to be overweight and obese adults. We need to promote lifestyle interventions for these kids. We have to find a way to get kids eating healthy and physically active. And, it has been very difficult to create those long-term behavior changes,” Hill said.

Future considerations

“Part of our goal, if we are successful, is to create a greater number of metabolically healthy obese,” Hill said. Physicians cannot obtain nonobese status in all individuals, but they could possibly get more obese people to a metabolically healthy state, he said.

Bessesen agreed, suggesting that the goal should be to deliver the best care to those who are not metabolically healthy.

“We shouldn’t get off track in thinking that this metabolically healthy obese is a majority. It is a minority. It’s not zero, but it’s 25% or maybe 30% of the obese population. That means 70% or 75% of obese patients do have health problems,” Bessesen said. “We are not doing as good a job as we should in addressing those people’s needs. For the future, my hope is that we don’t let this metabolically healthy obese issue get us off track from delivering the care to most of the people who do have health problems related to their weight.”

Hill questioned where future reimbursement issues would lie.

“A lot of our most effective treatments are fairly expensive. But, with widespread reimbursement for obesity, there are a couple questions: One question is who qualifies for being reimbursed? Is it just being obese, or do you have to be obese plus some risk factors?” he said. “If you reimburse for the treatment of obesity, we desperately need some criteria for effective programs. The field is poised to take on some of these really important questions.” — by Suzanne Bryla Reist

Appleton SL. Diabetes Care. 2013;doi:10.2337/dc12-1971.
Guo F. Obesity. 2014; 22:110-118.
Hill JO. Ann Intern Med. 2013;159:789-790.
Kramer CK. Ann Intern Med. 2013;159:758-769.
Mørkedal B. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2013.11.035.
Phillips CM. J Clin Endocrinol Metab. 2013;doi:10.1210/jc.2013-2038.
Stefan N. Lancet Diabetes Endocrinol. 2013;doi:10.1016/S2213-8587(13)70062-7.
Caroline M. Apovian, MD, FACP, FACN, can be reached at Boston University School of Medicine, Center for Nutrition and Weight Management, Boston Medical Center; 732 Harrison Ave., 2nd Floor, Boston, MA 02118; email: caroline.apovian@bmc.org.
Daniel Bessesen, MD, can be reached at the Anschutz Health and Wellness Center, 12348 E. Montview Blvd., Aurora, CO 80045; email: daniel.bessesen@ucdenver.edu.
W. Timothy Garvey, MD, can be reached at the University of Alabama at Birmingham, Director, UAB Diabetes Research Center, 1720 Second Ave. South, Birmingham, AL 35294-3360; email: garveyt@uab.edu.
James O. Hill, PhD, can be reached at the Anschutz Health and Wellness Center, 12348 E. Montview Blvd., Aurora, CO 80045; email: james.hill@ucdenver.edu.
Dale A. Schoeller, PhD, can be reached at the University of Wisconsin-Madison, Nutritional Sciences, 1415 Linden Drive, Madison, WI 53706; email: dschoell@nutrisci.wisc.edu.
Disclosure: Apovian has participated on advisory boards for Abbott Nutrition;, Allergan, Inc.; Amylin Pharmaceuticals; Arena Pharmaceuticals; EnteroMedics Inc.; GI Dynamics, Inc.; Johnson & Johnson Services, Inc.; Merck & Co., Inc.; Novo Nordisk, Inc.; NutriSystem, Inc.; Orexigen Therapeutics; sanofi-aventis US LLC; and Zafgen and has received research funding from Amylin Pharmaceuticals; Aspire Bariatrics, Inc.; the Dr. Robert C. and Veronica Atkins Foundation; Eli Lilly & Co.; GI Dynamics, Inc.; GlaxoSmithKline; MetaProteomics, LLC; Orexigen Therapeutics; Pfizer, Inc.; and sanofi-aventis US LLC. Bessesen is on the Data Safety Monitoring Board for EnteroMedics. Hill has served as a consultant for the following companies: Coca-Cola, Curves, General Mills, International Dairy Federation, McCormicks, McDonalds, Novo Nordisk, Retrofit, Takeda Pharmaceuticals and Walt Disney Company. Garvey has provided research for AstraZeneca, Merck, Sanofi, Vivus and Weight Watchers; served on advisory boards for Alkermes, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, Janssen, LipoScience, Novo Nordisk, Takeda and Vivus; and has been on the speakers’ list for Merck. Stefan, Kramer, Mørkedal, Phillips and Schoeller do not have any related financial disclosures.

POINT/COUNTER

Is it cost-effective to treat patients who fall into the category of metabolically healthy obese?

POINT

It is cost-effective to treat the metabolically healthy obese.

Health economics relating to obesity treatment still lacks an adequate evidence base. Much data come from bariatric surgery, few from diet and lifestyle interventions. Many analyses rely upon modeling of outcomes that are oftenrestricted to cardiovascular and metabolic (CVM) outcomes, with the dangers therefore of bias and self-fulfilling outcomes if applied to those without CVM disease. Few have been powered sufficiently to look at the influence of baseline disease status.

Nicholas Finer

Nicholas Finer

Several studies have shown that so-called ‘metabolic healthy obese individuals’ are still at increased risk of developing diabetes and cardiovascular disease compared to the normal population and that metabolic healthiness is a transient state for many (eg, Appleton SL. Diabetes Care. 2013; doi:10.2337/dc12-1971; Aung K. J Clin Endo Metab. 2013; doi:10.1210/jc.2013-2832; Bradshaw PT. Obesity. 2013; doi:10.1002/oby.20248), although one UK study suggested protection from cardiovascular and all cause mortality over a 7-year period (Hamer M. J Clin Endo Metab. 2012; doi:10.1210/jc.2011-3475). While body mass index is used to define obesity (≥30 kg/m2), it is known to be a poor measure of body fat, let alone body fat distribution. It is not surprising therefore, that individuals with equivalentdegrees of obesity severity defined by BMI, may vary widely in their phenotype relating to health, obesity-related risks and diseases. All these factors suggest we need better clinical ‘staging’ of patients with overweight and obesity — the Edmonton Obesity Staging System is one such example (Kuk JL, Appl Physiol Nutr Metab. 2011; doi:10.1139/h11-058).

When it comes to the health economics of obesity treatment, the cost-efficacy in any individual will depend upon the severity/complexity of their obesity and its associated diseases, the efficacy of treatment at producing weight loss, any non-weight-loss-related benefits, and importantly, the time line considered. Thus bariatric surgery in a young woman with a BMI of 42 but no associated comorbidities or medication costs, will, over a 5-year period, be likely to be less cost-effective than a similarly obese individual aged 55 with diabetes, sleep apnea, and hypertension. However, over a 30-year period, the cost efficacy may favor the young person who has ‘more of a lifetime’ in which health care costs can be saved. Sadly, in England now, most commissioners of health care are only able to look at 1- to 2-year business plans. Of course, with more marginally effective interventions (eg, diet, exercise and even pharmacotherapy), the more modest weight loss may make little impact on patients with severe and complex obesity, compared with those with more modest health impairment. Again, not all of the costs of obesity relate to cardiovascular and metabolic disease, so the balance could again tip in favor of the uncomplicated, metabolically normal obese individual if weight loss allows them to return to work.

It is cost-effective to treat the metabolically healthy obese, and vice versa, provided the right treatment is provided at the right time, and evaluated over a period appropriate to health needs, ie, the long-term.

Nicholas Finer, MD, PhD, is a Consultant Endocrinologist and Bariatric Physician, Professor at the University College London Institute for Cardiovascular Science, London, England.

Disclosure: Finer reports no relevant financial disclosures.

COUNTER

The notion that obesity treatments — will even remotely prove cost-effective — is wishful thinking at best.

Metabolically healthy obese individuals, best described as having Edmonton Obesity Staging System (EOSS) Stage 0 obesity, like everyone else, are at risk for further weight gain. Thus, even Stage 0 obese individuals will benefit from treatments aimed at preventing further weight gain.

Arya M. Sharma,

Arya M. Sharma

That said, the question is whether or not Stage 0 obese individuals will also stand to benefit from treatments aimed at weight loss. Studies in obese individuals with higher stages of obesity (including those with preclinical risk factors — often referred to as having Stage 1 obesity) show that the considerable cost of weight loss treatments barely break even. Even diet and exercise come at a cost.

Indeed, the only obesity treatment that shows even a remote trend towards cost-effectiveness is bariatric surgery for severely obese individuals with type 2 diabetes (and even these numbers have been challenged). Thus, the notion that obesity treatments in individuals with Stage 0 obesity will even remotely prove cost-effective — even in the long-term — is wishful thinking at best.

It is thus prudent to focus our scarce obesity management resources on those who stand to benefit the most, namely those, who already have weight-related health issues (Stage 1+). That, unfortunately, is the vast majority of individuals with obesity.

Arya M. Sharma, MD, FRCPC, is a Professor and Chair in Obesity Research and Management at the University of Alberta, Edmonton, Alberta, Canada.

Disclosure: Sharma is a consultant for Abbott, Arena, Glaxo-Smith-Kline, Merck, Novo Nordisk, Sanofi-Aventis and Vivus; he is on the speaker bureau for Novo Nordisk.

Though the American Medical Association and American Association of Clinical Endocrinologists have both deemed obesity a disease, experts still debate that classification among themselves. Within that debate lies the question of whether patients should be categorized as metabolically healthy obese, and what this all means for both patient and physician moving forward in promoting effective management and treatment strategies for obesity.

Although the term “metabolically healthy obese” has yet to be defined with universally accepted criteria, it is widely used in the field, and according to two studies conducted in 2013, about one-third of the obese population may not be at increased risk for metabolic complications. As more research is published, this phenomenon of metabolically healthy obese is stirring debate among experts regarding the definition and management of these patients.

James O. Hill, PhD 

James O. Hill, PhD, Anschutz professor of health and wellness and executive director of the Anschutz Health and Wellness Center at the University of Colorado, treats all of his obese patients in the same manner via the implementation of a healthy lifestyle. Photo courtesy of the University of Colorado.

James O. Hill, PhD, Anschutz professor of health and wellness and executive director of the Anschutz Health and Wellness Center at the University of Colorado, told Endocrine Today that someone who is currently metabolically healthy may not remain so over time, and he does not treat these patients differently than other patients with obesity.

“Metabolically healthy obese is not a permanent characteristic of a person. Metabolic health is probably the result of a lifestyle. There are people that we can say are metabolically healthy, but if those people don’t maintain a healthy lifestyle, the chances are they won’t stay metabolically healthy,” Hill said. “I treat every patient the same because I promote a healthy lifestyle.”

Some experts have said there is a need to create a category of metabolically healthy obese to stratify patients in the clinical management of obesity to help optimize risks vs. benefits of treatment for optimal benefit of care. Others said obesity is the disease on which there is a focus, and all patients with obesity should be treated as such, taking into consideration the severity of the disease.

Daniel Bessesen

Daniel Bessesen

“The whole goal here is to, over time, develop a more nuanced view of this that puts into account all of the data. There is a tendency for people to polarize and say, ‘Yes, it is a disease’ and ‘No, it’s not,’” Daniel Bessesen, MD, professor of medicine in the division of endocrinology at the University of Colorado School of Medicine and associate director of the Anschutz Health and Wellness Center in Aurora, Colo., told Endocrine Today. “The truth is, it has many qualities of a disease, but the condition of obesity has some qualities that are unique.”

Disease vs. modifiable risk factor

Tied to ideas surrounding the best ways to manage patients who are metabolically healthy obese is the main question about obesity itself and its status as a disease.

W. Timothy Garvey, MD, co-author of the 2011 American Association of Clinical Endocrinologists position statement that declared obesity a disease supported that statement in an interview with Endocrine Today.

“In that position statement, we outlined a rationale for that based on the American Medical Association’s own definition of what a disease is,” Garvey, Butterworth professor and chair in the department of nutrition sciences at the University of Alabama at Birmingham and director of the UAB Diabetes Research Center in Birmingham, Ala., said Hill, lead author of an editorial titled “The Myth of Healthy Obesity” that recently appeared in the Annals of Internal Medicine, said: “By calling obesity a disease, we actually enhance our ability to treat it. That is why I’m supportive of calling it a disease.

PAGE BREAK

If it is a disease, it will lead to reimbursements for treatments, and it will lead to better treatments in the long run. You certainly can argue that excessive body fat affects almost every body system in a negative way. We can debate about how you get the extra fat, but once someone has the extra fat, it is negatively affecting every system, so I think it is fair to call obesity a disease.”

Caroline M. Apovian, MD, echoed that sentiment in an interview with Endocrine Today.

Caroline M. Apovian

Caroline M. Apovian

“The pathways to appetite and satiety centers in the brain seem to be disrupted due to inflammation. Whether or not the excess adipose tissue causes inflammation and other comorbidities is a separate issue,” Apovian, professor of medicine and pediatrics at Boston University School of Medicine and director of the Center for Nutrition and Weight Management at Boston Medical Center, said.

Bessesen said obesity may be more of a significant but modifiable risk factor, rather than a disease.

“Data suggests that not everybody with a BMI of ≥30 has a problem that is an urgent health problem. There is a spectrum of risk. Not everybody with a BMI of ≥30 has the same risk. There are other metabolic factors — blood pressure, blood sugar, lipid levels and inflammations — that all play into the ultimate health effects of a person’s weight. So, obesity may be more clearly thought of as a significant risk factor and a modifiable risk factor. If we say obesity is a disease, and that people don’t choose to be obese, then a logical response to that is that people have no power at all over their weight. And that is clearly wrong, too,” Bessesen said.

He said he treats all patients with obesity, but using resources to treat patients with obesity who are not going to benefit from therapy is not consistent with a cost-effective approach to treatment.

Definition of metabolically healthy obesity

Despite the lack of a universally accepted definition, the term ‘metabolically healthy obese’ is often defined in relation to cardiovascular risk, whereas obesity, as a whole, is associated with a range of complications other than CV.

According to Norbert Stefan, MD, head of the department of pathophysiology of prediabetes at the Institute for Diabetes Research and Metabolic Diseases in Tübingen, Germany, and colleagues, who wrote a viewpoint article in The Lancet Diabetes & Endocrinology, the term is used to describe patients considered obese (BMI ≥30) but who lack major CV risk factors. The risk for CVD is no higher than that of nonobese individuals, according to the article. Compared with obese individuals with major CV risk factors, metabolically healthy obese also have a lower risk for CV morbidity and mortality. Stefan and colleagues identified other criteria that have been used to define metabolically healthy obesity in literature. These include an absence of abdominal obesity based on waist circumferences; an absence of metabolic syndrome components; insulin sensitivity on the basis of a homeostatic model assessment of insulin resistance (HOMA-IR); and those with a high level of cardiorespiratory fitness.

Norbert Stefan

Apovian said she feels that metabolically healthy obese patients, by definition, do not have a high risk for developing type 2 diabetes. The definition also precludes inflammation, she added.

“There is usually less inflammation in those who are metabolically healthy obese because this would lead to inflammation in the liver, pancreas and endothelium, which would predispose the patients to develop comorbidities,” Apovian said.

PAGE BREAK

“Metabolically healthy obese do exist, at least from the cardiometabolic disease perspective,” Garvey said. “People who say there is no such thing as metabolically healthy obese are making a mistake. The error is that they consider metabolically healthy as people who don’t have the syndrome. In that case, they are missing a lot of risk in people who just have one or two traits.”

Dale A. Schoeller, PhD, professor emeritus of nutritional sciences at the University of Wisconsin-Madison, told Endocrine Today that the term metabolically healthy obese is appropriate, depending on how it is used. Obesity without other metabolic complications does happen, he said.

“A lot of metabolic consequences increase with age. Not everyone who is obese is going to run into a problem with any of the comorbidities. But the percentages of ‘healthy obese’ go down with age,” Schoeller said.

Garvey, conversely, said the metabolically healthy aspect of these obese patients should be considered in relation to their insulin sensitivity, which is a lifetime, not lifestyle, characteristic.

Dale A. Schoeller

“What really defines this pool of obese patients is weight accretion on an insulin-sensitive background. There is a wide variation in insulin sensitivity, a trait that is identifiable early in life. Actually, while insulin sensitivity can be affected by lifestyle, the trait overall is relatively stable,” Garvey said. “People who develop obesity and are relatively insulin sensitive are not at increased risk of cardiovascular disease and are at a much decreased risk for diabetes throughout their lives, compared with people who gain excessive weight and are insulin resistant. This was clearly the case in our cardiometabolic disease staging of subjects in NHANES and the CARDIA study national cohort.”

Long-term risks

Some experts have advised that there is no healthy pattern of obesity, suggesting that despite the term metabolically healthy, these patients are at risk for complications in the long term.

In a systematic review of data and meta-analysis, Caroline K. Kramer, MD, and colleagues conducted a study at Leadership Sinai Centre for Diabetes at Mount Sinai Hospital in Toronto, and concluded: “Compared with metabolically healthy normal-weight individuals, obese persons are at increased risk for adverse long-term outcomes even in the absence of metabolic abnormalities, suggesting that there is no healthy pattern of increased weight.”

Kramer and colleagues evaluated data from studies that examined all-cause mortality or CV events or both in patient groups defined by BMI and metabolic status based on the presence or absence of metabolic syndrome components. The researchers found that metabolically healthy obese did not have increased risk for events compared with metabolically healthy normal-weight individuals when data with less than 10 years of follow-up were included. Elevated risk was found in metabolically healthy obese individuals vs. the normal-weight individuals when the researchers used data with 10 or more years follow-up. Among all metabolically unhealthy individuals, risk was comparable.

The study did not include lifestyle and physical fitness, leading to speculation on the data. “There was no increased risk in the metabolically healthy obese group until the researchers pulled out the 10-year group,” Bessesen said.

Additionally, the Look AHEAD trial was designed to show whether weight loss through a lifestyle intervention resulted in lower mortality among patients with type 2 diabetes. This study was stopped early due to futility because the overall number of endpoints were not significantly different between groups, Bessesen explained.

“The number of people who had CV events in that study was much lower than the researchers thought it was going to be. One interpretation of that is that weight management is just one of many strategies to lower CVD — including taking lipid-lowering medicines, treating BP and lowering blood sugars. And, it may be that if a group of people like the people in that study were physically active and had all of their risk factors managed well, the benefits of weight loss are fairly modest compared to that,” he said.

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Another study recently published in the Journal of the American College of Cardiology by Bjørn Mørkedal, MD, PhD, of Norwegian University of Science and Technology in Trondheim, Norway, and colleagues concluded that compared with metabolically healthy normal-weight participants, those who were obese had an elevated risk for heart failure regardless of metabolic status, particularly in patients with long-lasting or severe obesity. The researchers did not find a substantially increased risk for first incidence acute myocardial infarction in metabolically healthy obese patients vs. normal-weight patients considered metabolically healthy.

Apovian concurs: “Metabolically healthy obese have less CV risk because of lower risk of developing type 2 diabetes, hypertension, elevated lipids; however, they may still develop right-sided heart failure from the direct effects of excess adipose tissue on the heart and lungs,” she said.

Garvey said this increased risk often comes from a misclassification as metabolically healthy when risk factors do exist. In theory, truly metabolically healthy person would not have this increased risk, he said.

“Again, the studies that claim that there are no metabolically healthy obese compare people with metabolic syndrome and without metabolic syndrome.Because metabolic syndrome diagnostic criteria have high specificity and low sensitivity for identifying insulin resistance and cardiometabolic disease, many people placed incorrectly in the ‘low-risk’ group may be insulin resistant and have one or two metabolic syndrome risk factors, and will still be at high risk of future diabetes (even though they do not meet diagnostic criteria for the metabolic syndrome),” Garvey explained.

Schoeller said surveillance is important with obesity, even in the absence of metabolic risk factors, because the “risk of developing chronic illness with increasing age is higher than a nonobese patient.”

Treatment, management of metabolically healthy obese

Clinicians face a spectrum of risk factors when managing patients with obesity.

“I treat all forms of obesity with diet and exercise behavioral therapy as well as medications for weight loss and adjust medications that may cause weight gain,” Apovian said.

Hill said considering an obese person metabolically healthy does not address other risk factors.

“Patients who are metabolically healthy because they don’t have a risk for CVD may have risk factors for diabetes, orthopedic conditions or cancers. So, simply saying they are metabolically healthy because they don’t have a CV risk, doesn’t mean they aren’t at increased risk for other things that are associated with obesity,” Hill said.

Bessesen said it is clear that obesity predisposes to a range of illnesses — diabetes, high BP, cancer, joint problems, sleep apnea, reproductive problems — but, it may still be useful to stratify patients as metabolically healthy obese because there is a “gradation of risk.”

“It goes from pretty low if all of those variables are normal to pretty high if all of those variables are all abnormal. And so how does a clinician decide who to treat and how does a patient decide what to think about that?” Bessesen said. “It is useful to be aware of the gradation of risk, and to not treat all obese patients as if they have a single disease that needs a single treatment and will have the same benefits. There will be a range of benefits.”

Garvey said there are other reasons to treat patients aside from metabolic health, but physicians need to decide based on optimal benefit-to-risk ratio of the intervention.

“We will treat metabolically healthy obese if they are not healthy due to the biomechanical complications of obesity,” Garvey said. “If they do not have any complications at all, we are going to be less aggressive with those patients.

“Some patients may be interested in a cosmetic effect for weight loss … and that is valid. But those patients are not the patients who would most benefit from weight-loss therapy. So we would not tend to use more aggressive, extensive, intense or risky interventions in those patients. That wouldn’t be consistent with the optimal benefit-to-risk ratio of the intervention,” Garvey said.

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Another tool for physicians to stratify treatments is the Edmonton Obesity Staging System (EOSS), Apovian said.

“It separates comorbidities of obesity into medical, functional and mental. The comorbidities of obesity include functional and mental as well, so that even if you do not develop diabetes and CVD, you could still have depression and physical limitations from obesity and have an increase in mortality. Any mental or physical impairments would require treatment if you consider obesity to be a disease,” Apovian said.

Obesity as an inflammatory process

A recent study published in the Journal of Clinical Endocrinology & Metabolism, by Catherine Phillips, BSc, PhD, of University College Cork in Ireland, and colleagues, showed “lower levels of inflammation may account for better metabolic health in obese and non obese people.”

Research connecting inflammatory markers to the process of obesity is emerging, but some clinicians said they need more data before using it in making clinical decisions in practice.

“I absolutely think that it is great science that is coming together,” Hill said. However, it is not clear that inflammation is the only mediator between obesity and other negative conditions, he added.

“Inflammation is a link between obesity and some of these metabolic diseases, but obesity is probably linked to negative outcomes through other mechanisms as well,” Hill said.

W. Timothy Garvey

W. Timothy Garvey

“In terms of how we rigorously use inflammatory markers to make clinical decisions, we just need a lot more data,” Garvey said.

Metabolic health and overweight children

Children who are overweight or obese have different considerations compared with adults because children are generally healthier overall, clinicians said.

“Children are more resilient. They are healthier, in general. Problems happen at higher weights than they do in adults. But there clearly are some children who have health problems for their weight. A lot of younger people are heavy, but they don’t have a lot of metabolic health problems, yet. So, there is some interaction between weight and health over time,” Bessesen said.

Metabolic syndrome traits may be found in children, but considerations may be different than in adults, Garvey said.

“In children, generalized obesity carries some importance that is not as readily apparent in adults, and that is both insulin resistance (high insulin levels) and general adiposity (BMI values that are above 95% in that age group) confer increased risk of metabolic syndrome in adulthood,” Garvey said.

Lifestyle interventions may be difficult but are the key to counteract that risk in children, Hill said.

“We know that overweight and obese children are not going to grow out of it. They are going to grow up to be overweight and obese adults. We need to promote lifestyle interventions for these kids. We have to find a way to get kids eating healthy and physically active. And, it has been very difficult to create those long-term behavior changes,” Hill said.

Future considerations

“Part of our goal, if we are successful, is to create a greater number of metabolically healthy obese,” Hill said. Physicians cannot obtain nonobese status in all individuals, but they could possibly get more obese people to a metabolically healthy state, he said.

Bessesen agreed, suggesting that the goal should be to deliver the best care to those who are not metabolically healthy.

“We shouldn’t get off track in thinking that this metabolically healthy obese is a majority. It is a minority. It’s not zero, but it’s 25% or maybe 30% of the obese population. That means 70% or 75% of obese patients do have health problems,” Bessesen said. “We are not doing as good a job as we should in addressing those people’s needs. For the future, my hope is that we don’t let this metabolically healthy obese issue get us off track from delivering the care to most of the people who do have health problems related to their weight.”

Hill questioned where future reimbursement issues would lie.

“A lot of our most effective treatments are fairly expensive. But, with widespread reimbursement for obesity, there are a couple questions: One question is who qualifies for being reimbursed? Is it just being obese, or do you have to be obese plus some risk factors?” he said. “If you reimburse for the treatment of obesity, we desperately need some criteria for effective programs. The field is poised to take on some of these really important questions.” — by Suzanne Bryla Reist

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Appleton SL. Diabetes Care. 2013;doi:10.2337/dc12-1971.
Guo F. Obesity. 2014; 22:110-118.
Hill JO. Ann Intern Med. 2013;159:789-790.
Kramer CK. Ann Intern Med. 2013;159:758-769.
Mørkedal B. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2013.11.035.
Phillips CM. J Clin Endocrinol Metab. 2013;doi:10.1210/jc.2013-2038.
Stefan N. Lancet Diabetes Endocrinol. 2013;doi:10.1016/S2213-8587(13)70062-7.
Caroline M. Apovian, MD, FACP, FACN, can be reached at Boston University School of Medicine, Center for Nutrition and Weight Management, Boston Medical Center; 732 Harrison Ave., 2nd Floor, Boston, MA 02118; email: caroline.apovian@bmc.org.
Daniel Bessesen, MD, can be reached at the Anschutz Health and Wellness Center, 12348 E. Montview Blvd., Aurora, CO 80045; email: daniel.bessesen@ucdenver.edu.
W. Timothy Garvey, MD, can be reached at the University of Alabama at Birmingham, Director, UAB Diabetes Research Center, 1720 Second Ave. South, Birmingham, AL 35294-3360; email: garveyt@uab.edu.
James O. Hill, PhD, can be reached at the Anschutz Health and Wellness Center, 12348 E. Montview Blvd., Aurora, CO 80045; email: james.hill@ucdenver.edu.
Dale A. Schoeller, PhD, can be reached at the University of Wisconsin-Madison, Nutritional Sciences, 1415 Linden Drive, Madison, WI 53706; email: dschoell@nutrisci.wisc.edu.
Disclosure: Apovian has participated on advisory boards for Abbott Nutrition;, Allergan, Inc.; Amylin Pharmaceuticals; Arena Pharmaceuticals; EnteroMedics Inc.; GI Dynamics, Inc.; Johnson & Johnson Services, Inc.; Merck & Co., Inc.; Novo Nordisk, Inc.; NutriSystem, Inc.; Orexigen Therapeutics; sanofi-aventis US LLC; and Zafgen and has received research funding from Amylin Pharmaceuticals; Aspire Bariatrics, Inc.; the Dr. Robert C. and Veronica Atkins Foundation; Eli Lilly & Co.; GI Dynamics, Inc.; GlaxoSmithKline; MetaProteomics, LLC; Orexigen Therapeutics; Pfizer, Inc.; and sanofi-aventis US LLC. Bessesen is on the Data Safety Monitoring Board for EnteroMedics. Hill has served as a consultant for the following companies: Coca-Cola, Curves, General Mills, International Dairy Federation, McCormicks, McDonalds, Novo Nordisk, Retrofit, Takeda Pharmaceuticals and Walt Disney Company. Garvey has provided research for AstraZeneca, Merck, Sanofi, Vivus and Weight Watchers; served on advisory boards for Alkermes, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, Janssen, LipoScience, Novo Nordisk, Takeda and Vivus; and has been on the speakers’ list for Merck. Stefan, Kramer, Mørkedal, Phillips and Schoeller do not have any related financial disclosures.
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POINT/COUNTER

Is it cost-effective to treat patients who fall into the category of metabolically healthy obese?

POINT

It is cost-effective to treat the metabolically healthy obese.

Health economics relating to obesity treatment still lacks an adequate evidence base. Much data come from bariatric surgery, few from diet and lifestyle interventions. Many analyses rely upon modeling of outcomes that are oftenrestricted to cardiovascular and metabolic (CVM) outcomes, with the dangers therefore of bias and self-fulfilling outcomes if applied to those without CVM disease. Few have been powered sufficiently to look at the influence of baseline disease status.

Nicholas Finer

Nicholas Finer

Several studies have shown that so-called ‘metabolic healthy obese individuals’ are still at increased risk of developing diabetes and cardiovascular disease compared to the normal population and that metabolic healthiness is a transient state for many (eg, Appleton SL. Diabetes Care. 2013; doi:10.2337/dc12-1971; Aung K. J Clin Endo Metab. 2013; doi:10.1210/jc.2013-2832; Bradshaw PT. Obesity. 2013; doi:10.1002/oby.20248), although one UK study suggested protection from cardiovascular and all cause mortality over a 7-year period (Hamer M. J Clin Endo Metab. 2012; doi:10.1210/jc.2011-3475). While body mass index is used to define obesity (≥30 kg/m2), it is known to be a poor measure of body fat, let alone body fat distribution. It is not surprising therefore, that individuals with equivalentdegrees of obesity severity defined by BMI, may vary widely in their phenotype relating to health, obesity-related risks and diseases. All these factors suggest we need better clinical ‘staging’ of patients with overweight and obesity — the Edmonton Obesity Staging System is one such example (Kuk JL, Appl Physiol Nutr Metab. 2011; doi:10.1139/h11-058).

When it comes to the health economics of obesity treatment, the cost-efficacy in any individual will depend upon the severity/complexity of their obesity and its associated diseases, the efficacy of treatment at producing weight loss, any non-weight-loss-related benefits, and importantly, the time line considered. Thus bariatric surgery in a young woman with a BMI of 42 but no associated comorbidities or medication costs, will, over a 5-year period, be likely to be less cost-effective than a similarly obese individual aged 55 with diabetes, sleep apnea, and hypertension. However, over a 30-year period, the cost efficacy may favor the young person who has ‘more of a lifetime’ in which health care costs can be saved. Sadly, in England now, most commissioners of health care are only able to look at 1- to 2-year business plans. Of course, with more marginally effective interventions (eg, diet, exercise and even pharmacotherapy), the more modest weight loss may make little impact on patients with severe and complex obesity, compared with those with more modest health impairment. Again, not all of the costs of obesity relate to cardiovascular and metabolic disease, so the balance could again tip in favor of the uncomplicated, metabolically normal obese individual if weight loss allows them to return to work.

It is cost-effective to treat the metabolically healthy obese, and vice versa, provided the right treatment is provided at the right time, and evaluated over a period appropriate to health needs, ie, the long-term.

Nicholas Finer, MD, PhD, is a Consultant Endocrinologist and Bariatric Physician, Professor at the University College London Institute for Cardiovascular Science, London, England.

Disclosure: Finer reports no relevant financial disclosures.

COUNTER

The notion that obesity treatments — will even remotely prove cost-effective — is wishful thinking at best.

Metabolically healthy obese individuals, best described as having Edmonton Obesity Staging System (EOSS) Stage 0 obesity, like everyone else, are at risk for further weight gain. Thus, even Stage 0 obese individuals will benefit from treatments aimed at preventing further weight gain.

Arya M. Sharma,

Arya M. Sharma

That said, the question is whether or not Stage 0 obese individuals will also stand to benefit from treatments aimed at weight loss. Studies in obese individuals with higher stages of obesity (including those with preclinical risk factors — often referred to as having Stage 1 obesity) show that the considerable cost of weight loss treatments barely break even. Even diet and exercise come at a cost.

Indeed, the only obesity treatment that shows even a remote trend towards cost-effectiveness is bariatric surgery for severely obese individuals with type 2 diabetes (and even these numbers have been challenged). Thus, the notion that obesity treatments in individuals with Stage 0 obesity will even remotely prove cost-effective — even in the long-term — is wishful thinking at best.

It is thus prudent to focus our scarce obesity management resources on those who stand to benefit the most, namely those, who already have weight-related health issues (Stage 1+). That, unfortunately, is the vast majority of individuals with obesity.

Arya M. Sharma, MD, FRCPC, is a Professor and Chair in Obesity Research and Management at the University of Alberta, Edmonton, Alberta, Canada.

Disclosure: Sharma is a consultant for Abbott, Arena, Glaxo-Smith-Kline, Merck, Novo Nordisk, Sanofi-Aventis and Vivus; he is on the speaker bureau for Novo Nordisk.