The prognosis for people with T2D is not good, with 10-year survival rates around 50% (1), yet its seriousness is often underestimated. Surgical and non-surgical weight loss studies (2–5) have conclusively demonstrated that 10-15% body weight loss will lead to remission of type 2 diabetes (HbA1c<48 mmol/mol, without glucose-lowering medication for at least 3 months) in the majority of individuals with short duration disease. Remission is a relatively new concept, and prioritizing this as a principal target at diagnosis would represent a major shift in clinical care, where treatments have historically aimed to ‘control’ T2D.

It is well established that weight gain is the dominant cause of T2D among individuals who have an underlying predisposition to metabolic syndrome (6, 7). Many people can gain weight, even to high degrees of obesity, by depositing excess energy as fat into subcutaneous sites, without developing metabolic and macrovascular complications. However, a large subset of the population (probably predisposed by genetic and/or epigenetic factors) also start to deposit fat into ectopic sites and vital organs such as the heart, liver and pancreas. Excess fat damages organ functions, leading to development of hypertension, dyslipidemia, and T2D, and ultimately to multisystem metabolic failure and progressive vascular complications. These end-stage complications are not reversible. However, T2D should be reversible by treating the earlier underlying process of body fat accumulation.

If weight gain is the dominant driver of T2D, then weight loss is the logical solution for management. This tenet is strongly supported by consistent evidence that relatively modest weight loss at an earlier stage, with pre-diabetes, can arrest the disease-process. Randomised trials in Finland and North America both reported 58% reductions in 4-year progression from prediabetes to T2D with weight loss of about 7-kg, maintained at 4-kg over 4 years (8, 9) subsequently repeated elsewhere (10).

Once T2D has developed, the clock starts ticking towards the arrival of permanent, painful and disabling microvascular complications, despite helpful guideline-directed medications. Bariatric surgery has demonstrated remissions to a non-diabetic state for at least 2 years in 70-80% of participants (11, 12), with weight losses ranging from 20-40%. However, bariatric surgery cannot be provided to all the vast numbers of people with T2D, and many are not interested in a surgical procedure for weight loss (13). Also, many people with T2D, particularly with Asian heritage, have BMI too low to warrant bariatric surgery.

The question, arises - how much weight loss is needed to achieve remission of T2D? The likelihood appears to be with weight loss above 10-kg/% of total body weight, for most people. A well-conducted randomized controlled trial of bariatric surgery found that 15% (~15-kg) weight loss resulted in remissions for nearly all participants (2). A T2D clinic audit from Scotland, where all were seen by dietitians at each visit, and were followed from diagnosis to death, found that for the average T2D patient, each 1-kg weight loss in the first year was associated with 3-4 months longer survival (14). Reliable data were available up to 14-kg weight loss, at which point survival was similar to the general population. A recent study of 5,928 patients with T2D who underwent bariatric surgery found that T2D remission was more likely with each 5% increase in total weight loss until 20% total weight loss, where remission rates did not increase substantially (3).

Can weight loss of >10-kg/% of total body weight, if that is required for diabetes remission, be reliably achieved without bariatric surgery? One option, already widely available and used by the general population, is to use low-calorie total diet replacements (TDRs).

In a proof-of-concept study, eleven T2D participants consumed a 600 kcal/d liquid formula diet, supplemented with non-starchy vegetables, for 8 weeks. An age-, sex- and weight-matched group of 8 non-diabetic participants was also studied. Average weight loss was ~15-kg or ~15% of initial body weight in the seven T2D participants who completed the 8 weeks’ diet. This led to a return of normal beta cell function and hepatic glucose output, in association with marked decreases in pancreatic and liver fat (15).

A second study was conducted to assess the feasibility of achieving >15-kg weight loss over a longer duration (12 months) through a weight loss programme in routine primary care. Participants consumed a micronutrient-replete low-energy liquid diet (810–833 kcal/day) for 12 weeks or 20-kg weight loss (whichever occurred sooner), followed by structured food reintroduction (FR; 6-8 weeks) and continued support for weight loss maintenance. Of 91 participants who entered the programme, 30 (33%) had maintained weight loss of ≥15-kg at 12 months. Most preferred the commercial formula diet product, rather than having to make decisions about foods and control portion sizes themselves. Few elected to use optional orlistat (16).

The Diabetes Remission Clinical Trial (DiRECT) was designed to investigate whether a weight management program delivered within routine primary care, thus potentially accessible to most people with T2D, could achieve the necessary weight loss to sustain remissions of T2D cost-effectively. Trial and baseline participant characteristics are outlined in Table 1 , and intervention components in Table 2 . All participants continued to receive routine diabetes care under current clinical guidelines.

A recent systematic review (25) found only two randomised controlled trials (DIADEM-I and DiRECT), of non-surgical weight management to examine remissions of T2D. The DIADEM-I trial was conducted to assess the generalizability of the DiRECT results, using a near-identical intervention protocol, to people with early T2D from the Middle East and north Africa. At 12 months, diabetes remission occurred in 61% of intervention participants (mean 12-kg weight loss) compared with 12% in the control group (mean 4-kg weight loss). The greater 12-month remission rates in DIADEM-I (61%) than DiRECT (46%) probably reflected shorter duration of diabetes (<2 years) and slightly greater weight loss, with more remissions in the control group also (12% in DIADEM-I vs. 4% in DiRECT) (5).

T2D remissions have also been reported with low-carbohydrate (ketogenic) diets, but in an open-label, non-randomised study only 19% achieved remission at 12 months, despite an average weight loss of 13.8-kg over 12-months. The protocol did not include withdrawal of glucose-lowering medication, so a higher figure is likely, but recent review evidence suggests no special advantage for low carbohydrate diets in diabetes care (25, 26).

In a remarkable English GP practice, patients with newly diagnosed and pre-existing T2D were offered advice on a low carbohydrate diet. An audit between 2013 and 2019 reported that of 473 patients with T2D, 27% opted to follow the low carbohydrate diet for a mean duration of 23 months T2D remission was achieved by 12.5% of patients, using intention-to-treat analysis (and 46% of ‘completers’ who adhered to the diet), with significant improvements in weight, blood pressure and lipid profiles (27).

In line with a well-conducted meta-analysis showing no overall clinically significant benefit for low-carbohydrate diets (26), a systematic review and meta-analysis of 8 studies reporting remissions (n=264) found no benefit for T2D remissions at 6 or 12 months with low or very-low carbohydrate diets. There was a short-term advantage for achieving HbA1c<6.5% more often (57%) than control groups (31%) at 6 months. This effect was lost at 12 months (28).

The field investigating type 2 diabetes remission continues to grow, but at an overview of the current evidence points to remission being most likely after ‘double-digit’ weight loss (>10kg/%, preferably >15kg/%), achieved as early as possible following diagnosis. A TDR induction phase to initiate weight loss has the strongest evidence, with actively supported transition onto a sustainable eating pattern thereafter. Low carbohydrate diets may help a proportion of patients achieve sufficient weight loss, but further research and better long-term data are required for weight loss maintenance and lasting remissions before this can be routinely recommended.

The success of DiRECT has led to improved service provision for the wider population of people living with T2D. For example, in the UK, a major investment was made by the Scottish Government to specifically target type 2 diabetes prevention and remission in all NHS health board areas, using the evidence-based DiRECT/Counterweight-Plus diet programme (29) NHS England is evaluating interventions for remission in 5,000 people with T2D (30), using a variety of approaches which follow the ‘DiRECT Principles’, with impressive preliminary results (31).

Although the DiRECT/Counterweight Plus programme is highly cost-effective, indeed cost-saving, current dietetic services are typically under-funded and under-staffed to manage the numbers of people with T2D, and as a result, access to this intervention is limited in comparison to the numbers eligible. Although funding is a major consideration, potential solutions to improve scalability include delivering TDR intervention in a group-setting, which also provides opportunity for peer support. This approach was used in the PREVIEW trial, which reported average weight loss of 11% body weight in over 2000 people with pre-diabetes taking part in an 8-week TDR group intervention, with very low drop out and only a fraction progressing to T2D at the 3-year study end point (32). Further evidence in support of group-based TDR programmes come from studies in people with osteoarthritis, sleep apnoea and psoriasis, where weight losses of 10-20% body weight have been documented (31, 33, 34).

Traditionally, weight management interventions have taken place in a face-to-face format. However, the healthcare delivery landscape has changed rapidly in recent years, with remotely delivered weight management programmes becoming commonplace due to restrictions imposed by Covid-19, together with significant advances in interactive digital technologies. Digital healthcare offers improved convenience and accessibility for many individuals, especially those of working age, and provides cost savings to health services. Importantly, outcomes for weight management appear to be at least comparable to traditional approaches (35). As healthcare delivery and diabetes care continues to evolve, and the demand for scalability to deal with the double burden of obesity and type 2 diabetes grows, it is likely that digital delivery will become the first line approach, and closer working partnerships between healthcare and industry will be required.

The publicity around DiRECT and DIADEM-1 has raised public expectations, to the degree that a failure to achieve remission could be psychologically damaging, and demanding of management. For some, greater weight loss may be successful, but even after bariatric surgery, remission rates are similar to DiRECT. While most people diagnosed as T2D have a weight-loss-responsive disease characterised by ectopic fat accumulation in liver and pancreas, small numbers have a different cause of persistent beta-cell injury.

While losing weight is hard for people, in particular for those with longstanding obesity, maintaining weight loss is invariably a harder task, and specific research is needed to define how to optimise weight-loss maintenance. There is extensive and consistent RCT evidence that weight loss differences between diets are marginal, and optimising individual adherence appears to be more important than macronutrient composition (36) though tailoring diets to personal preference is not always associated with better outcomes (20). Managing life events, day-to-day stress and negative emotions is likely to be critical for weight loss maintenance in the long term (37). Regular physical activity and exercise on its own has only limited effect on weight loss for most people, but valuable for maintaining muscle mass and preventing weight regain (38). Modern weight management medications such as GLP-1 agonists operate using physiological pathways to control both appetite and insulin secretion after eating, and are much more potent, and safer, than older drugs. If combined with a good behavioural intervention, they are able to help many more people achieve and maintain weight losses of over 10%, or over 15% (39–41). These drugs are also glucose lowering so remission cannot be claimed without withdrawing them and implementing non-pharmacological weight-loss maintenance. Looking to the future, innovative approaches to prevent weight gain by stimulating endogenous GLP-1 and PYY are currently being trialed, using oral hydrogels (42) and food-products such as inulin propionate ester (43). Weight regain threatens the sustainability of T2D remission, and whilst weight loss maintenance is undermined by interacting physiological, behavioural and environmental factors, emerging pharmacotherapies used in combination with multi-component weight management programmes offer promise in addressing this problem.

It is time to rethink treatment targets for T2D, and to aim for remission at diagnosis when motivation for change is often high, and disease progression is at an early stage. Despite expert guidelines and numerous medications to lower HbA1c, blood pressure and lipids, people diagnosed with T2D remain at risk of multiple complications over the long term, and substantial reductions in life expectancy. However, in light of evidence demonstrating that weight loss ≥10% body weight can reliably induce remission in most people early in the disease course, we can now offer people hope that a better prognosis is possible. This new knowledge is beginning to be translated into routine care settings and the adoption of digital technology by health care providers will facilitate future scalability and delivery of such interventions. Multi-component weight management incorporating an initial period of TDR offer the best bet for substantial weight loss and T2D remission, and with this in mind, we should no longer persist in offering people ineffective strategies for this treatment target, and instead prioritise programmes with a proven evidence base for delivering weight losses of ≥10% body weight.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

JN drafted the manuscript. GT and ML critically reviewed the manuscript for important intellectual content, and edited drafts. All authors reviewed and approved the final manuscript.

Aspects of this work were supported by the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. This included journal publication costs, overheads costs, and author honoraria (JCN only).

JN has worked as a clinical research coordinator at INQUIS Clinical Research. He has also received research support from Glycemia Consulting Inc. GT reports funding for PhD fees, conference attendance and departmental research support from Cambridge Weight Plan outside the submitted work. ML has had departmental research funding from Diabetes UK, NIHR, Novo Nordisk, has received personal fees for lecturing and consultancy from Novo Nordisk, Merck, Eli Lilly, Sanofi, Nestle, Oviva, and has provided unpaid medical consultancy to Counterweight Ltd.

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