Can remission of type 2 diabetes last?

Remission of type 2 diabetes is now seen as a real alternative to a lifetime of medication and worry about complications. The down side is that it may not last, and the issue of relapse was in the spotlight at the Diabetologia symposium on remission at EASD 2022.

Relapse of type 2 diabetes is currently defined as the resurgence of diabetes after a period of remission. It differs from not achieving remission in the first place and may be influenced by different factors. Speaking at this year’s EASD Annual Meeting, Dr Blandine Laferrere, Associate Professor in the Division of Endocrinology at Columbia University Medical Center, said: “It’s difficult to discuss relapse, because we don’t have a lot of data on it. It’s easier – and more interesting – to publish on remission.”

There are two important aspects to relapse, she continued. First, there is the temporal aspect, which depends on how often someone is monitored. So it may be difficult to know how long someone has been in remission or relapse. But time spent in remission before relapse could be very important – and the longer the better. There will also be degrees of relapse. Some will have an HbA1c just above the diagnostic level and just need to go back on metformin. They will be very different from those with higher HbA1c, who may need to go back on insulin. 

Relapse scenarios

People arrive at type 2 remission by different routes. Dr Lafererre went on to describe some scenarios and how they affect the chance of later relapse. For instance, in a meta-analysis of trials of short-term intensive insulin therapy (IIT), 60 to 70% went into remission, but 30% of these relapsed after 12 months. In another study of ITT, followed by either a GLP-1 receptor agonist or placebo, duration of diabetes was found to be a significant factor in the likelihood of relapse. At three months of follow-up, the relapse rate was 40% for those with diabetes duration of less than two years, and 90% for those with a longer duration than this. The influence of diabetes duration is similar to what is found in remission – the shorter the duration, the higher the chance of remission.

An animal study shed some light on what might be happening here. In diabetes, the beta cell de-differentiates, but in insulin therapy it differentiates again. So the mechanism of relapse on IIT might be that the beta cells de-differentiate again after insulin is discontinued. And beta cell function is likely to be worse in those with a longer duration of diabetes. 

Some people achieve type 2 remission after pharmacotherapy – particularly with GLP-1 receptor agonists. Dr Lafererre referred to a study where participants were given exenatide or nothing for 12 weeks after a remission intervention with either intensive lifestyle change or insulin. Those on exenatide did not relapse, until they were taken off it – when they relapsed at the same rate as the controls. Many other GLP-1 receptor agonists have shown the same. “So, there is no permanent benefit of the GLP-1 receptor agonists on the beta cell,” Dr Lafererre noted.

Then, with lifestyle intervention, there is the problem of sustainability. Dr Lafererre has extracted some data from the Look AHEAD trial, although it was not actually aimed at remission or relapse. Over 4,000 people were randomised to either intensive lifestyle intervention or to diabetes education. One third of those in the lifestyle group relapsed per year, and half of those in the education group, over the course of follow-up. 

“What could be the mechanism here?” she asked. “We don’t have measures of beta cell function in Look AHEAD, unfortunately. There was over 8% weight loss in the lifestyle group. Weight regain could perhaps explain some of the relapse, although this is an association and not a mechanism.”

Finally, for those who have achieved remission through bariatric surgery, there is a lot of data to mine the factors affecting relapse. For instance, it seems that the treatment someone has before surgery is important – with insulin giving higher relapse rates than either diet or oral hypoglycaemic agents. “Pre-operative insulin was shown to be a factor in predicting relapse in almost all the studies,” Dr Lafererre noted.

Duration of diabetes is also a factor, with a recent study showing relapse rates at 10 years after surgery of 20% for those who had had diabetes for less than four years, but 94% for those who had had the condition for longer than this.

Of course, it is hard to make direct comparisons, as rates of relapse after bariatric surgery vary tremendously – between 12% and 94% – depending upon the time of follow-up of the study.

Although there is little information about the mechanism of relapse after surgery, Dr Lafererre believes it involves poor beta cell function at the start – which could be indicated by someone having to take insulin long term before they have surgery. This function continues to decline over time, in some people, despite surgery and weight loss. 

Her own lab has looked at beta cell function over time. “I wish more people would do this,” she said. One question they looked at was whether beta cell function recovers fully in clinical remission. For this, they selected people whose duration of diabetes was less than two years, to make sure they went into remission. They were then studied three years after surgery. “The beta cell function did not normalise and this surprised me tremendously, because they were all in full remission.”

So, clearly there is more to be learned about the role of beta cell function in relapse. Other possible mechanisms include insulin resistance, weight regain or lower weight loss after surgery. “And no-one has studied the possible role of being less fit or poor diet. There is also genetics and socioeconomic status to consider, and decreased sensitivity to incretins, where glucose toxicity comes back,” Dr Lafererre concluded.

Conclusions

To achieve remission and prevent relapse it’s important to intervene very early, prior to starting insulin, and try to sustain those lifestyle changes. There is also a role for pharmacotherapy such as short-term insulin, tirzepatide, and a metformin/SGLT-2 inhibitor combination, all of which may preserve beta cell function. “I believe pharmacotherapy should be looked at in a very positive way here,” Dr Lafererre said. “It would be very interesting to have more studies on short-term sequential insulin therapy to see if we can sustain the improvement in beta cell function, which is really the goal of preventing relapse.”

For more on this topic, see the following EASD e-Learning modules:

• Lifestyle intervention Module 1: Understanding the causes of type 2 diabetes and how to achieve remission, by Professor Roy Taylor
• Management of hyperglycaemia in type 2 diabetes Modules 1 and 2, by Professor Melanie Davies

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.