Dr Pam Brown Provides Seven Key Learning Points for Primary Care from a Consensus Report on Defining Remission in Diabetes
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Find implementation actions for STPs and ICSs at the end of this article
Type 2 diabetes is a major public health epidemic;1 rates of type 2 diabetes continue to rise across the UK and globally, and the personal and financial costs of the disease are huge.2 Studies attempting to demonstrate the feasibility of reducing blood glucose to the point where the criteria for a diagnosis of type 2 diabetes are no longer met have used a wide variety of nomenclature, including ‘cure’,3 ‘remission’,3 ‘reversal’,1 ‘resolution’,1 and ‘mitigation’.4 The glucose thresholds used to define this state vary between different countries and organisations,3,5 which can cause confusion and uncertainty as to whether people with type 2 diabetes have achieved a glucose level low enough, and for long enough, to qualify as ‘in remission’. A 2020 systematic scoping review6 identified 96 unique definitions of diabetes remission used since 2009, further highlighting the need for clarity. Examples of the two most commonly used definitions for diabetes remission are shown in Box 1.3,5
|Box 1: Common Definitions of Diabetes Remission3,5|
In 2009, a consensus group of experts from the ADA defined diabetes remission as follows (with the patient no longer taking glucose-lowering medications in each case):3
The 2019 PCDS/ABCD position statement on remission included the following three criteria:5
ADA=American Diabetes Association; HbA1c =glycated haemoglobin; FPG=fasting plasma glucose; PCDS=Primary Care Diabetes Society; ABCD=Association of British Clinical Diabetologists
The joint Primary Care Diabetes Society (PCDS) and Association of British Clinical Diabetologists (ABCD) position statement describes diabetes remission as an achievable outcome in people with type 2 diabetes, and highlights the central role of weight loss and need for ongoing support to maintain remission.5 The Diabetes REmission Clinical Trial (DiRECT) study sought to clarify the weight loss needed to achieve remission of type 2 diabetes, proposing a weight loss goal of 15 kg.7 However, diabetes remission is not a specified goal in current clinical guidelines and management algorithms, which may reflect the lack of consensus on an agreed definition. The 2021 Consensus report: definition and interpretation of remission in type 2 diabetes8 collates the summary and conclusions of discussions between an international, multidisciplinary group, including representatives from the American Diabetes Association, the European Association for the Study of Diabetes, Diabetes UK, the Endocrine Society, the Diabetes Surgery Summit, and an oncologist. The authors stress that the report is based on expert opinion, and is designed to propose definitions and ways to assess glycaemia that facilitate the collection and analysis of data that may, in future, lead to clinical guidance.8 It is not intended to establish treatment guidelines, recommend when to pursue remission, or favour any specific intervention for achieving remission.8
This article will explore the implications of this consensus report for UK primary care, and share seven key actions around remission of diabetes.
1. Start to Use the New Consensus Definition of Reemission
The consensus report agrees with previous guidance that ‘remission’—a word commonly used in cancer treatment—is the appropriate term, rather than ‘cure’, ‘resolution’, or ‘reversal’, because the improvement may not be permanent, and ongoing monitoring and support is required to reduce the risk of relapse.
According to the consensus report, the recommended definition of remission is now:8
- glycated haemoglobin (HbA1c) less than 48 mmol/mol (less than 6.5%), measured by a standardised and quality-assured method when no longer taking any glucose-lowering medication
- maintenance of this HbA1c level for at least 3 months after discontinuation of any glucose-lowering medication.
Notably, this definition of remission requires HbA1c to be less than 48 mmol/l for a shorter duration than the 6 months advocated by the previous PCDS/ABCD position statement used in the UK.5,8 Therefore, it may be the case that more people currently living with diabetes will now meet the definition, and can be coded accordingly.
Determining Remission When HbA1c is an Unreliable Measure
In some people, HbA1c can be influenced by factors that make it unsuitable for diagnosing remission of type 2 diabetes, including variant haemoglobin, differing glycation rates, and alterations to the survival of erythrocytes.8 Local laboratories will be able to provide advice on when it is best to use an indicator other than HbA1c for diagnosis and monitoring. In these cases, continuous glucose monitoring (CGM) can be used to measure mean 24-hour glucose levels, and from this an HbA1c equivalent to the mean glucose, called an ‘estimated HbA1c’ or ‘glucose management indicator’, can be calculated.8 If this is less than 6.5% (48 mmol/mol), it can be used to confirm remission.8 This technique will usually require assistance from secondary care.
A fasting plasma glucose (FPG) level of less than 7 mmol/l can also be used to confirm remission if other methods are unsuitable,8 but use of the plasma glucose level 2 hours after a 75-g oral glucose challenge is not recommended by the consensus report because bariatric surgery may alter response to glucose load.8
Given that FPG and CGM readings change more rapidly than HbA1c, it is not necessary to wait 3 months after treatment is discontinued to check for remission but, because these readings are more variable, the report recommends that testing should be repeated to confirm remission or relapse.8
Cessation of Pharmacotherapy Before Testing
All drug therapy with specific effects on glucose lowering should have been stopped for at least 3 months before the biochemical test to confirm remission, irrespective of whether the drug was being used for type 2 diabetes or for other reasons (for example, use of glucagon-like peptide-1 receptor agonists for weight loss).8 This ensures that any effects on HbA1c have dissipated, and that the retrospective measurement period (about 12 weeks) has been free of drug treatment.8 Lifestyle and behaviour changes aimed at weight loss and maintenance should continue. In addition, weight-loss drugs, which may have indirect effects on improving glucose levels via weight loss, can be continued in the 3 months preceding biochemical testing.8
Intervals Between HbA1c Tests
The consensus report sets out the initial interval before HbA1c tests can confirm remission, as shown in Table 1.8 Once remission has been confirmed, testing should be repeated after at least 3 months—and at least at 12-monthly intervals thereafter to detect ongoing remission or relapse to type 2 diabetes.8
Table 1: Interventions and Temporal Factors in Determining Remission of type 2 Diabetes8
|InterventionA||Interval Required Before Testing of HbA1c Can Reliably Evaluate the Response||Subsequent Measurements of HbA1c to Document Continuation of Remission|
|Pharmacotherapy||At least 3 months after cessation of any pharmacotherapy|
No more often than every 3 months, and at least annually
|Surgery||At least 3 months after the procedure and 3 months after cessation of any pharmacotherapy|
|Lifestyle||At least 6 months after beginning the intervention and 3 months after cessation of any pharmacotherapy|
Note A: Documentation of remission should include a measurement of HbA1c just before intervention
Adapted with permission from Riddle M, Cefalu W, Evans P et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care 2021; 44 (10): 2438–2444.
2. Discuss Remission with Patients in Diabetes Consultations
Now that there is a growing evidence base that type 2 diabetes remission is achievable with significant weight loss of 10–15 kg, we owe it to people living with diabetes to discuss remission as a management option, particularly in the first 6 years or so after diagnosis, and in people who are not yet taking insulin. Although the DiRECT study and NHS remission pilots restricted recruitment to those who were diagnosed in the previous 6 years,7,9 other studies have shown that people who have lived longer with type 2 diabetes and those who are on insulin can still achieve remission.10,11
When discussing remission, it is important to know whether a remission pilot or service is available in your local area and, if not, how to access weight-management services that can help support patients to achieve the significant weight loss needed for remission. A leaflet that summarises the dietary options and weight-loss targets that may achieve type 2 diabetes remission will assist with informed decision making around remission (for an example, see bit.ly/3qP0Phw). If your practice is in a remission pilot site catchment area, you will have the opportunity to participate in training to help optimise these conversations and support people to decide if remission is something they wish to pursue.
Not everyone will want to actively pursue remission, but everyone with type 2 diabetes (particularly those with a recent diagnosis) should know enough about remission to make an informed choice.
3. Learn About Different Routes to Remission
Professor Roy Taylor emphasises that anyone developing type 2 diabetes has exceeded their ‘personal fat threshold’;12 that is, they are storing more fat than their personal fat stores can accommodate, causing fat from diet and liver manufacture to accumulate at ectopic sites, including the muscles, liver, and pancreas, and resulting in lipotoxicity, insulin resistance, and damage to pancreatic beta cells. In many individuals, weight loss can help to achieve remission,12 particularly in the early years of type 2 diabetes. Even unintentional weight loss, as is commonly seen in frail elderly individuals, can result in remission. It is important to identify remission, so that medication can be stopped or optimised.4
To achieve the significant weight loss required to attain remission, more intensive dietary or lifestyle changes are required than those needed to achieve small amounts of weight loss. In the DiRECT study,7 46% of the intervention group overall, and 86% of those achieving the target weight loss of 15 kg or more, achieved remission at 12 months. The intervention itself consisted of:
- withdrawal of antidiabetic and antihypertensive drugs
- 3–5 months of total diet replacement (TDR), consisting of approximately 850 calories per day
- food reintroduction and ongoing support to 12 months.
In contrast, the LookAHEAD study used a more moderate calorific reduction to 1200–1800 calories per day using a low-fat, relatively high-carbohydrate diet. In this study, overall, only 11.5% achieved either partial or complete remission by US definitions at 1 year, with rates of up to 21% among those who achieved significant weight loss.13
Low- or very-low-carbohydrate diets may induce weight loss, but are also thought to aid people in achieving remission levels of glycaemia by providing a much decreased glucose load.4 Some authors have therefore suggested that reduced glycaemia without weight loss should be termed ‘type 2 diabetes mitigation’ rather than remission,4 because the improvements may be dependent on continuation of the restricted diet.
It is important to individualise dietary discussions, as no one diet will suit everyone. Remission maintenance will depend on helping people to choose a realistic dietary approach. The same lifestyle changes that aid weight loss and remission will be beneficial for type 2 diabetes and other chronic health conditions,4 so even if remission is not achieved, it is possible that a number of other outcomes would still be worth the effort—for example:
- reduction in glucose-lowering medication
- tighter glycaemic control
- improved symptoms
- possible reduced risks of cardiovascular disease, obesity, and cancer.
Increasing physical activity is not a prerequisite for remission and, in the TDR phase of the DiRECT study, participants were encouraged not to change or increase their activity.7 However, physical activity can counteract insulin resistance, and will aid weight maintenance in the longer term.14
The evidence base for interventions supporting remission in people with type 2 diabetes is expanding; see Box 2 for a brief summary of the interventions.1,7,11,15–25
|Box 2: Interventions with Evidence for Type 2 Diabetes Remission1,7,11,15–25|
Low-calorie Diet and TDR
Low-carbohydrate and Very Low-carbohydrate Diets
Unprocessed, Whole-food, Largely Plant-based Diet
4. Understand When Pursuing Remission is Not Recommended
Caution is required in those with high HbA1c values because rapidly lowering their HbA1c, whether to induce remission or improve glycaemic control, may result in worsening of microvascular complications, including diabetic retinopathy.8 For this reason, the consensus report warns against trying to achieve rapid HbA1c reduction in people with retinal changes beyond microaneurysms (more than background retinopathy).8 Retinal screening should be arranged if sudden HbA1c reduction occurs in known retinopathy.8
People treated with sodium–glucose co-transporter-2 (SGLT-2) inhibitors should not follow very low-carbohydrate, ketogenic diets because these are likely to increase the risk of diabetic ketoacidosis, which is otherwise low when using these drugs.26
5. Explore your Local Pathway for Access to Remission or Weight-management Programmes
Remission pilot programmes using TDR are ongoing across 10 sites in England and in the other UK nations,9 although many of these have been disrupted by the pandemic (see Box 3).9,27–29 When discussing remission in our clinics, it is important that we know whether there is access to a local remission service and how this operates, if there is no remission service available and a patient wishes to pursue remission, be aware of the support that can be provided, for example, through referral to a local nutrition and dietetic department or weight-management service.
6. Review ‘Type 2 Diabetes in Remission’ and Remove ‘Diabetes Resolved’ Coding
‘Diabetes mellitus in remission’ or ‘type 2 diabetes in remission’ codes should already be in use, and people in this population should receive a diabetes review at least annually that includes an HbA1c test to confirm that they are still in remission.8 During the COVID-19 pandemic, ensuring that people currently in remission have their HbA1c measured will have been a lower priority than managing those with significant hyperglycaemia to reduce their risks, so many people in remission are likely to be overdue for review. When there is spare capacity in practice systems, these should be scheduled.
In addition, it is important to run a search for the two ‘diabetes resolved’ codes to check that these have not been used historically, which may result in people being erroneously removed from the diabetes register and no longer considered for reviews. There may also be some overlap in coding, with some people having both a remission and a resolved code. When removing the resolved codes, take care to leave an appropriate audit trail, so that it is clear when and why this has been removed.
Discuss how to amend coding when someone previously in remission relapses again with your computer system user group and local colleagues. It is important to agree whether the person should be coded as having new type 2 diabetes, but practices are likely to want to ensure that the original diagnosis date is still clear. There is no guidance on this in the consensus report.
7. Ensure that Long-term Follow Up Continues
Weight gain, stress from daily life, other illnesses, poor sleep, drugs that cause weight gain, an inability to maintain healthy lifestyle changes, or dietary lapse (if using a low-carbohydrate diet to achieve remission) can all result in a relapse of type 2 diabetes in people who have previously achieved remission. Lifestyle changes reduce the underlying causative factors of type 2 diabetes, making longer-term remission more likely, but ongoing monitoring is still needed.8
Even if remission is maintained and relapse does not occur, the risk and progression of microvascular and macrovascular complications (retinopathy, nephropathy, neuropathy, and cardiovascular disease) may continue.8 The 2021 consensus report reminds us that there is no evidence that any of the usual diabetes assessments can safely be discontinued once people are in remission.8 Diabetic retinopathy screening must continue, as should attendance at a diabetic eye clinic for those who have previously been referred, even if remission is achieved.8 Also, annual foot checks, blood pressure and weight measurements, and assessments of renal function and HbA1c should carry on.8
The consensus report reiterates guidance from the previous ABCD/PCDS position statement that at least annual measurement of HbA1c is required for those in remission, and that systems for recall should already be in place,5,8 although it is possible that these have been disrupted during the pandemic. People who have recently achieved remission may initially prefer more frequent HbA1c checks, and these can be carried out every 3–6 months, and can be motivational in terms of encouraging weight maintenance or further weight loss. Early identification of weight regain and any impact on glycaemia may prompt remedial action, as occurred in the DiRECT study, where short courses of TDR rescue therapy and/or orlistat were available.30
The consensus report’s authors did not feel able to say whether drugs such as metformin should be used to help maintain remission and prevent relapse, but they were clear that, where drug treatment is used, ongoing or new remission cannot be confirmed.8 Treatment with SGLT-2 inhibitors for chronic stable heart failure with reduced ejection fraction or to slow progression of chronic kidney disease will have glucose-lowering effects (if the estimated glomerular filtration rate is sufficiently high).8 These provide important benefits and may be continued, but it will not be possible to confirm remission.8
What Are the Practical Benefits of Striving for Remission for People with Diabetes?
Receiving a diagnosis of type 2 diabetes can have a significant impact on mental health, and knowing that diabetes remission has been achieved through self-management can have a very positive effect. Even if remission is not attained, making lifestyle changes and achieving significant weight loss can have a beneficial effect on mood, physical function, and other chronic diseases. Benefits will therefore accrue for the majority of people living with type 2 diabetes.
The consensus report—and the evolving evidence base for remission and its associated benefits—should reinvigorate our efforts to routinely discuss remission, refer people who wish to pursue it to weight management and remission pathways as they become available, and support more people to achieve remission, particularly those early in the course of their type 2 diabetes journey. We can optimise our use of the resources available locally, and work closely with dietetic and weight management colleagues and our own practice teams, to actively help people achieve ‘double-digit’ weight loss to facilitate remission. In addition, the clear definition of remission in the report provides clarity for our coding and conversations.
HbA1c=glycated haemoglobin; eHbA1c =estimated HbA1c; CGM=continuous glucose monitoring; FPG=fasting plasma glucose; BP=blood pressure
|Box 3: Remission Across the UK9,27–29|
Dr Pam Brown
Editor-in Chief, Diabetes and Primary Care; GP with an interest in diabetes, obesity, and lifestyle medicine; Tutor, University of Warwick/iHeed global Diabetes Diploma; Guidelines in Practice editorial advisory consultant for diabetes and obesity
|I am grateful to Ashif Ali, Chirag Bakhai, Laurie Eyles, Lesley Hamilton, Lara Jackson, Brian Kennon, Harry MacMillan, Jacqueline Walker, Catherine Washbrook-Davies, and Jason White for contributing information on remission pilots and plans for the individual nations.|
|Useful Resources for Patients|
|Implementation Actions for STPs and ICSs|
Written by Dr David Jenner, GP, Cullompton, Devon
The following implementation actions are designed to support STPs and ICSs with the challenges involved in implementing new guidance at a system level. Our aim is to help you to consider how to deliver improvements to healthcare within the available resources.
STP=sustainability and transformation partnership; ICS=integrated care system; ABCD=Association of British Clinical Diabetologists; PCDS=Primary Care Diabetes Society