No evidence of compensatory changes in energy balance, despite reductions in body weight and liver fat, during dapagliflozin treatment in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, cross-over trial (ENERGIZE).

AIM: This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1 H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). RESULTS: In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2 , glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (-2.84 vs. -0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI -127.9 to 139.3, p = .933); 15.8 g (95% CI -147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction -4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. CONCLUSIONS: The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.

A randomised, controlled, double blind study to assess mechanistic effects of combination therapy of dapagliflozin with exenatide QW versus dapagliflozin alone in obese patients with type 2 diabetes mellitus (RESILIENT): study protocol.

INTRODUCTION: The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity. METHODS AND ANALYSIS: 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA1c ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) energy balance (energy intake and energy expenditure measured by indirect calorimetry); (2) appetite (between and within meals) and satiety quotient; (3) body composition including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include metabolic changes in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), central nervous system responses to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and changes in cardiovascular function (using transthoracic echocardiography, cardiac MR and duplex ultrasonography). ETHICS AND DISSEMINATION: This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants. TRIAL SPONSOR: University of Liverpool. TRIAL REGISTRATION NUMBER: ISRCTN 52028580; EUDRACT number 2015-005242-60.

A web-based weight loss programme including breakfast cereals results in greater loss of body mass than a standardised web-based programme in a randomised controlled trial.

OBJECTIVE: To test the hypothesis that promoting breakfast cereal consumption, as part of a web-based programme, results in loss of body mass. METHODS: Single centre, single blind, randomised parallel study. Test group followed a fully interactive website (B) with 'prescribed' breakfast cereals. Control group followed website (A) giving standard advice on weight loss.Study site visits at 0, 4, 12 and 24 weeks for measurements of height, weight, skinfolds, body fat, waist and hip circumference. 180 subjects were randomly allocated to two equal groups.Subjects were in good health and aged 19­50 years, with a BMI ranging from 25­40 kg/m 2 .At baseline there was no difference in mean age or BMI between the two groups. RESULTS: The percentage change in body mass loss was greater when following website B than website A (n = 90; ITT repeated measures p = 0.013). For completers (website A: n = 62, website B: n= 64), the percentage change in body mass loss was also greater for website B than website A (repeated measures p = 0.023). CONCLUSION: The advice and motivation offered by an interactive website, including provision and consumption of breakfast cereals, results in significantly greater loss of body mass compared to the use of a standard website. It is not possible to discern which of the three factors is responsible.

Short term (14 days) consumption of insoluble wheat bran fibre-containing breakfast cereals improves subjective digestive feelings, general wellbeing and bowel function in a dose dependent manner.

This study investigated whether increasing insoluble (predominantly wheat bran) fibre over 14 days improves subjective digestive feelings, general wellbeing and bowel function. A single centre, multi-site, open, within subjects design with a 14 day non-intervention (baseline) monitoring period followed by a 14 day fibre consumption (intervention) period was performed. 153 low fibre consumers (<15 g/day AOAC 985.29) completed a daily symptom diary for 14 days after which they consumed one bowl of ready-to-eat breakfast cereal containing at least 5.4 g fibre (3.5 g from wheat bran) for 14 days and completed a daily symptom diary. Significant improvements were demonstrated in subjective perception of bowel function (e.g., ease of defecation) and digestive feelings (bloating, constipation, feeling sluggish and digestive discomfort). Significant improvements were also found in subjective perception of general wellbeing (feeling less fat, more mentally alert, slim, happy and energetic whilst experiencing less stress, mental and physical tiredness, difficulty concentrating and fewer headaches). In general, improvements in study outcomes increased with increasing cereal/fibre consumption. However, consuming an additional minimum 5.4 g of fibre (3.5 g wheat bran) per day was shown to deliver measurable and significant benefits for digestive health, comfort and wellbeing. Encouraging consumption of relatively small amounts of wheat bran could also provide an effective method of increasing overall fibre consumption.

A randomized trial comparing a group exercise programme for back pain patients with individual physiotherapy in a severely deprived area.

PURPOSE: To compare a group exercise programme known as the Back to Fitness programme with individual physiotherapy for patients with non-specific low back pain from a materially deprived area. METHOD: This was a randomized controlled trial including 237 physiotherapy patients with back pain lasting more than six weeks. Participants were allocated to either the Back to Fitness programme or to individual physiotherapy, and followed up at three months and 12 months after randomization. The main outcome measure was the Roland Disability Questionnaire. Secondary measures were: SF12, EQ5D, Pain Self-Efficacy Scale. Health care diaries recording patients' use of health care resources were also collected over a 12-month period. RESULTS: There were no statistically significant differences in change scores between groups on the primary outcome measure at three months (CI - 2.24 to 0.49) and at 12 months (CI - 1.68 to 1.39). Only minor improvements in disability scores were observed in the Back to Fitness group at three months and 12 months respectively (mean change scores; - 0.89, - 0.77) and in the individual physiotherapy arm (mean change scores; - 0.02, - 0.63). Further analysis showed that patients from the most severely deprived areas were marginally worse at three month follow-up whereas those from more affluent areas tended to improve (CI 0.43 to 3.15).

High fear-avoiders of physical activity benefit from an exercise program for patients with back pain.

STUDY DESIGN: A subgroup analysis of patient outcomes from a randomized controlled trial comparing a Back to Fitness program with usual general practitioner care. OBJECTIVES: To test whether patients with high scores on measures of fear-avoidance and distress/depression benefit the most. SUMMARY OF BACKGROUND DATA: A fitness program, ongoing since the 1980s, was developed for use in the community and has been shown to be effective in reducing disability. Detailed analyses are needed to identify patient groups who benefit. Recent evidence points to the potentially important role of fear, distress, and depression. METHOD: Data from 98 patients allocated to normal general practitioner care and 89 patients allocated to a group exercise program were analyzed after categorizing baseline scores on fear-avoidance beliefs (high/low) and distress/depression (at risk/normal). The main outcome measure was the Roland Disability Questionnaire. Outcomes were compared between the intervention and control groups at 6 weeks, 6 months, and 12 months. RESULTS.: High fear-avoiders fared significantly better in the exercise program than in usual general practitioner care at 6 weeks and at 1 year. Low fear-avoiders did not. Patients who were distressed or depressed were significantly better off at 6 weeks, but the benefits were not maintained long-term. CONCLUSION: Patients with high levels of fear-avoidance beliefs could significantly benefit from the Back to Fitness program. The benefits of the exercise program for patients with high levels of distress/depression appear to be short-term only. Average attendance was only 4 to 5 classes, which may not be sufficient for more recalcitrant cases. Further research is indicated.

Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes.

OBJECTIVE: Phytoestrogen consumption has been shown to reduce risk factors for cardiovascular disease. Type 2 diabetes confers an adverse cardiovascular risk profile particularly in women after menopause. The aim of this study was to determine whether a dietary supplement with soy protein and isoflavones affected insulin resistance, glycemic control, and cardiovascular risk markers in postmenopausal women with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 32 postmenopausal women with diet-controlled type 2 diabetes completed a randomized, double blind, cross-over trial of dietary supplementation with phytoestrogens (soy protein 30 g/day, isoflavones 132 mg/day) versus placebo (cellulose 30 g/day) for 12 weeks, separated by a 2-week washout period. RESULTS: Compliance with the dietary supplementation was >90% for both treatment phases. When compared with the mean percentage change from baseline seen after 12 weeks of placebo, phytoestrogen supplementation demonstrated significantly lower mean values for fasting insulin (mean +/- SD 8.09 +/- 21.9%, P = 0.006), insulin resistance (6.47 +/- 27.7%, P = 0.003), HbA(1c) (0.64 +/- 3.19%, P = 0.048), total cholesterol (4.07 +/- 8.13%, P = 0.004), LDL cholesterol (7.09 +/- 12.7%, P = 0.001), cholesterol/HDL cholesterol ratio (3.89 +/- 11.7%, P = 0.015), and free thyroxine (2.50 +/- 8.47%, P = 0.004). No significant change occurred in HDL cholesterol, triglycerides, weight, blood pressure, creatinine, dehydroepiandrosterone sulfate, androstenedione, and the hypothalamic-pituitary-ovarian axis hormones. CONCLUSIONS: These results show that dietary supplementation with soy phytoestrogens favorably alters insulin resistance, glycemic control, and serum lipoproteins in postmenopausal women with type 2 diabetes, thereby improving their cardiovascular risk profile.