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Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial).

ABSTRACT: INTRODUCTION:The primary aim of this study is to compare the efficacy of three short-term glucose-lowering interventions (exercise, metformin and dapagliflozin) on glycaemic variability in overweight or obese men and women with elevated diabetes risk (ie, prediabetes, defined as haemoglobin A1c (HbA1c)39-47?mmol/mol / 5.7%-6.4%). The secondary aims are to investigate the effects of the interventions on body composition and cardiometabolic risk factors. METHODS AND ANALYSIS:The Pre-D Trial is an investigator-initiated, randomised, controlled, parallel, open-label, superiority trial. The study aims to assign 120 participants in a 1:1:1:1 ratio to receive one of four interventions for 13 weeks: (1) dapagliflozin (10?mg once daily); (2) metformin (850?mg twice daily); (3) exercise (interval training, 5 days a week, 30?min per session); or (4) control (lifestyle advice). After the 13 weeks of intervention, a follow-up period of 13 weeks will follow to study the long-term effects of the interventions. The primary endpoint is reduction from baseline to end-of treatment (13 weeks) in mean amplitude of glycaemic excursions measured by continuous glucose monitoring. The secondary endpoints include concomitant changes in various measures of glucose metabolism, body weight, cardiorespiratory fitness, blood pressure, plasma lipids, objectively measured physical activity and dietary intake. ETHICS AND DISSEMINATION:The study protocol has been approved by the Ethics Committee of the Capital Region and the Danish Medicines Agency. Approval of data and biobank storage has been obtained from the Danish Data Protection Board. The study will be carried out according to the Declaration of Helsinki and to the regulations for good clinical practice. The results from this trial will allow a number of research questions concerning the effect of exercise versus dapagliflozin or metformin in HbA1c-defined prediabetes to be addressed. TRIAL REGISTRATION:NCT02695810.

SUBMITTER: Færch K

PROVIDER: S-EPMC5734208 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial).

Færch Kristine K Amadid Hanan H Nielsen Lea Bruhn LB Ried-Larsen Mathias M Karstoft Kristian K Persson Frederik F Jørgensen Marit Eika ME Jørgensen Marit Eika ME

BMJ open 20170606 5

<h4>Introduction</h4>The primary aim of this study is to compare the efficacy of three short-term glucose-lowering interventions (exercise, metformin and dapagliflozin) on glycaemic variability in overweight or obese men and women with elevated diabetes risk (ie, prediabetes, defined as haemoglobin A<sub>1c</sub> (HbA<sub>1c</sub>)39-47 mmol/mol / 5.7%-6.4%). The secondary aims are to investigate the effects of the interventions on body composition and cardiometabolic risk factors.<h4>Methods an ...[more]

PMID: 28592573

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Project description:ObjectiveTo evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia.DesignRandomised, double blind, placebo controlled trial.SettingReferral hospital in Cape Town, South Africa.Participants180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo.Intervention3 g of oral extended release metformin or placebo daily, in divided doses, until delivery.Main outcome measureThe primary outcome was prolongation of gestation.ResultsOf 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm.ConclusionsThis trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible.Trial registrationPan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.

Project description:Aims/hypothesisWe determined whether the time of day of exercise training (morning vs evening) would modulate the effects of consumption of a high-fat diet (HFD) on glycaemic control, whole-body health markers and serum metabolomics.MethodsIn this three-armed parallel-group randomised trial undertaken at a university in Melbourne, Australia, overweight/obese men consumed an HFD (65% of energy from fat) for 11 consecutive days. Participants were recruited via social media and community advertisements. Eligibility criteria for participation were male sex, age 30-45 years, BMI 27.0-35.0 kg/m2 and sedentary lifestyle. The main exclusion criteria were known CVD or type 2 diabetes, taking prescription medications, and shift-work. After 5 days, participants were allocated using a computer random generator to either exercise in the morning (06:30 hours), exercise in the evening (18:30 hours) or no exercise for the subsequent 5 days. Participants and researchers were not blinded to group assignment. Changes in serum metabolites, circulating lipids, cardiorespiratory fitness, BP, and glycaemic control (from continuous glucose monitoring) were compared between groups.ResultsTwenty-five participants were randomised (morning exercise n = 9; evening exercise n = 8; no exercise n = 8) and 24 participants completed the study and were included in analyses (n = 8 per group). Five days of HFD induced marked perturbations in serum metabolites related to lipid and amino acid metabolism. Exercise training had a smaller impact than the HFD on changes in circulating metabolites, and only exercise undertaken in the evening was able to partly reverse some of the HFD-induced changes in metabolomic profiles. Twenty-four-hour glucose concentrations were lower after 5 days of HFD compared with the participants' habitual diet (5.3 ± 0.4 vs 5.6 ± 0.4 mmol/l, p = 0.001). There were no significant changes in 24 h glucose concentrations for either exercise group but lower nocturnal glucose levels were observed in participants who trained in the evening, compared with when they consumed the HFD alone (4.9 ± 0.4 vs 5.3 ± 0.3 mmol/l, p = 0.04). Compared with the no-exercise group, peak oxygen uptake improved after both morning (estimated effect 1.3 ml min-1 kg-1 [95% CI 0.5, 2.0], p = 0.003) and evening exercise (estimated effect 1.4 ml min-1 kg-1 [95% CI 0.6, 2.2], p = 0.001). Fasting blood glucose, insulin, cholesterol, triacylglycerol and LDL-cholesterol concentrations decreased only in participants allocated to evening exercise training. There were no unintended or adverse effects.Conclusions/interpretationA short-term HFD in overweight/obese men induced substantial alterations in lipid- and amino acid-related serum metabolites. Improvements in cardiorespiratory fitness were similar regardless of the time of day of exercise training. However, improvements in glycaemic control and partial reversal of HFD-induced changes in metabolic profiles were only observed when participants exercise trained in the evening.Trial registrationanzctr.org.au registration no. ACTRN12617000304336.FundingThis study was funded by the Novo Nordisk Foundation (NNF14OC0011493).

Project description:AIM:To assess the effects of once-weekly exenatide on 24-hour glucose control and variability. MATERIALS AND METHODS:This double-blind, placebo-controlled trial randomized metformin-treated adults with type 2 diabetes to once-weekly exenatide 2.0 mg or placebo. Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10. The primary outcome was change in CGM-measured 24-hour mean glucose level. RESULTS:In the once-weekly exenatide (n = 60) and placebo (n = 56) groups (modified intention-to-treat population), the baseline glycated haemoglobin (HbA1c) concentrations were 8.2% and 8.0%, respectively, and the fasting plasma glucose (FPG) concentration was 9.86 and 9.32 mmol/L, respectively. Once-weekly exenatide significantly (p < 0.001) reduced 24-hour mean glucose level versus placebo (week 4, -1.44 vs -0.29 mmol/L; week 10, -1.71 vs -0.17 mmol/L), with consistent control throughout the week. Once-weekly exenatide significantly reduced FPG and 2-hour postprandial glucose (PPG) levels versus placebo at week 4 (FPG, -1.65 vs -0.11 mmol/L; PPG, -1.79 vs -0.11 mmol/L) and week 10 (FPG, -2.32 vs -0.28 mmol/L; PPG, -2.46 vs -0.33 mmol/L). At week 10, once-weekly exenatide reduced the mean amplitude of glucose excursions (MAGE; -0.84 vs 0.16 mmol/L) and standard deviation (s.d.) of mean glucose (-0.35 vs 0.04 mmol/L). By week 10, once-weekly exenatide-treated participants spent more time in euglycaemia (once-weekly exenatide, 77% vs placebo, 58%), less time in hyperglycaemia (22% vs 42%), and a similar time in hypoglycaemia (0.7% vs 0.3%). Common adverse events were injection-site nodule (once-weekly exenatide, 10.0% vs placebo, 0.0%), urinary tract infection (6.7% vs 8.9%) and nausea (6.7% vs 0.0%). CONCLUSIONS:In metformin-treated participants with type 2 diabetes, once-weekly exenatide significantly improved daily glucose control and reduced glycaemic variability at weeks 4 and 10, as shown by reductions in 24-hour glucose, FPG and PPG levels, MAGE and s.d., and increased time spent in euglycaemia.

Project description:BackgroundManagement of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.MethodsThis was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.ResultsA total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg).ConclusionsDapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.Trial registrationClinicalTrials.gov: NCT00528879.

Dataset Information

Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial).

Publications

Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial).

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