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  • Diabetic foot ulcers (DFUs) are a result of diabetes complications and can lead to amputations and death
  • Scientists and clinicians struggle to reduce the vast and escalating burden of DFUs
  • In wealthy countries like the UK there are specialist multidisciplinary diabetic foot clinics
  • New and innovative therapies are beginning to emerge, which accelerates the rate of complete wound closure for DFUs
  • Notwithstanding new products coming to market, the best therapy is prevention
  
The vast and rapidly growing burden of diabetic foot ulcers and amniotic tissue
 
This Commentary discusses diabetic foot ulcers (DFUs) within the context of chronic wounds. Although chronic wounds tend to be an overlooked area of medicine and do not feature prominently in the popular media; NHS England, spends £5bn a year treating 2m patients with chronic wounds. The incidence rates of people affected with wounds are rising fast and some experts suggest that nearly 60% of all wounds become chronic. According to Una Adderley, a wound expert and Director of NHS England’s National Wound Care Strategy Programme, therapy in England for chronic wounds is patchy and suboptimal, “leading to non-healing or delayed healing (which) increases the number of people living with chronic wounds. Too many people are receiving care for which there is little evidence that it works and too few are receiving care for which there is strong evidence that it works”.
 
According to a 2019 report by the consulting firm MarketsandMarkets the global wound care market in 2019 is estimated to be US$20bn and projected to reach US$25bn by 2024. Market drivers include the vast and fast-growing incidence rates of hard-to-heal chronic wounds, a large proportion of which are associated with diabetes, increasing R&D spending, technological developments, the growing use of regenerative medicine in wound care, recent advances in molecular data that have contributed to genome sequencing, and the increasing use of AI in the management of wound care solutions. The chronic wound care markets of North America and Europe are expected to grow at a CAGR of ~4.5% for the next 5 years, but the highest CAGR is expected in Asia where the vast pool of patients is increasing significantly, and favourable reimbursement policies are expected to persist in the region for the next decade. 

When accompanied by an underlying condition such as diabetes, chronic wounds in the form of DFUs, are challenging to heal and have a deleterious effect on your quality of life: you experience pain, suffering, disfigurement, anxiety impaired mobility, malodour and social isolation. Because the prevalence of diabetes is increasing worldwide, DFUs have become a large, severe and growing public health issue as described in two research papers published in 2019.
 
One, published in the May 2019 edition of Diabetic Medicine, reports findings of an 18 year study of DFUs, and suggests that although current therapies in the UK result in better than previously reported survival in persons < 65 years (10 year survival is 85%), treatments fail to, “reduce recurrent incidence (of DFUs and) cumulative prevalence of all ulcers continues to increase”; from 20.7 to 33.1 per 1,000 persons between 2003 to 2017. The second paper, published in the January-March 2019 edition of the International Journal of Applied Basic Research, report sfindings of a prospective Indian study of 63 patients >18 with DFUs and shows the increase in the severity of DFUs and the consequent increase in the rate of hospital readmissions, amputations and mortality.
 
In this Commentary
 
This Commentary briefly describes the increasing prevalence of diabetes and its complications, the causes and symptoms of DFUs, which benefit from specialist multidisciplinary clinics and strategies to prevent them deteriorating to the point where the only therapy is amputation. We complete the Commentary by briefly mentioning how human amniotic membrane is being used in the current standard of care as a therapy for DFUs and describe the findings of two amniotic membrane studies. Notwithstanding these and other new product offerings coming to market, which accelerate the closure of DFUs, the most efficacious therapy for DFUs is prevention.
 
Diabetes and DFUs
 
Diabetes is a chronic disease that occurs either when your pancreas does not produce enough insulin or when your body cannot effectively use the insulin it produces. Insulin is a hormone that regulates your blood sugar level. High blood sugar levels (hyperglycaemia) is a common effect of uncontrolled diabetes and can lead to serious complications, which include blindness, kidney failure, heart attacks, stroke, diabetic foot ulcers (DFUs), and lower limb amputations. According to the World Health Organization, the global prevalence of diabetes among people >18 has risen from 4.7% in 1980 to 8.5% in 2014. Today, some 422m people worldwide have diabetes, which has increased from 108m in 1980. There is expected to be some 642m people >18 living with diabetes by 2040.
 
If you have diabetes you are prone to ulcers because your increased blood sugar levels create thick, sticky blood, which can lead to  peripheral artery disease (PAD), neuropathy (a loss of sensation due to nerve damage), and/or problems with circulation due to damage to your small blood vessels, which reduce your body’s ability to heal injuries.
 
Signs and symptoms of DFUs include numbness in your toes and a loss of feeling in your feet, painful tingling sensations, blisters, minor abrasions and cuts without pain that do not heal, skin discoloration and temperature changes  With a loss of sensation, a minor injury to your foot can go unnoticed and untreated, and quickly lead to an ulcer. If you are living with diabetes, ulceration is an ongoing challenge. Only about 66% of DFUs eventually heal without surgery. If you have had a foot ulcer you are at increased risk of further ulceration. Studies suggest that around 25% of people living with diabetes who become ulcer-free have developed new ulcers within 3 months, and 34% to 41% within 12 months. Some foot ulcers are painful, and treatment often requires that you spend a significant amount of time visiting clinics to frequently change your wound dressings. The poor prognosis of DFUs is often attributed to other complications of diabetes such as peripheral neuropathy, peripheral vascular disease and persistent hyperglycaemia. Managing diabetic foot ulcers is a major challenge for healthcare systems globally and the main cause of more than half of nontraumatic lower limb amputations: every 30 seconds in the world, a lower limb is amputated due to diabetes. Amputations have life-altering repercussions for patients and represent a significant burden for the healthcare industry as a whole. Between 0.03% and 1.5% of people with DFUs require an amputation and most amputations start with ulcers.

 
Major amputations and mortality rates
 
For major amputations, the prognosis is poor because your other limb is at risk.  Research suggests that only around 50% of patients survive for two years after major diabetes related amputations. The one-year mortality rate has been estimated at 32.7% after major amputation and 18.3% after minor amputation if you have diabetes. Five-year cumulative mortality for patients with diabetes undergoing a first major amputation has been estimated at 68% to 78.7%. Thus, if you have diabetes and a DFU you have almost a 50% chance of being dead within five years, which is significantly higher than for people with either breast (18%) or prostate (8%) cancers.

 
The UK
 
In the UK some 70,000 to 90,000 people living with diabetes have DFUs at any one time. If you have diabetes you are about 23 times more likely to experience an amputation than someone without diabetes. In England, diabetes leads to more than 9,000 lower limb amputations each year. Each week in England some 169 people undergo an amputation procedure as a result of diabetes. Analysis by the charity Diabetes UK found that between 2014 and 2017, 26,378 people had lower limb amputations linked to diabetes, which represented a 19% rise from 2010 to 2013. Diabetes affects almost 3.7m people in the UK. In 2017 NHS England launched a special transformation fund aimed at improving patients with diabetes access to specialist multidiscipline foot care clinics to help avoid amputations.

 
Specialist multidisciplinary treatment centres
 
In the video below Hisham Rashid, Consultant Vascular Surgeon at King’s College Hospital, London, describes a DFU and explains why they benefit from specialist multidisciplinary treatment centres. “DFUs have similar features to other ulcers, and often present in the toes and heal areas of the foot with the loss of skin and an exposed base with infection and necrosis. The significant difference is that a DFU usually comes with multiple pathologies, which, in addition to infection, include neuropathy and peripheral vascular disease. DFUs do not heal quickly and often require vascular surgeons working closely with radiologists, orthopaedic surgeons to correct any deformity and a microbiology unit to manage infection,” says Rashid.

 
What are diabetic foot ulcers?
 
Why does therapy for diabetic foot ulcers complications require a special center?

Rashid also explains that different therapies are used to heal DFUs. “If the patient has peripheral artery disease (ischaemia) then this has to be treated first with an angioplasty or a bypass or both to improve blood circulation into the foot. Once this is achieved, the ulcer is debrided and dressed. There are different dressings, which include negative pressure dressing, which sucks the blood into the tissues and thereby promotes healing. Sometimes skin graphs are necessary to get the tissue to heal faster. This can be done as a day surgery using local anaesthetic,” says Rashid.
 

How do diabetic foot ulcers heal?

Prevention of DFUs
 
Given the severity of DFUs and their vast and rapidly increasing burden on individuals with diabetes and healthcare systems, increasing attention is being devoted to prevention,  which involves adequate glycaemic control and modification of risk factors. While education is an obligation of healthcare professionals, it is crucial that people living with diabetes themselves increase their awareness and understanding of the condition and integrate regular feet examination and care into their daily lives.  In the video below, Roni Sharvanu Saha, Consultant in Acute Medicine, Diabetes and Endocrinology, St George’s Hospital, London, suggests that, “We’re getting better at understanding why DFUs occur, and better at examining peoples’ feet. In England, if you have diabetes you are entitled to a clinical examination of your feet at least twice a year. Checks include whether you have any minor abrasions, or whether you can distinguish hot and cold water with your feet, and  signs that you might have problems with your circulation and nervous system. Ensuring that people living with diabetes receive regular checks means that if you have reduced or poor circulation, you’re referred to the correct specialty team in order to protect you from developing DFUs. Prevention is better that cure. If we can get better at examining feet, outcomes will improve. If diabetes is not controlled complications will occur”.
 
 
New therapies and amniotic membrane
 
With the well-being of millions of people living with diabetes at stake, there is a pressing need for therapies that bring DFUs to closure as quickly as possible. The current standard of care (SOC) regimen for DFUs involves maintaining a moist wound environment, debriding nonviable tissue, relieving pressure with an offloading boot and preventing or managing wound infection. Even with a good SOC, DFUs are notoriously slow to close, creating a demand for new and innovative medicines and techniques to enhance closure. Increasingly, there are advanced therapies to facilitate healing DFUs when traditional approaches fail.
 
An example of a relatively new product to help close DFUs is human amniotic membrane.  Amniotic membrane has been used for wound healing purposes since the early 20th century, but it represents a relatively recent and promising advanced therapy to accelerate healing in DFUs. Amniotic membrane is derived from the human placental sac that supports the foetus by forming the inner lining of the amniotic cavity. Functions of amniotic membrane include the exchange of water-soluble molecules and the production of cytokines and growth factors  to facilitate the development of the foetes. The anatomic makeup of amniotic membrane dictates its functionality, and a significant characteristic is its ability to produce a wide variety of regenerative growth factors that facilitate foetal development. These growth factors, in combination with various other cytokines, have substantial potential benefits in wound healing, which include creating a structural scaffold for tissue proliferation, modulating the immune response, reducing inflammation, stimulating angiogenesis and facilitating tissue re-modelling.

 
Two studies of human amniotic membrane products used in wound healing

Two small but significant prospective cohort studies on the effectiveness of human amniotic tissue to treat DFUs were reported in the journal Wounds. One in the March 2016 edition and another in the November 2017 edition. The first is a prospective, randomized, multicentre, controlled study and the second a retrospective cohort study of 20 patients. In both studies amniotic membrane is used in combination with SOC, including debridement, well-controlled offloading, management of bacterial burden, and adequate perfusion.
 
Both studies suggested that the use of amniotic membrane is more likely to: (i) lead to complete wound closure, (ii) accelerate the rate of wound closure, and (iii) present no additional safety risks when compared to SOC alone in the treatment of DFUs. The first study demonstrated a statistically significant advantage of an amniotic membrane as compared to SOC in facilitating closure of chronic DFUs. 45% of participants achieved complete wound closure, while 0% of SOC participants alone achieved complete wound closure within 6 weeks. Further, there appears to be no increased rate of adverse events associated with the use of amniotic membrane in these wounds. The second study was a retrospective cohort study using a human amniotic membrane on 20 patients presenting with DFUs and venous leg ulcers. Patients underwent a 2-week ‘run-in’ period with good SOC; and if upon their return the ulcer had closed ≥ 30% in area, the subject was excluded from participation in the study. All wounds were effectively closed in approximately 10 weeks, DFUs in 12 weeks and venous leg ulcers in 9 weeks, and no adverse events were noted, suggesting that the therapy using human amniotic membrane is safe.
 
Discussion
 
The most significant limitation of both studies is their small sample size, which decreases the generalizability of their findings. Notwithstanding, the studies suggest that amniotic tissue products are efficacious options for DFUs when used in conjunction with the current SOC, which includes aggressive sharp debridement, adequate offloading and the application of sterile dressings. Further, amniotic membrane, like most biologic tissue products, requires significant processing and therefore its cost is relatively high: on average between US$500 to US$1,000 per application. Notwithstanding, these costs are significantly less than the average annual therapy cost of US$28,000 per patient for SOC for a DFU. And therefore, using amniotic tissue in the therapy for DFUs could result in significant savings for healthcare systems. Tissue storage as well as the time and skill required to apply amniotic membranes also represent challenges inherent to these products.
 
Takeaways
 
Millions of people are living with diabetes, which, if not managed appropriately can lead to life-changing complications. A DFU is one such complication, which often starts with a minor abrasion on your ankle or toe that you do not feel and therefore tend not to perceive to be important, until that is, it quickly escalates into a chronic wound that does not heal and eventually leads to a lower limb amputation. In most wealthy nations, health providers are aware of the dangers of DFUs and have set up multi-disciplinary diabetic foot clinics to treat and manage the condition. However, access to such clinics is patchy and the prevalence of DFUs continues to increase, and the eye-watering costs of treating and managing DFUs continue to escalate. In recent years, the therapy for DFUs has been improved by technological advances. We describe one of these: the use of amniotic tissue in conjunction with standard of care protocols. Recent research findings suggest that the use of amniotic tissue holds out the possibility not only of significant therapeutic benefits, but also of substantial cost savings for healthcare systems. Notwithstanding, perhaps the most efficacious therapy for DFUs is prevention. This means investing in effective education and awareness programs, good glycaemic control and appropriate footwear; encouraging people living with diabetes to participate in regular foot examinations and screening for peripheral neuropathy and peripheral arterial disease, and insisting that early telltale signs of foot wounds, no matter how minor, should be immediately referred to a specialist clinic.
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Dr. Vidya Kanthi qualified at UCL in 2007 and entered the Specialist GP Register in 2012, subsequently joining the Hertfordshire Performer’s List in 2016. Dr. Kanthi is a Clinical Diabetes Lead in her Clinical Commissioning Group (CCG) and is also a Project Lead for Herts Valleys Integrated Diabetes Service.

In her role as an NHS GP Appraiser, Vidya is responsible for assessing the quality of care provided by a myriad of GP’s across the South East. Dr. Kanthi is also an Educational Supervisor for the national Physician Associate training programme.


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  • Diabulimia is when people with type-1 diabetes (T1DM) ration their insulin to lose weight
  • People with T1DM who reduce their insulin lose weight but increase their likelihood of serious complications and death
  • Diabulimia is neither an official medical nor psychiatric disease state but its prevalence is relatively high and increasing
  • Diabulimia is challenging to diagnose partly because it is a portmanteau of 2 separate conditions and people with the condition often keep the bulimic aspect secret
  • Recently research into the condition and a clinic dedicated to diabetes and eating disorders have been launched in London
  • These initiatives are expected to increase our understanding of diabulimia, improve screening and treatment options and provide integrated medical and psychiatric support for people with the condition

Diabulimia - the world's most dangerous eating disorder

In January 2019 the UK’s National Institute for Health Research (NIHR) awarded clinician scientist Marietta Stadler, from King's College Hospital, London, £1.2m to fund research into diabulimia, an eating disorder in which people living with T1DM deliberately and regularly restrict their prescribed insulin dosage for the purpose of weight loss.

Diabulimia is a media-coined term and only recently has it been considered as a separate disease state although it is still not formally recognised as such. We start this Commentary by briefly describing some aspects of the history of the condition.
  • On 27th September 2011 Sian, the 24-year-old daughter of UK parliamentarian George Howarth, died from complications related to T1DM. As a teenager Sian had not kept up with her medication, she had missed appointments with doctors and dieticians, and was suffering from depression as a result of the condition. Sian had also developed neuropathy, which is damage to the nerves caused by T1DM. Since his daughter’s death Howarth has campaigned to raise awareness of diabulimia.
  • In 2012 Maryjeanne Hunt published a book entitled Eating to Lose: Healing from a Life of Diabulimia, in which she describes her struggle with the condition.
  • On 13th February 2013 the UK’s South London and Maudsley NHS Trust (SLaM) published an   article entitled, The Growing Problem of Diabulimia. According to Janet Treasure, Professor of Psychiatry and Director of Eating Disorder Services at SLaM, “it is estimated that 40% of T1DM females aged between 15-30 regularly omit insulin for weight control”.
  • In the July 2014 edition of Clinical Nursing Studies, a review paper concluded that diabulimia, “is not often recognized by primary healthcare providers or members of the individual’s family. If diabulimia is detected early, interventions can be implemented to minimize the risk of early morbidity and mortality”.
  • In January 2017 the UK's first diabetes and eating disorder out-patient service began working with young women living with diabulimia. Until then people in the UK with diabetes and eating disorders have been able to seek help for one or the other of the conditions, but never together. At the time of the clinic’s launch, Jonathan Valabhji, NHS England’s national clinical director for diabetes and obesity, said: “As a diabetes clinician I’ve seen first-hand the devastating impact that this condition can have on people and their families, and so these services are an important step forward in the recognition of diabulimia”.
  • In early 2017 the UK’s National Institute of Health and Care Excellence (NICE) upgraded its guidelines and quality standards for T1DM to feature psychological support related to the increased prevalence of eating disorders and the potential for insulin omission in people with T1DM.
  • On 4 August 2017, 27-year-old teacher Megan Davison, who had diabulimia, committed suicide. "In the absence of the help she needed, she couldn't see any way of carrying on," said her mother.
  • In September 2017, BBC Three aired a documentary entitled Diabulimia: The World's Most Dangerous Eating Disorder.
  • On 2nd November 2017, the Scottish Parliament debated a motion on raising public awareness of diabulimia.
 
Diabulimia 
 
Diabulimia merges the words ‘diabetes’ and ‘bulimia’. Diabetes is a disease in which your body’s ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose in your blood. Bulimia is an eating disorder where you binge on food and then purge it by vomiting, laxatives, diuretics, exercise or other purging behaviours to prevent weight gain. Diabulimia is a term coined by the media and used by the general public. Although not well-known, diabulimia is a dangerous eating disorder among people with T1DM and describes the deliberate and regular administration of insufficient insulin to maintain glycaemic control for the purpose of causing weight loss by ‘purging’ calories via excess glucose in the urine. While not formally recognised either as a medical term or as a mental health condition in its own right, the Diagnostic Statistical Manual of Mental Disorders(DSM-5),   considers that insulin omission in order to lose weight is a clinical feature of anorexia nervosa and bulimia. Diabulimia has also been recognised in the 2017 UK’s National Institute of Health and Care Excellence (NICE) guidance for eating disorders.
  
Insulin restriction and T1DM

To understand why insulin reduction causes weight loss, it helps to understand T1DM, which is a heterogeneous chronic lifetime disorder for which there is no known cure. T1DM is characterized by the destruction of pancreatic beta cells, culminating in absolute insulin deficiency and accounts for between five and 10% of the total cases of diabetes worldwide. In 2014 there were an estimated 422m people diagnosed with diabetes worldwide. The global prevalence of diabetes among adults over 18 has risen from 4.7% in 1980 to 8.5% in 2014.
Typically, T1DM has an early onset, but can occur at any age. It requires regular daily attention, which for children or adolescents can be daunting. The nutritional anomalies associated with the condition have important consequences (see below) and can be a physical and emotional struggle. To be diagnosed with T1DM represents a hard experience that requires subsequent psychological adaptation. Unfortunately, this often does not occur and can be followed by frustration and the non-acceptance of the disease.

T1DM occurs when your immune system attacks cells in your pancreas that make insulin and renders the pancreas unable to produce the hormone, which is needed to allow glucose (a sugar that circulates in your blood) to enter your cells to produce energy. When you consume food, your body converts it into glucose, which enters your bloodstream. Insulin helps to turn glucose into energy. Without a properly functioning insulin system, your body cannot break down glucose so it stays in your bloodstream and can be dangerous.

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If you are a person living with T1DM you must regularly check your blood glucose levels. Based on these levels and what you plan to eat, you must give yourself insulin. If you either fail to do so, or under-dose, your body cannot absorb glucose and it accumulates in your blood, a condition known as ‘hyperglycaemia’, in which case, your body attempts to compensate for the excess glucose, goes into starvation mode and starts to break down muscle and fat, releasing acids called ketones. The ketones build up, leading to diabetic ketoacidosis (DKA), which can be fatal.
 
Epidemiology

Data from large global epidemiological studies of T1DM reported in a paper published in the February 2014 edition of Diabetes Research and Clinical Practice, suggest that there are 0.5m children aged
It is estimated that as many as 11% of adolescent women with T1DM meet the criteria for a full-syndrome eating disorder. This is significant when compared to the incidence of eating disorders among women in general. It is estimated that between 0.5% and 3.7% of women suffer from anorexia nervosa, and an estimated 1.1% to 4.2% of women have bulimia in their lifetime. A paper in the June 2000 edition of the British Medical Journal, suggests that adolescent females with T1DM are 2.4 times more likely to develop eating disorders than peers of the same age without diabetes, and 1.9 times more likely to display symptoms of an eating disorder that does not meet the full diagnostic criteria. Other studies show that about 35% of females with T1DM have diabulimia.

 
Signs and symptoms

Diabulimia is challenging to diagnose and many primary care doctors and endocrinologists who treat people with T1DM may not recognize diabulimia among their patient population. This is partly because diabulimia is not an officially recognised disease state, partly because eating disorders and diabetes tend to be treated separately by different specialists, and partly because people with diabulimia may be ashamed and reluctant to seek help.

The most obvious sign of diabulimia is weight loss. Another common sign is poor blood-glucose control, as measured by elevated A1c levels, particularly if the person has a prior history of good control. Health professionals may wish to attune themselves to the classic signs of diabetes and the common symptoms of eating disorders. The former includes excessive urination, extreme thirst, constant hunger and fatigue. The latter includes dietary restrictions and heightened concerns about weight and body image.

 
Manipulating insulin to control weight
 
At the time of diagnosis with T1DM people have often lost a significant amount of weight. Regular doses of insulin are essential for controlling blood sugar levels and successfully managing the condition. However, a common side effect of such treatment is weight gain, and this can lead to a vicious circle. Insulin therapy can lead to weight gain; increasing weight may require increasing dosages of insulin to control blood glucose, which can lead to increased hunger and dietary intake, which can increase weight and enhanced concerns about body image.

Deliberately not taking or misusing insulin to cause weight loss is a purging behaviour that is uniquely available to individuals with T1DM. Weight loss can be achieved by decreasing the prescribed dose of insulin, omitting insulin entirely, delaying the appropriate dose, or manipulating the insulin itself to render it inactive. But when you have T1DM, you need insulin to live. Without it, you may lose weight, but more significantly you can lose your sight, harm your kidneys, damage the nerves in your feet and threaten your life.

 
Diets, social media and the thin ideal
 
The management of T1DM is further complicated because it also entails the careful selection of food, eating precise portions and the constant monitoring of carbohydrates. Because of the early onset of T1DM and the ubiquitous use of social media among children and adolescents, which often propagate the “thin ideal”; it seems reasonable to suggest that children and adolescents with T1DM are inherently more prone to issues revolving around food. Thus, in addition to manipulating insulin many people with T1DM commonly restrict their food intake, engage in bingeing and purging, misuse laxatives and adhere to overly strict exercise regimens to overcome body dissatisfaction.   
 
In the US the cost of insulin results in rationing dosages
 
It seems worth mentioning that a significant proportion of people with T1DM in the US appear to be forced into a similar state of diabulimia because of the high cost of insulin, lack of medical insurance cover (about 10% of the US population [33m] do not have healthcare insurance), and relatively high levels of co-payments for medical insurance. These aspects of the American healthcare ecosystem tend to drive a percentage of people with T1DM to reduce or ration their prescribed dosage of insulin, and their disease state then assumes similar manifestations to diabulimia.

According to research findings published in the June 2018 edition of Diabetes Care, about 27% of the 1.25m people in the US with T1DM say that affording insulin has impacted their daily life. For people with T1DM, “access to insulin is literally a matter of life and death. The average list price of insulin has skyrocketed in recent years, nearly tripling between 2002 and 2013 . . . . [and]  . . . individuals with diabetes are often forced to choose between purchasing their medications or paying for other necessities, exposing them to serious short- and long-term health consequences,” say the authors.

According to T1International, a charity which advocates affordable and accessible diabetes care, "People (in the US) spend most of their life in fear of losing their insurance, of running out of insulin and the cost going up, or of having to stay in terrible jobs or relationships to ensure they keep their health insurance coverage. . . . In the  worst case, folks are rationing insulin which has led to many reported deaths and excruciating complications."
 
Research aimed at improve treatment
 
Given the extent of diabulimia and the significant medical risks associated with the condition, more clinical and technological research aimed to improve its treatment is critical to the future health of this at-risk population. Stadler’s research referred in the opening paragraph of this Commentary is significant. Interestingly, the National Institute for Health Research only supports projects which potentially have a, "clear benefit to patients and the public". Stadler’s research is expected to take five years, aims to provide a better understanding of diabulimia and devise a 12-module treatment plan for people with the condition.
 
Clinic for people with diabulimia
 
People with diabulimia could only seek professional help for their eating disorder and T1DM separately, but never together: that was until January 2017 when an out-patients’ clinic opened in London specifically for people with T1DM and eating disorders. The clinic is led by Khalida Ismail, Professor of Psychiatry and Medicine at King's College, London and the lead psychiatrist for diabetes at King's Health Partners, London, which is comprised of King's College London, Guy's and St Thomas' NHS Foundation Trust, King's College Hospital NHS Foundation Trust and South London and Maudsley NHS Foundation Trust. Ismail wants to unite psychiatrists and diabetes experts. "They never meet patients together and it's an inefficient use of current resources . . . . we'd actually be saving money by joining up services," she says.
 
Takeaways
 
Diabulimia represents one of the most complex patient problems to be treated both medically and psychologically. Standard treatments for eating disorders are not usually appropriate for cases of diabulimia. Treatment for eating disorders tend to involve removing the focus on food, which is contrary to best practice for the management of T1DM. It is important for clinicians and researchers to better understand risk factors, screening tools and treatment options for diabulimia. Also, there needs to be better access to diabetes specialist psychological services that can provide the integrated support that people with diabulimia need. The London clinic for diabetes and  eating disorders and Stadler’s research are a good start.
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Bridging the gap between medical science and policy to reduce the biggest 21st 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 21st 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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Excess weight and type-2 diabetes linked to 16% of cancers in the UK

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Weight loss surgery to treat T2DM

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 21st 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, 20th 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 2017 research project found that only 6 out of 18 FDA-approved blood glucose monitoring (BGM) systems tested were accurate
  • Each day BGM systems are used by millions of people with diabetes to help them self-manage their condition, and avoid devastating and costly complications
  • Thousands of similar smart devices support the prevention and self management of other chronic lifetime conditions, whose prevalence levels are high
  • The increasing demand for healthcare, its escalating costs, and rapidly evolving technologies are driving the growth of such remote self-managed devices
  • The most valuable aspect of such devices is the data they produce
  • These data tend to be under valued and under utilized by healthcare providers
  • This has created an opportunity for giant technology companies to enter the healthcare market with a plethora of smart devices and start utilizing the data they collect to enhance patient outcomes and lower costs
  • Giant technology companies could dis-intermediate GPs and re-engineer primary care
 

Digital blood glucose monitors and the disruptive impact of giant tech companies on healthcare


A 2017 research project, which tested 18 FDA-approved digital blood glucose monitoring (BGM) systems, which are used daily by millions of people with diabetes to check the concentration of glucose in their blood, found that only 6 were accurate. The research, led by David Klonoff of the Diabetes Research Institute at San Mateo, California, was funded by Abbott Laboratories.
 
This Commentary describes both traditional and next-generation BGM systems, and Klonoff’s research. The Commentary suggests that BGM systems are just one part of a vast, global, rapidly growing market for consumer healthcare devices, and argues that the most valuable aspect of these devices is the data they collect. With some notable exceptions, healthcare professionals do not optimally utilize these data to enhance care and reduce costs. This has created for an opportunity for technology companies to enter the healthcare market and re-engineer primary care. The one thing, which might slow the march of giant technology companies into mainstream healthcare, is the privacy issue.
 

Traditional and next-generation BGM systems
 
Traditional BGM systems
Regularly, each day, BGM systems are used by millions of people with diabetes to help them manage their condition. Managing diabetes varies from individual to individual, and peoples with diabetes usually self-monitor their blood glucose concentration from a small drop of capillary blood taken from a finger prick. They then apply the blood to a chemically active disposable 'test-strip'. Different manufacturers use different technology, but most systems measure an electrical characteristic, and use this to determine the glucose level in the blood. Such monitoring is the most common way for a person with diabetes to understand how different foods, medications, and activities affect their condition. The challenge for individuals with diabetes is that blood glucose levels have to be tested up to 12 times a day. People obliged to do this find finger pricking painful, inconvenient and intrusive, and, as a consequence, many people with diabetes do not check their glucose levels as frequently as they should, and this can have significant health implications. If your levels drop too low, you face the threat of hypoglycemia, which can cause confusion or disorientation, and in its most severe forms, loss of consciousness, coma or even death. Conversely, if your blood glucose levels are too high over a long period, you risk heart disease, blindness, renal failure and lower limb amputation.
 

Next generation BGM system
Abbott Laboratories Inc. markets a BGM system, which eliminates the need for routine finger pricks that are necessary when using traditional glucose monitors. Instead of finger pricks and strips, the BGM system, which measures interstitial fluid glucose levels, comprises a small sensor and a reader. An optional companion app for Android mobile devices is also available. The sensor is a few centimetres in diameter and is designed to stay in place for 10 days. It is applied to the skin, usually on the upper arm. A thin (0.4 mm), flexible and sterile fibre within the sensor is inserted in the skin to a depth of 5 mm. The fibre draws interstitial fluid from the muscle into the sensor, where glucose levels are automatically measured every minute and stored at 15-minute intervals for 8 hours. Glucose levels can be seen at any time by scanning the reader over the sensor. When scanned the sensor provides an answer immediately. It also shows an 8-hour history of your blood glucose levels, and a trend arrow showing the direction your glucose is heading. The device avoids the pain, and inconvenience caused by finger-prick sampling, which can deter people with diabetes from taking regular measurements. In the UK the system costs £58 for the reader, plus £58 for a disposable sensor, which must be replaced every 10 days and from November 2017 have been available on the NHSAbbott Laboratories is a global NASDAQ traded US MedTech Company, with a market cap of US$86bn; annual revenues of US$21bn, and a diabetes care division, which produces annual revenues of some US$600m.
 
Klonoff’s research on BGM systems

BGM systems used by Klonoff and his team for their research were acquired over-the-counter and independent of their manufacturers. All were tested according to a protocol developed by a panel of experts in BGM surveillance testing.
 
Klonoff’s research specified that for a BGM system to be compliant, a blood glucose value must be within 15% of a reference plasma value for a blood glucose >100 mg/dl, and within 15 mg/dl of a reference plasma value for a blood glucose approved” a BGM system had to pass all 3 trials.  Only 6 out of 18 passed by achieving an overall compliance rate of 95% or higher. 

 

The FDA
Klonoff’s findings add credibility to patients’ concerns about the accuracy of BGM systems, which triggered responses from both manufactures and the US Food and Drug Administration  (FDA). Manufacturers suggest that increasing the accuracy of BGM systems would raise their costs, and reduce their availability, which patients do not want. The FDA tightened approvals for BGM systems, and in 2016 issued 2 sets of guidelines, one for clinical settings, and another for personal home-use. The guidelines only apply to new products, and do not impact BGM systems already on the market. So while the FDA’s tighter accuracy requirements are a positive change, there are a significant number of less-accurate BGM systems still on the market. 
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The convergence of MedTech and pharma and the role of biosensors

 

Next-generation BGM systems
Next generation BGM systems use ‘sensing’ technology, and have the capacity to automatically track and send blood glucose readings to the user’s smartphone, then onto their healthcare provider through the cloud where they can be amalgamated with other data. Analytics can then track an individual’s data, and compare them to larger aggregated data sets to detect trends, and provide personalized care.

Large rapidly growing remote self-managed device market

Although BGM systems address a vast global market, they represent just one part of a much larger, rapidly growing, remote monitoring market to help prevent and self-manage all chronic lifetime conditions, while improving healthcare utilization, and reducing costs. In 2015 some 165,000 healthcare apps were downloaded more than 3bn times. Of these, 44% were medical apps, and 12% were apps for managing chronic lifetime conditions. Today, mobile devices enable people to use their smartphones to inspect their eardrums, detect sleep apnoea, test haemoglobin, vital signs such as blood pressure, and oxygen concentration in the blood. This is a significant advance from the early precursor of activity tracker and step counting.

Chronic lifetime conditions
21st century healthcare in developed countries is predominantly about managing chronic lifetime illnesses such as diabetes, cancer, heart disease and respiratory conditions. These 4 diseases have high prevalence levels, relatively poor outcomes, and account for the overwhelming proportion of healthcare costs. For instance, in the US alone, almost 50% of adults (117m) suffer from a chronic lifetime condition, and 25% have multiple chronic conditions. 86% of America’s $2.7 trillion annual health care expenditures are for people with chronic health conditions. This chronic disease pattern is replicated throughout the developed world, and has significant healthcare utilization and cost implications for public and private payers, individuals, and families.
 
Healthcare providers tend not to optimally utilize data

Although personal remote devices are increasingly important in the management of chronic conditions, the data these devices create are underutilized, despite their potential for improving outcomes and reducing costs. This is partly because doctors and health providers neither have the capacity nor the resources to exploit the full potential of these data; partly because doctors tend to resist technology to improve doctor-patient interactions, and partly because remote healthcare devices have not been validated for clinical use. 

Validation
Although health professionals tend to prefer to use more expensive medical grade devices, which ensure data validity, but often drive up costs, research validating the data collected by remote self-managed devices for clinical use is beginning to emerge. In 2016 Analog Devices, a US multinational semiconductor company specializing in data conversion and signal processing technology, and LifeQa private US company with advanced bio-mathematical capabilities, announced a joint venture to establish whether data from wearable’s are accurate enough for clinical use.
 
A study published in 2017 in the journal Nature Biotechnologyprovides some validation for data derived from apps to be used clinically. Using ResearchKit, an open source framework introduced by Apple in 2015 that allows researchers and developers to create powerful apps for medical research, the 6-month study enrolled 7,600 smartphone users who completed surveys on how they used an app to manage their asthma. Researchers then compared these patient-reported data with similar data from traditional asthma research, and found that there were no significant differences. Although there still remains some methodological challenges, the findings gave scientists confidence that data derived from an app could be reliable enough for clinical research. If data from self-managed remote monitoring devices are validated, then such devices could be used to unobtrusively and cost effectively enter the daily lives of patients to collect meaningful healthcare patient data, which could be used to enhance outcomes. Early research adopters of ResearchKit include the University of Oxford, Stanford Medicine, and the Dana-Farber Cancer Institute.

 
Giant technology companies entering healthcare market
 
The increasing validation of data generated by mobile devices and the continued underutilization of such data by health providers has created an opportunity for giant global technology companies to enter the healthcare market by: (i) developing and marketing self-monitoring devices directly to consumers, (ii) collecting, integrating, storing and analysing data generated by these remote devices, and (iii) supporting research initiatives to validate data from remote devices for clinical use.
 

Apple Inc.
Just one example of giant technology companies entering the healthcare market is Apple Inc., which has a market cap of about US$1tn and 700m users worldwide. In 2017, Apple announced that it has been testing a BGM system, which pairs with the company’s existing Watch wearable. In August 2017, the US Patent and Trademark Office officially published a series of 50 newly granted patents to Apple. One covers an invention relating to health data, and more specifically to a smartphone that computes health data. 
 
The technology involves emitting light onto a user’s body part and measuring the amount of light reflected back. This data can then help to determine body fat, breathing and even emotional health. This, and other patents issued to Apple fuel rumors that the company is preparing to turn its flagship smartphone into a predominantly healthcare-focused device.

 
Takeaway
 
Given the size and momentum of technology giants entering the healthcare market, and given the powerful demographic, technological, social and economic drivers of this market, it seems reasonable to assume that in the medium term, giant technology companies are well positioned to dis-intermediate primary care doctors, and re-engineer primary care. One thing that could slow this march, is the question of privacy. Health records are as private as private gets - from alcohol or drug abuse to sexually transmitted diseases or details of abortions: things we may never want to reveal to employers, friends or even family members. Significantly, these data are permanent, and privacy at this point is non-negotiable.
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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 21st 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.
 
21st 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 21st 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 21st century communications infrastructures if they are to be efficacious.
 
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