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Chowdhury T.A.,The Royal London Hospital | Grant P.,Oxford Center for Diabetes
Clinical medicine (London, England) | Year: 2016

Optimal management of diabetes involves a multidisciplinary approach. Prioritisation of lifestyle change, blood pressure and lipid control, and regular screening for complications are advocated in most international guidelines. Good glucose control, however, remains an important aim of treatment, although it is increasingly recognised that glucose targets should be individualised, with less stringent targets for older patients with significant comorbidities.In recent years, a number of newer therapies for hyperglycaemia have become available. This review aims to discuss currently available options for patients with type 2 diabetes, and also discusses potential new therapies that may be on the horizon in the future. © Royal College of Physicians 2016. All rights reserved.


Gough S.C.L.,Oxford Center for Diabetes | Kiljanski J.,Eli Lilly and Company | Heinemann L.,Science and Co
Diabetes, Obesity and Metabolism | Year: 2015

Biosimilar insulins are likely to enter clinical practice in Europe in the near future. It is important that clinicians are familiar with and understand the concept of biosimilarity and how a biosimilar drug may differ from its reference product. The present article provides an overview of biosimilars, the European regulatory requirements for biosimilars and safety issues. It also summarizes the current biosimilars approved in Europe and the key clinical issues associated with the use of biosimilar insulins. © 2014 The Authors.


Yang J.,Queensland Institute of Medical Research | Yang J.,University of Queensland | Ferreira T.,University of Oxford | Morris A.P.,University of Oxford | And 17 more authors.
Nature Genetics | Year: 2012

We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium. © 2012 Nature America, Inc. All rights reserved.


Zoungas S.,George Institute for Global Health | Zoungas S.,University of Sydney | Chalmers J.,George Institute for Global Health | Neal B.,George Institute for Global Health | And 26 more authors.
New England Journal of Medicine | Year: 2014

Background In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up.Methods We invited surviving participants, who had previously been assigned to perindopril- indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events.Results The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P = 0.03) and 0.88 (95% CI, 0.77 to 0.99; P = 0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucosecontrol group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.Conclusions The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. Copyright © 2014 Massachusetts Medical Society. All rights reserved.


Yashiro H.,Takeda Pharmaceutical | Yashiro H.,Oxford Center for Diabetes | Tsujihata Y.,Takeda Pharmaceutical | Tsujihata Y.,Oxford Center for Diabetes | And 4 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2012

G protein-coupled receptor 40 (GPR40)/free fatty acid 1 (FFA1) is a G protein-coupled receptor involved in free fatty acid-induced insulin secretion. To analyze the effect of our novel GPR40/FFA1-selective agonist, [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl) propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875), on insulin and glucagon secretion, we performed hormone secretion assays and measured intracellular Ca 2+ concentration ([Ca 2+] i) in both human and rat islets. Insulin and glucagon secretion were measured in static and dynamic conditions by using groups of isolated rat and human pancreatic islets. [Ca 2+] i was recorded by using confocal microscopy. GPR40/FFA1 expression was measured by quantitative polymerase chain reaction. In both human and rat islets, TAK-875 enhanced glucose-induced insulin secretion in a glucose-dependent manner. The stimulatory effect of TAK-875 was similar to that produced by glucagon-like peptide-1 and correlated with the elevation of β-cell [Ca 2+] i. TAK-875 was without effect on glucagon secretion at both 1 and 16 mM glucose in human islets. These data indicate that GPR40/FFA1 influences mainly insulin secretion in a glucose-dependent manner. The β-cell-specific action of TAK-875 in human islets may represent a therapeutically useful feature that allows plasma glucose control without compromising counter-regulation of glucagon secretion, thus minimizing the risk of hypoglycemia. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.


Gough S.C.L.,Oxford Center for Diabetes | Harris S.,University of Western Ontario | Woo V.,University of Manitoba | Davies M.,University of Leicester
Diabetes, Obesity and Metabolism | Year: 2013

All the basal insulin products currently available have suboptimal pharmacokinetic (PK) properties, with none reliably providing a reproducible and peakless pharmacodynamic (PD) effect that endures over 24 h from once-daily dosing. Insulin degludec is a novel acylated basal insulin with a unique mechanism of protracted absorption involving the formation of a depot of soluble multihexamer chains after subcutaneous injection. PK/PD studies show that insulin degludec has a very long duration of action, with a half-life exceeding 25 h. Once-daily dosing produces a steady-state profile characterized by a near-constant effect, which varies little from injection to injection in a given patient. Clinically, insulin degludec has been shown consistently to carry a lower risk of nocturnal hypoglycaemia than once-daily insulin glargine, in both basal+bolus and basal-only insulin regimens. The constancy of the steady-state profile of insulin degludec also means that day-to-day irregularities at the time of injection have relatively little PD influence, thereby offering the possibility of greater treatment flexibility for patients. © 2012 Blackwell Publishing Ltd.


Sorli C.,Billings Clinic Research Center | Warren M.,Physicians East | Oyer D.,Northwestern University | Mersebach H.,Novo Nordisk AS | And 2 more authors.
Drugs and Aging | Year: 2013

Background and Objective Elderly patients with diabetes are more vulnerable to the occurrence and effects of hypoglycaemia; therefore, treatments with low risk of hypoglycaemia are preferred in this population. This study aimed to compare hypoglycaemia rates between insulin degludec (IDeg) and insulin glargine (IGlar) in elderly patients. Methods Hypoglycaemia data from patients ≥65 years of age with type 1 (T1DM) or type 2 (T2DM) diabetes from seven randomised, treat-to-target phase IIIa trials were used to compare IDeg and IGlar in a pre-planned metaanalysis. Overall, 917/4345 (21 %) randomised patients in the seven trials were elderly (634 IDeg, 283 IGlar). Overall confirmed hypoglycaemia was defined as<3.1 mmol/L or severe hypoglycaemia (symptoms requiring external assistance). Nocturnal hypoglycaemia included confirmed episodes from 0001 to 0559 hours (inclusive). Treatment comparisons of hypoglycaemia in T1DM patients were not performed due to low numbers of elderly patients with T1DM randomised (43 IDeg, 18 IGlar); statistical comparisons were also not made for severe hypoglycaemia due to the low number of events. Results In elderly patients with T2DM, the rate of overall confirmed hypoglycaemia was significantly lower with IDeg than IGlar [estimated rate ratio (ERR) 0.76 (0.61; 0.95)95 % CI]; nocturnal confirmed hypoglycaemia was also significantly lower with IDeg [ERR 0.64 (0.43; 0.95)95 % CI]. Confirmed hypoglycaemia occurred in the majority of T1DM patients, whereas severe episodes occurred infrequently and at similar rates in both treatment groups in T1DM and T2DM. Conclusion Results of this pre-planned meta-analysis in elderly patients with diabetes demonstrate a significant reduction in hypoglycaemic events with IDeg relative to IGlar ©Springer International Publishing Switzerland 2013.


Gough S.C.L.,Oxford Center for Diabetes
Diabetes, Obesity and Metabolism | Year: 2012

Liraglutide, a once-daily glucagon-like peptide-1 receptor agonist, is approved for use as monotherapy in the USA and Japan (but not in Europe or Canada) and in combination with selected oral agents (all regions) for the treatment of patients with type 2 diabetes. Guidance from local advisory bodies is emerging on the most appropriate place for liraglutide in the treatment pathway. It is apparent from its phase 3 clinical trial programme that liraglutide provides superior glycaemic control compared with that achieved with other antidiabetic agents used early in the treatment pathway (e.g. glimepiride and sitagliptin). Key additional benefits include a low incidence of hypoglycaemia and clinically relevant weight loss, although these benefits may be ameliorated by concomitant sulphonylurea (SU) treatment and, in the case of hypoglycaemia, reduction of the SU dose may be necessary. Overall, the profile of liraglutide is similar and, in some aspects, superior to twice-daily exenatide. The implementation of liraglutide therapy is straightforward, with simple dose titration from the starting dose of 0.6 to 1.2 mg/day after 1 week; some patients may benefit from additional titration to 1.8 mg/day. Treatment is self-administered by subcutaneous injection. This contrasts with other agents used early in the treatment pathway, but clinical data suggest patients' overall treatment satisfaction with liraglutide is similar (1.2 mg) or better (1.8 mg) than that with sitagliptin despite differing administration methods. Some patients may experience nausea when initiating liraglutide treatment, but the titration regimen is designed to improve tolerability and clinical data indicate nausea is transient. © 2012 Blackwell Publishing Ltd.


Gough S.C.L.,Oxford Center for Diabetes | Bhargava A.,Iowa Diabetes and Endocrinology Center | Jain R.,Aurora Advanced Healthcare | Mersebach H.,Novo Nordisk AS | And 2 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-The 200 units/mL formulation of insulin degludec (IDeg 200 units/mL) contains equal units of insulin in half the volume compared with the 100 units/mL formulation. We compared the efficacy and safety of IDeg 200 units/mL once daily with 100 units/mL insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS-In this 26-week, open-label, treat-to-target trial, subjects (n = 457;mean HbA1c 8.3% [67 mmol/mol], BMI 32.4 kg/m2, and fasting plasma glucose [FPG] 9.6mmol/L [173.2mg/dL]) were randomized to IDeg 200 units/mL or IGlar, both given once daily in combination with metformin with or without a dipeptidyl peptidase-4 inhibitor. Basal insulin was initiated at 10 units/day and titrated weekly to an FPG target of <5 mmol/L (<90 mg/dL) according to mean prebreakfast self-measured blood glucose values from the preceding 3 days. RESULTS-By 26 weeks, IDeg reduced HbA1c by 1.30% and was not inferior to IGlar. Mean observed FPG reductions were significantly greater with IDeg than IGlar (-3.7 vs. -3.4 mmol/L [-67 vs. -61 mg/dL]; estimated treatment difference: -0.42 [95% CI -0.78 to -0.06], P = 0.02). Despite this difference, rates of overall confirmed hypoglycemia were not higher with IDeg than with IGlar (1.22 and 1.42 episodes/patient-year, respectively), as were rates of nocturnal confirmed hypoglycemia (0.18 and 0.28 episodes/patient-year, respectively). Mean daily basal insulin dose was significantly lower by 11% with IDeg 200 units/mL compared with IGlar. IDeg was well-tolerated, and the rate of treatment-emergent adverse events was similar across groups. CONCLUSIONS-In this treat-to-target trial in insulin-naïve patients with T2DM, IDeg 200 units/mL improved glycemic control similarly to IGlar with a low risk of hypoglycemia. © 2013 by the American Diabetes Association.


Pal A.,Oxford Center for Diabetes | Mccarthy M.I.,Oxford Center for Diabetes | Mccarthy M.I.,University of Oxford | Mccarthy M.I.,Oxford Biomedical Research Center
Clinical Genetics | Year: 2013

The increasing worldwide prevalence of type 2 diabetes (T2D) motivates efforts to use genetics to define key pathways involved in disease predisposition, and thereby to improve management of the disease. Research over the past 5years has taken the total number of genetic loci implicated in T2D susceptibility beyond 60, and the emphasis is now shifting to the translation of these genetic insights into clinical value. Clinical translation may flow from the identification of novel therapeutic targets, but opportunities also exist with respect to individual prediction, diagnostic biomarkers and therapeutic optimization. To date, the main clinical impact has been seen for relatively rare, monogenic forms of diabetes rather than common T2D. However, the advent of high throughput sequencing approaches may herald discovery of rare and low frequency variants that offer greater translational potential. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

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