Curing type 2 diabetes? The DiRECT study and its potential impact on primary care
Historically, type 2 diabetes has been seen as a condition that, once diagnosed, cannot be cured, reversed or put into remission, but a recent study challenges this view – and not only that, the intervention is one that could be carried out by practice nurses
Type 2 diabetes (T2D) is a condition which makes its presence felt. It is a largely preventable disorder which, in the majority of cases, is linked to poor lifestyle choices – inactivity and an unhealthy diet – resulting in overweight and obesity.1 A diagnosis of T2D will usually require some significant lifestyle changes and multiple drug treatments as glycaemic control, blood pressure and lipid management are all targeted in order to reduce the risk of complications.2 Regular blood tests and trips for check-ups will interfere with day to day life and family members or carers may be involved in taking people backwards and forwards for appointments. Overall, 10% of the NHS budget is spent on diabetes and at any time one in six NHS beds is taken up by someone with diabetes, meaning that diabetes affects all of us through its impact on resource allocation for other areas of healthcare.3
There is no known cure for diabetes, which is why the NHS Diabetes Prevention Programme (DPP) has been implemented with the aim of prevention, in lieu of cure. The programme, which is running in various locations nationally, supports the identification of ‘at risk’ groups, using known risk factors and blood tests to identify those at highest risk, and offers them lifestyle and behavioural based interventions aimed at reducing that risk.4 The main gist of the DPP is to encourage people to eat more healthily, take more exercise and lose weight. The latest report on the effect of the programme has shown that it is already performing above expectations with more people being referred to the programme than anticipated and more people actually attending for follow up following referral than expected.4
Being overweight or obese, particularly when that weight is held around the middle – central obesity – is known to be a key risk factor for T2D. Specifically, it is thought that it is fat accumulation in the liver and the pancreas which is linked to T2D,5 and losing weight through a very low calorie diet (VLCD) of around 600-700 kcal has been shown to normalise liver fat content within one week and pancreas fat content within 8 weeks as well as improving insulin resistance.6 Now, a new study by Lean et al7 has confirmed that people who have already been diagnosed with T2D can become normoglycaemic if they lose 15kg post diagnosis. This study, along with previous studies which have suggested that diabetes can be cured, reversed or put into remission6,8 has sparked much debate as to whether this really constitutes a cure or is simply an indication of good control. However, tight glycaemic control soon after diagnosis of T2D has been shown to confer benefits in the longer term – the so-called legacy effect – so even if this is not really a ‘cure’ for T2D, the potential benefits of a period of tight glucose control remain likely.9
DiRECT
The Diabetes Remission Clinical Trial (DiRECT) was published at the International Diabetes Federation meeting in December 2017.7 The stated aim of the study was to find a practical management solution for T2D in primary care, based around weight management. The study assessed the impact of primary care-based weight loss interventions on diabetes remission. In a previous 2 year long randomised controlled trial comparing gastric banding with standard dietary advice, Dixon et al found that a 15 kg weight loss achieved saw the greatest number of people whose diabetes went into remission, with only 13% of the conventional study group reversing their diabetes, compared with 73% of those who had gastric banding.10 On that basis, the DiRECT study group offered an intensive weight loss programme with the aim of losing 15kg. Furthermore, all medication for diabetes and hypertension was stopped in the active arm of the study. In all other respects, however, guideline-based best practice in diabetes was maintained, including in the control group.
There were two primary outcomes for the study: the number who achieved and maintained 15kg or more weight loss at 12 months and the number who had remission of their diabetes, defined as having an HbA1c of <48mmol/mol without taking diabetes medication for at least 2 months. The interventions were largely carried out by general practice nurses (GPNs) or dietitians, all of whom had attended 8 hours of training about the programme. See Box 1.
BOX 1. DiRECT – GENERAL PRACTICE NURSE-LED INTERVENTIONPatients attended their own GP practiceProgramme delivered and supervised by the GPN or a dietitian8 hour training prior to commencement and mentoring on the jobIndividual hour-long appointments x 2 then follow up appointments of 25-30 minutes:Total Diet Replacement: 2-weeklyFood Reintroduction: 2-weeklyMaintenance: 4-weekly
The inclusion criteria for the study make for interesting reading. Men and women age 20–65 years with a BMI of between 27–45kg/m2 who had had a diagnosis of T2D within the past 6 years were eligible to take part as long as they had an HbA1c ≥48 mmol/mol, or ≥43 mmol/mol if they were on diabetes medication. Those who could not take part included anyone taking insulin or anti-obesity drugs; people with cancer or a recent history of severe heart failure or a myocardial infarction; anyone who was pregnant or planning a pregnancy; those who had severe renal impairment; those with learning difficulties, addiction problems, severe depression or psychosis; and people who reported a weight loss of >5kg within the past 6 months.
At the end of the recruitment period, participants were equally matched between the intervention and control groups with 149 people in each arm. The ‘average’ participant was a 54 year old man (59% of participants were male) with a BMI of 35kg/m2, weighing 106kg (average woman’s weight was 91kg). Participants had had diabetes for 3 years on average and their HbA1c was 59mmol/mol. There was an even spread across all levels of deprivation, meaning that the more deprived communities were well represented. Half of the participants were on one glycaemic agent, one-in-four was on two or more glycaemic agents and one-in-four was on diet alone. Although these are statistical averages, it is worth considering that the NICE guidelines for type 2 diabetes state that anyone who has an HbA1c of 48mmol/mol or more should be offered medication to bring their blood glucose into target ranges, which are associated with a reduction in long term cardiovascular complications.11
The diet itself was a very low calorie diet (VLCD) consisting of meal replacement shakes and soups to a total daily value of 830kcal with 61% being carbohydrate, 26% protein and 13% fat. A fluid intake of 2.25 litres per day was recommended along with a fibre supplement. Participants were encouraged to be physically active for 30 minutes a day. After a minimum of 12 weeks and a maximum of 20, food was gradually reintroduced to the diet by adding a 400 kcal meal every 2-3 weeks. As food was reintroduced, physical activity target levels were increased and participants were given step counters to use. This ‘food replacement’ stage lasted 2-8 weeks. Once a weight loss of 15kg or more had been achieved, a food-based maintenance programme was offered containing 50% carbohydrate, 35% fat and 15% protein and this stage lasted for the rest of the year. Physical activity was again an important component of this stage of the intervention with participants being encouraged to increase their step rate up to 15,000 steps/day.
Relapse is now considered to be a normal part of the change cycle,12 and provision for this was built into the DiRECT study. Anyone who gained 2kg or more, or whose diabetes control deteriorated so that their HbA1c was >48mmol/mol, was offered orlistat and a brief return to total diet replacement followed by food reintroduction.
The findings of the study showed that of the 149 participants 36 achieved a weight loss of 15kg or more – 24% of the study group. No participant in the control group (n149) achieved this, making the result highly statistically significant. In terms of the co-primary outcome, remission of diabetes (meaning HbA1c was less than 48mmol/mol off all blood glucose lowering medication for at least 2 months), 68 of the 149 (46%) participants achieved this outcome versus 6 out of 149 (4%) people in the control group – another highly statistically significant result.
The results also showed that although weight loss of 15kg or more was associated with the highest diabetes remission rate, smaller losses were still linked to diabetes remission. Overall, 6.7% of all study participants achieved diabetes remission with a weight loss of up to 5kg and 33.9% of participations achieved remission with a weight loss of 5–10kg. Once people had lost 10-15kg, the figure increased to 57.1% and the 15kg+ group saw a staggering remission rate of 86.1%. There were no withdrawals in either group due to serious adverse events.
Quality of life measurements (EuroQol 5 Dimensions: https://euroqol.org/) were used to assess the impact on study participants. Quality of life improved by 7.2 points in the intervention group but decreased by 2.9 points in the control group.
It is worth considering the definition of ‘remission’ used in this study and comparing it with others.13 In DiRECT, people were said to be in remission if, after at least 2 months off medication, their HbA1c was less than 48mmol/mol or if the fasting blood glucose (FBG) was less than 7mmol and 2 hour glucose was less than 11mmol. These results had to be repeated on two tests at least 2 months apart and reviewed annually for the term ‘remission’ to be applied appropriately. Buse et al14 offered two ‘remission’ options: partial remission or complete remission. In partial remission, both the HbA1c and the FBG need to fit certain parameters. The HbA1c needs to be less than 48mmol/mol and the FBG needs to be between 5.6mmol and 6.9mmol. This FBG would fit the parameters of impaired fasting glycaemia as defined by the International Diabetes Federation as part of the spectrum of signs which make up metabolic syndrome.15 For complete remission, Buse et al state that the HbA1c should be 42mmol/mol (i.e. the non-diabetic range) and the FBG should be less than 5.6mmol.
BENEFITS OF DIABETES REMISSION
It is obvious that there are significant potential benefits to reversing diabetes, both for the individual and to the NHS and society as a whole. People with diabetes are often charged more for insurance and may be stigmatised and restricted in some areas of their life – for example career choices. Being able to lose weight and ‘undo’ their diagnosis is likely to be hugely rewarding and will hopefully act as an incentive to maintain healthier eating and activity behaviours. For the NHS, significant cost savings may be possible through a reduced need for medication and reviews – for example annual retinopathy, nephropathy and neuropathy screening. The Look AHEAD study demonstrated that a 10% weight loss was associated with a 21% decrease in cardiovascular disease over the following decade.16 Most of the money spent on treating diabetes is spent on treating the complications of the condition,17 so any intervention which leads to remission of diabetes is likely to be cost-effective, even more so when the intervention in question is as cost-effective as the DiRECT study suggests it can be.
OTHER WEIGHT LOSS INTERVENTIONS IN T2D
Frigg et al18 carried out a study on people with diabetes who had lost weight following laparoscopic gastric banding. After four years, 75% of participants had seen their diabetes improve to the extent that people were talking about it being ‘cured’. In a meta-analysis of 4070 gastric band patients in 2009, Buchwald et al reported that 78% has seen their diabetes resolve.19 Bariatric surgery may have a part to play then, but it is expensive (albeit arguably cost-effective in the long run) and is under-resourced.
In a simpler approach to weight management, Kahleova et al20 looked at the role of meal size and frequency in people with diabetes. The results indicated that both weight and glycaemic control improved if people ate two larger meals (breakfast and lunch) daily when compared with those who were allowed to have the same energy intake over six small meals. Both groups were given 500 calories a day less than the recommended daily amount and followed the two-meal approach for 12 weeks before crossing over onto the six-meal intervention (or vice versa). At the end of the 24 week programme it was found that even though both arms supplied the same amount of energy, participants lost more weight on the 2 meal arm than the 6 week arm (average 3.7kg v 2.3kg). Furthermore, the two-meal regimen resulted in greater improvements in the amount of fat deposits in the liver and in fasting glucose levels. Fasting plasma glucagon levels also decreased in the two-meal arm, whereas it increased in the six-meal arm.
DISCUSSION
Historically, T2D has been seen as a condition that, once diagnosed, cannot be cured, reversed or put into remission. The DiRECT study challenges this view and provides some evidence to suggest that T2D is a complication of obesity and is therefore not necessarily a permanent condition if weight loss can be achieved and sustained. The results from this study indicate that almost three-out-of-four people with T2D can achieve remission following a weight loss of 10kg or more, but that smaller losses can also increase the possibility of achieving remission. VLCDs may help some people to achieve weight loss but it appears to be the weight loss itself rather than the VLCD, necessarily, which matters. In terms of cost-effectiveness, however, VLCDs have the edge over more expensive interventions such as bariatric surgery. Longer studies are being completed and there is also a need to look at different ‘at risk’ groups beyond those studied in DiRECT to see whether they will benefit in the same way. Overall, however, the potential gains from an intensive weight loss programme such as that implemented in DiRECT is information that needs to be shared with patients who have a diagnosis of T2D, especially if they have been diagnosed recently. They can then make an informed decision as to whether this approach might work for them. A particularly exciting aspect of this study is that it shows that a GPN-led primary care based weight loss intervention can be highly effective in helping people to lose weight and reverse their diabetes. However, there is no specific mention of what proportion of programme leads were GPNs versus dietitians and in the study, the decision was made purely on who was available. At this stage, however, there are very few GPNs trained in supporting people through a programme like DiRECT and this may impact on the likelihood of success rate in the real life setting.
The current advice from NICE for people who are trying to lose weight is to eat a nutritionally sound diet combined with adequate levels of activity, such as walking 10,000 steps a day.21 However, the studies mentioned above serve as a reminder that a personalised approach to weight loss interventions should be taken which aims to address the specific needs of each individual. To that end GPNs should maintain an open mind about how best to support people who want to lose weight.
On the surface, it would seem that it matters less who supports people to lose weight, or even necessarily by which method. What matters most is that we put weight management at the top of our list of lifestyle interventions along with smoking cessation. It all about using (evidence-based) common sense.
RESOURCESInformation, education and training for healthcare professionalsEducation for Healthhttps://www.educationforhealth.org/Primary Care Diabetes Societyhttp://www.pcdsociety.orgDiabetes UKhttps://www.diabetes.org.uk/professionals
REFERENCES
1. Tuomilehto J, Lindstrom L, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.
2. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia 2016;59(11):2298-307
3. Diabetes UK. State of the Nation report, 2016 https://www.diabetes.org.uk/Global/get-involved/campaigns/ Diabetes%20UK%20State%20of%20the%20Nation%202016.pdf
4. Barron E, Clark R, Hewings R,et al. Progress of the Healthier You: NHS Diabetes Prevention Programme: referrals, uptake and participant characteristics Diabetic Medicine 2017;Dec 20 [Epub ahead of print] http://dx.doi.org/10.1111/dme.13562
5. Taylor R. Pathogenesis of Type 2 diabetes: Tracing the reverse route from cure to cause. Diabetologia 2008;51:1781-1789
6. Lim EL, Hollingsworth KG, Aribisala BS, et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54(10):2506-2514.
7. Lean MEJ, Leslie WS, Barnes AC, et al (2017) Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 2017 Dec 4 [Epub ahead of print] DOI: https://doi.org/10.1016/S0140-6736(17)33102-1
8. Lean MEJ, Brosnahan N, McLoone P, et al. Feasibility and indicative results from a 12 month low energy liquid diet treatment and maintenance programme for severe obesity Br J Gen Pract 2013;63(607):e115-24
9. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865
10. Dixon JB, O’Brien Pe, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA 2008;299:316–323
11. NICE (2015 – updated 2017) Type 2 diabetes in adults https://www.nice.org.uk/guidance/ng28/resources/type-2-diabetes-in-adults-management-1837338615493
12. Prochaska J, DiClemente C. Stages and processes of self-change in smoking: toward an integrative model of change. Journal of Consulting and Clinical Psychology 1983;5:390–395.
13 McCombie L et al (2017) Beating type 2 diabetes into remission. BMJ 358:j4030 https://doi.org/10.1136/bmj.j4030
14. Buse JB, et al. How Do We Define Cure of Diabetes? Diabetes Care 2009;32(11): 2133-2135. https://doi.org/10.2337/dc09-9036
15. International Diabetes Federation. The IDF Consensus worldwide definition of the metabolic syndrome, 2014. http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf
16. The LookAHEAD Research Group (2016) Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. The Lancet Diabetes & Endocrinology 2016;4:913-921
17. Diabetes UK. Cost of Diabetes report, 2014. https://www.diabetes.org.uk/Documents/Diabetes%20UK%20Cost%20of%20Diabetes%20Report.pdf
18. Frigg A, et al. Reduction in Co-morbidities 4 Years after Laparoscopic Adjustable Gastric Banding Obes Surg 2004;14: 216. https://doi.org/10.1381/096089204322857591
19. Buchwald H, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 2009;122:248–256.e5
20. Kahleova H, et al. Eating two larger meals a day (breakfast and lunch) is more effective than six smaller meals in a reduced-energy regimen for patients with type 2 diabetes: a randomised crossover study. Diabetologia 2014;57:1552-60
21. NICE CG189. Obesity: identification, assessment and management of overweight and obesity in children, young people and adults, 2014. http://www.nice.org.uk/guidance/CG189