Jason Oke

Global Prevalence of Chronic Kidney Disease – A Systematic Review and Meta-Analysis

Chronic kidney disease (CKD) is a global health burden with a high economic cost to health systems and is an independent risk factor for cardiovascular disease (CVD). All stages of CKD are associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life. CKD is usually asymptomatic until later stages and accurate prevalence data are lacking. Thus we sought to determine the prevalence of CKD globally, by stage, geographical location, gender and age. A systematic review and meta-analysis of observational studies estimating CKD prevalence in general populations was conducted through literature searches in 8 databases. We assessed pooled data using a random effects model. Of 5,842 potential articles, 100 studies of diverse quality were included, comprising 6,908,440 patients. Global mean(95%CI) CKD prevalence of 5 stages 13·4%(11·7–15·1%), and stages 3–5 was 10·6%(9·2–12·2%). Weighting by study quality did not affect prevalence estimates. CKD prevalence by stage was Stage-1 (eGFR>90+ACR>30): 3·5% (2·8–4·2%); Stage-2 (eGFR 60–89+ACR>30): 3·9% (2·7–5·3%); Stage-3 (eGFR 30–59): 7·6% (6·4–8·9%); Stage-4 = (eGFR 29–15): 0·4% (0·3–0·5%); and Stage-5 (eGFR<15): 0·1% (0·1–0·1%). CKD has a high global prevalence with a consistent estimated global CKD prevalence of between 11 to 13% with the majority stage 3. Future research should evaluate intervention strategies deliverable at scale to delay the progression of CKD and improve CVD outcomes.

Meta-analysis of individual patient data in randomised trials of self monitoring of blood glucose in people with non-insulin treated type 2 diabetes

Objective To assess the effectiveness of self monitoring blood glucose levels in people with non-insulin treated type 2 diabetes compared with clinical management without self monitoring, and to explore the effects in specific patient groups. Design Meta-analysis based on individual participant data. Data sources Medline, Embase, and a recent systematic review of trials on self monitoring of blood glucose. Chief investigators of trials published since 2000 were approached for additional information and individual patient data. Inclusion criteria Randomised controlled trials in patients with non-insulin treated type 2 diabetes comparing an intervention using self monitoring of blood glucose with clinical management not using self monitoring. Trials published from 2000 with at least 80 participants were included. Data collection Individual patient data were collected from electronic files and checked for integrity. Analysis All randomised participants were analysed using the intention to treat principle. A random effects model of complete cases was used to assess efficacy, a sensitivity analysis comprised imputed data, and prespecified subgroup analyses were carried out for age, sex, previous use of self monitoring, duration of diabetes, and levels of glycated haemoglobin (HbA1c) at baseline. Results 2552 patients were randomised in the six included trials. A mean reduction in HbA1c level of −2.7 mmol/mol (95% confidence interval −3.9 to −1.6; 0.25%) was observed for those using self monitoring of blood glucose levels compared with no self monitoring at six months. The mean reduction in HbA1c level between groups was 2.0 mmol/mol (3.2 to 0.8; 0.25%) at three months (five trials) and 2.5 mmol/mol (4.1 to 0.9; 0.35%) at 12 months (three trials). These estimates were unchanged after imputing missing data, and estimates of effect in trials with higher loss to follow-up or a possibility of co-intervention compared with those with lower loss to follow-up and no co-intervention did not differ significantly (P=0.21). The difference in HbA1c levels between groups was consistent across age, baseline HbA1c level, sex, and duration of diabetes, although the numbers of older and younger people and those with HbA1c levels >86 mmol/mol (10%) were insufficient for interpretation. No changes occurred in systolic blood pressure (−0.2 mm Hg, 95% confidence interval −1.4 to 1.0), diastolic blood pressure (−0.1 mm Hg, −0.9 to 0.6), or total cholesterol level (−0.1 mol/L, 95% confidence interval −0.2 to 0.1). Conclusions Evidence from this meta-analysis of individual patient data was not convincing for a clinically meaningful effect of clinical management of non-insulin treated type 2 diabetes by self monitoring of blood glucose levels compared with management without self monitoring, although the difference in HbA1c level between groups was statistically significant. The difference in levels was consistent across subgroups defined by personal and clinical characteristics.

Efficacy and effectiveness of screen and treat policies in prevention of type 2 diabetes: systematic review and meta-analysis of screening tests and interventions

Objectives To assess diagnostic accuracy of screening tests for pre-diabetes and efficacy of interventions (lifestyle or metformin) in preventing onset of type 2 diabetes in people with pre-diabetes. Design Systematic review and meta-analysis. Data sources and method Medline, PreMedline, and Embase. Study protocols and seminal papers were citation-tracked in Google Scholar to identify definitive trials and additional publications. Data on study design, methods, and findings were extracted onto Excel spreadsheets; a 20% sample was checked by a second researcher. Data extracted for screening tests included diagnostic accuracy and population prevalence. Two meta-analyses were performed, one summarising accuracy of screening tests (with the oral glucose tolerance test as the standard) for identification of pre-diabetes, and the other assessing relative risk of progression to type 2 diabetes after either lifestyle intervention or treatment with metformin. Eligibility criteria Empirical studies evaluating accuracy of tests for identification of pre-diabetes. Interventions (randomised trials and interventional studies) with a control group in people identified through screening. No language restrictions. Results 2874 titles were scanned and 148 papers (covering 138 studies) reviewed in full. The final analysis included 49 studies of screening tests (five of which were prevalence studies) and 50 intervention trials. HbA1c had a mean sensitivity of 0.49 (95% confidence interval 0.40 to 0.58) and specificity of 0.79 (0.73 to 0.84), for identification of pre-diabetes, though different studies used different cut-off values. Fasting plasma glucose had a mean sensitivity of 0.25 (0.19 to 0.32) and specificity of 0.94 (0.92 to 0.96). Different measures of glycaemic abnormality identified different subpopulations (for example, 47%of people with abnormal HbA1c had no other glycaemic abnormality). Lifestyle interventions were associated with a 36% (28% to 43%) reduction in relative risk of type 2 diabetes over six months to six years, attenuating to 20% (8% to 31%) at follow-up in the period after the trails. Conclusions HbA1c is neither sensitive nor specific for detecting pre-diabetes; fasting glucose is specific but not sensitive. Interventions in people classified through screening as having pre-diabetes have some efficacy in preventing or delaying onset of type 2 diabetes in trial populations. As screening is inaccurate, many people will receives an incorrect diagnosis and be referred on for interventions while others will be falsely reassured and not offered the intervention. These findings suggest that “screen and treat” policies alone are unlikely to have substantial impact on the worsening epidemic of type 2 diabetes. Registration PROSPERO (No CRD42016042920).

An explanatory randomised controlled trial of a nurse-led, consultation-based intervention to support patients with adherence to taking glucose lowering medication for type 2 diabetes

BackgroundFailure to take medication reduces the effectiveness of treatment leading to increased morbidity and mortality. We evaluated the efficacy of a consultation-based intervention to support objectively-assessed adherence to oral glucose lowering medication (OGLM) compared to usual care among people with type 2 diabetes.MethodsThis was a parallel group randomised trial in adult patients with type 2 diabetes and HbA1c≥7.5% (58 mmol/mol), prescribed at least one OGLM. Participants were allocated to a clinic nurse delivered, innovative consultation-based intervention to strengthen patient motivation to take OGLM regularly and support medicine taking through action-plans, or to usual care. The primary outcome was the percentage of days on which the prescribed dose of medication was taken, measured objectively over 12 weeks with an electronic medication-monitoring device (TrackCap, Aardex, Switzerland). The primary analysis was intention-to-treat.Results211 patients were randomised between July 1, 2006 and November 30, 2008 in 13 British general practices (primary care clinics). Primary outcome data were available for 194 participants (91.9%). Mean (sd) percentage of adherent days was 77.4% (26.3) in the intervention group and 69.0% (30.8) in standard care (mean difference between groups 8.4%, 95% confidence interval 0.2% to 16.7%, p = 0.044). There was no significant adverse impact on functional status or treatment satisfaction.ConclusionsThis well-specified, theory based intervention delivered in a single session of 30 min in primary care increased objectively measured medication adherence, with no adverse effect on treatment satisfaction. These findings justify a definitive trial of this approach to improving medication adherence over a longer period of time, with clinical and cost-effectiveness outcomes to inform clinical practice.Trial registrationCurrent Controlled Trials ISRCTN30522359

Optimal strategies for identifying kidney disease in diabetes: Properties of screening tests, progression of renal dysfunction and impact of treatment - Systematic review and modelling of progression and cost-effectiveness

BACKGROUND Annual screening for adults with type 2 diabetes to detect the early onset of kidney disease is widely recommended, but the recommendations are based on a limited methodological approach. In addition, there are continuing uncertainties about underlying rates of progression of the condition and the benefits of treatments with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. OBJECTIVES We aimed to estimate the clinical value and cost-effectiveness of different screening intervals to diagnose early diabetic kidney disease. DATA SOURCES We used the following databases for the literature review (searched January 2005 to August 2010): MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews. Individual patient data were obtained from the Oxford Regional Prospective Diabetes Study and the Collaborative Atorvastatin Diabetes Study. METHODS Data from systematically identified randomised trials reporting the impact on renal outcomes of angiotensin-converting enzyme inhibitors and angiotensin 2 receptor blockers for type 1 and type 2 diabetes patients with normoalbuminuria and microalbuminuria were pooled to derive estimates of effect. Individual patient data for type 1 and type 2 diabetes patients were used to obtain parameters describing progression and variability of measurement over time for the albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate. Based on accepted diagnostic thresholds, we modelled whether these tests accurately identified patients who were developing early diabetic kidney disease and required intensification of treatment. Cost-effectiveness analyses were carried out using simulation outcome models to estimate the incremental costs per quality-adjusted life-year (QALY) for different screening intervals. RESULTS In total, 49 trials (n = 34,082 patients) were eligible for inclusion in the systematic review. For type 1 diabetes, pooled estimates of urinary albumin excretion (UAE) for treated patients with microalbuminuria were on average 67% [95% confidence interval (CI) 54% to 77%] lower at the end of the trial than for untreated patients. There was no significant treatment effect for patients with normoalbuminuria (p interaction = 0.006). For treated patients with type 2 diabetes and normoalbuminuria or microalbuminuria, UAE was lower by, on average, 21% (95% CI 97% to 32%) or 27% (95% CI 15% to 38%), respectively. The proportion (95% CI) of men and women with type 1 diabetes screened annually for microalbuminuria over 6 years and inaccurately identified as having microalbuminuria would be 48% (43% to 53%) and 55% (48% to 61%), respectively. The corresponding proportions for type 2 diabetes are 36% (32% to 42%) and 48% (41% to 55%). Decreasing the screening interval to 3-yearly would reduce this for men with type 1 diabetes to 38% (33% to 44%), with an increase in those not identified over 6 years from 1.5% (95% CI 1% to 2%) to 4% (95% CI 3% to 5%). For type 1 diabetes, incremental cost per QALY [standard deviation (SD)] of a 5-yearly compared with a 4-yearly screening interval was £3612 (£6586), increasing to £9601 (£34,112) for annual compared with 2-yearly screening. The probability that the intervention is cost saving is around 25%, and it has around an 80% chance of being below a cost-effectiveness threshold of £30,000. For type 2 diabetes, incremental cost per QALY (SD) of a yearly compared with a 2-yearly screening interval was £606 (£1782). The intervention is almost certainly below a cost-effectiveness threshold of £5000. CONCLUSIONS These results support current UK guidance, which recommends annual screening with ACR to identify early kidney disease in patients with diabetes, despite a high false-positive rate leading to, at worst, unnecessary or, at best, early therapeutic intervention. For type 1 diabetes, screening costs for annual compared with 2-yearly screening are well within the bounds of accepted cost-effectiveness. Annual screening is even more cost-effective in type 2 diabetes than in type 1 diabetes. Identification of alternative markers for developing diabetic nephropathy may improve targeting of treatment for those at high risk. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Development of a cost-effectiveness model for optimisation of the screening interval in diabetic retinopathy screening.

BACKGROUND The English NHS Diabetic Eye Screening Programme was established in 2003. Eligible people are invited annually for digital retinal photography screening. Those found to have potentially sight-threatening diabetic retinopathy (STDR) are referred to surveillance clinics or to Hospital Eye Services. OBJECTIVES To determine whether personalised screening intervals are cost-effective. DESIGN Risk factors were identified in Gloucestershire, UK using survival modelling. A probabilistic decision hidden (unobserved) Markov model with a misgrading matrix was developed. This informed estimation of lifetime costs and quality-adjusted life-years (QALYs) in patients without STDR. Two personalised risk stratification models were employed: two screening episodes (SEs) (low, medium or high risk) or one SE with clinical information (low, medium-low, medium-high or high risk). The risk factor models were validated in other populations. SETTING Gloucestershire, Nottinghamshire, South London and East Anglia (all UK). PARTICIPANTS People with diabetes in Gloucestershire with risk stratification model validation using data from Nottinghamshire, South London and East Anglia. MAIN OUTCOME MEASURES Personalised risk-based algorithm for screening interval; cost-effectiveness of different screening intervals. RESULTS Data were obtained in Gloucestershire from 12,790 people with diabetes with known risk factors to derive the risk estimation models, from 15,877 people to inform the uptake of screening and from 17,043 people to inform the health-care resource-usage costs. Two stratification models were developed: one using only results from previous screening events and one using previous screening and some commonly available GP data. Both models were capable of differentiating groups at low and high risk of development of STDR. The rate of progression to STDR was 5 per 1000 person-years (PYs) in the lowest decile of risk and 75 per 1000 PYs in the highest decile. In the absence of personalised risk stratification, the most cost-effective screening interval was to screen all patients every 3 years, with a 46% probability of this being cost-effective at a £30,000 per QALY threshold. Using either risk stratification models, screening patients at low risk every 5 years was the most cost-effective option, with a probability of 99-100% at a £30,000 per QALY threshold. For the medium-risk groups screening every 3 years had a probability of 43-48% while screening high-risk groups every 2 years was cost-effective with a probability of 55-59%. CONCLUSIONS The study found that annual screening of all patients for STDR was not cost-effective. Screening this entire cohort every 3 years was most likely to be cost-effective. When personalised intervals are applied, screening those in our low-risk groups every 5 years was found to be cost-effective. Screening high-risk groups every 2 years further improved the cost-effectiveness of the programme. There was considerable uncertainty in the estimated incremental costs and in the incremental QALYs, particularly with regard to implications of an increasing proportion of maculopathy cases receiving intravitreal injection rather than laser treatment. Future work should focus on improving the understanding of risk, validating in further populations and investigating quality issues in imaging and assessment including the potential for automated image grading. STUDY REGISTRATION Integrated Research Application System project number 118959. FUNDING DETAILS The National Institute for Health Research Health Technology Assessment programme.

Statistical models for the control phase of clinical monitoring.

The rise in the prevalence of chronic conditions means that these are now the leading causes of death and disability worldwide, accounting for almost 60% of all deaths and 43% of the global burden of disease. Management of chronic conditions requires both effective treatment and ongoing monitoring. Although costs related to monitoring are substantial, there is relatively little evidence on its effectiveness. Monitoring is inherently different to diagnosis in its use of regularly repeated tests, and increasing frequency can result in poorer rather than better statistical properties because of multiple testing in the presence of high variability. We present here a general framework for modelling the control phase of a monitoring programme, and for the estimation of quantities of potential clinical interest such as the ratio of false to true positive tests. We show how four recent clinical studies of monitoring cardiovascular disease, hypertension, diabetes and HIV infection can be thought as special cases of this framework; as well as using this framework to clarify the choice of estimation and calculation methods available. Noticeably, in each of the presented examples over-frequent monitoring appears to be a greater problem than under-frequent monitoring. We also present recalculations of results under alternative conditions, illustrating conceptual decisions about modelling the true or observed value of a clinical measure.

People’s willingness to accept overdetection in cancer screening: population survey

Objectives To describe the level of overdetection people would find acceptable in screening for breast, prostate, and bowel cancer and whether acceptability is influenced by the magnitude of the benefit from screening and the cancer specific harms from overdetection. Design Online survey. Women were presented with scenarios on breast and bowel cancer, men with scenarios on prostate and bowel cancer. For each particular cancer, we presented epidemiological information and described the treatment and its consequences. Secondly, we presented two different scenarios of benefit: one indicating a 10% reduction in cancer specific mortality and the second indicating a 50% reduction. Setting Online survey of the population in the United Kingdom. Participants Respondents were part of an existing panel of people who volunteer for online research and were invited by email or online marketing. We recruited 1000 respondents, representative for age and sex for the UK population. Main outcome measures Number of cases of overdetection people were willing to accept, ranging from 0-1000 (complete screened population) for each cancer modality and each scenario of benefit. Results There was large variability between respondents in the level of overdetection they would find acceptable, with medians ranging from 113 to 313 cases of overdetection per 1000 people screened. Across all scenarios, 4-7% of respondents indicated they would accept no overdetection at all compared with 7-14% who thought that it would be acceptable for the entire screened population to be overdetected. Acceptability in screening for bowel cancer was significantly lower than for breast and prostate cancer. People aged 50 or over accepted significantly less overdetection, whereas people with higher education levels accepted more; 29% of respondents had heard of overdetection before. Conclusions Acceptability of overdetection in cancer screening is variable. Invitations for screening should include clear information on the likelihood and consequences of overdetection to allow people to make an informed choice.

Establishing an evidence base for frequency of monitoring glycated haemoglobin levels in patients with Type 2 diabetes: projections of effectiveness from a regression model.

Diabet. Med. 29, 266–271 (2012)

Differences in insulin treatment satisfaction following randomized addition of biphasic, prandial or basal insulin to oral therapy in type 2 diabetes

Aim: No differences in patient health status as measured by the EuroQol‐5 Dimension (EQ‐5D) questionnaire were observed at 1 year between groups randomized to addition of biphasic, prandial or basal insulin to oral therapy in the treat‐to‐target in type 2 diabetes trial. We further investigated insulin treatment satisfaction between groups.