Rapid Weight Loss Keeps Promise of T2D Remission for 2 Years

Liam Davenport

March 07, 2019

LIVERPOOL — Type 2 diabetes patients who achieve rapid weight loss with a calorie-restricted liquid diet followed by gradual food reintroduction and a weight loss maintenance programme can reach and remain in remission at two years, the results of a UK study reveal.

The findings, from almost 300 patients enrolled in the Diabetes Remission Clinical Trial (DiRECT), show that giving a commercial formula (the Cambridge Weight Plan) followed by dedicated weight loss maintenance allowed 36% of patients to attain remission of their diabetes and sustain it for 24 months.

The results were given over three presentations during a session at the Diabetes UK Professional Conference dedicated to DiRECT, and published simultaneously online by The Lancet Diabetes & Endocrinology.

Remission Results

These results follow 1-year data published by The Lancet in 2017, which indicated that programme achieved type 2 diabetes remission in 46% of patients.

At both time points, the number of patients in the standard-care control arm who achieved remission was negligible.

The 2-year data also show that the degree of weight loss was important, with 64% of patents who lost at least 10kg over the study period in remission at the end of follow-up.

In addition, 70% of those who were in remission at 1 year remained so by 2 years.

Importantly, the weight loss intervention was associated with large falls in the proportion of patients taking diabetes medications, as well as reductions in HbA1c and triglycerides.

Quality of life improved with the intervention over control patients and, as the study went on, the intervention arm recorded fewer serious adverse events, suggesting an accrual of benefits over time.

Not 'An Inevitably Progressive Disease'

Co-lead researcher Prof Roy Taylor, professor of medicine and metabolism, Newcastle University, Newcastle upon Tyne, commented in a news release that the results "finally pull down the curtain on the era of type 2 diabetes as an inevitably progressive disease".

He said: "We now understand the biological nature of this reversible condition. However, everyone in remission needs to know that evidence to date tells us that your type 2 diabetes will return if you regain weight."

Prof Mike Lean, chair of human nutrition, University of Glasgow, who co-led the study, said that "proving" that more than two-thirds of patients who lose more than 10kg can be put into type 2 diabetes remission "is incredibly exciting".

He added: "People with type 2 diabetes and healthcare professionals have told us their top research priority is ‘can the condition be reversed or cured?’."

"We can now say, with respect to reversal, that yes it can. Now we must focus on helping people maintain their weight loss and stay in remission for life."

'Exciting times'

Speaking to Medscape News UK, Prof Taylor agreed that these are "exciting times" for diabetes management.

He said that, while "the biology is clear" on how "removing fat allows the body to wake up" and achieve type 2 diabetes remission, "the human aspect needs to be considered".

He explained: "Can the diet be made better in any way? And, especially, how can we help people, moving forwards?"

Prof Taylor noted that the data also showed that so-called 'rescue plans' for patients who started to regain weight during follow-up "were highly effective in keeping people on track, and those people who fell off the wagon were able to be rescued".

He said: "That’s a big message, because Rescue Plans were a feature of DiRECT, but haven’t much been recognised outside."

Prof Taylor emphasised that, while "everybody" can lose 15kg of weight, the other main aspect is the "matter of long-term weight maintenance".

"That’s really where the major goal is now."

'Life-changing'

Dr Elizabeth Robertson, director of research at Diabetes UK, which funded DiRECT, commented in a news release: "Remission of type 2 diabetes can be life-changing; DiRECT offers one potential solution.

"We are committed to working with the researchers and the NHS to ensure these exciting findings reach people with type 2 diabetes as soon as possible."

She added: "But we know type 2 diabetes is a complex condition, and this approach will not work for everyone."

"That’s why we’re continuing to invest in further research, to understand the biology underlying remission and find ways to make remission a reality for as many people as possible."

Study Details

In the first presentation Alison Barnes, a diabetes specialist dietitian at Newcastle University, reminded the audience that the DiRECT study involved 49 GP practices in Scotland and the North East of England.

Twenty six were assigned to a control group, offering usual diabetes care following best practice guidelines, with the remaining 23 practices assigned to the structured weight management programme.

The intervention began with withdrawal of anti-diabetic and antihypertensive medications, followed by total diet replacement with a low-calorie liquid diet, delivering 825–853 kcal per day, for 3–5 months.

Subsequently, the patients had stepped food reintroduction over 6–8 weeks, then structured support for weight-loss maintenance over the next 24 months, with an average of 7.7 practice appointments (of the 12 offered) during year 2.

Between 2014 and 2016, 306 diabetes patients were recruited.

They were representative of the type 2 diabetes population, with 59% of the patients male and 21% living in the most deprived areas.

The patients had an average age of 54.4 years, and a mean body mass index (BMI) of 34.6 kg/m2. The mean duration of type 2 diabetes was 3.0 years, or less than 6 years overall, and none of the patients were on insulin.

Complete data on 149 patients each from the control and intervention groups were available for intention-to-treat analysis.

To applause from the audience, Alison Barnes revealed that, at 24 months, 36% of patients in the intervention group had achieved type 2 diabetes remission versus just 3% of those in the control arm (p<0.0001).

This compares with 46% and 4%, respectively, at 12 months (p<0.0001).

Crucially, the data demonstrate that the percentage of patients taking diabetes medications decreased markedly in the intervention group, from 75% at baseline to 40% at 24 months.

In contrast, the proportion of patients in the control group taking diabetes medications increased during the study period, from 77% at baseline to 84% at 24 months.

The reduction in reliance on diabetes medications was mirrored by a notable 6 mmol/mol fall in HbA1c levels in the intervention group over the study period (p=0.0063), versus a modest increase of 0.4 mmol/mol in the control arm.

Summarising, Alison Barnes said the results show that "durable remission of short-duration type 2 diabetes is attainable in a primary care setting".

Weight Loss

Next, Naomi Brosnahan, a dietitian at the School of Medicine, Dentistry & Nursing, University of Glasgow, focused on the degree of weight loss achieved in DiRECT.

She explained that the weight loss maintenance period of the intervention was, in effect, integrated into the intervention from day 1 of the total dietary replacement.

It was reinforced with monthly practice nurse or dietician appointments, during which blood pressure and glucose and weight were reviewed.

These allowed discussion of weight and remission expectations with the patients and strategies to limit weight gain.

Naomi Brosnahan said that this resulted in far greater mean weight loss in the intervention group at 24 months versus controls, at 7.6 kg and 2.3 kg reductions, respectively.

At 1 year, the average weight loss had been 10.0 kg in the intervention group and 1.0 kg in the control group.

Weight loss of 15 kg or more was achieved by 11% of the intervention group by 24 months, compared with just 2% of patients in the control arm (p<0.0001).

Naomi Brosnahan said that remission at 24 months was closely tied to weight loss.

Just 5% of patients who lost <5 kg achieved remission at 24 months.

This compared with 29% of those who lost 5–10 kg, 60% of those who lost 10–15 kg, and 70% among patients who lost ≥15 kg.

More broadly, 64% of patients whose weight dropped by ≥10 kg were in type 2 diabetes remission at 24 months.

Further analysis revealed that weight trajectory over the course of the study was critical for achieving remission.

Typically, patients who never went into remission had a mean weight loss versus baseline of 5.8 kg at 12 months and 5.6 at 24 months.

Those who were in remission at 12 months but not at 24 months had a weight loss versus baseline of 12.0 kg at 1 year but regained weight during year 2, finishing at an overall average weight loss of 4.9 kg at 24 months.

Patients who were in remission throughout follow-up had greater mean weight loss versus baseline at both time points, at 15.5 kg at 12 months and 11.3 kg at 24 months.

Rescue Plans

Naomi Brosnahan next looked at rescue plans for patients who regained more than 2 kg in weight or relapsed. These turned out to be a crucial part of weight loss maintenance in patients taking part in DiRECT.

These plans consisted of a review with the patient discussing the causes of weight gain and their behavioural strategies, alongside a brief return to the total diet replacement and/or food reintroduction phases.

In addition, patients were offered orlistat (Xenical, Roche), although Naomi Brosnahan noted that none of the patients used it during the first 12 months, and only three did between 12 and 24 months.

She said that half of patients took up a rescue plan during weight loss maintenance.

They were just as likely to achieve type 2 diabetes remission at 24 months, with 37% of both rescue plan and non-rescue plan patients in remission, although weight loss was slightly lower among rescue plan patients. 

Naomi Brosnahan commented: "What this tells us is that rescue plans can help maintain weight and therefore help to maintain remission of type 2 diabetes." 

She concluded her presentation by saying that "the critical factor for the success of type 2 diabetes remission was not only achieving weight loss, but it was the maintenance of that weight loss."

She added: "We appreciate there was modest weight regain in our intervention group but, in fact, the weight loss that we’ve achieved in the direct intervention remains greater than most other lifestyle interventions to date."

Secondary Outcomes

Finally, George Thom, a dietitian in the Human Nutrition Department, University of Glasgow, looked at secondary outcomes in the DiRECT study.

He said that the intervention was associated with a borderline significant reduction in systolic blood pressure at 24 months compared with the control group, at a mean adjusted difference of -3.43 mmHg (p=0.04).

Intervention was also linked to a significant reduction in the proportion of patients on antihypertensive medicines at 24 months, at 47% versus 60% in the control group, or an adjusted odds ratio of 0.31 (p=0.0058).

Significant reductions in triglyceride levels were also seen with the intervention versus the control group (p=0.006).

These changes, together, led to an improvement in cardiovascular disease risk.

Specifically, patients who achieved remission had an average QRISK for cardiovascular disease at baseline of 16.1% and a mean heart age of 70.4 years.

At 24 months, by which time they were in what was termed a post-diabetes state, their QRISK score (a scoring system to predict cardiovascular risk) was 8.2% and their mean heart age was 60.8 years.

While there was no difference in serious adverse events between the intervention and control groups overall and between baseline and 12 months, George Thom reported that there was a significant reduction in serious adverse events associated with the intervention between 12 and 24 months (p=0.029).

Finally, there was a borderline significant increase in quality of life scores for patients in the intervention group versus controls (p=0.03).

George Thom said: "To summarise our secondary outcomes, it’s pretty much a win-win, win-win, win-win scenario for our intervention group."

He continued: "Type 2 diabetes has been traditionally viewed and treated as a progressive and lifelong condition.

"However, we have shown this is not the case, and essentially type 2 diabetes is a complication of excess body weight."

He concluded: "We believe that, in newly diagnosed patients with type 2 diabetes, conversations need to start by targeting remission.

"The data is clear that this is eminently possible and we should be aspirational about helping our patients to achieve that."

Ethnicity

During the post-presentation discussion, a doctor practising in the Middle East highlighted that the population in DiRECT was "almost exclusively Caucasian", asking how well the data could be extrapolated to his patient population.

Dr Lean replied by underlining that, rather than just being Caucasian, the study cohort was almost entirely British Caucasian, "and that we need to have data from groups such as your own".

Noting that diabetes remission projects are being "actively explored" in a number of different populations, he continued: "I suspect that probably the principles may be very much the same.

"What we don’t know is whether, because type 2 diabetes develops with lesser degrees of obesity in people of Asian origin, less weight loss is going to be effective.

"On the other hand, the disease may progress more rapidly. We don’t have answers to that yet."

Prof Taylor added that his sense is that the biology "is likely to be the same" between different populations.

He noted, however, that there could be a "big difference" in the social environment and pressures to maintain weight loss between cultures and ethnicities.

This study was funded by Diabetes UK as a strategic research initiative. The diet formula was donated by Cambridge Weight Plan.

Lean reports research grants and personal fees for lecturing and consultancy from Novo Nordisk and consultancy fees from Counterweight Ltd, Novartis, and Eli Lilly. Taylor reports educational lecture fees from Eli Lilly and Novartis and advisory board fees from Wilmington Healthcare. Barnes reports lecture fees from Novo Nordisk and Napp Pharmaceuticals. Thom reports funding of PhD fees and conference expenses from Cambridge Weight Plan. Brosnahan was previously employed by Counterweight Ltd and reports personal fees for freelance work and share holdings from Counterweight Ltd and funding of PhD fees and conference attendance from Cambridge Weight Plan.

Diabetes UK Professional Conference. Main clinical outcomes of DiRECT at 2 years. Presented 5 March.

Lancet Diabetes Endocrinol 2019. doi: 10.1016/ S2213-8587(19)30068-3

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