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Bridging the gap between medical science and policy to reduce the biggest 21st century healthcare burden

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Bridging the gap between medical science and policy to reduce the biggest 21^st century healthcare burden

In November 2018 the Mayor on London Sadiq Khan, announced that junk food adverts will be banned on all London transport from February 2019 in an attempt to reduce the “ticking time bomb” of childhood obesity in the city.

London has one of the highest obesity rates in Europe with some 40% of 10 to 11-year olds either overweight or obese, with children from more deprived areas disproportionately affected. Obesity is a common and costly source of type-2 diabetes (T2DM), which is much more aggressive in youngsters and complications of the condition - blindness, amputations, heart disease and kidney failure - can present earlier. What is happening in London and the UK is replicated in varying degrees in cities and nations throughout the world: there is a global epidemic of obesity and T2DM, which together is often referred to as ‘diabesity’.

The “good” news is that at the same time Khan announced the advertising ban, the UK’s national news outlets were reporting the product of four decades of scientific research, which suggested that T2DM could be reversed by a liquid diet of 800-calories a day for three months.

Although this offers hope for millions of people, an unresolved challenge is whether this simple and cheap therapy will be implemented effectively to significantly dent the burden of diabesity, which arguably is the biggest healthcare challenge of the 21^st century.

In this Commentary

We describe some of the research behind the news reports about the therapy to reverse T2DM. Although the scientists’ innovative solution of a low-calorie liquid diet has been adopted enthusiastically by some healthcare providers and organizations specifically set up to dent the burden of diabesity, it is questionable whether the gap between science and policy can be bridged. This, we suggest, is because the prevalence of diabesity is growing at a significantly faster rate than the effect of programs to prevent and reduce the condition.

Obesity and T2DM

Obesity, which is a significant risk of T2DM, is a complex, multifaced condition, with genetic, behavioural, socioeconomic and environmental origins. Diet and sedentary lifestyles may affect energy balance through complex hormonal and neurological pathways that influence satiety. Also, urbanization, the food environment and the marketing of processed foods are contributory factors to becoming overweight and obese. Notwithstanding, the main driver of weight gain is energy intake exceeding energy expenditure.

T2DM is a chronic, progressive metabolic disease, which until recently has been perceived as incurable. Although genetic predisposition partly determines the condition’s onset, being overweight and obese are significant risk factors. Generally accepted clinical guidelines to treat the condition is to reduce glycated haemoglobin (HbA1c) - blood sugar (glucose) - levels. The HbA1c test assesses your average level of blood sugar over the past two to three months. The normal range for HbA1c is 4% to 5.9%. In well-controlled diabetic patients HbA1c levels are less than 6.5% or 48mmol/moll. High levels of HbA1c mean that you are more likely to develop diabetes complications, such as serious problems with your heart, blood vessels, eyes, kidneys, and nerves. T2DM is treated primarily with drugs and generic lifestyle advice, but many patients still develop vascular complications and life expectancy remains up to six years shorter than in people without diabetes.

Obesity

The Organisation for Economic Co-operation and Development’s (OEDC) 2017 Health at a Glance Report warned that obesity in the UK has increased by 92% in the past two decades. Two-thirds of the UK’s adult population are overweight and 27% have a body mass index (BMI) of 30 and above, which is the official definition of obesity. In 2017 there were 0.6m obesity-related hospital admissions in the UK, an 18% increase on the previous year. Each year, obesity cost NHS England in excess of US$10bn in treatment alone.

A 2018 World Health Organization (WHO) report suggests that obesity globally has almost tripled since 1975. In 2016, more than 1.9bn adults, 18 years and older, were overweight. Of these over 650m were obese. According to a 2018 WHO report on childhood obesity 41m children under the age of 5 were overweight or obese in 2016 and over 340m children and adolescents aged 5-19 were overweight or obese.

Bad diets

Diets in the UK, and in most wealthy advanced industrial economies, tend to have insufficient fruit and vegetables, fibre and oily fish and too much added sugar, salt and saturated fat. Rising consumption of processed food and sugary drinks are significant contributors to the global obesity epidemic. A typical 20-ounce soda contains 15 to 18 teaspoons of sugar and upwards of 240 calories. A 64-ounce cola drink could have up to 700 calories. People who consume such drinks do not feel as full as if they had eaten the same number of calories from solid food and therefore do not compensate by eating less. While healthy diets are challenging for most populations, low income levels and poor education are associated with less healthy diets.

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T2DM brief epidemiology

Almost 4.6m people in the UK and 30m Americans are living with diabetes: 90% of whom have T2DM. It is estimated that 12.3m people in the UK and some 70m in the US are considered pre-diabetic, which is when you have high blood glucose levels, but not high enough to be diagnosed with diabetes. The first WHO Global report on diabetes published in 2016 suggests that 422m adults (1 in 11) worldwide are living with the condition, which has quadrupled over the past three decades. The International Diabetes Federation (IDF) estimates that this figure will rise to 642m by 2040. A further challenge is the undiagnosed. A December 2017 paper in Nature Reviews: Endocrinology suggests 46% of all cases of diabetes globally are undiagnosed and therefore at enhanced risk of complications. Until complications develop, most T2DM patients are managed within primary care, which constitutes a significant part of general practice activity. International data suggest that medical costs for people with diabetes are two to threefold greater than the average for people without diabetes.

T2DM treated but not cured

The most common therapy for T2DM patients who are overweight is metformin, which is usually prescribed when diet and exercise alone have not been enough to control your blood glucose levels. Metformin reduces the amount of sugar your liver releases into your blood and also makes your body respond better to insulin. Insulin is a hormone produced by your pancreas that allows your body to use sugar from carbohydrates in food that you eat for energy or to store glucose for future use. The hormone helps to keep your blood sugar levels from getting too high (hyperglycaemia) or too low (hypoglycaemia). Metformin does not cure T2DM and does not get rid of your glucose, but simply transfers your excess sugar from your blood to your liver. When your liver rejects your excess sugar, the medicine passes the glucose onto other organs: kidneys, nerves, eyes and heart. Much of your excess sugar gets turned into fat and hence you become overweight or obese. T2DM has long been understood to progress despite glucose-lowering therapy, with 50% of patients requiring insulin therapy within 10 years. This seemingly inexorable deterioration in control has been interpreted to mean that T2DM is treatable but not curable. Research briefly described in this Commentary suggests that T2DM can be beaten into ‘remission’, but it requires losing a lot of weight and keeping it off.

Reversing T2DM

Over the past decade a series of studies, led by Roy Taylor, Professor of Medicine and Metabolism at the University of Newcastle, England and colleagues from Glasgow University have explored the notion that losing weight could be the solution for controlling T2DM and lowering the risk of debilitating and costly complications.

Findings of a study in the December 2017 edition of the Lancet, suggested that nearly 50% of people living with T2DM who had participated in a low-calorie liquid diet of about 800 calories a day for three to five months had lost weight and had reverted to a non-T2DM state. The study was comprised of 298 adults between 20 and 65 who had been diagnosed with T2DM within the past six years drawn from 49 primary care practices in Scotland and Tyneside in England. Half of the practices put their patients on the low-calorie diet, while the rest were in a control group and received the standard of care of anti-diabetic medicines to manage their blood glucose levels. About 46% of 149 individuals with T2DM who followed a weight loss regimen achieved ‘remission’, which the study defined as a HbA1c of less than 6.5% after one year. Only 4% of the control group managed to achieve ‘remission’. ‘Remission’ rather than ‘cure’ was used to describe the reversal of T2DM because if patients put weight back on, they may become diabetic again. Results improved according to the amount of weight lost: 86% of those who lost more than 33 pounds attained remission, while 57% of those who lost 22 to 33 pounds reached that goal.

Another paper by Taylor and his colleagues published in the October 2018 edition of Cell Metabolism, examined reasons why substantial weight loss - (15kg) in some patients - produces T2DM remission in which all signs and symptoms of the condition disappear, while in other patients it does not. Using detailed metabolic tests and specially developed MRI scans, Taylor observed that fat levels in the blood, pancreas and liver were abnormally high in people with T2DM. But after following an intensive weight loss regimen, all participants in the study were able to lower their fat levels. As fat decreased inside the liver and the pancreas, some participants also experienced improved functioning of their pancreatic beta cells, which store and release insulin, controls the level of sugar in their blood and facilitates glucose to pass into their cells as a source of energy. The likelihood of regaining normal glucose control depends on the ability of the beta cells to recover. But, losing less than 1gm of fat from your pancreas through diet can re-start your normal production of insulin and thereby reverse T2DM.

“The good news for people with T2DM is that our work shows that you are likely to be able to reverse T2DM by moving that all important tiny amount of fat out of your pancreas. At present, this can only be done through substantial weight loss,” says Taylor.

While a significant proportion of participants in Taylor’s study responded to the weight loss program and achieved T2DM remission, others did not. To better understand this, researchers focused on 29 participants who achieved remission after dieting and 16 who dieted but continued to have T2DM. Taylor and his colleagues observed that people who were unable to restart normal insulin production had lived with T2DM for a longer time than those that could. Individuals who had lived with T2DM for an average of 3.8 years could not correct their condition through weight loss, while those who had the condition for an average of 2.7 years were able to regain normal blood sugar control.

“Many [patients] have described to me how embarking on the low-calorie diet has been the only option to prevent what they thought - or had been told - was an inevitable decline into further medication and further ill health because of their diabetes. By studying the underlying mechanisms, we have been able to demonstrate the simplicity of T2DM and show that it is a potentially reversible condition. but commencing successful major weight loss should be started as early as possible,” says Taylor.

Click on Newcastle University to find out more information about reversing T2DM by weight loss.

Bridging the gap between science and policy

Taylor and his colleagues describe their research findings as “very exciting” because “they could revolutionise the way T2DM is treated”, but caution that a series of management issues will need to be overcome before their therapy becomes common practice. This includes, (i) familiarizing primary care doctors and T2DM patients with the treatment regimen, (ii) establishing a generally accepted standard for what actually constitutes “remission”. Taylor and colleagues recommend “remission” to be when a patient has not taken diabetes medicines for at least two months and then has two consecutive HbA1c levels, taken two months apart, which are less than 6.5%. Researchers also recommend that data on T2DM reversal rates should be routinely collected, stored, analysed and reported.

Notwithstanding, the ‘elephant in the room’ is the vast extent of diabesity, the eye-watering rate at which it is growing and the general ineffectiveness of policy makers and prevent programs to dent the burden. Research findings presented at the 2018 European Congress on Obesity in Vienna emphasize the magnitude of the problem. If current trends continue, almost a quarter (22%) of the world’s population will be obese by 2045 (up from 14% in 2017), and 12% will have T2DM (up from 9% in 2017). Findings also suggest that in order to prevent the prevalence of T2DM from going above 10% by 2045, global obesity levels must be reduced by 25%. The problem is no less grave at the national level. For example, in the UK, if current trends continue obesity will rise from 32% today to 48% in 2045, while diabetes levels will rise from 10.2% to 12.6%, a 28% rise. This is unsustainable. Here’s the challenge for policy makers.

To stabilise UK diabetes rates over the next 25 years at 10%, which is high and extremely costly, obesity prevalence must fall from 32% to 24%. Similarly, in the US, if current trends continue over the next 25 years, then to keep diabetes rates stable over the same period, obesity in the US would have to be reduced by 10%: from 38% today to 28%.

Takeaways

Taylor and his colleagues have delivered a simple and cheap solution to one of the biggest burdens of the 21^st century. But unless there is effective strategy to implement this solution the four decades of research undertaken by Taylor and his colleagues will be wasted. Previous Commentaries have described the vast and crippling burden of diabesity and the failure of well-funded programs to make any significant dent in this vast and escalating burden, which is out of control. We have suggested, this is partly because, at the operational level, programs have tended to be predicated upon inappropriate, old fashioned, 20^th century organizational methods and technology and focused on “activities” rather than “outcomes”. At a policy level, government agencies have systematically failed to slow the rise of processed food becoming the “new tobacco”. Most UK endeavours to reduce the burden of diabesity are like putting up an umbrella to fend off a tsunami. This must change if we are to harness and effectively deploy the research findings of Professor Taylor et al.

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A new therapeutic approach to pre-diabetes

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A recent study suggests that a drug combined with dietary and lifestyle changes can prevent those with pre-diabetes from progressing to full blown type-2 diabetes (T2DM)
T2DM kills millions and cost billions
35% of adults in the UK, and 50% in the US now have prediabetes
The UK has launched the world’s first nationwide diabetes prevention program called Healthier You based on personal education and training
Prevalence rates of T2DM are still rising
Research on the gut-brain axis suggests that drugs have a role to play in preventing T2DM
An optimum strategy might consist of appropriate drug therapy combined with appropriate education, which leverages ubiquitous 21^st century communications infrastructures

A new therapeutic approach to pre-diabetes

Findings of an international clinical study published in The Lancet in 2017 suggest that 3.0mg of the drug liraglutide, may reduce diabetes risk by 80% in individuals with pre-diabetes and obesity, and thereby significantly contribute to the prevention of type-2 diabetes (T2DM). The study investigated whether 3.0mg of liraglutide would delay the onset of T2DM safely in people with pre-diabetes.

Liraglutide is the active solution in a drug marketed as Victoza, which obtained FDA approval in 2010. Victoza is available in 6 mg/ml pre‑filled pens, and is used as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. Victoza is used also as an add-on to other diabetes medicines, when these, together with exercise and diet, are not providing adequate control of blood glucose.

Pre-diabetes

Pre-diabetes is a condition that develops when your blood sugar levels are at the very high end of the normal range, but not quite high enough for a diagnosis of T2DM. Risk factors include age, weight and ethnicity. People of South Asian origin are up to six times more likely to develop pre-diabetes as a genetic susceptibility means they start to develop insulin resistance at a much lower Body Mass Index (BMI). With pre-diabetes your body begins to have trouble using the hormone insulin, which is necessary to transport glucose, which your body uses for energy, into your cells via the bloodstream. Pre-diabetes means that your body either does not make enough insulin or it does not use it well (insulin resistance). If you do not have enough insulin or if you are insulin resistant, you can build up too much glucose in your blood, leading to higher-than-normal blood glucose level and perhaps pre-diabetes. Blood glucose is measured using a test called HbA1c, which provides a picture of your blood sugar levels over the past two to three months. It counts the number of glucose molecules stuck to the red blood cells, which reveals how much sugar you have carried in your blood over the two to three month lifespan of the red blood cell. If your blood sugar is between 5.7 to 6.4%, this is called pre-diabetes (6.5 is officially diabetes). Dr Roni Sharvanu Saha, a consultant in acute medicine, diabetes and endocrinology at St George's Hospital, London describes pre-diabetes:

Prevalence and cost

It is estimated that 35% of adults in the UK, and 50% in the US now have pre-diabetes. Around 5-10% of these will progress to "full-blown" T2DM in any given year. Because there are no obvious symptoms for pre-diabetes the overwhelming majority of people with the condition do not know they have it, and are not aware of the long-term risks to their health, which include T2DM and its complications: heart attack, stroke, kidney failure, blindness and lower limb amputation. Over the past decade, the prevalence of T2DM has increased by almost two-thirds, and is now one of the world’s most common long-term health conditions.

An estimated £14bn is spent each year on treating diabetes and its complications in the UK. Treating obesity-linked illnesses costs £10bn a year. The annual medical cost of treating diabetes in the US is about US$176bn, and the cost of diabetes in reduced productivity is some US$69bn each year.

The gut-brain axis

The study published in The Lancet was led by John Wilding, Professor of Medicine, University of Liverpool, and is a continuation of work he started in 1996 when part of a team at Hammersmith Hospital in London, which first showed that the hormone GLP-1, on which liraglutide is based, was involved in the control of food intake.

Over the past two decades scientists have increased their understanding of the two-way communications between the gut and the brain, not only through nerve connections between the organs, but also through biochemical signals, such as hormones that circulate in the body. Dr Sufyan Hussain, Specialist Registrar and Honorary Clinical Lecturer in Diabetes, Endocrinology and Metabolism at Imperial College London, describes the gut-brain axis.

Targeting gut-brain pathways

An increasing number of different gut microbial species are now postulated to regulate brain function in health and disease. The westernized diet, which is high in saturated fats, red meats, and carbohydrates, and low in fresh fruits and vegetables, whole grains, seafood, and poultry, is hypothesized to be the cause of high obesity levels in many countries. For example, 63% and 69% of adults in the UK and US respectively are either overweight or obese, and therefore at risk of T2DM. Experimental and epidemiological evidence suggest that the gut microbiota is responsible for significant immunologic, neuronal, and endocrine changes that lead to obesity. The gut–brain axis influences obesity, and researchers such as Wilding have targeted communication pathways between the nervous system and the digestive system in an attempt to treat metabolic disorders.

Bariatric surgery and diabetes

A previous HealthPad Commentary describes how bariatric surgery is associated with gut-brain signals, which promote the remission of diabetes in patients. Many of the mechanisms that underlie how bariatric surgery produces metabolic benefits remain unclear, but researchers do know that such surgical procedures elevate levels of the hormones peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) that help to reduce appetite and have effects on the central nervous system.

Liraglutide

Liraglutide is a GLP-1 receptor agonist, which interacts with the part of the brain that controls appetite and energy intake. The drug slows food leaving the stomach, helps prevent your liver from making too much sugar, and helps the pancreas to produce more insulin when your blood sugar levels are high. The most common side effects with liraglutide are nausea and diarrhoea.

The clinical study

The three-year study followed 2,254 adults with pre-diabetes at 191 research sites in 27 countries worldwide. Participants were randomly allocated to either liraglutide or a placebo delivered by injection under the skin once daily for 160 weeks. Participants in the study were also placed on a reduced calorie diet and advised to increase their physical activity. The study showed that three years of continuous treatment with once-daily 3.0mg of liraglutide, in combination with diet and increased physical activity, reduces the risk of developing T2DM by 80% and results in greater sustained weight loss compared to the placebo.

"On the basis of our findings, liraglutide 3.0mg can provide us with a new therapeutic approach for patients with obesity and pre-diabetes to substantially reduce their risk of developing type 2 diabetes and its related complications . . . . It is very exciting to see a laboratory observation translated into a medicine that has the potential to help so many people, even though it has taken over 20 years,” says Wilding.

World’s first nationwide diabetes prevention program

NHS England, Public Health England and Diabetes UK launched the world’s first nationwide diabetes prevention strategy, Healthier You, in 2016. It provides personal coaches to educate people at risk of T2DM in healthy eating and lifestyle, and personal trainers to provide bespoke physical exercise programs that are expected to help people lose weight. By 2020 Healthier You expects to be rolled out to the whole country with 100,000 referrals available each year after that.

Extrapolating from previous studies

International clinical studies have shown evidence that lifestyle interventions such as those used in Healthier You can prevent or delay the onset of T2DM. However, the validity of generalizing the results of previous prevention studies is uncertain. Interventions that work in some societies may not work in others, because social, economic, and cultural forces influence diet and exercise. The UK’s Public Accounts Committee has expressed doubts about the way Healthier You is setting about its task, and has warned that, "By itself, it will not be enough to stem the rising number of people with diabetes".

Failure of the diabetes establishment and the Public Accounts Committee

Healthier You is a slow, labor-intensive and expensive program, which is unlikely to have more than a relatively small impact.Let us explain. Assume that after 2020 Healthier You obtains its projected annual 100,000 referrals, and that they all successfully reduce their blood glucose levels with diet and exercise. Also assume that the prevalence of pre-diabetes in the UK does not increase, (which is not the case) then Healthier You will take more than 110 years to counsel the estimated 11.5m people in the UK with pre-diabetes: which is long after most people with pre-diabetes would have died from natural causes.

21^st century communications

Successfully changing the diets and lifestyles of the 11.5m people in the UK believed to have pre-diabetes, and slowing their progression to T2DM will require 21^st century technologies. Inexpensive and ubiquitous healthcare technologies used to educate and support diets and lifestyles abound. Increasingly people are demanding devices that track weight, blood pressure, daily exercise and diet. From apps to wearable’s, healthcare technology lets people feel in control of their health, while also providing health professionals with more patient data than ever before. With more than 100,000 healthcare apps, rapid growth in wearables, and 75% of the UK population now owning a smartphone, digital technology is well positioned to significantly improve healthcare education and management.

Takeaways

Has Healthier You missed the elephant in the room? Wilding’s study suggests that an exercise and diet program needs to be complemented with a sustained program of appropriate drugs if we are to reduce those with pre-diabetes from progressing to full blown T2DM. Further, simple arithmetic suggests that the education element of such a strategy about diet and lifestyle should leverage ubiquitous 21^st century communications infrastructures if they are to be efficacious.

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Pre-diabetes

Roni Sharvanu Saha

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Sufyan Hussain

Consultant Physician in Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust

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Dr Sufyan Hussain is Consultant Physician in Diabetes and Endocrinology at Guy's and St Thomas' NHS Foundation Trust, London, Honorary Senior Clinical Lecturer at King's College London and Honorary Clinical Lecturer in Diabetes, Endocrinology and Metabolism at Imperial College Healthcare NHS Trust and Imperial College London.

A former Wellcome Trust Clinical Research Fellow And Darzi Fellow in Clinical Leader ship at Imperial College London, Dr Hussain completed his medical degree and MA in molecular sciences from the University of Cambridge. He served as a Visiting Research Fellow at Joslin Diabetes Center, Harvard Medical School.

He completed a PhD in neuroendocrinology investigating how the brain controls appetite and blood glucose.