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Predictors of type 2 diabetes remission in the Diabetes Remission Clinical Trial (DiRECT).
Thom, G, Messow, CM, Leslie, WS, Barnes, AC, Brosnahan, N, McCombie, L, Al-Mrabeh, A, Zhyzhneuskaya, S, Welsh, P, Sattar, N, et al
Diabetic medicine : a journal of the British Diabetic Association. 2021;(8):e14395
Abstract
AIM: To identify predictors of type 2 diabetes remission in the intervention arm of DiRECT (Diabetes Remission Clinical Trial). METHODS Participants were aged 20-65 years, with type 2 diabetes duration of <6 years and BMI 27-45 kg/m2 , and were not receiving insulin. Weight loss was initiated by total diet replacement (825-853 kcal/day, 3-5 months, shakes/soups), and weight loss maintenance support was provided for 2 years. Remissions (HbA1c <48 mmol/mol [<6.5%], without antidiabetes medications) in the intervention group (n = 149, mean age 53 years, BMI 35 kg/m2 ) were achieved by 68/149 participants (46%) at 12 months and by 53/149 participants (36%) at 24 months. Potential predictors were examined by logistic regression analyses, with adjustments for weight loss and effects independent of weight loss. RESULTS Baseline predictors of remission at 12 and 24 months included being prescribed fewer antidiabetes medications, having lower triglyceride and gamma-glutamyl transferase levels, and reporting better quality of life with less anxiety/depression. Lower baseline HbA1c was a predictor at 12 months, and older age and male sex were predictors at 24 months. Being prescribed antidepressants predicted non-remission. Some, but not all effects were explained by weight loss. Weight loss was the strongest predictor of remission at 12 months (adjusted odds ratio per kg weight loss 1.24, 95% CI 1.14, 1.34; P < 0.0001) and 24 months (adjusted odds ratio 1.23, 95% CI 1.13, 1.35; P <0.0001). Weight loss in kilograms and percentage weight loss were equally good predictors. Early weight loss and higher programme attendance predicted more remissions. Baseline BMI, fasting insulin, fasting C-peptide and diabetes duration did not predict remission. CONCLUSIONS Other than weight loss, most predictors were modest, and not sufficient to identify subgroups for which remission was not a worthwhile target.
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Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.
Johnstone, J, Meade, M, Lauzier, F, Marshall, J, Duan, E, Dionne, J, Arabi, YM, Heels-Ansdell, D, Thabane, L, Lamarche, D, et al
JAMA. 2021;(11):1024-1033
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Abstract
IMPORTANCE Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. OBJECTIVE To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). DESIGN, SETTING, AND PARTICIPANTS Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). INTERVENTIONS Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. MAIN OUTCOMES AND MEASURES The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. RESULTS Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). CONCLUSIONS AND RELEVANCE Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02462590.
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Dietary Intervention in Pregnant Women with Gestational Diabetes; Protocol for the DiGest Randomised Controlled Trial.
Kusinski, LC, Murphy, HR, De Lucia Rolfe, E, Rennie, KL, Oude Griep, LM, Hughes, D, Taylor, R, Meek, CL
Nutrients. 2020;(4)
Abstract
Gestational diabetes mellitus (GDM) annually affects 35,000 pregnancies in the United Kingdom, causing suboptimal health outcomes to the mother and child. Obesity and excessive gestational weight gain are risk factors for GDM. The Institute of Medicine recommends weight targets for women that are overweight and obese, however, there are no clear guidelines for women with GDM. Observational data suggest that modest weight loss (0.6-2 kg) after 28 weeks may reduce risk of caesarean section, large-for-gestational-age (LGA), and maternal postnatal glycaemia. This protocol for a multicentre randomised double-blind controlled trial aims to identify if a fully controlled reduced energy diet in GDM pregnancy improves infant birthweight and reduces maternal weight gain (primary outcomes). A total of 500 women with GDM (National Institute of Health and Care Excellence (NICE) 2015 criteria) and body mass index (BMI) ≥25 kg/m2 will be randomised to receive a standard (2000 kcal/day) or reduced energy (1200 kcal/day) diet box containing all meals and snacks from 28 weeks to delivery. Women and caregivers will be blinded to the allocations. Food diaries, continuous glucose monitoring, and anthropometry will measure dietary compliance, glucose levels, and weight changes. Women will receive standard antenatal GDM management (insulin/metformin) according to NICE guidelines. The secondary endpoints include caesarean section rates, LGA, and maternal postnatal glucose concentrations.
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Improving child weight management uptake through enhanced National Child Measurement Programme parental feedback letters: A randomised controlled trial.
Sallis, A, Porter, L, Tan, K, Howard, R, Brown, L, Jones, A, Ells, L, Adamson, A, Taylor, R, Vlaev, I, et al
Preventive medicine. 2019;:128-135
Abstract
This single-blind, pragmatic, cluster randomised controlled trial aims to investigate uptake of children's weight management services in response to enhanced National Child Measurement Programme (NCMP) letters providing weight status feedback to parents in three English counties in 2015. Parents of 2642 overweight or very overweight (obese) children aged 10-11 years received an intervention or control letter informing them of their child's weight status. Intervention letters included (i) a visual tool to help weight status recognition, (ii) a social norms statement, and for very overweight children, (iii) a prepopulated booking form for weight management services. The primary outcome was weight management service enrolment. Additional outcome measures included attendance at and contact made with weight management services, and a number of self-report variables. A small effect was observed, with intervention parents being significantly more likely to enrol their children in weight management services (4.33% of Intervention group) than control parents (2.19% of Control group) in both unadjusted (OR = 2.08, p = .008) and adjusted analyses (AOR = 2.48, p = .001). A similar picture emerged for contact with services (4.80% Intervention vs. 2.41% Control; OR = 2.10, p = .003; AOR = 2.46, p < .001) and attendance at services, although group differences in the latter measure were not significant after corrections for multiple comparisons (1.89% Intervention vs. 1.02% Control; AOR = 2.11, p = .047). No effects were found on self-report variables. Theoretically informed weight status feedback letters appear to be an effective strategy to improve enrolment in paediatric weight management services.
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Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial.
Lean, MEJ, Leslie, WS, Barnes, AC, Brosnahan, N, Thom, G, McCombie, L, Peters, C, Zhyzhneuskaya, S, Al-Mrabeh, A, Hollingsworth, KG, et al
The lancet. Diabetes & endocrinology. 2019;(5):344-355
Abstract
BACKGROUND The DiRECT trial assessed remission of type 2 diabetes during a primary care-led weight-management programme. At 1 year, 68 (46%) of 149 intervention participants were in remission and 36 (24%) had achieved at least 15 kg weight loss. The aim of this 2-year analysis is to assess the durability of the intervention effect. METHODS DiRECT is an open-label, cluster-randomised, controlled trial done at primary care practices in the UK. Practices were randomly assigned (1:1) via a computer-generated list to provide an integrated structured weight-management programme (intervention) or best-practice care in accordance with guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700 people). Allocation was concealed from the study statisticians; participants, carers, and study research assistants were aware of allocation. We recruited individuals aged 20-65 years, with less than 6 years' duration of type 2 diabetes, BMI 27-45 kg/m2, and not receiving insulin between July 25, 2014, and Aug 5, 2016. The intervention consisted of withdrawal of antidiabetes and antihypertensive drugs, total diet replacement (825-853 kcal per day formula diet for 12-20 weeks), stepped food reintroduction (2-8 weeks), and then structured support for weight-loss maintenance. The coprimary outcomes, analysed hierarchically in the intention-to-treat population at 24 months, were weight loss of at least 15 kg, and remission of diabetes, defined as HbA1c less than 6·5% (48 mmol/mol) after withdrawal of antidiabetes drugs at baseline (remission was determined independently at 12 and 24 months). The trial is registered with the ISRCTN registry, number 03267836, and follow-up is ongoing. FINDINGS The intention-to-treat population consisted of 149 participants per group. At 24 months, 17 (11%) intervention participants and three (2%) control participants had weight loss of at least 15 kg (adjusted odds ratio [aOR] 7·49, 95% CI 2·05 to 27·32; p=0·0023) and 53 (36%) intervention participants and five (3%) control participants had remission of diabetes (aOR 25·82, 8·25 to 80·84; p<0·0001). The adjusted mean difference between the control and intervention groups in change in bodyweight was -5·4 kg (95% CI -6·9 to -4·0; p<0·0001) and in HbA1c was -4·8 mmol/mol (-8·3 to -1·4 [-0·44% (-0·76 to -0·13)]; p=0·0063), despite only 51 (40%) of 129 patients in the intervention group using anti-diabetes medication compared with 120 (84%) of 143 in the control group. In a post-hoc analysis of the whole study population, of those participants who maintained at least 10 kg weight loss (45 of 272 with data), 29 (64%) achieved remission; 36 (24%) of 149 participants in the intervention group maintained at least 10 kg weight loss. Serious adverse events were similar to those reported at 12 months, but were fewer in the intervention group than in the control group in the second year of the study (nine vs 22). INTERPRETATION The DiRECT programme sustained remissions at 24 months for more than a third of people with type 2 diabetes. Sustained remission was linked to the extent of sustained weight loss. FUNDING Diabetes UK.
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Type 2 diabetes remission: economic evaluation of the DiRECT/Counterweight-Plus weight management programme within a primary care randomized controlled trial.
Xin, Y, Davies, A, McCombie, L, Briggs, A, Messow, CM, Grieve, E, Leslie, WS, Taylor, R, Lean, MEJ
Diabetic medicine : a journal of the British Diabetic Association. 2019;(8):1003-1012
Abstract
AIM: The Counterweight-Plus weight management programme achieved 46% remission of Type 2 diabetes at 1 year in the DiRECT trial. We estimated the implementation costs of the Counterweight-Plus programme and its 1-year cost-effectiveness in terms of diabetes remission, compared with usual care, from the UK National Health Service (NHS) perspective. METHODS Within-trial total costs included programme set-up and running costs (practitioner appointment visits, low-energy formula diet sachets and training), oral anti-diabetes and anti-hypertensive medications, and healthcare contacts. Total costs were calculated for aggregated resource use for each participant and 95% confidence intervals (CI) were based on 1000 non-parametric bootstrap iterations. RESULTS One-year programme costs under trial conditions were estimated at £1137 per participant (95% CI £1071, £1205). The intervention led to a significant cost-saving of £120 (95% CI £78, £163) for the oral anti-diabetes drugs and £14 (95% CI £7.9, £22) for anti-hypertensive medications compared with the control. Deducting the cost-savings of all healthcare contacts from the intervention cost resulted an incremental cost of £982 (95% CI £732, £1258). Cost per 1 year of diabetes remission was £2359 (95% CI £1668, £3250). CONCLUSIONS Remission of Type 2 diabetes within 1-year can be achieved at a cost below the annual cost of diabetes (including complications). Providing a reasonable proportion of remissions can be maintained over time, with multiple medical gains expected, as well as immediate social benefits, there is a case for shifting resources within diabetes care budgets to offer support for people with Type 2 diabetes to attempt remission. (Clinical Trial Registry No.: ISRCTN03267836).
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Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study).
Marwood, L, Taylor, R, Goldsmith, K, Romeo, R, Holland, R, Pickles, A, Hutchinson, J, Dietch, D, Cipriani, A, Nair, R, et al
BMC psychiatry. 2017;(1):231
Abstract
BACKGROUND Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group. METHODS The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.
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Randomised controlled trial of the effectiveness of community group and home-based falls prevention exercise programmes on bone health in older people: the ProAct65+ bone study.
Duckham, RL, Masud, T, Taylor, R, Kendrick, D, Carpenter, H, Iliffe, S, Morris, R, Gage, H, Skelton, DA, Dinan-Young, S, et al
Age and ageing. 2015;(4):573-9
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BACKGROUND exercise can reduce osteoporotic fracture risk by strengthening bone or reducing fall risk. Falls prevention exercise programmes can reduce fall incidence, and also include strengthening exercises suggested to load bone, but there is little information as to whether these programmes influence bone mineral density (BMD) and strength. OBJECTIVE to evaluate the skeletal effects of home (Otago Exercise Programme, OEP) and group (Falls Exercise Management, FaME) falls prevention exercise programmes relative to usual care in older people. METHODS men and women aged over 65 years were recruited through primary care. They were randomised by practice to OEP, FaME or usual care. BMD, bone mineral content (BMC) and structural properties were measured in Nottingham site participants before and after the 24-week intervention. RESULTS participants were 319 men and women, aged mean(SD) 72(5) years. Ninety-two percentage of participants completed the trial. The OEP group completed 58(43) min/week of home exercise, while the FaME group completed 39(16) and 30(24) min/week of group and home exercise, respectively. Femoral neck BMD changes did not differ between treatment arms: mean (95% CI) effect sizes in OEP and FaME relative to usual care arm were -0.003(-0.011,0.005) and -0.002(-0.010,0.005) g cm(-2), respectively; P = 0.44 and 0.53. There were no significant changes in BMD or BMC at other skeletal sites, or in structural parameters. CONCLUSIONS falls prevention exercise programmes did not influence BMD in older people. To increase bone strength, programmes may require exercise that exerts higher strains on bone or longer duration.
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Movement as Medicine for Type 2 Diabetes: protocol for an open pilot study and external pilot clustered randomised controlled trial to assess acceptability, feasibility and fidelity of a multifaceted behavioural intervention targeting physical activity in primary care.
Avery, L, Sniehotta, FF, Denton, SJ, Steen, N, McColl, E, Taylor, R, Trenell, MI
Trials. 2014;:46
Abstract
BACKGROUND Physical activity (PA) and nutrition are the cornerstones of diabetes management. Several reviews and meta-analyses report that PA independently produces clinically important improvements in glucose control in people with Type 2 diabetes. However, it remains unclear what the optimal strategies are to increase PA behaviour in people with Type 2 diabetes in routine primary care. METHODS This study will determine whether an evidence-informed multifaceted behaviour change intervention (Movement as Medicine for Type 2 Diabetes) targeting both consultation behaviour of primary healthcare professionals and PA behaviour in adults with Type 2 diabetes is both acceptable and feasible in the primary care setting. An open pilot study conducted in two primary care practices (phase one) will assess acceptability, feasibility and fidelity. Ongoing feedback from participating primary healthcare professionals and patients will provide opportunities for systematic adaptation and refinement of the intervention and study procedures. A two-arm parallel group clustered pilot randomised controlled trial with patients from participating primary care practices in North East England will assess acceptability, feasibility, and fidelity of the intervention (versus usual clinical care) and trial processes over a 12-month period. Consultation behaviour involving fidelity of intervention delivery, diabetes and PA related knowledge, attitudes/beliefs, intentions and self-efficacy for delivering a behaviour change intervention targeting PA behaviour will be assessed in primary healthcare professionals. We will rehearse the collection of outcome data (with the focus on data yield and quality) for a future definitive trial, through outcome assessment at baseline, one, six and twelve months. An embedded qualitative process evaluation and treatment fidelity assessment will explore issues around intervention implementation and assess whether intervention components can be reliably and faithfully delivered in routine primary care. DISCUSSION Movement as Medicine for Type 2 Diabetes will address an important gap in the evidence-base, that is, the need for interventions to increase free-living PA behaviour in adults with Type 2 diabetes. The multifaceted intervention incorporates an online accredited training programme for primary healthcare professionals and represents, to the best of our knowledge, the first of its kind in the United Kingdom. This study will establish whether the multifaceted behavioural intervention is acceptable and feasible in routine primary care. TRIAL REGISTRATION Movement as Medicine for Type 2 Diabetes (MaMT2D) was registered with Current Controlled Trials on the 14th January 2012: ISRCTN67997502. The first primary care practice was randomised on the 5th October 2012.
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Effect of insulin therapy on plasma leptin and body weight in patients with type 2 diabetes.
Carey, PE, Stewart, MW, Ashworth, L, Taylor, R
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2003;(6):372-6
Abstract
AIMS: This study set out to define relationships between changes in plasma leptin and changes in body weight, plasma insulin and blood glucose control during a 12-month crossover study of once-daily Ultratard or twice-daily Insulatard insulin. PATIENTS AND METHODS Fasting plasma leptin and insulin were measured during a multicentre cross-over study involving 60 subjects with type 2 diabetes (fasting glucose > 8 mM). After a 2-month run-in, there were two 6-month periods of treatment with Insulatard or Ultratard insulin. RESULTS Mean plasma leptin increased significantly in both groups after insulin therapy was instigated (12.8 +/- 8.1 to 22.9 +/- 13.1 ng/ml in the Insulatard group; 12.1 +/- 7.2 to 19.2 +/- 12.3 ng/ml in the Ultratard group). Weight also increased significantly in both groups (82.4 +/- 14.3 kg to 88.8 +/- 14.3 kg and 82.2 +/- 15.3 kg to 85.3 +/- 15.2 kg respectively). The increase in plasma leptin correlated well with the increase in weight (R = 0.416, p = 0.001), and this correlation continued after the crossover point. Plasma leptin correlated with BMI throughout the study (R = 0.540, p = 0.000). CONCLUSION The sustained rise in body weight despite a substantial increase in plasma leptin suggests that either resistance to the hypothalamic action of leptin develops when insulin therapy is begun in type 2 diabetes, or that resetting of the set point for body weight occurs such that a larger body mass is tolerated for a given level of plasma leptin.