Experts recently discussed if lasting remission from diabetes is feasible in the real-world setting at this year’s Annual Meeting of the European Association for the Study of Diabetes (EASD) in Hamburg, Germany.
Professor Roy Taylor of Newcastle University, Newcastle, UK, spoke in support of the motion
Professor Taylor argued that through a series of studies in which people with type 2 diabetes were put on low-calorie diets, he has shown that lasting remission of type 2 diabetes is indeed feasible in the real world.
He began the overview of his research by describing the Counterpoint study which, in 2011, established that it is possible to reverse type 2 diabetes by following a very low-calorie diet.1
It also showed that type 2 diabetes is caused by excess fat in the liver and pancreas and loss of this intra-organ fat is key to remission.
Counterpoint was, however, a short proof-of-concept study, and a further study was needed to demonstrate that the return to normal lasted beyond the low-calorie diet phase.
The Counterbalance and DiRECT Trials
In 2016 the Counterbalance study, 30 people with type 2 diabetes followed a very low calorie diet (800 calories a day from shakes and soups) for eight weeks before returning to normal eating.
This demonstrated that if weight loss is maintained, type 2 diabetes can be reversed for at least six months.2
However, both of the studies were conducted in a research center and it was important to establish whether type 2 diabetes could be reversed in primary care, where it is routinely managed.
The DiRECT trial, which was delivered by GP practices and coordinated between Newcastle and Glasgow, was designed to answer this question. 298 people with type 2 diabetes participated in this randomized controlled trial, which involved 12 weeks on a very low-calorie diet, followed by weight-loss maintenance support.
Long-term Study Outcomes and Implications
Professor Taylor says: “In 2018 this ground-breaking study showed that it is possible to obtain remission from type 2 diabetes through a dietary intervention in primary care. At 1 year, the intervention group were 10 kg (22lb) lighter, on average, than at baseline and almost half (46%) were in remission from diabetes – they were off all glucose-lowering drugs. At 2 years, they were still 8.8kg (19.4lb) lighter than at baseline and 36% were in remission.3
“We then extended the study for a further three years to investigate the longer-term benefits of the program. Participants in the extension study received nurse or dietitian appointments at their GP surgery every three months, during which they were offered advice on maintaining their weight loss. Those who were most successful in avoiding weight regain remained in remission. After five years, they were still 8.9kg (19.6lb) below baseline and were still in remission. However, this was only 23% of those who were in remission at 2 years, as the intervention group as a whole had regained some weight. The message here is that only those who can keep the weight off stay in remission – and that it is certain that type 2 diabetes will return in those who return to their original weight.”
Professor Taylor’s body of work has also established the underlying cause of type 2 diabetes – and the biology of remission.
He has shown that excess fat in the liver prevents insulin from working properly. It also increases the normal process of export of fat to the body’s tissues, including the pancreas, where it stops the insulin-producing beta cells from working properly.
Weight regain causes the return of increased liver fat, increased fat export from the liver, and a decline in beta cell function.
National Implications and Real-World Applicability
The DiRECT results have inspired a national remission program in England4, in which a very low-calorie diet is used to promote weight loss and so the reversal of type 2 diabetes.
Early results from NHS England’s Type 2 Diabetes Path to Remission program show 10.3kg (22.1lb) weight loss at 12 months, which is on par with the DiRECT trial.
Professor Taylor says: “It is therefore clear that the necessary weight loss to achieve remission of type 2 diabetes is feasible in the real world – and this leads to lasting remission provided that sufficient support is provided to avoid weight regain.
“Avoiding weight regain is challenging but it is possible and it can lead to long-lasting remission.”
Professor Kamlesh Khunti, of the University of Leicester, Leicester UK spoke against the motion
Professor Khunti argued that lasting remission of type 2 diabetes is not feasible in the real world. He used evidence from studies on lifestyle interventions, including low-calorie diets, GLP-1 receptor agonists, and bariatric surgery to explain why.
He explained that remission through lifestyle interventions, including low-calorie diets, has been tested in a number of studies but these have shown that behavior change is difficult to maintain long-term.
Critique of Lifestyle Interventions and Remission Definition
This includes the DiRECT trial, which is often cited as evidence that weight loss achieved through a low-calorie diet can put type 2 diabetes into remission. However, at five years, DiRECT reported data on only 53 people with sustained remission, which is approximately 7% of those who were initially randomized to the low-calorie diet.
“The cost-effectiveness analysis of the DiRECT study is also questionable,” says Professor Khunti.
“Other studies have shown that weight lost through lifestyle changes is eventually regained. Changes in circulating hormone levels increase appetite, encouraging weight regain. Weight regain also results in collateral fattening – where some of the muscle mass that was lost is replaced by fat. In addition, studies haven’t shown that low-calorie diets reduce the risk of microvascular complications of diabetes, such as retinopathy and neuropathy, nor the risk of macrovascular complications, such as coronary artery disease.”
Another key issue is the definition of remission. The most current definition by the American Diabetes Association, EASD, and Diabetes UK defines remission as an HbA1c < 6.5% for three months after cessation of glucose-lowering therapies. Unfortunately, the results of most interventions fail to satisfy this definition.
For example, GLP1-receptor agonists, a family of drugs that are used to treat type 2 diabetes and obesity, have demonstrated remarkable results in terms of reversing type 2 diabetes.
Striking as these results are, they would not be classed as remission by the current definition as the participants were not able to stop taking glucose-lowering medication.
Comparing Other Interventions and Concluding Remarks
The most compelling data for long-term remission comes from bariatric or weight loss surgery, where almost a third of people are still in remission after 15 years.5
“Metabolic surgery has also demonstrated microvascular and macrovascular benefits. This is also the case for GLP-1 receptor agonists,” says Professor Khunti. “However, bariatric surgery is quite a drastic procedure and is not practical for the whole population. It is also associated with severe adverse events, some of which can be fatal.
“In summary, lasting remission is not possible in the real-world setting – at least with the current definition of remission. Perhaps it is time to think about the terminology; with a definition such as possibly ‘remission of hyperglycemia with or without glucose-lowering therapy’, remission would be more achievable for more people in the real world.”
- “Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol” by E. L. Lim, K. G. Hollingsworth, B. S. Aribisala, M. J. Chen, J. C. Mathers and R. Taylor, 9 June 2011, Diabetologia.
- “Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes” by Sarah Steven, Kieren G. Hollingsworth, Peter K. Small, Sean A. Woodcock, Andrea Pucci, Benjamin Aribisala, Ahmad Al-Mrabeh, Ann K. Daly, Rachel L. Batterham and Roy Taylor, 1 December 2015, Diabetes Care.
- “Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial” by Michael E J 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, Paul Welsh, Sharon Kean, Ian Ford, Alex McConnachie, Claudia-Martina Messow, Naveed Sattar and Roy Taylor, 6 March 2019, The Lancet Diabetes & Endocrinology.
- “Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications” by Lars Sjöström, Markku Peltonen, Peter Jacobson, Sofie Ahlin, Johanna Andersson-Assarsson, Åsa Anveden, Claude Bouchard, Björn Carlsson, Kristjan Karason, Hans Lönroth, Ingmar Näslund, Elisabeth Sjöström, Magdalena Taube, Hans Wedel, Per-Arne Svensson, Kajsa Sjöholm and Lena M. S. Carlsson, 11 June 2014, JAMA.