A Complications-Centric Approach to the Treatment of Obesity

A Holistic Perspective

The Algorithm for the Medical Care of Patients with Obesity, published by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology in 2016 focuses on the whole patient and includes specific treatment algorithms for the management of patients with overweight and obesity. It proposes a “complications-centric model” for the treatment of obesity (Figure 6-1). This evidence-based approach to the treatment of obesity incorporates lifestyle, medical and surgical options, balances risks and benefits and emphasizes medical outcomes that address the complications of obesity rather than cosmetic treatment goals.

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Obesity as a Disease

Of particular interest regarding this algorithm is its stated fundamental premise namely: “Obesity is a disease with genetic, environmental and behavioral determinants that confers increased morbidity and mortality.” This premise is not new. The 1998 National Heart, Lung and Blood Institute (NHLBI) Clinical Guidelines for Clinical Treatment of Overweight and Obesity also stated that “obesity is a complex multifactorial chronic disease that develops from an interaction of genotype and the environment.” There is considerable evidence that obesity is associated with cardiometabolic and other comorbidities and consequently, with increased risk for morbidity, mortality, decreased quality of life and increased health care cost.

A resolution stating that obesity should be reclassified as a multi-metabolic and hormonal disease state was presented to the American Medical Association (AMA) House of Delegates at its June 2013 meeting by the AACE, and supported by the American College of Cardiology, the Endocrine Society and the American Society for Reproductive Medicine, as well as the American Academy of Pediatrics, the American Academy of Family Physicians and the American Society of Bariatric Physicians. This resolution was ultimately accepted by the AMA House of Delegates.

From Weight Loss to Risk Reduction

Obesity is typically defined in terms of anthropometric measures, primarily body mass index (BMI), which originally was designed as an epidemiologic research tool, i.e., a rough population-level indicator of body weight. Many observational studies have consistently reported strong associations between elevated BMI values and morbidity and mortality risk. In one large study, for example, each five-point increase in BMI >25 was associated with increases of 29% for overall mortality, 41% for vascular mortality and 210% for diabetes-related mortality. However, BMI is not an optimal method for measuring actual “body fatness” in an individual. For example, as the 1998 NHLBI Guidelines pointed out, some people with a BMI in the “normal” range can have excessive body fat, as well as metabolic dysfunctions. Others with BMIs in the same obesity range have no excess fat or cardiometabolic dysfunction. Conversely, some individuals with high BMIs are normal metabolically and may have normal blood pressure and cholesterol levels.

The difference between the long-established (1998) NHLBI Clinical Guidelines for Overweight and Obesity and the AACE guidelines does not reside in their specific clinical assessment and treatment recommendations. Rather, the AACE Obesity Treatment Algorithm adopts a complications-centric model that focuses on risk assessment, staging and stage-specific interventions, one of which is weight loss treatment itself. Thus, one difference between a BMI-centric model and a complications-centric model is that the primary treatment goal of the former is weight loss itself, while with the complications-centric model, the primary treatment goal is reduction of the risk for (or at least slowing the progression of) the many comorbidities associated with obesity. In other words, in the AACE algorithm, weight loss itself is a key therapeutic intervention for risk reduction in an individual patient.

The Premise: Weight Loss Reduces Comorbidity and Mortality Risk

A fundamental premise of the complications-centric approach is that weight loss resulting from diet and lifestyle changes alone or in combination with pharmacologic or surgical treatment can reduce the risk of many of the obesity-associated comorbidities in a progressively “dose-related” manner.

For example, 1-year results from the ongoing Look AHEAD (Action for Health in Diabetes) trial provide empirical support for the assertion that modest weight losses of 5% to 10% of initial weight are sufficient to produce significant, clinically relevant improvements in cardiovascular disease (CVD) risk factors in patients with overweight or obesity and type 2 diabetes (T2D). Look AHEAD is a multicenter, randomized clinical trial assessing the long-term effects of lifestyle interventions on CV morbidity and mortality in 5,145 patients with overweight or obesity with T2D who were randomized to intensive lifestyle intervention (ILI) or to usual care.

After 1 year, patients were divided into the following categories based on their weight changes from baseline to 1 year: gained >2%; remained weight stable (±2%); lost ≥2% to 5%; lost ≥5% to 10%; lost ≥10% to 15%; or lost ≥15%. There was a strong graded association for changes in glucose, glycosylated hemoglobin (A1C), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides and high-density lipoprotein (HDL) cholesterol (all P values <0.0001). Each higher increment of weight loss was associated with greater improvements in the risk factor. Furthermore, the odds of having a clinically meaningful improvement in risk were strongly related to the magnitude of weight loss achieved such that the odds of a clinically meaningful improvement also increased with each weight loss increment.

Evaluation, Risk Assessment and Disease Staging

According to the 2016 AACE/ACE Obesity Treatment Algorithm, patients who will benefit the most from medical and surgical intervention have obesity-related comorbidities. Therefore, the guidelines recommend that the primary factor guiding treatment planning and evaluation should be the presence and severity of complications, not BMI per se. Much, if not most, of the relevant information for clinical risk assessment and disease staging of overweight/obesity is readily available to the clinician in routine clinical practice. Additional information can be obtained from several validated assessment and disease staging tools.

Edmonton Obesity Staging System (EOSS)

As mentioned previously, BMI is not a perfect measure of health. In 2009, Sharma and colleagues proposed a new clinical staging system for obesity—the Edmonton Obesity Staging System (EOSS)—intended to complement (but not replace) current anthropometric classifications of obesity. This measure ranks individuals with overweight/obesity according to a 5-point ordinal scale, which incorporates obesity-related comorbidities and functional status (Table 6-1). The EOSS is based on simple clinical assessments that include medical history and clinical and functional assessments, as well as simple routine diagnostic investigations.

Subsequently, Padwal and colleagues assessed the ability of the EOSS to predict all-cause mortality using a nationally representative US population sample (NHANES III [1988–1994] and NHANES [1999–2004] with mortality follow-up through to the end of 2006). Final unweighted sample sizes were 4367 individuals with overweight/obesity from the NHANES III 1988–1994 population and 3600 from the NHANES 1999–2004 population. EOSS scores were a strong predictor of increasing all-cause mortality in the overall population (Figure 6-2). This predictive ability was independent of BMI and the presence of other risk factors such as metabolic syndrome. The results also were similar among individuals who never smoked.

There are several limitations of this staging system. For example, the comorbidities within EOSS, such as diabetes and OA, were initially and arbitrarily assigned to be equivalent in terms of their burden of illness. Therefore, it is not yet clear whether certain comorbidities should receive a higher weighting. Another limitation is that the EOSS was based on analysis of total mortality data only. A final limitation is that even though the EOSS system is based on a simple clinical rationale, its sensitivity, specificity, reliability and utility in clinical practice has not yet been assessed. Such studies are currently underway.

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Metabolic Syndrome

The metabolic syndrome is “a complex cluster of interrelated risk factors for CV disease and diabetes which occur together more often than by chance alone.” These risk factors include dyslipidemia, central obesity, hypertension, and/or insulin resistance.

Different diagnostic criteria for the metabolic syndrome have been proposed by various organizations, including the:

National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)

WHO

International Diabetes Foundation (IDF)

AACE

AHA/NHLBI.

However, in 2009, a joint meeting of International Diabetes Foundation (IDF) Task Force on Epidemiology and Prevention, NHLBI, AMA, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity resulted in a unified set of diagnostic criteria. Three abnormal findings out of the five listed in Table 6-2 would support a diagnosis of metabolic syndrome. The main difference among previous criteria was whether a measure of central adiposity, such as waist circumference, should be an obligatory component, and if so, what measurement cut points should be used. It was agreed that measurement of waist circumference should not be an obligatory component, but that waist measurement should continue to be a useful preliminary screening tool.

The presence of the metabolic syndrome is a clinically useful indicator of high morbidity and mortality risk. However, it is not an absolute risk since it does not consider many of the patient-specific factors that determine absolute risk such as age, sex, ethnicity, cigarette smoking and LDL-cholesterol levels. Nonetheless, patients with the metabolic syndrome are at twice the risk of developing CVD over the subsequent 5 to 10 years as those without the syndrome. In addition, the metabolic syndrome confers a 5-fold increase in the risk developing T2D.

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Cardiometabolic Disease Staging System

Given the strong relationship between a diagnosis of cardiometabolic syndrome and increased risk of morbidity and mortality, Guo and associates proposed the 5-stage Cardiometabolic Disease Staging (CMDS) system (Table 6-3) for predicting the progressively increased risk for future T2D and all-cause and CVD mortality. In order to demonstrate the progressive risk of the cardiometabolic disease spectrum, they validated the CMDS by using two large national cohorts, the CARDIA (Coronary Artery Risk Development in Young Adults [study]) study for incident diabetes and the National Health and Nutrition Examination Survey (NHANES) III linked mortality file for all-cause or CVD mortality.

Based on the 10-year follow-up period data from the CARDIA study, there were 203 cases of newly-diagnosed diabetes resulting in an overall crude cumulative diabetes incidence of 6.1%. The cumulative diabetes incidence across risk levels ranged across from 1.8%, 5.9%, 18.2% and 41.8% at Stage level 0 to Stage 3, respectively (Figure 6-3). Among individuals with overweight or obesity, the cumulative diabetes incidence was 8.9% overall and ranged from 2.2% 7.3%, 19.0% and 41.0% at Stage levels 0 to Stage 3, respectively. In addition to risk-stage–associated increases in cumulative incidence of diabetes, the HRs for diabetes also increased exponentially from 2.83 at stage 1 to 23.5 at stage 3. The impact of risk stage on diabetes incidence was similar in both genders and in White and Black people.

Over a median follow-up of 173 months in the NHANES III cohort, there were 1,012 ascertained all-cause mortality cases, resulting in a cumulative overall mortality rate of 14.7 per 1,000 person-years. As with the progressive increases in cumulative diabetes incidence, the cumulative mortality rates also increased progressively with advancing CMDS risk stage (P <0.001 for trend). They ranged from 6.5 per 1,000 person-years at stage 0 to 29.2 per 1,000 person-years at stage 4 (Figure 6-4). In this cohort, there also were 404 cases of CVD-related deaths. The overall CVD cumulative mortality rate was 5.4 per 1,000 person-years overall, and the rates also increased according to risk stage (P <0.001 for trend), ranging from 0.7 per 1,000 person-years at stage 0 to 14.3 per 1000 person-years at stage 4.

This study demonstrates that CMDS staging can discriminate a wide range of risk for diabetes, CVD mortality, and all-cause mortality independent of BMI, and can be used as a risk assessment tool to guide intervention. In particular, such a tool can be useful in a complications-centric approach to the treatment of obesity wherein the goal of weight loss is to ameliorate the complications of obesity. However, prospective interventional trials are needed to further validate the use of the CMDS will enhance patient outcomes and the cost-effectiveness of care.

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A Medical Model for Management of Patients with Overweight/Obesity

Historically, the management of individuals with overweight/obesity focused primarily on weight loss and employed dietary/lifestyle interventions with the occasional addition of a very limited number of weight-reducing, modestly effective, pharmacologic agents. Bariatric surgery, although generally more effective than the other options, was generally reserved for more severe or refractory cases. However, there has been a gradual change in the understanding and appreciation of obesity, its complex pathophysiology, interrelationships with a broad spectrum of comorbidities, as well as increased mortality. As noted previously, obesity is a disease in its own right, a disease that cannot be defined for clinical management solely by specific increments in total body weight.

In contrast to earlier BMI-centric guidelines (see Table 6-4 for BMI-centric treatment recommendations), the AACE guidelines are based on a complications-centric model for treatment of patients with overweight or obesity (see Figure 6-1 for an overview algorithm and Figure 6-5 for therapy intensification). The goal is to identify those patients who will benefit most from obesity treatment, namely, those who have obesity-related complications. Given that medications and surgical procedures have inherent risks for patients and increase the cost of health care delivery, it is important to develop and employ risk assessment steps in order to optimize the benefit/risk ratio for each patient.

There are several weight-loss medications currently in use. The new generation of anti-obesity drugs allows the provider to individualize therapy and use combination treatments in order to target the multiple pathways that contribute to the disease. Most importantly, the newer agents have been shown to not only result in significant weight loss but also to have significant beneficial effects on various cardiometabolic and anthropometric parameters.

In addition to the evolution of drug treatment, there have been new and refined options for dietary and lifestyle interventions and further advances in bariatric surgery. Therefore, many conceptual and technological advances, including the complications-centric algorithm, expanding availability of unique new medications and surgical interventions, have enabled a medical model for the identification, assessment and management of patients with overweight/obesity.

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