Publications by authors named "John Ph Wilding"

9 Publications

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A andomisd, controlled, double blind tudy to assess mechanstic effects of combination therapy of dapagflozin with xenatide QW versus dapagliflozin alone i obese patients with ype 2 diabetes mellitus (RESILIENT): study protocol.

BMJ Open 2021 07 20;11(7):e045663. Epub 2021 Jul 20.

Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.

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, HbA ≥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 intake and energy expenditure measured by indirect calorimetry); (2) (between and within meals) and satiety quotient; (3) including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and (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.
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http://dx.doi.org/10.1136/bmjopen-2020-045663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292819PMC
July 2021

Dapagliflozin for the treatment of type 2 diabetes mellitus - an update.

Expert Opin Pharmacother 2021 Jul 28:1-8. Epub 2021 Jul 28.

Department of Diabetes and Endocrinology, Liverpool University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Aintree University Hospital, Liverpool, UK.

Introduction: Diabetes is a global health concern with a prevalence of 463 million people. Importantly, despite the availability of numerous antidiabetic medications, type 2 diabetes mellitus (T2DM) is still associated with significant morbidity and mortality worldwide. One particular drug of interest is dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used in the treatment of Type 2 Diabetes Mellitus (T2DM).

Areas Covered: This review outlines the current use and pharmacology of dapagliflozin, with a specific focus on recent evidence regarding benefits in patients with cardiovascular and chronic kidney disease. The article includes an overview of the efficacy and safety of this drug and provides the reader with the expert opinion and perspectives of the authors.

Expert Opinion: Increasing evidence of the beneficial effects on morbidity and mortality in patients with Type 2 diabetes and concurrent heart failure, acute MI and renal failure are likely to see the usage of dapagliflozin in patients with these comorbidities increase over the next 5 years.
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http://dx.doi.org/10.1080/14656566.2021.1953471DOI Listing
July 2021

The expanding role of SGLT2 inhibitors beyond glucose-lowering to cardiorenal protection.

Ann Med 2020 Oct 27:1-32. Epub 2020 Oct 27.

Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.

The kidney plays a major physiological role in glucose homeostasis but also contributes to the pathophysiology of type 2 diabetes (T2D), mediated by renal sodium glucose cotransporters (SGLTs). This recognition led to development of SGLT2 inhibitors that inhibit proximal renal tubular renal glucose and sodium reabsorption. The glucoretic and natriuretic effect of SGLT2 inhibitors is associated with reductions in HbA levels, body weight, systolic blood pressure and triglycerides.Major vascular complications of T2D include cardiovascular disease and chronic kidney disease (CKD). Results from several cardiovascular outcome trials (CVOTs) with these drugs have highlighted benefits in reducing major adverse cardiovascular events by 11%, reducing the risk of cardiovascular death or hospitalisation for heart failure (HF) by 23% and reducing risk of progression of renal disease by 45%. Their cardiorenal benefits are apparent across a range of eGFRs (within CKD1-3 groups) and the presence or absence of ischaemic heart disease, HF or T2D. In patients with HF with reduced ejection fraction (HFrEF), similar risk reductions in cardiovascular death and HF events are also seen; results from studies in patients with HF with preserved ejection fraction (HFpEF) are awaited. Cardiorenal benefits have been recently reported in patients with CKD, regardless of the presence or absence of T2D.Indications for use of SGLT2 inhibitors has extended beyond glucose-lowering to a central role in cardiorenal protection. This review will first explore the mechanisms by which glycaemic control, weight loss and cardiovascular risk factors are modulated therapeutically with SGLT2 inhibitors. Subsequently we outline putative mechanisms underpinning the cardiorenal benefits seen, including in HF and CKD, in the context of completed and ongoing clinical studies. Treatment strategies with SGLT2 inhibitors in individuals with CKD or HF, with and/or without T2D are increasingly appealing. Combination therapy with complementary therapeutic agents is also explored.
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http://dx.doi.org/10.1080/07853890.2020.1841281DOI Listing
October 2020

Randomised, cOntrolled Multicentre trial of 26 weeks subcutaneous liraglutide (a glucagon-like peptide-1 receptor Agonist), with or without contiNuous positive airway pressure (CPAP), in patients with type 2 diabetes mellitus (T2DM) and obstructive sleep apnoEa (OSA) (ROMANCE): study protocol assessing the effects of weight loss on the apnea-hypnoea index (AHI).

BMJ Open 2020 07 22;10(7):e038856. Epub 2020 Jul 22.

Department of Cardiovascular & Metabolic Medicine, University of Liverpool, Liverpool, UK.

Introduction: Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA.

Methods And Analysis: This is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea-hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function.

Ethical Approval: The study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.

Trial Registration Numbers: ISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.
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http://dx.doi.org/10.1136/bmjopen-2020-038856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380950PMC
July 2020

Dapagliflozin and cardiovascular outcomes in patients with Type 2 diabetes.

Future Cardiol 2020 03 9;16(2):77-88. Epub 2020 Jan 9.

Obesity & Endocrinology Research, Institute of Ageing & Chronic Disease, University of Liverpool, Liverpool, L9 7AL, UK.

The relationship between cardiovascular disease, heart failure (HF) and Type-2 diabetes (T2DM) is widely recognized. Cardiovascular (CV) outcome trials are required for all new glucose-lowering agents to confirm safety with respect to CV risk. CV outcome trials with SGLT2i inhibitors have shown CV benefit, with reductions in major CV events and HF. This review focuses on the DECLARE-TIMI 58 trial with dapagliflozin in T2DM, which showed noninferiority for major adverse cardiovascular events and reduction in hospitalization for HF and associated CV mortality in a broad range of patients with T2DM. The DAPA-HF trial of dapagliflozin in people with HF with reduced ejection fraction with and without T2DM confirms benefits for those with HF.
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http://dx.doi.org/10.2217/fca-2019-0065DOI Listing
March 2020

The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial.

Am Heart J 2018 06 7;200:83-89. Epub 2018 Feb 7.

TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.

Background: Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD).

Research Design And Methods: DECLARE-TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n=6,971) or multiple risk factors for ASCVD (n=10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of .0231.

Conclusion: The DECLARE-TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE-TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.
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http://dx.doi.org/10.1016/j.ahj.2018.01.012DOI Listing
June 2018

Combination therapy for obesity.

Authors:
John Ph Wilding

J Psychopharmacol 2017 11 13;31(11):1503-1508. Epub 2017 Nov 13.

Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Obesity is a chronic disease with serious consequences and although lifestyle modification is considered first line treatment, it is often ineffective, especially in the long term. Relatively few people with obesity will undergo the most effective currently available treatment of bariatric surgery. Pharmacotherapy can bridge the gap between lifestyle modification and surgery, but many monotherapies have only modest efficacy or require high doses with unacceptable side effects. As with many other areas of medicine, combination therapy is now becoming accepted as a way of optimising efficacy for weight management, whilst minimising adverse effects. Combinations may use different medications with complementary modes of action. Currently available combination therapies are low-dose phentermine and sustained release topiramate and naltrexone/bupropion. Many other possibilities exist and promising options include combination of phentermine with a sodium glucose co-transporter 2 inhibitor or combination of a glucagon-like peptide 1 agonist with other gut hormones or with a sodium glucose co-transporter 2 inhibitor. The ultimate aim is to match the efficacy of bariatric surgery with a combination of medicines, but this remains an elusive goal.
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http://dx.doi.org/10.1177/0269881117737401DOI Listing
November 2017

Urinary proteomic profiling in severe obesity and obstructive sleep apnoea with CPAP treatment.

Sleep Sci 2015 Apr-Jun;8(2):58-67. Epub 2015 Jul 17.

Department of Obesity & Endocrinology, University of Liverpool, UK.

Introduction: Obstructive sleep apnoea (OSA) is common in obesity and is associated with cardiovascular and metabolic complications. Continuous positive airway pressure (CPAP) in OSA may lead to physiological changes reflected in the urinary proteome. The aim of this study was to characterise the urinary proteome in severely obese adult subjects with OSA who were receiving CPAP compared with severely obese subjects without OSA.

Methods: Severely obese subjects with and without OSA were recruited. Subjects with OSA were receiving CPAP. Body composition and blood pressure measurements were recorded. Urinary samples were analysed by Capillary Electrophoresis-Mass Spectrometry (CE-MS).

Results: Twenty-seven subjects with OSA-on-CPAP (age 49±7years, BMI 43±7 kg/m(2)) and 25 controls without OSA (age 52±9years, BMI 39±4 kg/m(2)) were studied. Age and BMI were not significantly different between groups. Mean CPAP use for OSA patients was 14.5±1.0 months. Metabolic syndrome was present in 14(52%) of those with OSA compared with 6(24%) of controls (p=0.039). A urinary proteome comprising 15 peptides was identified showing differential expression between the groups (p<0.01). Although correction for multiple testing did not reach significance, sequences were determined for 8 peptides demonstrating origins from collagens, fibrinogen beta chain and T-cadherin that may be associated with underlying cardiovascular disease mechanisms in OSA.

Conclusions: The urinary proteome is compared in OSA with CPAP and without OSA in severe obesity. The effects of CPAP on OSA may lead to changes in the urinary peptides but further research work is needed to investigate the potential role for urinary proteomics in characterising urinary peptide profiles in OSA.
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http://dx.doi.org/10.1016/j.slsci.2015.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608901PMC
October 2015

Differential vascular dysfunction in response to diets of differing macronutrient composition: a phenomenonological study.

Nutr Metab (Lond) 2007 Jun 14;4:15. Epub 2007 Jun 14.

School of Clinical Sciences, University of Liverpool, Liverpool, UK.

Background: Vascular dysfunction can develop from consumption of an energy-rich diet, even prior to the onset of obesity. However, the roles played by different dietary components remain uncertain. While attempting to develop models of obesity in a separate study, we observed that two high-energy diets of differing macronutrient compositions affected vascular function differently in overweight rats.

Methods: Male Wistar rats (n = 6/group) were fed diets providing varying percentages of energy from fat and carbohydrate (CHO). For 10 weeks, they were fed either chow, as control diet (10% of energy from fat; 63% from CHO), chow supplemented with chocolate biscuit (30% fat; 56% CHO) or a high-fat diet (45% fat; 35% CHO). Blood concentrations of biochemical markers of obesity were measured, and epididymal fat pads weighed as a measure of adiposity. Mesenteric arteries were dissected and their contractile and relaxant properties analysed myographically. Data were tested by analysis of variance (ANOVA).

Results: Weight gain and plasma concentrations of glucose, insulin and leptin were similar in all groups. However, biscuit-fed animals showed increased food intake (+27%; p < 0.01) and elevated concentrations of TGs and NEFAs (+41% and +17%; both p < 0.05). High-fat-fed animals showed an increase only in NEFAs (+38%; p < 0.01). Arterial vasoconstriction in response to NA and KCl increased only in biscuit-fed rats (both p < 0.01), while vasorelaxation in response to CCh and SNP, but not histamine, was attenuated in both groups (both p < 0.01). Furthermore, whereas the effect of the high-fat diet was most pronounced in endothelium-dependent vasorelaxation, the biscuit diet had the greater effect on endothelium-independent vasorelaxation.

Conclusion: Vascular dysfunction resulting from consumption of a high-fat or combined relatively high-fat/high-CHO diet occurs through different physiological processes, which may be attributable to their differing macronutrient compositions. Combining potentially atherogenic macronutrients induces more extensive vascular impairment than that of high-fat alone, and may be attributable to the more marked dyslipidaemia observed with such a diet. Thus, these findings help clarify the role of dietary components in vascular impairment, which has implications for clinical approaches to preventing cardiovascular disease.
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http://dx.doi.org/10.1186/1743-7075-4-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1910600PMC
June 2007
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