LICAMM Cardiovascular risk in younger patients with double diabetes.

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.

<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 >58 mmol/mol) and body mass index >27 kg/m2 or >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> </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>

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