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1.  All-Cause and Cardiovascular Mortality in Middle-Aged People With Type 2 Diabetes Compared With People Without Diabetes in a Large U.K. Primary Care Database 
Diabetes Care  2013;36(8):2366-2371.
Middle-aged people with diabetes have been reported to have significantly higher risks of cardiovascular events than people without diabetes. However, recent falls in cardiovascular disease rates and more active management of risk factors may have abolished the increased risk. We aimed to provide an up-to-date assessment of the relative risks associated with type 2 diabetes of all-cause and cardiovascular mortality in middle-aged people in the U.K.
Using data from the General Practice Research Database, from 2004 to 2010, we conducted a cohort study of 87,098 people, 40–65 years of age at baseline, comparing 21,798 with type 2 diabetes and 65,300 without diabetes, matched on age, sex, and general practice. We produced hazard ratios (HRs) for mortality and compared rates of blood pressure testing, cholesterol monitoring, and use of aspirin, statins, and antihypertensive drugs.
People with type 2 diabetes, compared with people without diabetes, had a twofold increased risk of all-cause mortality (HR 2.07 [95% CI 1.95–2.20], adjusted for smoking) and a threefold increased risk of cardiovascular mortality (3.25 [2.87–3.68], adjusted for smoking). Women had a higher relative risk than men, and people <55 years of age had a higher relative risk than those >55 years of age. Monitoring and medication rates were higher in those with diabetes (all P < 0.001).
Despite efforts to manage risk factors, administer effective treatments, and develop new therapies, middle-aged people with type 2 diabetes remain at significantly increased risk of death.
PMCID: PMC3714501  PMID: 23435157
2.  The OxVALVE population cohort study (OxVALVE-PCS)—population screening for undiagnosed valvular heart disease in the elderly: study design and objectives 
Open Heart  2014;1(1):e000043.
Valvular heart disease (VHD) is an increasingly important cardiac condition, driven by an ageing population and lack of progress in the development of medical therapies. There is a dearth of accurate information to guide decision-makers in the development of strategies to combat VHD, and no population-based study has been performed specifically to investigate its contemporary epidemiology. This document describes the design and methodology of the OxVALVE population cohort study (OxVALVE-PCS), which was conceived to address this need.
Methods and analysis
Participants aged 65 years and older attending a participating general practice in Oxfordshire, UK, are invited to attend a screening examination. Exclusion criteria include previously diagnosed VHD, inability to provide consent, terminal illness or excessive frailty. Demographics, a focused cardiovascular history and vital signs are recorded at the initial screening examination, accompanied by an echocardiogram. Any finding of significant VHD triggers a separate, more formal echocardiographic assessment (including acquisition of a three-dimensional dataset) and collection of blood samples for future genetic and biomarker analysis. Participants provide consent for longitudinal follow-up and enrolment in future cohort substudies. We also assess the acceptability of community-based echocardiographic examination and compare self-assessed quality of life between those with and without VHD.
OxVALVE-PCS will provide contemporary epidemiological data concerning the community prevalence of undiagnosed VHD, facilitate accurate deployment of scarce resources to meet the anticipated increase in demand for VHD-associated healthcare and create a series of subcohorts with carefully defined genotypes and echocardiographic phenotypes for long overdue clinical studies.
Ethics and dissemination
This study was approved by the local research ethics committee (Southampton, UK; REC Ref: 09/H0502/58).
Results will be submitted for publication in peer-reviewed scientific journals.
PMCID: PMC4195926  PMID: 25332795
Valvular Disease
3.  Changes in HbA1c Level over a 12-Week Follow-up in Patients with Type 2 Diabetes following a Medication Change 
PLoS ONE  2014;9(3):e92458.
Current guidance about the interval needed before retesting HbA1c when monitoring for glycaemic control is based on expert opinion rather than well-powered studies. The aim of our work was to explore how fast HbA1c changes after a change in glucose-lowering medication. This has implications for whether routine HbA1c testing intervals before 12 weeks could inform diabetes medication adjustments.
This 12-week cohort study recruited patients from 18 general practices in the United Kingdom with non-insulin treated diabetes who were initiating or changing dose of oral glucose-lowering medication. HbA1c was measured at baseline and 2, 4, 8 and 12 weeks after recruitment. HbA1c levels at earlier time intervals were correlated with 12-week HbA1c. A ROC curve analysis was used to identify the 8-week threshold above which medication adjustment may be clinically appropriate.
Ninety-three patients were recruited to the study. Seventy-nine patients with no change in medication and full 12-week follow-up had the following baseline characteristics: mean±standard deviation age of 61.3±10.8 years, 34% were female and diabetes duration of 6.0±4.3 years. Mean HbA1c at baseline, 2, 4, 8 and 12 weeks was 8.7±1.5%, (72.0±16.8 mmol/mol) 8.6±1.6% (70.7±17.0 mmol/mol), 8.4±1.5% (68.7±15.9 mmol/mol), 8.2±1.4% (66.3±15.8 mmol/mol) and 8.1±1.4% (64.8±15.7 mmol/mol) respectively. At the end of the study 61% of patients had sub-optimal glycaemic control (HbA1c>7.5% or 59 mmol/mol). The 8-week change correlated significantly with the 12-week change in HbA1c and an HbA1c above 8.2% (66 mmol/mol) at 8 weeks correctly classified all 28 patients who had not achieved glycaemic control by 12 weeks.
This is the first study designed with sufficient power to examine short-term changes in HbA1c. The 12-week change in HbA1c can be predicted 8 weeks after a medication change. Many participants who had not achieved glycaemic control after 12 weeks may have benefitted from an earlier review of their HbA1c and medication.
PMCID: PMC3965408  PMID: 24667212
4.  Trials to Improve Blood Pressure Through Adherence to Antihypertensives in Stroke/TIA: Systematic Review and Meta‐Analysis 
The purpose of this study was to determine whether interventions including components to improve adherence to antihypertensive medications in patients after stroke/transient ischemic attack (TIA) improve adherence and blood pressure control.
Methods and Results
We searched MEDLINE, EMBASE, CINAHL, BNI, PsycINFO, and article reference lists to October 2012. Search terms included stroke/TIA, adherence/prevention, hypertension, and randomized controlled trial (RCT). Inclusion criteria were participants with stroke/TIA; interventions including a component to improve adherence to antihypertensive medications; and outcomes including blood pressure, antihypertensive adherence, or both. Two reviewers independently assessed studies to determine eligibility, validity, and quality. Seven RCTs were eligible (n=1591). Methodological quality varied. All trials tested multifactorial interventions. None targeted medication adherence alone. Six trials measured blood pressure and 3 adherence. Meta‐analysis of 6 trials showed that multifactorial programs were associated with improved blood pressure control. The difference between intervention versus control in mean improvement in systolic blood pressure was −5.3 mm Hg (95% CI, −10.2 to −0.4 mm Hg, P=0.035; I2=67% [21% to 86%]) and in diastolic blood pressure was −2.5 mm Hg (−5.0 to −0.1 mm Hg, P=0.046; I2=47% [0% to 79%]). There was no effect on medication adherence where measured.
Multifactorial interventions including a component to improve medication adherence can lower blood pressure after stroke/TIA. However, it is not possible to say whether or not this is achieved through better medication adherence. Trials are needed of well‐characterized interventions to improve medication adherence and clinical outcomes with measurement along the hypothesized causal pathway.
PMCID: PMC3828799  PMID: 23963756
blood pressure; hypertension; prevention; stroke
5.  Systematic Assessment of Etiology in Adults With a Clinical Diagnosis of Young-Onset Type 2 Diabetes Is a Successful Strategy for Identifying Maturity-Onset Diabetes of the Young 
Diabetes Care  2012;35(6):1206-1212.
Misdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young adult-onset type 1 and type 2 diabetes by extending genetic testing beyond current guidelines.
Individuals were selected for diagnostic sequencing if they displayed features atypical for their diagnostic label. From 247 case subjects with clinically labeled type 1 diabetes, we sequenced hepatocyte nuclear factor 1 α (HNF1A) and hepatocyte nuclear factor 4 α (HNF4A) in 20 with residual β-cell function ≥3 years from diagnosis (random or glucagon-stimulated C-peptide ≥0.2 nmol/L). From 322 with clinically labeled type 2 diabetes, we sequenced HNF1A and HNF4A in 80 with diabetes diagnosed ≤30 years and/or diabetes diagnosed ≤45 years without metabolic syndrome. We also sequenced the glucokinase (GCK) in 40 subjects with mild fasting hyperglycemia.
In the type 1 diabetic group, two HNF1A mutations were found (0.8% prevalence). In type 2 diabetic subjects, 10 HNF1A, two HNF4A, and one GCK mutation were identified (4.0%). Only 47% of MODY case subjects identified met current guidelines for diagnostic sequencing. Follow-up revealed a further 12 mutation carriers among relatives. Twenty-seven percent of newly identified MODY subjects changed treatment, all with improved glycemic control (HbA1c 8.8 vs. 7.3% at 3 months; P = 0.02).
The systematic use of widened diagnostic testing criteria doubled the numbers of MODY case subjects identified compared with current clinical practice. The yield was greatest in young adult-onset type 2 diabetes. We recommend that all patients diagnosed before age 30 and with presence of C-peptide at 3 years' duration are considered for molecular diagnostic analysis.
PMCID: PMC3357216  PMID: 22432108
6.  Quantifying the Effect of Metformin Treatment and Dose on Glycemic Control 
Diabetes Care  2012;35(2):446-454.
Metformin is the first-line oral medication recommended for glycemic control in patients with type 2 diabetes. We reviewed the literature to quantify the effect of metformin treatment on glycated hemoglobin (HbA1c) levels in all types of diabetes and examine the impact of differing doses on glycemic control.
MEDLINE, EMBASE, and the Cochrane Library were searched from 1950 to June 2010 for trials of at least 12 weeks’ duration in which diabetic patients were treated with either metformin monotherapy or as an add-on therapy. Data on change in HbA1c were pooled in a meta-analysis. Data from dose-comparison trials were separately pooled.
A total of 35 trials were identified for the main analysis and 7 for the dose-comparison analysis. Metformin monotherapy lowered HbA1c by 1.12% (95% CI 0.92–1.32; I2 = 80%) versus placebo, metformin added to oral therapy lowered HbA1c by 0.95% (0.77–1.13; I2 = 77%) versus placebo added to oral therapy, and metformin added to insulin therapy lowered HbA1c by 0.60% (0.30–0.91; I2 = 79.8%) versus insulin only. There was a significantly greater reduction in HbA1c using higher doses of metformin compared with lower doses of metformin with no significant increase in side effects.
Evidence supports the effectiveness of metformin therapy in a clinically important lowering of HbA1c used as monotherapy and in combination with other therapeutic agents. There is potential for using higher doses of metformin to maximize glycemic control in diabetic patients without increasing gastrointestinal effects.
PMCID: PMC3263873  PMID: 22275444
7.  Initiating Insulin as Part of the Treating To Target in Type 2 Diabetes (4-T) Trial 
Diabetes Care  2010;33(10):2178-2180.
To explore patients' and health professionals' experiences of initiating insulin as part of the Treating To Target in Type 2 Diabetes (4-T) randomized controlled trial.
Interviews were conducted with 45 trial participants and 21 health professionals and thematically analyzed.
Patients were generally psychologically insulin receptive when approached to participate in the 4-T trial. Their receptiveness arose largely from their personal experiences observing intensifying prior treatments and deteriorating blood glucose control over time, which led them to engage with and accept the idea that their diabetes was progressive. Health professionals also fostered receptiveness by drawing on their clinical experience to manage patients' anxieties about initiating insulin.
Previous studies may have overemphasized the problem of psychological insulin resistance and overlooked factors and treatment experiences that may promote insulin receptiveness among type 2 patients.
PMCID: PMC2945156  PMID: 20592050
8.  A1C to Detect Diabetes in Healthy Adults 
Diabetes Care  2010;33(9):2016-2017.
To evaluate the optimal interval for rechecking A1C levels below the diagnostic threshold of 6.5% for healthy adults.
This was a retrospective cohort study. Participants were 16,313 apparently healthy Japanese adults not taking glucose-lowering medications at baseline. Annual A1C measures from 2005 to 2008 at the Center for Preventive Medicine, a community teaching hospital in Japan, estimated cumulative incidence of diabetes.
Mean age (±SD) of participants was 49.7 ± 12.3 years, and 53% were male. Mean A1C at baseline was 5.4 ± 0.5%. At 3 years, for those with A1C at baseline of <5.0%, 5.0–5.4%, 5.5–5.9%, and 6.0–6.4%, cumulative incidence (95% CI) was 0.05% (0.001–0.3), 0.05% (0.01–0.11), 1.2% (0.9–1.6), and 20% (18–23), respectively.
In those with an A1C <6.0%, rescreening at intervals shorter than 3 years identifies few individuals (∼≤1%) with an A1C ≥6.5%.
PMCID: PMC2928354  PMID: 20566678
9.  Assessment of High-Sensitivity C-Reactive Protein Levels as Diagnostic Discriminator of Maturity-Onset Diabetes of the Young Due to HNF1A Mutations 
Diabetes Care  2010;33(9):1919-1924.
Despite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY).
Serum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded ∼11% of subjects in whom the single available hs-CRP measurement was >10 mg/l.
Geometric mean (SD range) hs-CRP levels were significantly lower (P ≤ 0.009) for HNF1A-MODY individuals, 0.20 (0.03–1.14) mg/l, than for any other group: autoimmune diabetes 0.58 (0.10–2.75) mg/l, type 2 diabetes 1.33 (0.28–6.14) mg/l, GCK-MODY 1.01 (0.19–5.33) mg/l, and nondiabetic 0.48 (0.10–2.42) mg/l. The ROC-derived C-statistic for discriminating HNF1A-MODY and type 2 diabetes was 0.8. Measurement of hs-CRP, either alone or in combination with current diagnostic criteria, was superior to current diagnostic criteria alone. Sensitivity and specificity for the combined criteria approached 80%.
Serum hs-CRP levels are markedly lower in HNF1A-MODY than in other forms of diabetes. hs-CRP has potential as a widely available, cost-effective screening test to support more precise targeting of MODY diagnostic testing.
PMCID: PMC2928334  PMID: 20724646
10.  Challenges of maintaining research protocol fidelity in a clinical care setting: A qualitative study of the experiences and views of patients and staff participating in a randomized controlled trial 
Trials  2011;12:108.
Trial research has predominantly focused on patient and staff understandings of trial concepts and/or motivations for taking part, rather than why treatment recommendations may or may not be followed during trial delivery. This study sought to understand why there was limited attainment of the glycaemic target (HbA1c ≤6.5%) among patients who participated in the Treating to Target in Type 2 Diabetes Trial (4-T). The objective was to inform interpretation of trial outcomes and provide recommendations for future trial delivery.
In-depth interviews were conducted with 45 patients and 21 health professionals recruited from 11 of 58 trial centres in the UK. Patients were broadly representative of those in the main trial in terms of treatment allocation, demographics and glycaemic control. Both physicians and research nurses were interviewed.
Most patients were committed to taking insulin as recommended by 4-T staff. To avoid hypoglycaemia, patients occasionally altered or skipped insulin doses, normally in consultation with staff. Patients were usually unaware of the trial's glycaemic target. Positive staff feedback could lead patients to believe they had been 'successful' trial participants even when their HbA1c exceeded 6.5%. While some staff felt that the 4-T automated insulin dose adjustment algorithm had increased their confidence to prescribe larger insulin doses than in routine clinical practice, all described situations where they had not followed its recommendations. Staff regarded the application of a 'one size fits all' glycaemic target during the trial as contradicting routine clinical practice where they would tailor treatments to individuals. Staff also expressed concerns that 'tight' glycaemic control might impose an unacceptably high risk of hypoglycaemia, thus compromising trust and safety, especially amongst older patients. To address these concerns, staff tended to adapt the trial protocol to align it with their clinical practices and experiences.
To understand trial findings, foster attainment of endpoints, and promote protocol fidelity, it may be necessary to look beyond individual patient characteristics and experiences. Specifically, the context of trial delivery, the impact of staff involvement, and the difficulties staff may encounter in balancing competing 'clinical' and 'research' roles and responsibilities may need to be considered and addressed.
PMCID: PMC3104488  PMID: 21542916
11.  Evaluation of Serum 1,5 Anhydroglucitol Levels as a Clinical Test to Differentiate Subtypes of Diabetes 
Diabetes Care  2010;33(2):252-257.
Assignment of the correct molecular diagnosis in diabetes is necessary for informed decisions regarding treatment and prognosis. Better clinical markers would facilitate discrimination and prioritization for genetic testing between diabetes subtypes. Serum 1,5 anhydroglucitol (1,5AG) levels were reported to differentiate maturity-onset diabetes of the young due to HNF1A mutations (HNF1A-MODY) from type 2 diabetes, but this requires further validation. We evaluated serum 1,5AG in a range of diabetes subtypes as an adjunct for defining diabetes etiology.
1,5AG was measured in U.K. subjects with: HNF1A-MODY (n = 23), MODY due to glucokinase mutations (GCK-MODY, n = 23), type 1 diabetes (n = 29), latent autoimmune diabetes in adults (LADA, n = 42), and type 2 diabetes (n = 206). Receiver operating characteristic curve analysis was performed to assess discriminative accuracy of 1,5AG for diabetes etiology.
Mean (SD range) 1,5AG levels were: GCK-MODY 13.06 μg/ml (5.74–29.74), HNF1A-MODY 4.23 μg/ml (2.12–8.44), type 1 diabetes 3.09 μg/ml (1.45–6.57), LADA 3.46 μg/ml (1.42–8.45), and type 2 diabetes 5.43 (2.12–13.23). Levels in GCK-MODY were higher than in other groups (P < 10−4 vs. each group). HNF1A-MODY subjects showed no difference in unadjusted 1,5AG levels from type 2 diabetes, type 1 diabetes, and LADA. Adjusting for A1C revealed a difference between HNF1A-MODY and type 2 diabetes (P = 0.001). The discriminative accuracy of unadjusted 1,5AG levels was 0.79 for GCK-MODY versus type 2 diabetes and 0.86 for GCK-MODY versus HNF1A-MODY but was only 0.60 for HNF1A-MODY versus type 2 diabetes.
In our dataset, serum 1,5AG performed well in discriminating GCK-MODY from other diabetes subtypes, particularly HNF1A-MODY. Measurement of 1,5AG levels could inform decisions regarding MODY diagnostic testing.
PMCID: PMC2809258  PMID: 19933992
12.  Protocol for SAMS (Support and Advice for Medication Study): A randomised controlled trial of an intervention to support patients with type 2 diabetes with adherence to medication 
BMC Family Practice  2008;9:20.
Although some interventions have been shown to improve adherence to medication for diabetes, results are not consistent. We have developed a theory-based intervention which we will evaluate in a well characterised population to test efficacy and guide future intervention development and trial design.
Methods and Design
The SAMS (Supported Adherence to Medication Study) trial is a primary care based multi-centre randomised controlled trial among 200 patients with type 2 diabetes and an HbA1c of 7.5% or above. It is designed to evaluate the efficacy of a two-component motivational intervention based on the Theory of Planned Behaviour and volitional action planning to support medication adherence compared with standard care. The intervention is delivered by practice nurses. Nurses were trained using a workshop approach with role play and supervised using assessment of tape-recorded consultations. The trial has a two parallel groups design with an unbalanced three-to-two individual randomisation eight weeks after recruitment with twelve week follow-up. The primary outcome is medication adherence measured using an electronic medication monitor over 12 weeks and expressed as the difference between intervention and control in mean percentage of days on which the correct number of medication doses is taken. Subgroup analyses will explore impact of number of medications taken, age, HbA1c, and self-reported adherence at baseline on outcomes. The study also measures the effect of dispensing medication to trial participants packaged in the electronic medication-monitoring device compared with conventional medication packaging. This will be achieved through one-to-one randomisation at recruitment to these conditions with assessment of the difference between groups in self-report of medication adherence and change in mean HbA1c from baseline to eight weeks. Anonymised demographic data are collected on non-respondents. Central randomisation is carried out independently of trial co-ordination and practices using minimisation to adjust for selected confounders.
The SAMS intervention and trial design address weaknesses of previous research by recruitment from a well-characterised population, definition of a feasible theory based intervention to support medication taking and careful measurement to estimate and interpret efficacy. The results will inform practice and the design of a cost-effectiveness trial [ISRCTN30522359].
PMCID: PMC2364626  PMID: 18405345

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