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Cardiovascular risk in younger patients with double diabetes.

PGR-P-166

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Ramzi Ajjan and Professor Sven Plein
<h2 class="heading hide-accessible">Summary</h2>

The term double diabetes has been used to describe individuals with type 1 diabetes (T1DM) who are overweight and display features of type 2 diabetes (T2DM) such as insulin resistance, hypertension and dysplipidaemia. Patients with double diabetes are at higher risk of diabetic vascular complications, thereby increasing diabetes-related morbidity and mortality. There are no established guidelines for the treatment of this group of patients, despite the documented increased risk of complications.

<h2 class="heading hide-accessible">Full description</h2>

<p>Recent work has shown that at least one member the sodium glucose transporter-2 inhibitors (SGLT-2i) reduces cardiovascular and all-cause mortality in patients with T2DM. Moreover, real life observational data have shown that all three agents in this class reduce heart failure in patients with diabetes The exact mechanisms for the beneficial cardiovascular effects are unclear but likely to be multifactorial involving different pathways including weight loss, a drop in blood pressure, improved insulin sensitivity and reduction in blood glucose. We hypothesise that the use of SGLT-2i in individuals with double diabetes reduces weight, increases insulin sensitivity and improves markers of cardiovascular health.</p> <h2>Research aim:</h2> <p>We propose to investigate whether the use of SGLT-2i in younger overweight T1DM diabetes patients, in addition to insulin therapy, results in weight reduction and improvement in glycaemic parameters, cardiovascular markers and quality of life measures.</p> <h2>Design:</h2> <p>This will be an open label, single centre, two arm study comparing standard insulin therapy, using multiple daily injections or an insulin pump, with the addition of SGLT2i to insulin in patients with double diabetes for a period 6 months.</p> <p>Inclusion criteria are patients with a known diagnosis of T1DM for at least 2 years, who meet all the following criteria: aged 18 to 40 years, suboptimal glycaemic control (HbA1c &gt;58 mmol/mol) and body mass index &gt;27 kg/m2 or &gt;25 kg/m2 in those of South Asian origin or a family history of T2DM.</p> <p>A total of 48 consenting adults will be randomised 1:1 to:</p> <p>Control group using insulin only for the treatment of glycaemia.</p> <p>Intervention group, treated with SGLT-2i in addition to insulin.</p> <p>Metabolic, cardiovascular and personal parameters will be analysed at baseline, 90, 180 and 365 days (the last time point at 6 months following cessation of intervention). The primary end point is reduction in weight and/or improvement in estimated glucose disposal rate (eGDR). Secondary and exploratory end points are:</p> <p>&nbsp;</p> <p>Glycated haemoglobin (HbA1c)</p> <p>Time spent in euglycaemia</p> <p>Time spent in hypoglycaemia</p> <p>Insulin doses</p> <p>Lipid profile</p> <p>Vascular inflammatory markers: C-reactive protein and complement C3</p> <p>Vascular thrombotic markers: fibrin clot structure and lysis</p> <p>Clinical vascular markers: blood pressure, microalbuminuria and cardiac function assessed by magnetic resonance imaging</p> <p>Health-related quality of life</p> <p>Hospital admissions for any cause</p> <h2>Outcome</h2> <p>This study in patients with double diabetes will establish safety and efficacy of SGLT2i in reducing weight, modulating glycaemic, inflammatory and thrombotic markers and improving quality of life. Data generated have the potential to change clinical management of younger individuals with double diabetes, helping to reduce morbidity and mortality in this high risk population.</p> <h2>References:</h2> <p>Pozzilli P, Guglielmi C. Double diabetes: a mixture of type 1 and type 2 diabetes in youth. Endocr.Dev. 2009;14:151-166.</p> <p>Pozzilli P. Type 1 diabetes mellitus in 2011: Heterogeneity of T1DM raises questions for therapy. Nat.Rev.Endocrinol. 2011;8:78-80.</p> <p>Erbey JR, Kuller LH, Becker DJ, Orchard TJ. The association between a family history of type 2 diabetes and coronary artery disease in a type 1 diabetes population. Diabetes Care 1998;21:610-614.</p> <p>Merger SR, Kerner W, Stadler M et al. Prevalence and comorbidities of double diabetes. Diabetes Res.Clin.Pract.</p> <p>Famulla S, Pieber TR, Eilbracht J et al. Glucose Exposure and Variability with Empagliflozin as Adjunct to Insulin in Patients with Type 1 Diabetes: Continuous Glucose Monitoring Data from a 4-Week, Randomized, Placebo-Controlled Trial (EASE-1). Diabetes Technol.Ther. 2017;19:49-60.</p> <p>Pieber TR, Famulla S, Eilbracht J et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes.Metab 2015;17:928-935.</p> <p>Khunti K, Davies M, Majeed A et al. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care 2015;38:316-322.</p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete a<a href="https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form"> Faculty Application Form</a> and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If you have already applied for other projects using the Faculty Application Form this academic session you do not need to complete this form again. Instead you should email fmhgrad to inform us you would like to be considered for this project.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>We welcome applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.</em></p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<h2 class="heading">Contact details</h2>

<p>For further information please contact the Graduate School Office<br /> e:<a href="mailto: fmhgrad@leeds.ac.uk"> </a><a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>


<h3 class="heading heading--sm">Linked research areas</h3>