The feasibility of durable remission in diabetes is a hotly debated topic, with one side citing successful studies and the other questioning long-term utility and current definitions of remission. Recently, at this year's annual meeting of the European Association for the Study of Diabetes (EASD) in Hamburg, Germany, experts discussed whether durable remission of diabetes is feasible in the real world.

Professor Roy Taylor of Newcastle University in the UK believes that through a series of studies on low-calorie diets in patients with type 2 diabetes, he has proven that lasting remission of type 2 diabetes is indeed feasible in the real world.

Outlining his research, he began by describing the Counterpoint study, which demonstrated in 2011 that it was possible to reverse type 2 diabetes with a very low-calorie diet.

The study also showed that type 2 diabetes is caused by excess fat in the liver and pancreas, and that reducing fat within the organs is key to relieving the condition.

However, Counterpoint was only a short-lived proof-of-concept study, and further research is needed to demonstrate that the return to normalcy process continues beyond the reduced-calorie diet phase.

Counterbalance and DiRECT trial

In the 2016 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 a normal diet.

The findings suggest that type 2 diabetes can be reversed for at least 6 months if weight loss is maintained.

However, both studies were conducted in research centres, and it will be important to determine whether type 2 diabetes can be reversed in primary care with routine management.

The DiRECT trial, delivered by GP practices and coordinated between Newcastle and Glasgow, aims to answer this question. 298 people with type 2 diabetes took part in this randomized controlled trial, which included a 12-week ultra-low-calorie diet followed by weight loss maintenance support.

Long-term research results and implications

Professor Taylor said: "In 2018, this ground-breaking study showed that it is possible to put type 2 diabetes into remission with dietary intervention in primary care. After 1 year, the intervention group were on average 10kg (22lb) lighter than at baseline, and almost half (46%) of people with diabetes were in remission - they stopped all diabetes medications. After 2 years, they were still 8.8kg (19.4lb) lighter than at baseline and 36% were in remission."

"We then extended the study for a further three years to investigate the long-term benefits of the programme. Participants in the extension study had appointments with a nurse or nutritionist at their GP surgery every three months, during which time they were given advice on maintaining their weight loss. Those who were most successful at avoiding weight regain remained in remission. After five years, their weight was still lower than at baseline 8.9 kilograms (19.6 pounds) and were still in remission. However, this represented only 23% of those in remission at two years, as the intervention group regained some weight overall. The message here is that only those who are able to maintain their weight will remain in remission - and it is certain that type 2 diabetes will return in those who return to their previous weight."

Professor Taylor's research has also identified the underlying causes of type 2 diabetes, as well as the biology of remission.

His research shows that excess fat in the liver prevents insulin from working properly. It also increases the normal process of fat export to body tissues, including the pancreas, preventing insulin-producing beta cells from working properly. Weight regain leads to an increase in liver fat, an increase in fat output from the liver, and a decrease in beta cell function.

National impact and real-world applicability

The DiRECT findings inspired a national remission program in England4 that uses a very low-calorie diet to promote weight loss and thereby reverse type 2 diabetes.

Early results from NHS England's Pathways to Remission for Type 2 Diabetes program show a weight loss of 10.3kg (22.1lb) after 12 months, matching results from the DiRECT trial.

Professor Taylor said: "It is therefore clear that in the real world it is possible to achieve remission in type 2 diabetes with the necessary weight loss, and that long-lasting remission can be achieved as long as sufficient support is provided to avoid weight regain. Avoiding weight regain is challenging, but it is possible and long-term remission can be achieved."

Professor Kamlesh Khunti from the University of Leicester in the UK spoke against the motion.

Professor Khunti believes that lasting remission of type 2 diabetes is not feasible in the real world. He draws on evidence from studies of lifestyle interventions such as low-calorie diets, GLP-1 receptor agonists and bariatric surgery to explain why.

He explained that relieving the condition through lifestyle interventions, including low-calorie diets, has been demonstrated in multiple studies, but these studies have shown that behavioral changes are difficult to maintain long-term.

Criticisms of definitions of lifestyle intervention and remission

These include the DiRECT trial, which is often cited as evidence that weight loss through a low-calorie diet can put type 2 diabetes into remission. However, DiRECT reported data on only 53 sustained responders after five years, about 7 percent of those initially randomized to the low-calorie diet.

Professor Khunti said: "The cost-benefit analysis of the DiRECT study is also questionable. Other studies have shown that weight lost through lifestyle changes is eventually regained. Changes in circulating hormone levels can increase appetite and promote weight regain. Weight regain can also lead to collateral obesity - where some of the muscle lost is replaced by fat. In addition, studies have not 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 mitigation. The latest definition from the American Diabetes Association, EASD and Diabetes UK is that remission refers to HbA1c <6.5% three months after stopping antidiabetic treatment. Unfortunately, the results of most interventions do not meet this definition. For example, GLP1 receptor agonists used to treat type 2 diabetes and obesity have achieved significant results in reversing type 2 diabetes.

Although these results are alarming, they do not qualify as remission by current definitions because participants were not able to stop taking their glucose-lowering medications.

Compare other interventions

The most compelling long-term remission data comes from bariatric or bariatric surgery, with nearly one-third of people still in remission after 15 years.

"Metabolic surgery has also shown benefits on micro- and macro-vessels. The same goes for GLP-1 receptor agonists," said Professor Khunti. "However, bariatric surgery is a fairly drastic procedure and is not suitable for everyone. It is also associated with serious adverse events, some of which can be fatal. In summary, durable remission is unlikely in the real world - at least according to the current definition of remission. Perhaps it is time to think about the terminology; if it is defined as 'remission of hyperglycemia with or without antidiabetic therapy,' then in the real world, remission can be achieved in many more people."