According to World Health Organization (WHO) data, about 650 million people worldwide are obese. Women (41%) are more affected compared to men (31%).2
Obesity, is it a chronic disease?
French physiologist, Dr Claude Bernard coined the term homeostasis (milieu interieur) in late 1800 to describe the importance of maintaining the body’s internal balance in a close and wise relationship with nature, so that its equilibrium results from a continuous and delicate compensation. If we live out of balance of nature’s laws, diseases such as obesity and type 2 diabetes (T2DM) develop, said Dr Ruder.1
Obesity is a disease of disproportionate fat accumulation due to excessive eating. The disease is defined as discomfort, inconvenience, distress, or trouble. Distress is at the root of obesity. In its causality it is driven by feelings of distress that leave a void, leading to indulging behaviours such as overeating and being sedentary.1
“Our ancestors had a wise and close relationship with nature where eating was done with gratitude. Through the ages, however, our relationship with nature has changed, leading to an amplification of hedonistic desires. Although we know that certain excesses are not good for us, we are often unable to change our behaviour.”1
The fast-food industry stokes our hedonistic desires by producing food to ‘gratify the tongue’ aimed at increasing their profit margins, without taking the health and well-being of individuals into consideration.1
The marketing of these products, which we don’t need, is one of the drivers of the obesity pandemic. When a person is incited to consume products that are not good for them, he/she may become unable to regulate his/her behaviour. In addition, as a result of our modern way of working (eg technology), we are increasingly becoming sedentary. This is the perfect melting pot for an obesity pandemic.1
As a result of unhealthy eating habits and sedentary lifestyles, the body’s homeostasis is disrupted and we become physiologically unbalanced. This in turn has pathophysiological implications. The mind becomes unregulated and the intellect (logical discourse or executive functioning) remains undeveloped and not strong enough to manage the mind.1
Patients with obesity should be treated in a holistic and not mechanistic manner. This means that we need to take the mind, intellect, and body into consideration in order to develop effective management strategies.1
Classification of obesity
According to the WHO, obesity is defined as abnormal or excessive fat accumulation that may impair health.2
There are different ways to assess and measure obesity, but the most common measure is the body mass index (BMI), which is an inexpensive and easy assessable tool.1
Table 1: Classification of obesity2,3,4,5
1. WHO. Obesity & Overweight. 2020. Available from https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
2. Misra A, Chowbey P, Makker BM, et al. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. J Assoc Physicians India, 2009.
3. Stegenga H, Haines A, Jones K, et al. Identification, assessment, and management of overweight and obesity: summary of updated NICE guidance. BMJ, 2014.
4. Nakata Y, Okada M, Hashimoto K, et al. Weight Loss Maintenance for 2 Years after a 6-Month Randomised Controlled Trial Comparing Education-Only and Group-Based Support in Japanese Adults. Obes Facts, 2014.
Obesity is a chronic and multifactorial disease
In the past, obesity was explained in simple terms of energy intake that exceeds energy expenditure. Today the focus is more on what influences energy intake and expenditure, said Dr Ruder.1
In obese patients, homeostasis is disrupted as a result of hedonistic input (increased palatability or pleasure) and environmental factors (inactive lifestyle, smoking cessation, psychosocial factors).1
New research suggests that obesity is the result of dysfunction in the sub-cortical structures of the brain. Subcortical structures are a group of diverse neural formations deep within the brain and include the hypothalamus, area postrema and nucleus tractus solitarius.6
They are involved in complex activities such as regulation of body temperature, thirst, rate of breathing, hunger, and satiety. They act as information hubs of the nervous system, relaying and modulating information that passes to different areas of the brain.6
The sub-cortical areas of the brain are linked to the periphery (enteric nerves, vagal nerves, pancreas, stomach, small and large intestine, and adipose tissue).6
Gut hormones access the brain through multiple neurological pathways such as the arcuate nucleus and the suprachiasmatic nucleus. The arcuate nucleus, situated at the base of the hypothalamus, plays a role in many physiological functions such as feeding and metabolism.6
The suprachiasmatic nucleus is a bilateral structure located in the anterior part of the hypothalamus and is the central pacemaker of the circadian timing system. The hypothalamus is considered the most important.6
Badman and Flier explain that some peripheral signals can act directly on NPY/AgRP and pro-opiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons to promote particular appetite sensations via their effects on second-order neurons.7
For instance, ghrelin – the hunger hormone – can activate the hunger-promoting NPY/AgRP neurons to induce feelings of hunger. Conversely, glucagon-like peptide 1 (GLP-1) promotes satiety by activating CART/POMC neurons to promote feelings of satiety, while at the same time inhibiting the hunger-promoting NPY/AgRP neurons.7
Hypothalamic neurons are also influenced by anorexic and/or orexigenic signals from the nucleus tractus solitarius and the area postrema of the hindbrain, which in turn is influenced by peripheral signals acting on vagal afferents.7
The net result of this is a change in appetite and feeding behaviour, as well as other effectors of energy regulation, such as the metabolic rate and energy storage.7
Obesity-associated with increased mortality and morbidity
Obesity is not only associated with increased mortality but also with significantly increased morbidity, which can affect almost every organ system, warned Dr Ruder. The organs affected by obesity can be broadly grouped into three classes: metabolic, mechanical, and mental (eg depression and anxiety).1
According to Wang et al, the health burden from obesity is largely driven by an increased risk of T2DM, cardiovascular diseases (CVDs), and several forms of cancer. For instance, every additional 5kg/m2 in BMI increases a man’s risk of oesophageal cancer by 52% and for colon cancer by 24%, and in women, endometrial cancer by 59%, gall bladder cancer by 59%, and postmenopausal breast cancer by 12%. Excess body weight also contributes to non-fatal but costly or disabling disorders such as osteoarthritis.8
Furthermore, evidence suggests that excess body weight is linked to many additional disorders, including benign prostate hypertrophy, infertility, asthma, and sleep apnoea.8
Wang et al demonstrated that a 1% reduction in BMI is equivalent to a weight loss of roughly 1kg for an adult of average weight. This change might sound small but could have a substantial effect on consequent health burdens.8
They calculated that a 1% BMI reduction could avoid more than two million incident cases of diabetes in the United States, more than one million CVDs, and 73 000–127 000 cases of cancer, with a gain of about 16 million quality-adjusted life years.8
In the UK it would avoid more than 200 000 incident cases of diabetes, 122 000 CVDs, and more than 30 000 incident cases of cancer, with a gain of about three million quality-adjusted life-years over 20 years.8
Why is obesity not treated as a chronic disease?
High BMI accounted for four million deaths globally. More than 60% of deaths related to high BMI were due to CVDs. The disease burden related to high BMI has increased since 1990.9
Over the last 25 years, the prevalence of obesity has doubled in more than 70 of the 195 countries included in an analysis that assessed overweight and obesity trends between 1980 and 2015 among children and adults. The study showed that the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity.9
Despite the fact that obesity is increasing globally, it is still an undiagnosed and untreated disease, said Dr Alfaris, who specialises in obesity medicine.1
Caterson et al found that about 50% of people with obesity wait on average six years from when their weight struggle starts (mean age of 33-years), before they consult a healthcare professional. Yaemsiri et al found that 74% of overweight, and 29% of obese individuals (16 720) included in their analysis, never had a diagnosis of overweight/obesity.10,11
Although the majority of overweight/obese individuals (74% women, 60% men) pursued at least one weight management strategy, fewer (39% women, 32% men) pursued both dietary change and physical activity. Among overweight/obese adults, those with a diagnosis of overweight/obesity were more likely to diet (74% versus 52%), exercise (44% versus 34%), or pursue both (41% versus 30%) than those who remained undiagnosed.11
Saxon et al found that weight-loss medications are rarely prescribed to eligible patients. Phentermine accounted for >75% of all medication days, with a majority of patients filling it for more than four months. Less than 25% of prescribing providers accounted for approximately 90% of all prescriptions.12
This would be unacceptable in the management of any other chronic disease, said Dr Alfaris. According to her the main reason for this is the lack of training in obesity management across the continuum of care.1
Why do we need pharmacotherapy in obesity management?
According to Dr Wharton all diets lead to short-term weight loss, but eventually, the majority of patients will regain the weight. A meta-analysis of 29 long-term weight loss studies found that more than 50% of lost weight was regained within two years, and by five years more than 80% of lost weight was regained.13
Dr Wharton explained that the reason why people regain weight is as a result of so-called metabolic adaptation. Metabolic adaptation refers to the slowing down of one’s metabolic rate (metabolism) after long-term undereating and substantial fat loss, in an attempt to conserve energy.1
Studies show that for each kilogramme of lost weight, calorie expenditure decreases by about 20–30kcal/d whereas appetite increases by about 100kcal/d above the baseline level prior to weight loss. Despite these predictable physiologic phenomena, the typical response of the patient is to blame themselves as lazy or lacking in willpower, sentiments that are often reinforced by healthcare providers, state Hall and Kahan.13
Metabolic adaptation persists over time and is likely a proportional, but incomplete, response to contemporaneous efforts to reduce body weight, write Fothergill et al.
The team measured long-term changes in resting metabolic rate (RMR) and body composition in participants of The Biggest Loser competition. RMR was determined at the end of the 30-week competition and six years later.14
Of the 16 competitors, 14 participated in this study. Weight loss at the end of the competition was 58.3±24.9kg, and RMR decreased by 610±483 kcal/day. After six years, 41.0±31.3kg of the lost weight was regained, while RMR was 704±427 kcal/day below baseline and metabolic adaptation was -499±207kcal/day. Weight regain was not significantly correlated with metabolic adaptation at the competition’s end, but participants who maintained greater weight loss at six years also experienced greater concurrent metabolic slowing.14
Role of hormones
This means that hunger intensity does not go away when a patient loses weight, explained Dr Wharton. Hunger intensity is dictated by hormones and neurochemicals in the brain.1
Sumithran et al found that one year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss, do not revert to the levels recorded before weight loss.15
They enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss programme for whom a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, they examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.15
Weight loss (mean 13.5±0.5kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin, and amylin and to increases in levels of ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide. There was also a significant increase in subjective appetite.15
One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin, peptide YY, cholecystokinin, insulin, ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide, as well as hunger.15
In addition, said Dr Wharton, dieting depresses mitochondria functioning and gene expression. Mitochondria are important organelles for the adaptation to energy demand that play a central role in bioenergetics metabolism. Its disruption markedly affects energy homeostasis. As mentioned by Dr Ruder, the brain, more specifically the hypothalamus, is the main hub that controls energy homeostasis.1
Van der Kolk et al found that differentially regulated subcutaneous adipose tissue in mitochondria-related gene expressions may lead to alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.16
Chen et al investigated the potential of SHC517, a mitochondrial uncoupler, to reduce obesity. Mitochondrial uncouplers decrease caloric efficiency. They found that SHC517 reversed obesity without altering food intake or compromising lean mass.17
Obesity should be managed using evidence-based chronic disease management principles
Dr Wharton is one of the co-authors of the 2020 Canadian Adult Obesity Clinical Practice Guidelines: Pharmacotherapy in Obesity Management.18
The guideline recommends that all people living with obesity should have access to evidence-informed interventions. The three pillars of intervention include:18
Pillar 1: Implement multicomponent behaviour modification that includes management of sleep time and stress. Cognitive behavioural therapy and/or acceptance and commitment therapy are recommended.18
Pillar 2: According to the Canadian guideline, if a patient meets the criteria (BMI ≥30kg/m2 or BMI ≥27kg/m2 with obesity-related comorbidities (eg T2DM), pharmacotherapy can be initiated.18
There are several factors to be taken into consideration in determining the appropriate choice of pharmacotherapy for patients with overweight or obese.18
The mechanism of action, adverse side effects, safety, and tolerability of each agent must be considered in the context of each patient’s comorbidities and existing medications.18
The cost of medications as well as the mode (oral versus subcutaneous) and frequency of administration can be a barrier to patient adherence. It is important to assess concomitant medications that a patient is taking as possible contributors to weight gain and to consider alternatives where appropriate.18
Dr Wharton explained that in diabetes, prediabetes, hypertension, obstructive sleep apnoea, and polycystic ovarian syndrome, GLP-1RAs are recommended as first-line therapy.1
In Canada, liraglutide is considered the first choice for diabetes and prediabetes patients, naltrexone/ bupropion is the second choice and orlistat the third choice. Combination naltrexone/bupropion is not registered in South Africa for weight management.18
Liraglutide is a daily, subcutaneously administered, GLP-1 receptor analogue, which acts centrally on the POMC/CART neurons, resulting in improved satiation and satiety and reduction in hunger, with a transient effect to decrease gastric emptying.18
Liraglutide increases insulin release and suppresses glucagon during times of glucose elevation. Liraglutide is approved in Canada for the management of T2DM at a dose of 1.2mg or 1.8 mg daily, with near maximal therapeutic efficacy for HbA1C lowering at the 1.8 mg dose.18
Liraglutide was approved in Canada in 2015 for chronic obesity management at a dose of 3mg daily, in people with or without T2DM. The recommended starting dose of liraglutide is 0.6mg daily, with up-titration by 0.6mg each week until the 3mg target dose is achieved.18
Among people with normoglycaemia or prediabetes, liraglutide 3.0 mg with health behaviour modification resulted in an 8.0% weight loss at one year, compared to 2.6% on placebo (health behaviour) modification alone).18
In terms of categorical weight loss, 63.2% of patients on liraglutide lost ≥5% body weight at one year, compared with 27.1% of patients in the placebo group,1 33.1% and 10.6% of participants lost more than 10% of their body weight on liraglutide 3.0 mg and placebo, respectively.18
Patients with prediabetes were followed to three years, with sustained weight loss of -6.1% in the liraglutide group vs. -1.9% in placebo. Following a -6.0% weight loss with a low-calorie diet, liraglutide 3mg plus health behaviour counselling reduced weight by a further -6.2% at one year compared with -0.2% in the placebo group (ongoing health behaviour counselling alone).18
More patients on liraglutide 3mg were able to maintain the ≥5% run-in weight loss (81.4%) compared with those receiving placebo (48.9%). Fewer patients on liraglutide 3mg regained ≥5% body weight (1.9%) compared to placebo (17.5%).18
Assess the patient after three months on the therapeutic dose, based on whether they have been successful in preventing any of the aspects that are concerning, such as diabetes, prediabetes, and cravings. If these things have improved, continue treatment. If there are no or limited improvements, look at adding a second medication or stopping the first medication.18
Obesity management should be individualised and can either comprise one of the pillars mentioned above, or a combination of all three pillars, concluded Dr Wharton.1
Pillar 3: Recommended surgical interventions include sleeve gastrectomy, gastric bypass, or duodenal switch. Bariatric surgery can be considered:19
- For people with BMI ≥40 kg/m2 or BMI ≥35 kg/m2 with at least one obesity-related disease to reduce long term overall mortality, to induce control and possibly remission of T2DM, to improve many obesity-related diseases (eg cholesterol issues, hypertension, fatty liver), to induce long term weight loss, and to improve quality of life.
- In patients with poorly controlled T2DM despite optimal clinical management and Class I obesity (BMI between 30 and 35 kg/m2).
- For weight loss and/or to control obesity-associated diseases in patients with Class 1 Obesity (BMI 30-35), for whom optimal medical and behavioural management have been insufficient to produce significant weight loss.
These interventions should be supported by medical nutrition therapy (eg nutrition assessment, diagnostics, therapy, and counselling) and physical activity (30-60 minutes of aerobic activity on most days of the week at moderate to vigorous intensity), recommended Dr Wharton.1,18
1. Novo Nordisk Obesity Summit. https://app.gotowebinar.com/unified/index.html#/webinar/3063148551862069518/attend/9042421427299782923
2. WHO. Obesity & Overweight. 2020. Available from https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
3. Misra A, Chowbey P, Makker BM, et al. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. J Assoc Physicians India, 2009.
4. Stegenga H, Haines A, Jones K, et al. Identification, assessment, and management of overweight and obesity: summary of updated NICE guidance. BMJ, 2014.
5. Nakata Y, Okada M, Hashimoto K, et al. Weight Loss Maintenance for 2 Years after a 6-Month Randomised Controlled Trial Comparing Education-Only and Group-Based Support in Japanese Adults. Obes Facts, 2014.
6. Bosman R. SCALE-ing obesity. Specialist Forum, 2021.
7. Badman MK and Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science, 2005.
8. Wang YC, McPherson K, Marsh T, et al. Health and economic burden of the projected obesity trends in the USA and the UK. The Lancet, 2011.
9. The GBD 2015 Obesity Collaborators. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. NEJM, 2017.
10. Caterson ID, Alfadda AA, Auerbach P, et al. Gaps to bridge: Misalignment between perception, reality and actions in obesity. Diabetes Obes Metab, 2019.
11. Yaemsiri S, Slining MM, Agarwal SK, et al. Perceived weight status, overweight diagnosis, and weight control among US adults: the NHANES 2003-2008 Study. Int J Obes (Lond), 2011.
12. Saxon DR, Iwamoto SJ, Mettenbrink CJ, et al. Anti-Obesity Medication Use in 2.2 Million Adults Across 8 Large Healthcare Organizations: 2009-2015. Obesity (Silver Spring), 2019.
13. Hall K and Kahan S. Maintenance of lost weight and long-term management of obesity. Med Clin North Am, 2018.
14. Fothergill E, Guo J, Howard L, et al. Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity, 2016.
15. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. NEJM, 2011.
16. Van der Kolk BW, Muniandy M, Kaminska D, et al. Differential Mitochondrial Gene Expression in Adipose Tissue Following Weight Loss Induced by Diet or Bariatric Surgery. J Clin Endocrinol Metab, 2021.
17. Chen S-Y, Beretta M, Alexopoulos SJ, et al. Mitochondrial uncoupler SHC517 reverses obesity in mice without affecting food intake. J Metabol, 2021.
18. Pedersen SD, Manjoo P, Wharton S, et al. Canadian Adult Obesity Clinical Practice Guidelines: Pharmacotherapy in Obesity Management. https://obesitycanada.ca/guidelines/pharmacotherapy.
19. Pedersen S. From Pre- to Post-Bariatric Surgery: 2020 Canadian Adult Obesity Clinical Practice Guidelines. https://drsue.ca/2020/10/from-pre-to-post-bariatric-surgery-2020-canadian-adult-obesity-clinical-practice-guidelines/.