Royal Society of Medicine: Respect and Treat Obesity Like Any Other Endocrine Disease 

Becky McCall

Disclosures

September 30, 2020

Obesity should be respected equally with other endocrine diseases, and in managing patients with obesity, clinicians should make the most of the wide variety of treatments available and combine them if necessary.

This was the central message of a talk given by Dr Alex Miras, senior clinical lecturer and consultant in endocrinology at Imperial College London, to delegates gathered for the Royal Society of Medicine, Endocrinology and Diabetes section webinar series, entitled, EDN50: What's new in endocrinology and diabetes 2020?

He updated the virtual audience on the latest data and shared his expert opinion on lifestyle interventions, pharmacotherapy, bariatric surgery, and medical devices to improve weight, metabolic control, and diabetes-related microvascular complications.

Essentially, he said, obesity treatments only work if they increase satiety and reduce hunger. "All treatments are effectively trials for 3 to 4 months, so be ready to change if the patient doesn’t respond," he said, adding: "The treatment gap between non-surgery and surgery is getting smaller. I would also recommend you to be brave and use combination treatments."

A Potted History of Obesity as a Disease

Mean body mass index (BMI) has changed over recent years, so 150 years ago the mean BMI was 25 kg/m2 or less, said the clinician-researcher. "The environment has a large part to play. We are all surrounded by McDonalds but some of us maintain a healthy weight while others don’t. Why are some people more predisposed to obesity?"

Dr Miras pointed out that the contribution of genetics to our body weight is 70% to 80%, which is the same contribution that genes make to our height. "People with a high polygenic score [genes for weight and obesity] show a 12 kg difference from those with a low polygenic score at age 18."

He also highlighted that, contrary to popular belief, the genes linked to obesity are mainly expressed in the brain and central nervous system. "In particular, the obesity genes affect the white matter, including the hypothalamus and the brain stem, that controls appetite, hunger and satiety," he said. "The grey matter is not very good at supressing hunger, in the same way as we cannot supress breathing. We cannot think ourselves thin."

However, he noted that the brain can receive signals from the periphery, in particular the gut, which is the largest endocrine organ. "This is useful in finding ways to fool the system and achieve weight loss."

The World Health Organisation and many countries accept obesity as a chronic disease. However, here in the UK, the Minister for Health, Matt Hancock, does not accept it is a disease, he noted. "We choose to disagree."

"Importantly, we need to accept that obesity is a disease, and one of the brain, underpinned by genetics to a significant degree. I say the symptoms of this disease are high hunger and low fullness," asserted Dr Miras.

Treating Obesity – Identify the Responders

Turning to treating obesity as a disease, Dr Miras drew an analogy with smoking. "When someone arrives at the clinic with lung cancer, we don’t tell them to stop smoking, although it is a good idea to stop smoking. We treat them for the lung cancer because the prevention hasn’t worked for them."

With obesity, although prevention is important for the development of obesity, clinicians often return to this as a treatment for people with obesity, Dr Miras explained. "Prevention has not worked and these patients need treatment, and the only treatments that work are those that increase satiety and decrease hunger.

"I always tell my patients that if you go on a diet and feel hungry then it won’t work," he remarked.

Looking at each of the four key ways to treat obesity – low carbohydrate diet, drugs (such as liraglutide, Victosa, Novo Nordisk), devices (such as a duodenal liner), and bariatric surgery - Dr Miras said with any one method, some people will do very well, while others will not respond. "We need to identify the responders, which means understanding the metabolic dysregulation of someone with obesity and hitting the target with the right solution. A low carbohydrate diet will only work if a low carbohydrate diet relates to their metabolic dysfunction. Another patient might respond better to liraglutide, for example, so that is another target."

Once a response to a treatment is identified then it is essential to continue with the treatment long-term or there will be weight regain, he pointed out.

Dr Miras briefly reviewed some key trials from recent times that influence his prescribing habits.

The Look AHEAD randomised trial in patients with type 2 diabetes examined the long-term effects of a lifestyle intervention designed to achieve and maintain weight loss in individuals with type 2 diabetes who were also overweight or obese.

"This study found impressive reductions in weight in the first year but later on there was weight regain, and with physical fitness participants improved initially and then dropped back towards the control group. In terms of cardiovascular mortality, unfortunately, there was no benefit overall in the intervention groups," reported Dr Miras.

However, he asserted, those patients who lost more than 10% of body weight did experience significant reductions in CV outcomes. "This highlights the importance of choosing responders. Also, I believe that a 10% weight loss is a reasonable cut off point for significant improvements in health."

With the DiRECT trial, which involves starving a patient during the first few months and then reintroducing food gradually, Dr Miras remarked that there was a significant drop-out rate. "It is not my choice way of losing weight, but if the patient responds then carry on and that’s fine. Generally, I believe that a low carbohydrate and high protein diet is best for long term maintenance."

As an obesity physician, Dr Miras said he uses only one medication – orlistat (Xenical, Roche). It works by inhibiting lipases and therefore the absorption of dietary fat, so that the unabsorbed fat is excreted into the faeces. "It isn’t that effective, and people only lose around 2-3 kg in weight, but they also lose friends because of the side effects."

Now we are seeing significant improvements with use of glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 is secreted upon ingestion of food and signals that the stomach is ‘full’ by promoting satiety and reducing appetite in the brain. This is exactly what we want.

The SCALE trial of liraglutide shows a reduction in body weight of 8% over approximately a year, noted Dr Miras. "It isn’t yet approved by NICE [National Institute of Health and care Excellence] but hopefully this will happen in the next few months."

Dr Miras then referred to the UK-based STRIVE study that looks at use of liraglutide in severe and complex obesity. Participants receive standard care (obesity-specialist care), or a targeted prescribing pathway (obesity-specialist care plus targeted use of liraglutide 3.0mg, with pre-specified stopping rules for the medication. "If in the first 4 months a patient has not lost 5% of their body weight, then stop the treatment and start something else. This is true of whatever treatment is being given."

Semaglutide, another GLP-1 receptor agonist, at 2-4 mg will be available for use in weight loss in the UK in the next 18 months. "I think it will be a blockbuster drug with body weight loss of even 16%, which is coming close to what bariatric surgery can achieve," said Dr Miras. Oral semaglutide is already available in the UK for the treatment of diabetes.

The SELECT trial [Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity] investigates cardiovascular outcomes as well as weight loss. It looks at whether semaglutide may reduce the risk of having cardiovascular events in patients with overweight or obesity and with prior cardiovascular disease. 

Bupropion, a serotonin and noradrenaline re-uptake inhibitor used to aid smoking cessation, is another oral medication that can be used for obesity. It is available in the UK, but not endorsed for obesity by NICE, he said. "It can produce slightly more neuropsychiatric side effects."

Gap Between Non-surgery and Surgery Narrowing

Bearing all these pharmacotherapies in mind, Dr Miras pointed out that the treatment gap between lifestyle modification at one end of the weight loss scale, and gastric bypass at the other was narrowing. "It has been quite a wide gap. But slowly over the years it is getting narrower with use of medications but also with endoscopic treatments for obesity. These include, for example, gastric balloons, gastric reduction, aspiration therapy which involves removing food from the stomach after eating, and duodenal–jejunal bypass liners (EndoBarrier), and ablative duodenal resurfacing," said Dr Miras.

Duodenal–jejunal bypass liners are being trialled as a new alternative to more 'traditional' gastric bypass surgeries. The basic principle is that a sleeve is endoscopically-inserted into the duodenum, with an impervious liner extending into the small intestine, which prevents absorption of chyme by the duodenum or the proximal jejunum. 

"These are exciting ideas and interesting from a mechanistic perspective, but [they] usually have to be removed in 6-12 months, so these weight loss methods should be used as a bridge to something else, such as bariatric surgery, or [in preparation for] knee replacement surgery for example."

By far the most effective treatment for obesity is surgery, also known as bariatric surgery, said Dr Miras. "Gastric bypass is the most effective, but now sleeve gastrectomy has surpassed gastric bypass globally because it is laparoscopic and easier to do. Also, the gastric band, but this is infrequently performed these days."

National Institutes of Health/NICE guidelines recommend surgery for morbid obesity if BMI ≥ 40 kg/m2; BMI ≥ 35 with significant co-morbidities; and BMI ≥ 30 if the patient also has type 2 diabetes of less than 10 years duration, said Dr Miras.

"Currently we are combining treatment, so surgery and pharmacotherapy," said Dr Miras. "We did this in the GRAVITAS trial where we used a GLP-1 agonist (liraglutide) after surgery." Findings support the use of adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery.

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Obesity 

A number of audience members asked questions about use of GLP-1 agonists in obesity. In particular: how common are hypoglycaemic events with use of a GLP-1 agonist, and how long can a GLP-1 receptor agonist be used for?

"It is very unlikely that a patient will experience hypoglycemia, unless the patient is on other diabetes medications because they have type 2 diabetes too. In the absence of type 2 diabetes the incidence of hypoglycaemia is very low," he answered.

Regarding duration of use, Dr Miras said: "You can use a GLP-1 indefinitely in obesity if the drug results in weight loss; otherwise stop. We’ve been using this class of agent for over 13 years and they have proven incredibly safe."

Another question addressed how the NHS would be able to afford these many new treatments. "If we take 1% of the budget that goes towards the complications of obesity, for example, heart disease, or kidney disease, or osteoarthritis, then that is sufficient generally to pay for it," he said. "Long term cost effectiveness needs to be looked at for NICE. We need to remove the stigma in applying these treatments and apply them in the same way as we do with cancer or rheumatic disease."

COI: None declared.

Presented at the  Royal Society of Medicine, Endocrinology and Diabetes section webinar series, entitled, EDN50: What's new in endocrinology and diabetes 2020?    September 22,2020.

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