The relationship between low prolactin and type 2 diabetes.

Prolactin (PRL) is secreted throughout life in men and women. At elevated levels, its physiological role in pregnancy and lactation, and pathological effects, are well known. However clinical implications of low circulating PRL are not well established. We conducted a meta-analysis to examine the relationship between low PRL levels and type 2 diabetes. Five papers included cross-sectional studies comprising 8,720 men (mean age range 51.4-60 years) and 3,429 women (49.5-61.6 years), and four papers included cohort studies comprising 2,948 men (52.1-60.0 years) and 3,203 women (49.2-60.1 years). Individuals with pregnancy, lactation and hyperprolactinemia, drugs known to alter circulating PRL levels, or pituitary diseases had been excluded. Although most studies used quartiles to categorize PRL groups for analysis, PRL cut-off values (all measured by chemiluminescence immunoassay) were variably defined between studies: the lowest PRL quartiles ranged from 3.6 ng/ml to 7.2 ng/ml in men and between 4.5 ng/ml to 8 ng/ml in women; and the highest PRL quartiles ranged from 6.9 ng/ml to 13 ng/ml in men and 9.6 ng/ml to 15.8 ng/ml in women. Type 2 diabetes was defined variably using self-reported physician's diagnosis, fasting blood glucose, oral glucose tolerance test or glycated hemoglobin (HbA1C). In cross-sectional studies, compared to individuals in the highest PRL groups (reference), those in the lowest PRL groups had greater risk of type 2 diabetes both in men: odds ratio (OR) and 95% confidence interval = 1.86 (1.56-2.22) and in women: OR = 2.15 (1.63-2.85). In cohort studies, women showed a significant association between low PRL and type 2 diabetes: OR = 1.52 (1.02-2.28) but not men: OR = 1.44 (0.46-4.57). Relatively low heterogeneity was observed (I2 = 25-38.4%) for cross-sectional studies, but higher for cohort studies (I2 = 52.8-79.7%). In conclusion, low PRL is associated with type 2 diabetes, but discrepancy between men and women in the relationship within cohort studies requires further research.

Weight management using meal replacements and cardiometabolic risk reduction in individuals with pre-diabetes and features of metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

This review synthesized the evidence from randomized controlled trials comparing the effect of meal replacements (MRs) as part of a weight loss intervention with conventional food-based weight loss diets on cardiometabolic risk in individuals with pre-diabetes and features of metabolic syndrome. MEDLINE, EMBASE, and Cochrane Library were searched through January 16, 2024. Data were pooled using the generic inverse variance method and expressed as mean difference [95% confidence intervals]. The overall certainty of the evidence was assessed using GRADE. Ten trials (n = 1254) met the eligibility criteria. MRs led to greater reductions in body weight (-1.38 kg [-1.81, -0.95]), body mass index (BMI, -0.56 kg/m2 [-0.78, -0.34]), waist circumference (-1.17 cm [-1.93, -0.41]), HbA1c (-0.11% [-0.22, 0.00]), LDL-c (-0.18 mmol/L [-0.28, -0.08]), non-HDL-c (-0.17 mmol/L [-0.33, -0.01]), and systolic blood pressure (-2.22 mmHg [-4.20, -0.23]). The overall certainty of the evidence was low to moderate owing to imprecision and/or inconsistency. The available evidence suggests that incorporating MRs into a weight loss intervention leads to small important reductions in body weight, BMI, LDL-c, non-HDL-c, and systolic blood pressure, and trivial reductions in waist circumference and HbA1c, beyond that seen with conventional food-based weight loss diets.

The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT).

AIMS/HYPOTHESIS: High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. METHODS: We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. RESULTS: Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. CONCLUSIONS/INTERPRETATION: We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes. DATA AVAILABILITY: The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .

Appetite and its Regulation: Are there Palatable Interventions for Heart Failure?

PURPOSE OF REVIEW: Obesity is a major driver of heart failure (HF) incidence, and aggravates its pathophysiology. We summarized key reported and ongoing randomized clinical trials of appetite regulation and/or dietary energy restriction in individuals with HF. RECENT FINDINGS: Weight loss can be achieved by structured supervised diet programs with behavioural change, medications, or surgery. The new glucagon-like peptide-1 receptor agonists alone or in combination with other agents (e.g., glucose-dependent insulinotropic polypeptide and glucagon receptor agonists or amylin analogues) potently and sustainably reduce appetite, and, taken together with dietary advice, can produce substantial, life-changing, weight loss approaching that achieved by surgery. To date, data from the STEP-HFpEF trial show meaningful improvements in health status (Kansas City Cardiomyopathy Questionnaire). Effective weight management could relieve several drivers of HF, to complement the existing treatments for HF with both reduced and preserved ejection fraction. Further trials of weight loss interventions will provide more definitive evidence to understand their effects on clinical events in patients with HF.

Dietary weight-management for type 2 diabetes remissions in South Asians: the South Asian diabetes remission randomised trial for proof-of-concept and feasibility (STANDby).

Background: We aimed to assess whether a structured weight management programme incorporating a total diet replacement (TDR) (3-5 months ∼850 kcal/day formula diet) weight loss phase is acceptable to people of South Asian ethnicity and can achieve type 2 diabetes (T2D) remissions similarly to other populations. Methods: Adults of South Asian ethnicity, aged 18-65 years, with T2D for ≤4 years, and BMI 25-45 kg/m2 were recruited from primary care and social media, and randomised to commence TDR either immediately (iTDR), or delayed (dTDR) for 3-5 months as a usual care control arm during this period. Intervention effects were tested in randomised comparisons powered to detect significant weight loss, and in an expanded observational analysis to determine remission effect size, including both iTDR and dTDR groups. Acceptability in those recruited was explored by questionnaire and weight change. Trial registration: Current Controlled Trials, ISRCTN10720065. Date of Registration 27/09/2017. Findings: Twenty-five eligible individuals were recruited. Mean baseline (SD) age was 45.8 (11.1) years, weight 88.2 (13.7) kg, BMI 32.1 (3.8) kg/m2, HbA1c 60.4 (11.3) mmol/mol, liver fat by MRI 15.6 (9.4)%. In the RCT, mean(SD) weight change after TDR was -7.7 (7.2)% in the intervention group (n = 13), and -1.2 (1.4)% in the usual-care control group (n = 12) (p = 0.005), with T2D remission achieved by 5/13, compared to 0/12 respectively (p = 0.039). In the observational study, 23/25 started TDR and 19/23 participants completed the TDR phase. Median time spent in TDR was 105 days (IQR 77-134 days). T2D remission was achieved in 10/23 (43%), and weight changes were concordant with the RCT. Overall, 8/23 (35%) lost over 10% bodyweight. Absolute liver fat proportion near halved from 15.3% at the start of TDR to 8.6% (p < 0.001). Interpretation: In UK-based South Asians, TDR-led weight loss and T2D remission rates are comparable to those observed in white cohorts, and the intervention was acceptable in most of those recruited. There is potential to further improve outcomes, but one-third lost >10% body weight, and the mechanism underpinning T2D remission appears similar, driven by weight change with loss of excess ectopic body-fat. Funding: We gratefully acknowledge funding for the MRI scans from the, Miss MJM Smith Trust (registered charity: SC040586). No other external funds were provided for this trial. NS is supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217).

A Total Diet Replacement Weight Management Program for Difficult-to-Treat Asthma Associated With Obesity: A Randomized Controlled Feasibility Trial.

BACKGROUND: Obesity is often associated with uncontrolled, difficult-to-treat asthma and increased morbidity and mortality. Previous studies suggest that weight loss may improve asthma outcomes, but with heterogenous asthma populations studied and unclear consensus on the optimal method of weight management. The Counterweight-Plus Programme (CWP) for weight management is an evidence-based, dietitian-led total diet replacement (TDR) program. RESEARCH QUESTION: Can use of the CWP compared with usual care (UC) improve asthma control and quality of life in patients with difficult-to-treat asthma and obesity? STUDY DESIGN AND METHODS: We conducted a 1:1 (CWP to UC) randomized, controlled single-center trial in adults with difficult-to-treat asthma and BMI of ≥ 30 kg/m2. The CWP was a 12-week TDR phase (800 kcal/d low-energy formula) followed by stepwise food reintroduction and weight loss maintenance for up to 1 year. The primary outcome was the change in Asthma Control Questionnaire 6 (ACQ6) score over 16 weeks. The secondary outcome was change in Asthma Quality of Life Questionnaire (AQLQ) score. RESULTS: Thirty-five participants were randomized (36 screened) and 33 attended the 16-week follow-up (n = 17 in the CWP group, n = 16 in the UC group). Overall, mean ACQ6 score at baseline was 2.8 (95% CI, 2.4-3.1). Weight loss was greater in the CWP than UC group (mean difference, -12.1 kg; 95% CI, -16.9 to -7.4; P < .001). ACQ6 score improved more in the CWP than UC group (mean difference, -0.69; 95% CI, -1.37 to -0.01; P = .048). A larger proportion of participants achieved the minimal clinically important difference in ACQ6 score with CWP than with UC (53% vs 19%; P = .041; Number needed to treat, 3 [95% CI, 1.5-26.9]). AQLQ score improvement was greater in the CWP than UC group (mean difference, 0.76; 95% CI, 0.18-1.34; P = .013). INTERPRETATION: Using a structured weight management program results in clinically important improvements in asthma control and quality of life over 16 weeks compared with UC in adults with difficult-to-treat asthma and obesity. This generalizable program is easy to deliver for this challenging phenotype. Longer-term outcomes continue to be studied. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03858608; URL: www. CLINICALTRIALS: gov.

Overlooked and under-evidenced: Community health and long-term care service needs, utilization, and costs incurred by people with severe obesity.

Numbers of people with severe obesity (BMI ≥ 40 kg/m2 ), with need for community health and long-term care (LTC) services, are increasing, but documentation is lacking. We identified individuals with severe obesity known to community health and care professionals in a representative United Kingdom region and used an investigator-administered questionnaire to record needs and use of community health and LTC services. Data were verified against health and LTC records. Local and published sources informed detailed micro-costing. Twenty-five individuals (15 women) consented, aged 40-87 (mean = 62) years, BMI 40-77 (mean = 55) kg/m2 : 20 participants (80%) were housebound. Twenty-two different cross-sector community health and LTC services were used, including community equipment service (n = 23), district nursing (n = 20), occupational therapy (n = 14), and LTC (n = 12). Twenty-four (96%) participants used three or more services, with longest care episode lasting over 14 years. Total annual service costs incurred by participants varied from £2053 to £82 792; mean £26 594 (lower estimate £80 064; mean £22 462/upper estimate £88 870; mean £30 726), with greatest costs being for LTC. Individual costs for equipment (currently provided) and home adaptations (ever provided) ranged widely, from zero to £35 946. Total mean annual costs increased by ascending BMI category, up to BMI 70 kg/m2 . This study provides a framework with which to inform service provision and economic analysis of weight management interventions. People with severe obesity may need sustained care from multiple community care services.

Physical activity, inactivity and sleep during the Diabetes Remission Clinical Trial (DiRECT).

AIMS: As sustained weight loss is vital for achieving remission of type 2 diabetes, we explored whether randomisation to weight loss plus maintenance in the DiRECT trial was associated with physical activity, inactivity or sleep. METHODS: Participants were randomised to either a dietary weight management programme or best-practice care. The weight management group were encouraged to increase daily physical activity to their sustainable maximum. Objective measurement was achieved using a wrist-worn GENEActiv accelerometer for 7 days at baseline, 12 and 24 months in both groups. RESULTS: Despite average weight loss of 10 kg at 12 months in the intervention (n = 66) group, there were no differences in total physical activity or inactivity compared with the control (n = 104) at any time point. However, in our exploratory analysis, those who lost more than 10% of their baseline body weight performed on average 11 mins/day more light activity than the <10% group at 24 months (p = 0.033) and had significantly lower bouts of Inactivity30min (interaction, p = 0.005) across 12 and 24 months. At 24 months, the ≥10% group had higher daily acceleration (38.5 ± 12.1 vs. 33.2 ± 11.1 mg, p = 0.020), and higher accelerations in the most active 5-hour period (59.4 ± 21.8 vs. 50.6 ± 18.3 mg, p = 0.023). Wakefulness after sleep onset decreased in the intervention group compared with the control group and also in the ≥10% weight loss group at 12 and 24 months. CONCLUSIONS: Randomisation to a successful intensive weight loss intervention, including regular physical activity encouragement, was not associated with increased physical activity although sleep parameters improved. Physical activity was greater, and night-time waking reduced in those who maintained >10% weight loss at 12 and 24 months. TRIAL REGISTRATION ISRCTN03267836.

Challenges in obtaining accurate anthropometric measures for adults with severe obesity: A community-based study.

AIMS: The number of people with severe obesity (BMI ⩾40 kg/m2) is increasing rapidly, but is poorly documented, partly as a result of inappropriate standard anthropometric measurement methods for community-based people. METHODS: As part of a broader study, people receiving care services and with severe obesity were visited at home. The people were assessed for measurements using different weighing scales and a standard portable stadiometer. If the stadiometer could not be used, their half arm span and knee height were measured to estimate their height using standard predictive equations. RESULTS: Measurements were taken for 15 women and 10 men (n = 25) aged 40-87 years (mean 62 years). Weights ranged from 98.4 to 211.8 kg (mean 150 kg), with 16 participants requiring bariatric scales. For the six people who were unable to stand, we used wheelchair scales (n = 1), bed weighing scales (n = 2), routine weights from care home records (n = 2) or weight data from hospital records (n = 1). The standard portable stadiometer could only be used for one person; the others required alternative measures from which to estimate height. Large body habitus obscured bony landmarks, meaning alternative measures gave diverse heights. Fourteen participants had a ⩾8 cm difference in height between estimates from half arm span and knee height measurements. CONCLUSIONS: Standard practice commonly does not provide reliable measurements for people with severe obesity, particularly those with mobility difficulties. An inability to measure weight and height accurately can exclude people from appropriate care, obscuring the true numbers affected and the effectiveness of future service planning. Safe community care requires the availability of specialist scales and standardised methods for height estimation appropriate for older and disabled people with severe obesity.

Total Diet Replacement Within an Integrated Intensive Lifestyle Intervention for Remission of Type 2 Diabetes: Lessons From DiRECT.

The prognosis for people with type 2 diabetes (T2D) remains concerning, yet its seriousness is often underestimated. T2D is a manifestation, in susceptible individuals, of the disease-process of obesity, and at diagnosis, 10-year survival rates for T2D are around 50%. Here, we will examine: (a) the role of weight loss in T2D, (b) use of total diet replacements (TDRs) to induce weight loss, (c) the Diabetes Remission Clinical Trial (DiRECT) protocol and key results, (d) other dietary interventions related to T2D remission, (e) remission in real life, and (f) future directions. Remission of short-duration T2D will usually require 10-15% body weight loss, and results from the DiRECT trial demonstrated that this can be achieved within routine care in nearly half of all people undertaking a supported, TDR-led behavioural weight management programme. In light of these findings, which have since been replicated in the Diabetes Intervention Accentuating Diet and Enhancing Metabolism (DIADEM-I) trial conducted in the Middle East and North Africa, it is now time to prioritize weight loss programmes for T2D remission from diagnosis, and with increasing acceptance and availability of digital healthcare, there is an opportunity to scale up delivery of remission programmes in a cost effective manner.

The remote diet intervention to reduce Long COVID symptoms trial (ReDIRECT): protocol for a randomised controlled trial to determine the effectiveness and cost-effectiveness of a remotely delivered supported weight management programme for people with Long COVID and excess weight, with personalised improvement goals.

Objectves: The Remote Diet Intervention to Reduce Long COVID Symptoms Trial (ReDIRECT) evaluates whether the digitally delivered, evidence-based, cost-effective Counterweight-Plus weight management programme improves symptoms of Long COVID in people with overweight/obesity. Methods: Baseline randomised, non-blinded design with 240 participants allocated in a 1:1 ratio either to continue usual care or to add the remotely delivered Counterweight-Plus weight management programme, which includes a Counterweight dietitian supported delivery of 12 weeks total diet replacement, food reintroduction, and long-term weight loss maintenance. Randomisation is achieved by accessing a web-based randomisation system incorporated into the study web portal developed by a registered Clinical Trials Unit. We are using an innovative approach to outcome personalisation, with each participant selecting their most dominant Long COVID symptom as their primary outcome assessed at six months. Participants in the control arm enter the weight management programme after six months. We are recruiting participants from social media and existing networks (e.g., Long COVID Scotland groups), through newspaper advertisements and from primary care. Main inclusion criteria: people with Long COVID symptoms persisting > three months, aged 18 years or above, body mass index (BMI) above 27kg/m 2 (>25kg/m 2 for South Asians). The trial includes a process evaluation (involving qualitative interviews with participants and analysis of data on dose, fidelity and reach of the intervention) and economic evaluation (within-trial and long-term cost-utility analyses). Anticipated results: The recruitment for this study started in December 2021 and ended in July 2022. Project results are not yet available and will be shared via peer-reviewed publication once the six-months outcomes have been analysed. Trial registration: Current Controlled Trials ISRCTN12595520.

While most people infected with COVID-19 recover within a short amount of time, some people continue to have symptoms for 12 weeks or longer. This condition is known as Long COVID. Roughly two-thirds of people with Long COVID are overweight, a proportion similar to that found in the general population. Being overweight may worsen symptoms such as fatigue, breathlessness and pains. Weight management programmes in adults with overweight/obesity can reduce such symptoms, however we do not know how effective intentional weight loss is to reduce symptoms for people with Long COVID. The aim of this project is to test a well-established weight management programme, delivered and supported remotely, in people with Long COVID. The trial is conducted with 240 people with Long COVID, identified through their GP, patient groups, social media, or newspaper advertisements. A total of 120 individuals will receive the personalised, professionally supported weight management programme (treatment group), and 120 participants are allocated to usual care (control group). The one-year long weight management programme involves 12 weeks of total diet replacement (TDR) using soups and shakes, followed by food reintroduction and weight maintenance. Food based alternatives are available to those who are unable, or prefer not to, follow the TDR approach. The two groups will be compared for Long COVID symptoms, weight loss, quality of life and value for money after six months. After six months, the weight management programme will also be provided for the control group. Experiences while on the programme will be documented for 12 months for all participants. People with Long COVID have been involved extensively in developing this project. Their priorities are to reduce symptoms like fatigue, breathlessness and pain. They are keen to explore if effective weight management would help their symptoms and overall functioning, especially a programme that can be followed remotely from home. A group of patients and other stakeholders has been set up to provide advice throughout the project.

Participant experiences in the Diabetes REmission Clinical Trial (DiRECT).

INTRODUCTION: The Diabetes REmission Clinical Trial (DiRECT) has shown that sustained remission of type 2 diabetes in primary care is achievable through weight loss using total diet replacement (TDR) with continued behavioural support. Understanding participants' experiences can help optimise the intervention, support implementation into healthcare, and understand the process of behaviour change. METHODS: Thirty-four DiRECT participants were recruited into this embedded qualitative evaluation study. In-person and telephone interviews were conducted before the TDR; at week 6-8 of the TDR; 2 weeks into food reintroduction (FR); and at 1 year, to learn about participant experiences with the programme. Transcribed narratives were analysed thematically, and we used interpretation to develop overarching themes. RESULTS: Initiation of the TDR and transition to FR were challenging and required increased behavioural support. In general, adhering to TDR proved easier than the participants had anticipated. Some participants chose the optional extension of TDR. Rapid weight loss and changes in diabetes markers provided ongoing motivation. Further weight loss, behavioural support and occasional use of TDR facilitated weight loss maintenance (WLM). A process of behaviour adaptation to change following regime disruption was identified in three stages: (1) expectations of the new, (2) overcoming difficulties with adherence, and (3) acceptance of continuous effort and establishment of routines. CONCLUSIONS: The DiRECT intervention was acceptable and regularity, continuity, and tailoring of behavioural support was instrumental in its implementation in primary care. The adaptation process accounts for some of the individual variability of experiences with the intervention and highlights the need for programme flexibility.

Sex differences in intraorgan fat levels and hepatic lipid metabolism: implications for cardiovascular health and remission of type 2 diabetes after dietary weight loss.

AIMS/HYPOTHESIS: Type 2 diabetes confers a greater relative increase in CVD risk in women compared with men. We examined sex differences in intraorgan fat and hepatic VLDL1-triacylglycerol (VLDL1-TG) export before and after major dietary weight loss. METHODS: A group with type 2 diabetes (n = 64, 30 male/34 female) and a group of healthy individuals (n = 25, 13 male/12 female) were studied. Intraorgan and visceral fat were quantified by magnetic resonance and VLDL1-TG export by intralipid infusion techniques. RESULTS: Triacylglycerol content of the liver and pancreas was elevated in people with diabetes with no sex differences (liver 16.4% [9.3-25.0%] in women vs 11.9% [7.0-23.1%] in men, p = 0.57, and pancreas 8.3 ± 0.5% vs 8.5 ± 0.4%, p = 0.83, respectively). In the absence of diabetes, fat levels in both organs were lower in women than men (1.0% [0.9-1.7%] vs 4.5% [1.9-8.0%], p = 0.005, and 4.7 ± 0.4% vs 7.6 ± 0.5%, p< 0.0001, respectively). Women with diabetes had higher hepatic VLDL1-TG production rate and plasma VLDL1-TG than healthy women (559.3 ± 32.9 vs 403.2 ± 45.7 mg kg-1 day-1, p = 0.01, and 0.45 [0.26-0.77] vs 0.25 [0.13-0.33] mmol/l, p = 0.02), whereas there were no differences in men (548.8 ± 39.8 vs 506.7 ± 29.2 mg kg-1 day-1, p = 0.34, and 0.72 [0.53-1.15] vs 0.50 [0.32-0.68] mmol/l, p = 0.26). Weight loss decreased intraorgan fat and VLDL1-TG production rates regardless of sex, and these changes were accompanied by similar rates of diabetes remission (65.4% vs 71.0%) and CVD risk reduction (59.8% vs 41.5%) in women and men, respectively. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, women have liver and pancreas fat levels as high as those of men, associated with raised hepatic VLDL1-TG production rates. Dynamics of triacylglycerol turnover differ between sexes in type 2 diabetes and following weight loss. These changes may contribute to the disproportionately raised cardiovascular risk of women with diabetes.

Diets for weight management in adults with type 2 diabetes: an umbrella review of published meta-analyses and systematic review of trials of diets for diabetes remission.

AIMS/HYPOTHESIS: Weight reduction is fundamental for type 2 diabetes management and remission, but uncertainty exists over which diet type is best to achieve and maintain weight loss. We evaluated dietary approaches for weight loss, and remission, in people with type 2 diabetes to inform practice and clinical guidelines. METHODS: First, we conducted a systematic review of published meta-analyses of RCTs of weight-loss diets. We searched MEDLINE (Ovid), PubMed, Web of Science and Cochrane Database of Systematic Reviews, up to 7 May 2021. We synthesised weight loss findings stratified by diet types and assessed meta-analyses quality with A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. We assessed certainty of pooled results of each meta-analysis using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) (PROSPERO CRD42020169258). Second, we conducted a systematic review of any intervention studies reporting type 2 diabetes remission with weight-loss diets, in MEDLINE (via PubMed), Embase and Cochrane Central Register of Controlled Trials, up to 10 May 2021. Findings were synthesised by diet type and study quality (Cochrane Risk of Bias tool 2.0 and Risk Of Bias In Non-randomised Studies - of Interventions [ROBINS-I]), with GRADE applied (PROSPERO CRD42020208878). RESULTS: We identified 19 meta-analyses of weight-loss diets, involving 2-23 primary trials (n = 100-1587), published 2013-2021. Twelve were 'critically low' or 'low' AMSTAR 2 quality, with seven 'high' quality. Greatest weight loss was reported with very low energy diets, 1.7-2.1 MJ/day (400-500 kcal) for 8-12 weeks (high-quality meta-analysis, GRADE low), achieving 6.6 kg (95% CI -9.5, -3.7) greater weight loss than low-energy diets (4.2-6.3 MJ/day [1000-1500 kcal]). Formula meal replacements (high quality, GRADE moderate) achieved 2.4 kg (95% CI -3.3, -1.4) greater weight loss over 12-52 weeks. Low-carbohydrate diets were no better for weight loss than higher-carbohydrate/low-fat diets (high quality, GRADE high). High-protein, Mediterranean, high-monounsaturated-fatty-acid, vegetarian and low-glycaemic-index diets all achieved minimal (0.3-2 kg) or no difference from control diets (low to critically low quality, GRADE very low/moderate). For type 2 diabetes remission, of 373 records, 16 met inclusion criteria. Remissions at 1 year were reported for a median 54% of participants in RCTs including initial low-energy total diet replacement (low-risk-of-bias study, GRADE high), and 11% and 15% for meal replacements and Mediterranean diets, respectively (some concerns for risk of bias in studies, GRADE moderate/low). For ketogenic/very low-carbohydrate and very low-energy food-based diets, the evidence for remission (20% and 22%, respectively) has serious and critical risk of bias, and GRADE certainty is very low. CONCLUSIONS/INTERPRETATION: Published meta-analyses of hypocaloric diets for weight management in people with type 2 diabetes do not support any particular macronutrient profile or style over others. Very low energy diets and formula meal replacement appear the most effective approaches, generally providing less energy than self-administered food-based diets. Programmes including a hypocaloric formula 'total diet replacement' induction phase were most effective for type 2 diabetes remission. Most of the evidence is restricted to 1 year or less. Well-conducted research is needed to assess longer-term impacts on weight, glycaemic control, clinical outcomes and diabetes complications.

Banting Memorial Lecture 2021-Banting, banting, banter and bravado: Convictions meet evidence in the scientific process: Diabetes UK Professional Conference, 27 April 2021.

This personal account presents some glimpses into the clinical research processes which have made radical changes to our understanding of disease and treatment, and some characteristics of researchers, drawn from history and personal experiences around obesity and type 2 diabetes. Some summary messages emerge: The history of clinical diabetes research has shown how, perhaps through skilful leadership, combining very different personalities, skills and motivation can solve great challenges: Type 2 diabetes is a primary nutritional disease, secondary to the disease-process of obesity, not a primary endocrine disease. Type 2 diabetes is a manifestation of the disease-process of obesity, revealed by weight gain in people with underlying metabolic syndrome genetics/diathesis, mediated in large part at least by reversible ectopic fat accumulation impairing function of organs (liver, pancreas, brown adipose tissue). Treat overweight/obesity more seriously (defined as a disease-process with multiple organ-specific complications-not as a disease-state or BMI cut-off). Discuss the complications and risks of T2D openly: remission is as important as for cancers. Offer and support an optimal dietary weight management program as soon as possible from diagnosis, specifically aiming for remission: (a) Warn against non-evidence-based programs that look similar or claim to have similar potential: we have fully evidence-based programs; (b) Target sustained loss of >15 kg for Europeans (possibly less, e.g. >10 kg for Asians?). Increase future research support to enhance long-term weight loss maintenance. Several approaches need consideration: (a) Personalise diet compositions (recognising there is no intrinsic advantage from different carbohydrate/fat content). (b) Novel diet strategies (e.g. 5:2, time-restricted, flexible diet compositions). (c) New pharmaceutical agents as adjuncts to diet if necessary. (d) Novel food supplements to increase endogenous GLP-1 secretion.

A novel decision model to predict the impact of weight management interventions: The Core Obesity Model.

AIMS: Models are needed to quantify the economic implications of obesity in relation to health outcomes and health-related quality of life. This report presents the structure of the Core Obesity Model (COM) and compare its predictions with the UK clinical practice data. MATERIALS AND METHODS: The COM is a Markov, closed-cohort model, which expands on earlier obesity models by including prediabetes as a risk factor for type 2 diabetes (T2D), and sleep apnea and cancer as health outcomes. Selected outcomes predicted by the COM were compared with observed event rates from the Clinical Practice Research Datalink-Hospital Episode Statistics (CPRD-HES) study. The importance of baseline prediabetes prevalence, a factor not taken into account in previous economic models of obesity, was tested in a scenario analysis using data from the 2011 Health Survey of England. RESULTS: Cardiovascular (CV) event rates predicted by the COM were well matched with those in the CPRD-HES study (7.8-8.5 per 1000 patient-years across BMI groups) in both base case and scenario analyses (8.0-9.4 and 8.6-9.9, respectively). Rates of T2D were underpredicted in the base case (1.0-7.6 vs. 2.1-22.7) but increased to match those observed in CPRD-HES for some BMI groups when a prospectively collected prediabetes prevalence was used (2.7-13.1). Mortality rates in the CPRD-HES were consistently higher than the COM predictions, especially in higher BMI groups. CONCLUSIONS: The COM predicts the occurrence of CV events and T2D with a good degree of accuracy, particularly when prediabetes is included in the model, indicating the importance of considering this risk factor in economic models of obesity.

Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT).

AIMS/HYPOTHESIS: Our aim was to evaluate the safety and efficacy of a planned therapeutic withdrawal of all antihypertensive and diuretic medications, on commencing a formula low-energy diet replacement, targeting remission of type 2 diabetes. METHODS: Post hoc analysis of changes in BP, antihypertensive medication prescriptions and symptoms during the initial total diet replacement phase was performed in the intervention arm of the Diabetes Remission Clinical Trial (n = 143) and in the subset (n = 69) who discontinued antihypertensive medications at the start of total diet replacement. The Counterweight-Plus total diet replacement provided about 3470 kJ/day (830 kcal) with automatic reductions in all nutrients, including sodium, to achieve marked negative energy balance and rapid weight loss over 12-20 weeks, with regular BP monitoring and an antihypertensive reintroduction protocol based on current clinical guidelines. RESULTS: Of 143 intervention group participants who commenced total diet replacement, 78 (55%) were on treatment for hypertension at baseline. The overall mean BP fell significantly from the start of total diet replacement (week 1) and was significantly lower at week 20, after total diet replacement finished, and also at 12 and 24 months. Of the 78 participants previously on treatment for hypertension, 65 (83%) stopped all antihypertensive and diuretic medications as per protocol, and four (5%) stopped some drugs. These 69 participants experienced no immediate (within the first week) change in BP, but their mean BP fell significantly from 9 weeks. No excessive rises in BP were recorded in individuals, but antihypertensive medications were reintroduced during total diet replacement to manage raised BP for 19/69 (27.5%) participants, mostly within the first 3-7 weeks, despite some weight loss. Reintroduction of antihypertensive medications was necessary for 5/19 participants previously on one drug, and for 14/19 previously on two or more drugs. Of the 69 who stopped antihypertensives, 19 (28%) remained off medications at 24 months. Among the 53 participants who achieved sustained remissions of diabetes at 24 months (with a mean weight loss of 11.4 kg), 31 had been previously treated for hypertension. Twenty-seven stopped medication at baseline, and 15/27 required reintroduction of antihypertensive medications. Mild to moderate dizziness, suggesting some postural hypotension, was reported during total diet replacement by 51 participants, 15 of whom had recorded dizziness at baseline prior to starting total diet replacement, with nine of these on antihypertensive or diuretic medications. CONCLUSIONS/INTERPRETATION: Replacing antihypertensive medications with a 3470 kJ/day (830 kcal) diet to induce weight loss reduces BP substantially and may increase mild dizziness. It is safe to stop antihypertensives, but BP should be monitored regularly, particularly for those taking two or more antihypertensives, as over two-thirds will require reintroduction of some medications. Long-term support to maintain weight loss is vital. TRIAL REGISTRATION: ISRCTN registry, number 03267836.