Redefining obesity

As appeared on MDAtl.com.

Adiposity-Based Chronic Disease (ABCD) – A guide to medical management and updates in obesity medicine.

The global prevalence of obesity has nearly tripled since 1975. Obesity, which severely impacts the lives of both children and adults, has now been labeled a pandemic. The World Health Organization (WHO)1 estimates that at least 2.8 million people die each year due to being overweight or obese. More than two-thirds of all American adults fall into this category.

The physiological milieu promoting obesity involves complex, interrelated metabolic factors and neurohormonal pathways influenced by genetic, environmental and other external factors. In 2016, the American Association of Clinical Endocrinology (AACE) and the American College of Endocrinology (ACE) proposed a new name for obesity, adiposity-based chronic disease (ABCD), to direct attention toward the broad pathophysiology of obesity.

Adiposopathy describes the disease wherein pathogenic enlargement of adipocytes (fat cells and fat organs), promoted by positive caloric balance, results in anatomic/functional abnormalities leading to adverse clinical consequences. Scientists have identified more than 50 adipokines released by adipocytes, the most significant ones being leptin and adiponectin, which play a role in the pathology of this disease. Similarly, gut hormones such as ghrelin, glucagon-like peptide 1 (GLP-1) and gut microbiomes play a key role in weight gain.

Traditionally, body mass index (BMI) has been used to classify obesity, wherein a BMI of 25-29.9 is overweight, BMI of 30-39.9 is obesity and BMI>= 40 is defined as morbid obesity.

However, BMI has limitations in assessing adiposity in its true nature and is limited by factors like muscle mass, gender bias and other factors. With the increased correlation of obesity to metabolic diseases, it is necessary to further classify obesity.

1. Percent body fat (PBF): >=35% in women, and >=40% in men is defined as obesity. The word pre-obesity is also gaining popularity and is defined by PBF of 30-34% in women and 25-29% in men.
2. Waist circumference: Obesity is a waist circumference >=35 inches in women and >=40 inches in men.
3. Visceral and android fat in adults determined via DXA (Dual Xray Absorpitometry): This is a very promising tool as it directly correlates to adiposopathic metabolic diseases more than any of the above.

Weight gain results from a constant net positive balance between energy intake and total energy expenditure (basic metabolic rate + thermogenesis + physical activity). Conversely, weight loss is achieved by net negative balance.

It is a well-known fact that a multidisciplinary approach including diet, exercise and intense behavior modification is the key to successful weight loss. AACE/ACE algorithms2 for management of obesity have moved away from a BMI-centric approach to a more complications-centric approach. Pharmacotherapy and bariatric surgery are used as an adjunct to such lifestyle modifications.

For a healthy weight loss of 1-2 pounds per week, approximately 500 to 750 kcal reductions are mandatory. Lifestyle interventions emphasizing reduced caloric intake, increased physical activity and behavioral modification techniques are considered the first line of therapy for overweight and obesity. However, until recently, nonsurgical lifestyle interventions have failed to show a significant reduction in the cardiovascular events.

The Look AHEAD study3 was designed to assess the long-term effects of cardiovascular morbidity and mortality of an intensive weight loss program in patients with type 2 diabetes. The study revealed significant improvement in some CVD risk factors after mean follow-up of 9.6 years but no significant effect was observed on CVD mortality.

Another study, the Diabetes Prevention Program (DPP) study,4 showed that the sample group with lifestyle interventions averaged 5.5% weight loss and 58% reduction in incidence of diabetes as compared to the placebo sample group after a mean follow-up of 2.8 years.

Lifestyle Interventions

Physical Activity/Behavior Modifications. There is growing literature that suggests mindfulness-based strategies for eating behaviors (cognitive behavioral therapy and acceptance-based commitment therapy) are effective and superior to traditional models of behavioral weight management for both weight loss and other related parameters. Health benefits, modest weight loss and prevention of weight gain can be achieved by setting the following physical activity goals:

• At least 150 minutes/week of moderate physical activity or at least 75 minutes/week of vigorous intensity aerobic exercise.
• Resistance training two or more days per week.
• 5,000-10,000 steps per day.

A recent study by Jakcic, et al.5 demonstrated that individuals who exercise >= 200 minutes/week had greater 18-month weight losses, suggesting that a higher level of physical activity appears to be particularly important for long-term weight loss and maintenance.

Diet. There is no single diet plan that works for all. Recommendations are to use a diet program that works for the individual and is sustainable as a long-term lifestyle intervention. Some types of recommended diet plans are:

• Very Low Calorie Diet (VL CD), < 800 kcal/day, which usually involves meal replacements and close monitoring in a comprehensive weight-loss center.
• Low calorie diet, which is is 900 to 1500 kcal.
• Mediterranean diet, which focuses on consuming primarily vegetables, fruits, legumes, nuts, beans, cereals, grains, fish, and unsaturated fats such as olive oil, with a reduced emphasis on meat and dairy foods.
• Low glycemic diet, which emphasizes eating low glycemic index (GI) foods such as complex carbohydrates like brown rice and lentils instead of refined carbs like pasta or processed, sugary foods.
• Low-fat diet, which has less than 30% of fat.
• Low carbohydrate diet simply means less than 20 g of carbs and greater than 30% protein. This diet also referred to ketogenic diet has been shown to be effective in weight loss as well as glycemic control.

A study in 2008 published in The New England Journal of Medicine⁶ showed long-term sustainability and compliance being the major setback.

More recently, intermittent fasting as a diet tool is gaining popularity. There is good scientific evidence of circadian rhythm fasting when combined with healthy diet and lifestyle. The focus is on when you eat and not what you eat.

There are different models that have been studied: 5:2 (2 days of eating less than 800 cal); the alternate day fasting model; and the most commonly used time-restricted diet, where one eats for only 8 hours in a day. A recent study published in JAMA⁶ noted no difference in results in A1c levels, fat mass and total weight lost in one year among individuals following an intermittent fasting diet compared to other calorie restricted diets. But this is another diet plan that can be individualized to the need of the patient and might have better compliance than the keto diets. Perhaps the most intriguing but least researched benefit of intermittent fasting lies in the brain health14.

Pharmacotherapy: A Promising Future

Although dietary and lifestyle measures remain the fundamental focus for the fight against obesity, it is important to recognize early on in the process the non-responders to lifestyle interventions. When these measures do not yield favorable results, then pharmacological or surgical interventions are required.

Anti-Obesity Medications

Anti-obesity medications (AOMs) are indicated in all patients with a BMI greater than 30 or a BMI greater than 27-29.9 with other comorbidities. Medications, however, should only be used as an adjunct to lifestyle interventions and behavioral modifications. Their efficacy is determined by an expected weight loss goal of 5% at 3 months.

Obesity is a chronic disease. If and when medications are used, the treatment should be continued to attain the desired weight and to maintain it.

Several stimulant-type medications have been approved for decades for short-term use of less than 12 weeks. Phentermine (Lomaira, Adipex-P) is a sympathomimetic drug that suppresses appetite. It was initially approved in 1959 and traditionally dosed as 15 mg, 30 mg and 37.5 mg. In 2016, Lomaira 8mg, a short-acting phentermine, was approved by the Food and Drug Administration (FDA). One can take Lomaira before each meal; therefore, it is ideal for those dangerous early-evening cravings.

Orlistat (Xenical, Alli) was approved in 1999 as a pancreatic lipase inhibitor that reduces the absorption of ingested fat. Now it is approved for over-the-counter use at half the dose branded as Alli. The XENDOS trial7 showed that orlistat plus intensive behavior counseling led to twice the weight loss achieved in the placebo group.

With an evolving understanding of the underlying pathophysiology of obesity and gut hormones, an increasing number of drug targets are being identified. Since 2012, five new AOMs and one device have been approved by the FDA. These medications are centrally acting, leading to decreased appetite or increase satiety. However, one of these, lorcaserin (Belviq), approved in 2012, has since been taken off the market, due to increased risk of malignancy.

Phentermine-topiramate ER (Qsymia) was approved in 2012. While the SEQUEL trial8 proved its efficacy in weight loss (greater than 10% on average compared to 2% in placebo group), the EQUIP9 trial showed a reduction in the progression of type 2 diabetes mellitus by 76% compared to the placebo group when used in patients with severe obesity (BMI>=35).

Bupropion/naltrexone ER (contrave) was approved in 2014 as a drug that works at the hypothalamus level and decreases craving. When combined with lifestyle intervention, the combination drug led to a 12% weight loss as compared to the placebo group10.

Liraglutide (Saxenda) a GLP-1 agonist and once daily dose of 3mg injected subcutaneously, was approved in 2014. Approximately 5% weight loss was noted in 56 weeks11.

Plenity (Gelesis 100) is a hydrocellulose gel, unlike the other pharmacological therapies. It was approved by the FDA in 2019 as a device though it is a pill. Unlike other AOMs, Plenity can be used for patients with a BMI greater than 25. Three capsules are taken with 16 oz. of water, 20 to 30 minutes before meals twice daily. Plenity absorbs water and fills the stomach. Then water is reabsorbed in the large intestine and Plenity is excreted. The GLOW12 study showed an estimated weight loss of 6.4% versus 4.4% in the placebo groups over 24 weeks.

Semaglutide 2.4 mg (Wegovy), the latest addition and the most promising drug to date, was approved earlier this year (2021). Semaglutide is already approved at the dose of 1 mg once weekly (Ozempic) for diabetes management and was noted to reduce the risk of major cardiac events. Wegovy is approved as the first and only once-weekly GLP-1 receptor agonist medication for weight loss. Treatment with Semaglutide 2.4 mg resulted in significant reduction in body weight of 14.9% versus 2.4% in placebo groups. Th STEP 113 trial included all patients without type 2 diabetes and extended over a 68-week period. 83.5% patients lost >=5% of the body weight compared to 3.1% in the placebo group. 66% patients lost >10% of the weight compared to 12% in the placebo group. 47.9% of the patients lost >15% body weight as compared to 4.8% in placebo group

COVID-19 and Obesity

Obesity is a double whammy during the COVID-19 pandemic. The pandemic has caused many to put on pounds (shelter in place, depression, stress being some of the contributing factors) but obesity has emerged as a major risk for severe disease and death from the virus.

BMI is an independent risk factor for severe effects of COVID-19. A recent study in JAMA showed 77% of nearly 17,000 patients hospitalized with COVID-19 were overweight or obese. This reiterates the need for treating obesity.

Rapid scientific advancement has led to a better understanding of the pathophysiology of obesity and empowered physicians with better tools to treat this chronic disease. Individualized tailoring of treatment plans, including lifestyle modifications, nutrition and pharmacotherapy, should take into account personal preferences and individual metabolic factors. Despite this, insurance coverage for medications and lifestyle interventions remains problematic.

Adiposity-based chronic disease and its complications are among the leading causes of preventable and premature death and hence are a crucial public health concern that cannot be ignored.

1. World Health Organization. Global Health Risks [Internet], 2009. Available from http://www.who.int/healthinfo/global_burden_disease/global_health_risks/en. Accessed 24 September 2042.
2. Abrahamson MJ, Barzilay JI, et al.; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013;19:327–336pmid:23598536.
3. Pi-Sunyer X, Blackburn G, Brancati FL, et al.; Look AHEAD Research Group. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care 2007;30:1374–1383pmid:17363746
4. Wing RR, Hamman RF, Bray GA, et al.; Diabetes Prevention Program Research Group. Achieving weight and activity goals among diabetes prevention program lifestyle participants. Obes Res 2004;12:1426–1434pmid:15483207
5. Jakicic JM, Winters C, Lang W, Wing RR. Effects of intermittent exercise and use of home exercise equipment on adherence, weight loss, and fitness in overweight women: a randomized trial. JAMA 1999;282:1554–1560pmid:10546695
6. Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and ObesityThe TREAT Randomized Clinical Trial. Author MA Intern Med. 2020;180(11):1491-1499. doi:10.1001/jamainternmed.2020.4153↵
7. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155–161pmid:14693982
8. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012;20:330–342pmid:22051941
9. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95:297–308pmid:22158731
10. Greenway FL, Fujioka K, Plodkowski RA, et al.; COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2010;376:595–605pmid:20673995
11. Hollander P, Klein S, et al.; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013;37:1443–1451pmid:23812094
12. A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss. PMID: 30421844 PMCID: PMC6587502 DOI: 10.1002/oby.22347
13. Semaglutide Treatment Effect in People With Obesity – STEP 1 https://www.acc.org/latest-in-cardiology/clinical-trials/2021/02/18/19/23/step-1
14. Top 5 intermittent fasting benefits … – Medical News Today https://www.medicalnewstoday.com/articles/323605