Oxford Center for Diabetes Endocrinology and Metabolism

Oxford, United Kingdom

Oxford Center for Diabetes Endocrinology and Metabolism

Oxford, United Kingdom
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Karagiannis T.,Aristotle University of Thessaloniki | Bekiari E.,Aristotle University of Thessaloniki | Manolopoulos K.,Oxford Center for Diabetes Endocrinology and Metabolism | Paletas K.,Aristotle University of Thessaloniki | And 2 more authors.
Hippokratia | Year: 2010

Gestational diabetes mellitus (GDM) is defned as any degree of glucose intolerance with onset or frst recognition during pregnancy. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future. The global incidence of GDM is diffcult to estimate, due to lack of uniform diagnostic criteria. Various diagnostic criteria have been proposed. The beneft of treating GDM has also been controversial. The clinical signifcance of treating maternal hyperglycemia was made evident in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. The HAPO study demonstrated that there is a continuous association of maternal glucose levels with adverse pregnancy outcomes and served as the basis for a new set of diagnostic criteria, proposed in 2010 by the International Association of Diabetes and Pregnancy Groups (IADPSG). According to these criteria the diagnosis of GDM is made if there is at least one abnormal value (≥92, 180 and 153 mg/dl for fasting, one-hour and two-hour plasma glucose concentration respectively), after a 75 g oral glucose tolerance test (OGTT).


Nauck M.,Diabeteszentrum Bad Lauterberg | Frid A.,Skåne University Hospital | Hermansen K.,Aarhus University Hospital | Thomsen A.B.,Novo Nordisk AS | And 5 more authors.
Diabetes, Obesity and Metabolism | Year: 2013

Aims: To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2years in patients with type 2 diabetes. Methods: In the 26-week the Liraglutide Effect and Action in Diabetes (LEAD)-2 core trial, patients (n=1091) were randomized (2:2:2:1:2) to liraglutide (0.6, 1.2 or 1.8mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 18-80years old with HbA1c 7.0-11.0% (previous monotherapy ≥3months), or 7.0-10.0% (previous combination therapy ≥3months), and body mass index ≤40kg/m2. Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. Results: HbA1c decreased significantly with liraglutide (0.4% with 0.6mg, 0.6% with 1.2 and 1.8mg) versus 0.3% increase with metformin monotherapy (p<0.0001). HbA1c decrease with liraglutide was non-inferior versus 0.5% decrease with glimepiride. Liraglutide groups experienced significant weight loss (2.1, 3.0 and 2.9kg with 0.6, 1.2 and 1.8mg, respectively) compared to weight gain (0.7kg) with glimepiride (p<0.0001). Weight loss with liraglutide 1.2 and 1.8mg was significantly greater than with metformin monotherapy (1.8kg; p=0.0185 and p=0.0378 for 1.2 and 1.8mg, respectively). The occurrence of minor hypoglycaemia was <5.0% in all liraglutide groups, significantly less than with glimepiride (24.0%; p<0.0001). Liraglutide was well tolerated overall: gastrointestinal events were more common than with glimepiride or metformin monotherapy, but occurrence decreased with time. Conclusions: Liraglutide provided sustained glycaemic control over 2 years comparable to that provided by glimepiride. Liraglutide was well tolerated, and was associated with weight loss and a low rate of hypoglycaemia. © 2012 Blackwell Publishing Ltd.


Preda V.,Oxford Center for Diabetes Endocrinology and Metabolism | Preda V.,University of Sydney | Korbonits M.,Queen Mary, University of London | Cudlip S.,John Radcliffe Hospital | And 2 more authors.
European Journal of Endocrinology | Year: 2014

Aim: To study the prevalence of germline mutations of the aryl-hydrocarbon receptor interacting protein (AIP) gene in a large cohort of patients seen in the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), UK, with apparently sporadic pituitary adenomas, who were either diagnosed or had relevant clinical manifestations by the age of 40 years. Patients: We prospectively investigated all patients who were seen at Oxford University Hospital, OCDEM, and a tertiary referral centre, between 2012 and 2013, and presented with pituitary tumours under the age of 40 years and with no family history: a total of 127 patients were enrolled in the study. Methods: Leukocyte-origin genomic DNA underwent sequence analysis of exons 1-6 and the flanking intronic regions of the AIP gene (NM-003977.2), with dosage analysis by multiplex ligation-dependent probe amplification. Results: AIP variants were detected in 3% of the 127 patients, comprising four of 48 patients with acromegaly (8%), 0 of 43 with prolactinomas, 0 of the 20 patients with non-functioning adenomas, 0 of 15 with corticotroph adenomas and 0 of one with a thyrotroph adenomas. Definite pathogenetic mutations were seen in 2/4 variants, comprising 4.2% of patients with acromegaly. Conclusions: This prospective cohort study suggests a relatively low prevalence of AIP gene mutations in young patients with apparently sporadic pituitary adenomas presenting to a tertiary pituitary UK centre. Those with somatotroph macroadenomas have a higher rate of AIP mutation. These findings should inform discussion of genetic testing guidelines. © 2014 European Society of Endocrinology


Ratner R.E.,Georgetown University | Gough S.C.L.,Oxford Center for Diabetes Endocrinology and Metabolism | Mathieu C.,University Hospitals Leuven | Del Prato S.,University of Pisa | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2013

Aim: Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM). Methods: Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analysed. Results: Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.83[0.70;0.98]95%CI, RR:0.64[0.48;0.86]95%CI and RR:0.14[0.03;0.70]95%CI. In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [RR:0.83[0.74;0.94]95%CI and RR:0.68[0.57;0.82]95%CI). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.75[0.60;0.94]95%CI). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. Conclusions: The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes. © 2012 Blackwell Publishing Ltd.


Del Prato S.,University of Pisa | Foley J.E.,Novartis | Kothny W.,Novartis | Kozlovski P.,Novartis | And 5 more authors.
Diabetic Medicine | Year: 2014

Aims: Durability of good glycaemic control (HbA1c) is of importance as it can be the foundation for delaying diabetic complications. It has been hypothesized that early initiation of treatment with the combination of oral anti-diabetes agents with complementary mechanisms of action can increase the durability of glycaemic control compared with metformin monotherapy followed by a stepwise addition of oral agents. Dipeptidyl peptidase-4 inhibitors are good candidates for early use as they are efficacious in combination with metformin, show weight neutrality and a low risk of hypoglycaemia. We aimed to test the hypothesis that early combined treatment of metformin and vildagliptin slows β-cell deterioration as measured by HbA1c. Methods: Approximately 2000 people with Type 2 diabetes mellitus who were drug-naive or who were treated with metformin for less than 1 month, and who have HbA1c of 48-58 mmol/mol (6.5-7.5%), will be randomized in a 1:1 ratio in VERIFY, a 5-year multinational, double-blind, parallel-group study designed to compare early initiation of a vildagliptin-metformin combination with standard-of-care initiation of metformin monotherapy, followed by the stepwise addition of vildagliptin when glycaemia deteriorates. Further deterioration will be treated with insulin. The primary analysis for treatment failure will be from a Cox proportional hazard regression model and the durability of glycaemic control will be evaluated by assessing treatment failure rate and the rate of loss in glycaemic control over time as co-primary endpoints. Summary: VERIFY is the first study to investigate the long-term clinical benefits of early combination treatment vs. the standard-of-care metformin monotherapy with a second agent added by threshold criteria. © 2014 The Authors.


Rodbard H.W.,Endocrine and Metabolic Consultants | Buse J.B.,University of North Carolina at Chapel Hill | Woo V.,University of Manitoba | Vilsboll T.,Copenhagen University | And 3 more authors.
Diabetes, Obesity and Metabolism | Year: 2016

Aim: To evaluate, using post hoc analyses, whether the novel combination of a basal insulin, insulin degludec, and a glucagon-like peptide-1 receptor agonist, liraglutide (IDegLira), was consistently effective in patients with type 2 diabetes (T2D), regardless of the stage of T2D progression. Methods: Using data from the DUAL I extension [insulin-naïve patients uncontrolled on oral antidiabetic drugs (OADs), n=1660, 52weeks] and DUAL II (patients uncontrolled on basal insulin plus OADs, n=398, 26weeks) randomized trials, the efficacy of IDegLira was investigated with regard to measures of disease progression stage including baseline glycated haemoglobin (HbA1c), disease duration and previous insulin dose. Results: Across four categories of baseline HbA1c (≤7.5-9.0%), HbA1c reductions were significantly greater with IDegLira (1.1-2.5%) compared with IDeg or liraglutide alone in DUAL I. In DUAL II, HbA1c reductions were significantly greater with IDegLira (0.9-2.5%) than with IDeg in all but the lowest HbA1c category. In DUAL I, insulin dose and hypoglycaemia rate were lower across all baseline HbA1c categories for IDegLira versus IDeg, while hypoglycaemia was higher with IDegLira than liraglutide, irrespective of baseline HbA1c. In DUAL II, insulin dose and hypoglycaemia rate were similar with IDegLira and IDeg (maximum dose limited to 50U) independent of baseline HbA1c. The reduction in HbA1c with IDegLira was independent of disease duration and previous insulin dose but varied depending on pre-trial OAD treatment. Conclusions: IDegLira effectively lowered HbA1c across a range of measures, implying suitability for patients with either early or advanced T2D. © 2016 John Wiley & Sons Ltd.


PubMed | Endocrine and Metabolic Consultants, Copenhagen University, Oxford Center for Diabetes Endocrinology and Metabolism, Novo Nordisk AS and 2 more.
Type: Journal Article | Journal: Diabetes, obesity & metabolism | Year: 2016

To evaluate, using post hoc analyses, whether the novel combination of a basal insulin, insulin degludec, and a glucagon-like peptide-1 receptor agonist, liraglutide (IDegLira), was consistently effective in patients with type 2 diabetes (T2D), regardless of the stage of T2D progression.Using data from the DUAL I extension [insulin-nave patients uncontrolled on oral antidiabetic drugs (OADs), n=1660, 52weeks] and DUAL II (patients uncontrolled on basal insulin plus OADs, n=398, 26weeks) randomized trials, the efficacy of IDegLira was investigated with regard to measures of disease progression stage including baseline glycated haemoglobin (HbA1c), disease duration and previous insulin dose.Across four categories of baseline HbA1c (7.5-9.0%), HbA1c reductions were significantly greater with IDegLira (1.1-2.5%) compared with IDeg or liraglutide alone in DUAL I. In DUAL II, HbA1c reductions were significantly greater with IDegLira (0.9-2.5%) than with IDeg in all but the lowest HbA1c category. In DUAL I, insulin dose and hypoglycaemia rate were lower across all baseline HbA1c categories for IDegLira versus IDeg, while hypoglycaemia was higher with IDegLira than liraglutide, irrespective of baseline HbA1c. In DUAL II, insulin dose and hypoglycaemia rate were similar with IDegLira and IDeg (maximum dose limited to 50U) independent of baseline HbA1c. The reduction in HbA1c with IDegLira was independent of disease duration and previous insulin dose but varied depending on pre-trial OAD treatment.IDegLira effectively lowered HbA1c across a range of measures, implying suitability for patients with either early or advanced T2D.


Brand O.J.,Oxford Center for Diabetes Endocrinology and Metabolism | Gough S.C.L.,Oxford Center for Diabetes Endocrinology and Metabolism
Current Genomics | Year: 2011

The autoimmune thyroid diseases (AITD) include Graves' disease (GD) and Hashimoto's thyroiditis (HT), which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology. 2011 Bentham Science Publishers.


Ballav C.,Oxford Center for Diabetes Endocrinology and Metabolism | Gough S.C.L.,Oxford Center for Diabetes Endocrinology and Metabolism
Clinical Medicine Insights: Endocrinology and Diabetes | Year: 2013

The biguanide, metformin, is considered first-line treatment for type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor acts through the incretin pathway and has a glucose dependent mode of action. The complementary hypoglycemic properties of these drugs make fixed dose combination treatment an attractive prospect. Evidence from recent clinical trials suggests a beneficial effect of the combination on efficacy, demonstrated by significant improvement of hemoglobin A1c (HbA1c), fasting and postprandial glucose levels. The fixed dose combination is likely to have greater patient tolerability compared with monotherapy with either agent because of low rates of hypoglycemia, weight neutrality, and lower rates of side effects. High acquisition cost and paucity of long-term safety data are, however, potential barriers to their wider use. An overview of the pharmacology and clinical outcomes from recent trials of the metformin-sitagliptin combination and how the combination could ft into the type 2 diabetes treatment algorithm is presented in this review. © the author(s), publisher and licensee Libertas Academica Ltd.


PubMed | Oxford Center for Diabetes Endocrinology and Metabolism
Type: Journal Article | Journal: Current genomics | Year: 2012

The autoimmune thyroid diseases (AITD) include Graves disease (GD) and Hashimotos thyroiditis (HT), which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology.

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