This paper focuses on dietary strategies for weight loss and type 2 diabetes remission and includes two systematic reviews: (1) a systematic ‘umbrella review’ of published meta-analyses of RCTs of diets for weight loss in people with type 2 diabetes (PROSPERO CRD42020169258); (2) a systematic review of any intervention studies which report type 2 diabetes remission (PROSPERO CRD42020208878). Our paper is written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 [18] and the Synthesis Without Meta-analysis in systematic reviews: reporting guideline [19].

Detailed methods of both systematic reviews are presented in the electronic supplementary material (ESM) Methods and summarised in Fig. 1. The search strategy is in ESM Table 1. Fig. 1

Summary of the methodological processes of both systematic reviews. Detailed methods are presented in the ESM Methods. ^aThese types of NRSs provided intervention to participants and assessed outcomes at designated specific time points (baseline and at the end of intervention), although they could suffer from selection bias and confounding bias. ^bAMSTAR 2 level of quality assessment: high quality—the meta-analysis provides an accurate and comprehensive summary of the results of the available studies that addresses the question of interest; moderate—the meta-analysis has more than one weakness, but no critical flaws. It may provide an accurate summary of the results of the available studies; low—the meta-analysis has a critical flaw and may not provide an accurate and comprehensive summary of the available studies that address the question of interest; or critically low—the meta-analysis has more than one critical flaw and should not be relied on to provide an accurate and comprehensive summary of the available studies. CENTRAL, Cochrane Central Register of Controlled Trials; ROBINS-I, Risk Of Bias In Non-randomised Studies – of Interventions; T2D, type 2 diabetes

This study was conducted to inform practice and policy over dietary advice for weight management of people with type 2 diabetes. It has therefore focused on interventions in free-living individuals, with a view to long-term management. Based on methodological quality and certainty of the evidence, our umbrella review of meta-analyses found that VLEDs and formula meal replacements produce greater weight losses than conventional low-energy diets. The evidence does not favour LCDs above higher-carbohydrate diets, nor other dietary approaches, i.e., high-protein, Mediterranean, high-MUFA, vegetarian and low-glycaemic-index diets, above control diets. Currently popular intermittent fasting was only captured in systematic reviews without meta-analysis (high-risk-of-bias RCTs) [44, 45]. The evidence, albeit of variable ‘quality’, is rather consistent such that no one diet type is superior over others for weight management in type 2 diabetes.

While the evidence does not suggest important differences between macronutrient compositions in effectiveness, there may be differences in cost-effectiveness. The evidence on relative cost-effectiveness of weight-loss diet programmes is limited from head-to-head diet comparison trials, but one RCT showed that LCD was not more cost-effective than the standard weight-loss diet [61]. In the Doctor Referral of Overweight People to Low Energy total diet replacement Treatment (DROPLET) trial among people without diabetes, in routine practice, a total diet replacement programme (formula diets) with behavioural support proved more cost-effective than nurse-led dietary advice for long-term prevention of obesity-related diseases [62]. For diabetes remission, a total diet replacement programme was estimated to be both more cost-effective and cost-saving than standard care in the DiRECT trial, reflecting reduced need for medications and fewer diabetes complications [63].

Health benefits from weight management depend largely on long-term control of body weight. Most of the evidence cited relates to short-term outcomes, relevant to the initial weight loss induction phase of weight management. Few trials have reported data beyond 12 months, to reflect weight loss maintenance, which may demand different behavioural strategies. One large RCT of high-protein diet suggested benefit for weight loss maintenance, increasing satiety and energy expenditure, albeit for a maintenance phase of only 6 months after completing weight loss [64]. Nutrient-specific effects have been postulated, but are likely to be overwhelmed by variable behavioural responses to dietary advice [65]. Behavioural programmes help to sustain new behaviours, relationships with foods and adherence to dietary advice [66–68]. Consistent evidence is also accruing that long-term weight loss maintenance is better after more rapid early weight loss [69]. Thus, treatments effective for weight loss only in the short term may have long-term value if complemented with a good weight loss maintenance strategy. Practitioners can therefore be confident that a variety of diet types can all achieve the intended weight losses, and potentially remissions of type 2 diabetes, if their patients are able to adhere to the programme sufficiently.

The analyses contradict some popular claims about specific diets: in particular, ‘low-carb’ diets hold no overall advantage for weight loss when compared with higher-carbohydrate diets. However, we cannot conclude that any individual with type 2 diabetes, in any context, will do equally well with any diet advice, or that a skilled practitioner may not have greater success advising one diet type. The skills and empathy of practitioners may overcome any diet-specific effects on weight loss by providing consistent evidence-based support [70]. Realistic trials are required, in which individuals are offered choices, perhaps using n = 1 randomised trial designs.

Food is fundamental for personal and social wellbeing, and diets can be psychologically testing. Patient preferences, culture, context and lifestyle demand open conversation and shared decision making between practitioners and patients. For either medication or diet, weighing benefits against risks is vital: treatment benefits are often overestimated but harms underestimated [71]. Although all diet types are similarly effective for weight control, health risks were not systematically reported across the studies, and could differ [72]. More rapid early weight loss with more intensive programmes is associated with better longer-term weight outcomes [69], but severe caloric restriction without attention to nutrient content can have unwanted effects. Blood pressure falls with weight loss, and postural hypotension, common in older people and those with diabetes, is aggravated during rapid weight loss if diuretic or antihypertensive drugs are taken concurrently [73]. Hypoglycaemia is possible if hypoglycaemic drugs are also taken [74]. Diets other than nutritionally complete formula diets could incur vitamin and mineral deficiencies [75]. With ketogenic diets, heart failure and neurological problems from thiamine deficiency have been reported [76, 77], as well as reduced intakes of folate, iron and magnesium [12]. Replacing high-carbohydrate foods with red or processed meat (high animal protein and fat) increases sodium and long-chain saturated fat intakes, elevating LDL-cholesterol [15, 16] and potentially increasing cardiovascular disease risk [78–80]. High protein intake has been associated with kidney diseases in several observational studies [81]. Metabolic ketoacidosis with ketogenic diets is a hazard, particularly with sodium−glucose cotransporter 2 (SGLT2) inhibitors [82–87]. Meanwhile, extreme fat avoidance provokes cholelithiasis [88].

Current evidence on diets for type 2 diabetes remission is more limited. Only two RCTs had remission as the pre-specified outcome, both relatively large and using almost identical designs and diets, with very similar results, but in very different populations, notably with different durations of diabetes [51, 53, 89]. A large majority can achieve remission if they maintain sufficient weight loss.

NRSs (non-RCT, single-arm intervention) reported remission rates ranging from 3% to 75% by ITT, over various follow-up durations. The highest remission rates, up to 75%, were in people with newly diagnosed diabetes or with <2 years of type 2 diabetes duration. Much lower 20–22% remissions were reported with longer type 2 diabetes duration (8 years) or a very brief diet period (1 week). However, these studies did not all fully ascertain remission status, and they had critical risks of bias due to lack of comparator groups and/or randomisation. NRSs reflect performance among those who select and can adhere to a particular diet, and so usually reported better results than those featuring random assignment. In some cases, remission rates were reported for completers only, rather than using the ITT population to properly guide healthcare practice and policy. Despite extracting baseline data for ITT analysis, residual bias/confounding may remain with these study designs.

The main contributor to HbA_1c reduction and remission appears to be weight loss, irrespective of diet type. From the high-quality studies with high GRADE certainty, structured programmes with an intensive induction phase with total diet replacement were effective. Remission of diabetes occurs when a patient no longer satisfies the diagnostic criteria, without receiving glucose-lowering medication. To ascertain remission for those already prescribed glucose-lowering drugs, a therapeutic trial of withdrawing medication is necessary, with an appropriate protocol for re-introduction if necessary. Confirmation over a defined duration (e.g., 6 or 12 months) will be required for re-classifying individuals, and for legal or insurance purposes. The diagnostic HbA_1c cut-off for diabetes of 48 mmol/mol (6.5%) was defined by WHO as broadly the level where diabetes-specific microvascular complications start to emerge [90, 91]. However, many people in remission from type 2 diabetes remain in the pre-diabetes range of HbA_1c, where cardiovascular disease risk begins to rise [92, 93]. Lowering HbA_1c to very low levels with multiple medications among people with longstanding disease is associated with increased mortality rate, possibly by relative hypoglycaemia provoking arrythmias [94]. No such concerns have been reported in the small numbers who achieved and sustained HbA_1c < 42 mmol/mol (<6.0%) from diet restriction [89].

Most type 2 diabetes is treated in primary care, the setting for both published remission trials using an intensive ‘total diet replacement’ induction phase with formula diets [51]. Simpler food-based programmes may be effective. A service evaluation from one UK general practice reported weight loss and remission in 59 out of 128 patients who opted for, and persisted with, LCD advice for a mean 23 months [95]. This completers’ analysis omits information about numbers who declined the diet, who started but failed to persist and who did not provide outcome data at designated times. The LCD was routinely offered since 2013, and the total number of patients with type 2 diabetes was 473 at the time of evaluation, so these data imply that 12.5% of the practice achieved remission [95]. A population-based cohort study from 49 general practices in the UK (the Anglo–Danish–Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care [ADDITION-Cambridge]) included 867 participants with newly diagnosed type 2 diabetes; after being followed up for 5 years, there was an overall 30% remission (n = 257/867; ITT analysis). Loss of >10% of baseline body weight in the first year after diagnosis was associated with 70% higher chance of remission at 5 years [96]. Every 1 kg of weight loss was associated with 7% higher chance of remission at 5 years, regardless of specific diet regimens or lifestyle interventions [96]. There is therefore consistent evidence that remission should be attempted as early as possible from diabetes diagnosis [70, 96].

AMSTAR 2 assesses the quality of meta-analyses, prioritising critical domains, where errors and bias can impact pooled findings (ESM Table 2). Only one or two flaws can label a meta-analysis ‘low’ or ‘critically low’, with some criteria potentially subjective (e.g., adequacy of the literature search; ESM Table 2). In the umbrella review, many meta-analyses were of ‘low’ and ‘critically low’ AMSTAR 2 quality, predominantly through ‘no protocol reported’ (despite clear and sound methods) and no assessment of publication bias. Many meta-analyses had fewer than ten RCTs to permit assessment of publication bias by funnel plot [97]. If AMSTAR 2 criteria are relaxed for protocol reporting and publication bias, the meta-analyses allow some confidence in the consistent findings of little/no difference in weight loss between any diets.

Although the search strategy was wide and not language-restricted, most studies included European participants; results may not be equally applicable to other ethnic and/or deprived communities. South Asians develop type 2 diabetes at younger ages, more rapidly and with lower BMI, so may be more sensitive to weight loss, with physiological differences in insulin resistance, body composition and fat oxidation [98, 99].

The criteria used in the reported meta-analyses and studies focused on specific diet types. However, not all reported sufficient detail about macronutrient or micronutrient contents, or prescribed and reported energy intakes, including energy intake of nutrient-restricted ad libitum diets, which limits interpretation and transferability of results. Control diets used in the meta-analyses and source RCTs also varied, including ‘usual’ diets in different countries, as well as specified dietary regimens (Table 1). Despite this, differences in weight loss between intervention and control diets, commonly 0–2 kg, are of little clinical significance. Durations of interventions varied: as weight regain is frequent over a longer period, heterogeneity might be expected. However, duration did not introduce heterogeneity, probably because trials with longer follow-up tended to be evaluating more intensive interventions with greater initial weight loss, such that the net weight changes at endpoint are similar to short-term trials.

Given the extent of literature concluding that differences in weight control or HbA_1c from different diet compositions are not clinically significant, future trials of similar diet comparisons are unlikely to add useful information. Instead, evidence from clinical practice is needed to identify safe and effective approaches to achieve and maintain weight loss with available skills and training, to assess long-term outcomes from high-quality trials and prospective audits of practice with different diets. Interpretating the existing data might be enhanced through individual patient data meta-analysis. Alternatively, the very large amount of work entailed in conducting repeated meta-analyses, and the limitations of different inclusion criteria and detailed methods, support a prospective meta-analysis approach [100, 101]. All primary studies for inclusion should use an RCT design, with data analyses conducted ‘blind’. They should define the intervention clearly (e.g., diets, physical activity, and behavioural and psychological support), and address separately the induction (usually 3–6 months) and maintenance (≥12 months) phases of weight management, potentially employing different methods within a treatment programme.