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Type 2 diabetes reversed by intensive weight management programmes

Type 2 diabetes can be reversed following an intensive weight management programme, according a randomised trial in adults who have had the condition for up to six years. The study showed that after 1 year, participants had lost an average of 10kg, and nearly half had reverted to a non-diabetic state without using any diabetes treatment. The findings lend support to the widespread use of this type of intervention in the routine care of type 2 diabetes across health services.

"Our findings suggest that even if you have had type 2 diabetes for 6 years, putting the disease into remission is feasible," says Professor Michael Lean from the University of Glasgow who co-led the study. "In contrast to other approaches, we focus on the need for long-term maintenance of weight loss through diet and exercise and encourage flexibility to optimise individual results."

Worldwide, the number of people with type 2 diabetes has quadrupled over 35 years, rising from 108m in 1980 to 422m in 2014. This is expected to climb to 642m by 2040. This increase has been linked to rising levels of obesity and the accumulation of intra-abdominal fat. Type 2 diabetes affects almost 1 in 10 adults in the UK and costs the National Health Service (NHS) around £14bn a year.

"Rather than addressing the root cause, management guidelines for type 2 diabetes focus on reducing blood sugar levels through drug treatments. Diet and lifestyle are touched upon but diabetes remission by cutting calories is rarely discussed," explains Professor Roy Taylor from Newcastle University, UK, who co-led the study.

"A major difference from other studies is that we advised a period of dietary weight loss with no increase in physical activity, but during the long-term follow up increased daily activity is important. Bariatric surgery can achieve remission of diabetes in about three-quarters of people, but it is more expensive and risky, and is only available to a small number of patients."

Previous research by the same team confirmed the Twin Cycle Hypothesis that type 2 diabetes is caused by excess fat within the liver and pancreas-and established that people with the disease can be returned to normal glucose control by consuming a very low-calorie diet. But whether this type of intensive weight management is practicable and can achieve remission of type 2 diabetes in routine primary care was not known until now.

The Diabetes Remission Clinical Trial (DiRECT) included 298 adults aged 20-65 years who had been diagnosed with type 2 diabetes in the past 6 years from 49 primary care practices across Scotland and the Tyneside region of England between July 2014 and August 2016. Practices were randomly assigned to provide either the Counterweight-plus weight management programme delivered by practice dieticians or nurses (149 individuals) or best practice care under current guidelines (control; 149 individuals).

The weight management programme began with a diet replacement phase, consisting of a low-calorie formula diet (825-853 calories/day for 3 to 5 months), followed by stepped food reintroduction (2-8 weeks), and ongoing support for weight loss maintenance including cognitive behavioural therapy combined with strategies to increase physical activity. Antidiabetic and blood pressure-lowering drugs were all stopped at the start of the programme.

The primary outcomes were weight loss of 15 kg or more (sufficient to achieve remission of diabetes in most cases), and remission of diabetes. Remission was defined as achievement of a glycated haemoglobin A1c (HbA1c) level of less than 6.5% at 12 months, off all medications.

The weight loss programme was acceptable to most participants, with a dropout rate of 21%, mainly for social reasons (bereavement, change or loss of job, moving house). 128 (86%) participants in the weight management group and 147 (99%) participants in the control group attended the 12-month assessment. For those whose measurements of weight and HbA1c level were not available it was assumed that no remission had occurred.

Almost a quarter (36/149) of the weight management group achieved weight loss of 15 kg or more at 12 months, compared with none in the control group. Additionally, nearly half of the weight management group (68/149) achieved diabetes remission at 1 year, compared with six (4%) in the control group.

On average, participants in the weight management group shed 10kg of bodyweight compared to 1kg in the control group. Importantly, the results showed that remission was closely linked with the degree of weight loss and occurred in around 9 out of 10 people who lost 15 kg or more, and nearly three quarters (47/64) of those who lost 10kg or more.

The researchers also noted an improvement in average triglyceride (blood lipid) concentrations in the weight management group, and almost half remained off all antihypertensive drugs with no rise in blood pressure. Furthermore, the weight management group reported substantially improved quality of life at 12 months, with a slight decrease reported in the control group.

Overall, one person experienced serious adverse events possibly related to the treatment (biliary colic and abdominal pain) but continued in the study. Some participants experienced constipation, headache, and dizziness.

The authors note that the vast majority of participants were white and British, meaning that the findings may not apply to other ethnic and racial groups such as south Asians, who tend to develop diabetes with less weight gain.

According to Taylor: "Our findings suggest that the very large weight losses targeted by bariatric surgery are not essential to reverse the underlying processes which cause type 2 diabetes. The weight loss goals provided by this programme are achievable for many people. The big challenge is long-term avoidance of weight re-gain. Follow-up of DiRECT will continue for 4 years and reveal whether weight loss and remission is achievable in the long-term."

Writing in a linked Comment, Professor Emeritus Matti Uusitupa from the University of Eastern Finland discusses whether these findings should change treatment options for type 2 diabetes. He writes, "Lean and colleagues' results, in addition to those from other studies of type 2 diabetes prevention and some smaller interventions in this setting, indicate that weight loss should be the primary goal in the treatment of type 2 diabetes… The DiRECT study indicates that the time of diabetes diagnosis is the best point to start weight reduction and lifestyle changes because motivation of a patient is usually high and can be enhanced by the professional health-care providers. However, disease prevention should be maintained as the primary goal that requires both individual-level and population-based strategies, including taxation of unhealthy food items to tackle the epidemic of obesity and type 2 diabetes."

Summary
Background: Type 2 diabetes is a chronic disorder that requires lifelong treatment. We aimed to assess whether intensive weight management within routine primary care would achieve remission of type 2 diabetes.
Methods: We did this open-label, cluster-randomised trial (DiRECT) at 49 primary care practices in Scotland and the Tyneside region of England. Practices were randomly assigned (1:1), via a computer-generated list, to provide either a weight management programme (intervention) or best-practice care by guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700). Participants, carers, and research assistants who collected outcome data were aware of group allocation; however, allocation was concealed from the study statistician. We recruited individuals aged 20–65 years who had been diagnosed with type 2 diabetes within the past 6 years, had a body-mass index of 27–45 kg/m2, and were not receiving insulin. The intervention comprised withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825–853 kcal/day formula diet for 3–5 months), stepped food reintroduction (2–8 weeks), and structured support for long-term weight loss maintenance. Co-primary outcomes were weight loss of 15 kg or more, and remission of diabetes, defined as glycated haemoglobin (HbA1c) of less than 6·5% (<48 mmol/mol) after at least 2 months off all antidiabetic medications, from baseline to 12 months. These outcomes were analysed hierarchically. This trial is registered with the ISRCTN registry, number 03267836.
Findings: Between July 25, 2014, and Aug 5, 2017, we recruited 306 individuals from 49 intervention (n=23) and control (n=26) general practices; 149 participants per group comprised the intention-to-treat population. At 12 months, we recorded weight loss of 15 kg or more in 36 (24%) participants in the intervention group and no participants in the control group (p<0·0001). Diabetes remission was achieved in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19·7, 95% CI 7·8–49·8; p<0·0001). Remission varied with weight loss in the whole study population, with achievement in none of 76 participants who gained weight, six (7%) of 89 participants who maintained 0–5 kg weight loss, 19 (34%) of 56 participants with 5–10 kg loss, 16 (57%) of 28 participants with 10–15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more. Mean bodyweight fell by 10·0 kg (SD 8·0) in the intervention group and 1·0 kg (3·7) in the control group (adjusted difference −8·8 kg, 95% CI −10·3 to −7·3; p<0·0001). Quality of life, as measured by the EuroQol 5 Dimensions visual analogue scale, improved by 7·2 points (SD 21·3) in the intervention group, and decreased by 2·9 points (15·5) in the control group (adjusted difference 6·4 points, 95% CI 2·5–10·3; p=0·0012). Nine serious adverse events were reported by seven (4%) of 157 participants in the intervention group and two were reported by two (1%) participants in the control group. Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention. No serious adverse events led to withdrawal from the study.
Interpretation: Our findings show that, at 12 months, almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs. Remission of type 2 diabetes is a practical target for primary care.

Authors
Michael EJ Lean, Wilma S Leslie, Alison C Barnes, Naomi Brosnahan, George Thom, Louise McCombie, Carl Peters, Sviatlana Zhyzhneuskaya, Ahmad Al-Mrabeh, Kieren G Hollingsworth, Angela M Rodrigues, Lucia Rehackova, Ashley J Adamson, Falko F Sniehotta, John C Mathers, Hazel M Ross, Yvonne McIlvenna, Renae Stefanetti, Michael Trenell, Paul Welsh, Sharon Kean, Ian Ford, Alex McConnachie, Naveed Sattar, Roy Taylor

[link url="https://www.sciencedaily.com/releases/2017/12/171205091651.htm"]The Lancet material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33102-1/fulltext"]The Lancet article summary[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33100-8/fulltext"]Comment[/link]

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