John P. New

Type 2 Diabetes Whole-Genome Association Study in Four Populations: The DiaGen Consortium

Type 2 diabetes (T2D) is a common, polygenic chronic disease with high heritability. The purpose of this whole-genome association study was to discover novel T2D-associated genes. We genotyped 500 familial cases and 497 controls with >300,000 HapMap-derived tagging single-nucleotide-polymorphism (SNP) markers. When a stringent statistical correction for multiple testing was used, the only significant SNP was at TCF7L2, which has already been discovered and confirmed as a T2D-susceptibility gene. For a replication study, we selected 10 SNPs in six chromosomal regions with the strongest association (singly or as part of a haplotype) for retesting in an independent case-control set including 2,573 T2D cases and 2,776 controls. The most significant replicated result was found at the AHI1-LOC441171 gene region.

Serum phosphate and mortality in patients with chronic kidney disease

BACKGROUND AND OBJECTIVES Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets. RESULTS Mean (SD) eGFR was 32 (15) ml/min per 1.73 m(2), age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality. CONCLUSIONS In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.

Assessing the prevalence, monitoring and management of chronic kidney disease in patients with diabetes compared with those without diabetes in general practice.

Aims  To compare rates of chronic kidney disease (CKD) in patients with diabetes and management of risk factors compared with people without diabetes using general practice computer records, and to assess the utility of serum creatinine and albuminuria as markers of impaired renal function.

Predictors of remission of type 2 diabetes mellitus after laparoscopic gastric banding and bypass

BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with obesity and results in considerable morbidity and mortality. Our objectives were to evaluate the effect of laparoscopic bariatric surgery on the control of T2DM in morbidly obese patients in a U.K. population and to determine the predictors of T2DM remission after bariatric surgery. The study was performed at teaching university hospitals and affiliated private hospitals. METHODS Of 487 patients who underwent laparoscopic bariatric procedures from 2002 to 2007, 74 patients (15.2%) had established T2DM. The results are presented as the mean values. Multivariate analysis was used to identify the factors predictive of remission of T2DM after bariatric surgery. RESULTS The body mass index before laparoscopic gastric bypass (LGB; n = 48) and laparoscopic adjustable gastric banding (LAGB; n = 26) were comparable (52 versus 51 kg/m(2), P = .508). At a mean follow-up of 16.9 months, 41% had remission and 59% had experienced improvement in T2DM. Although the duration of follow-up was significantly longer for the patients who had undergone LAGB than for those who had undergone LGB (23 versus 13.4 months, P = .001), the percentage of excess weight loss (%EWL) was significantly greater after LGB than after LAGB (59.4% versus 48.8%, P = .031), with an associated greater remission rate of T2DM (50% versus 24%, P = .034). Multivariate analysis revealed a greater %EWL and younger age to be independent predictors of postoperative remission of T2DM, and LGB, longer follow-up, and female gender were independent predictors of a greater %EWL. CONCLUSION The %EWL was the only predictor of remission of T2DM that was influenced by the choice of bariatric procedure. In our study, LGB offered greater weight loss and a chance of remission of T2DM compared with LAGB and within 2 years of surgery.

Effectiveness of Fluticasone Furoate–Vilanterol for COPD in Clinical Practice

BACKGROUND Evidence for the management of chronic obstructive pulmonary disease (COPD) comes from closely monitored efficacy trials involving groups of patients who were selected on the basis of restricted entry criteria. There is a need for randomized trials to be conducted in conditions that are closer to usual clinical practice. METHODS In a controlled effectiveness trial conducted in 75 general practices, we randomly assigned 2799 patients with COPD to a once-daily inhaled combination of fluticasone furoate at a dose of 100 μg and vilanterol at a dose of 25 μg (the fluticasone furoate-vilanterol group) or to usual care (the usual-care group). The primary outcome was the rate of moderate or severe exacerbations among patients who had had an exacerbation within 1 year before the trial. Secondary outcomes were the rates of primary care contact (contact with a general practitioner, nurse, or other health care professional) and secondary care contact (inpatient admission, outpatient visit with a specialist, or visit to the emergency department), modification of the initial trial treatment for COPD, and the rate of exacerbations among patients who had had an exacerbation within 3 years before the trial, as assessed in a time-to-event analysis. RESULTS The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group. The numbers of other serious adverse events were similar in the two groups. CONCLUSIONS In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events. (Funded by GlaxoSmithKline; Salford Lung Study ClinicalTrials.gov number, NCT01551758 .).

The high prevalence of unrecognized anaemia in patients with diabetes and chronic kidney disease: a population-based study.

Background  Anaemia occurs early in the course of diabetes‐related chronic kidney disease (CKD). There is little evidence about the prevalence of anaemia in people with diabetes. The aim of this study was to assess the prevalence of anaemia, by stage of CKD, in the general diabetic population.

Factors Associated With Kidney Disease Progression and Mortality in a Referred CKD Population

BACKGROUND Knowing how kidney disease progresses is important for decision making in patients with chronic kidney disease (CKD) and for designing clinical services. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS We examined renal function trajectories in CRISIS (Chronic Renal Insufficiency Standards Implementation Study), in which 1,325 patients with CKD stages 3-5 and mean age of 65.1 years were followed up prospectively for a median of 26 months after referral to a regional nephrology center in the United Kingdom. By protocol, estimated glomerular filtration rate was determined every 12 months. PREDICTORS CKD stage defined as estimated glomerular filtration rate ≥ 45 (stage 3a), 30-44 (3b), 15-29 (4), and < 15 (5) mL/min/1.73 m². OUTCOMES Onset of renal replacement therapy (RRT), death, the composite end point of RRT or death, or decreasing CKD stage. RESULTS During a median follow-up of 26 months, 13% reached the end point of RRT (5.1 events/100 patient-years), 20% died (9.6 deaths/100 patient-years), and 33% reached the combined end point of RRT or death (14.7 events/100 patient-years). For stage 3a, baseline prevalence and annual probabilities of decreasing CKD stage, RRT, and death were 18.0%, 0.41, 0.01, and 0.02, respectively. Corresponding values for stage 3b were 32.5%, 0.22, < 0.01, and 0.06; for stage 4, 36.5%, 0.17, 0.03, and 0.10; and for stage 5, 13.2%, zero (by definition), 0.31, and 0.08, respectively. Markov model projections suggested a steady decrease for proportions with stages 3a, 3b, and 4; a steady increase for death and RRT; and a biphasic pattern for (non-RRT) stage 5, with a plateau in the first 2 years followed by a steady decrease. LIMITATIONS Single-center observational study. CONCLUSION This study suggests that death and RRT are the dominant outcomes in patients referred for management of CKD and that most patients spend comparatively little time in late stages without RRT.

Obtaining real-world evidence: the Salford Lung Study.

We need to assess clinical treatments in real-life settings outside of randomised controlled trials (RCTs). Pragmatic RCT (pRCT) data can supplement RCTs by providing effectiveness information to support healthcare decisions. Electronic health records can facilitate concurrent safety monitoring and data collection without direct patient contact for large randomised study populations in pRCTs. The Salford Lung Study is the worlds first phase III pRCT in asthma and chronic obstructive pulmonary disease (COPD), which aims to randomise over 7000 patients. This paper describes the hurdles overcome and the enormous effort and resource required to establish this comparative effectiveness study of a prelicence intervention. GlaxoSmithKline protocol HZC115151 Asthma study clinicaltrials.gov registration NCT01706198 COPD study clinicaltrials.gov registration NCT01551758

The use of eGFR and ACR to predict decline in renal function in people with diabetes

BACKGROUND There have been few attempts to estimate progression of kidney disease in people with diabetes in a single large population with predictive modelling. The aim of this study was to investigate the rate of progression of chronic kidney disease in people with diabetes according to their estimated glomerular filtration rate (eGFR) and presence of albuminuria. METHODS Data were collected on all people with diabetes in Salford, UK, where an eGFR could be calculated using the four-variable MDRD formula and urinary albumin-creatinine ratio (uACR) was available. All data between 2001 and 2007 were used in the model. Classification of albuminuria status was based on the average of their first two uACR measurements. A longitudinal mixed effect dynamic regression model was fitted to the data. Parameters were estimated by maximum likelihood. RESULTS For the analysis of the population, average progression of eGFR, uACR and drug prescribing were available in 3431 people. The regression model showed that in people with diabetes and macroalbuminuria, eGFR declined at 5.7% per annum, while the eGFR of those with microalbuminuria or without albuminuria declined at 1.5% and 0.3% per annum, respectively, independently of age (P < 0.0001). CONCLUSIONS The longitudinal effect of time on eGFR showed that people with diabetes and macroalbuminuria have an estimated 19 times more rapid decline in renal function compared with those without albuminuria. This study demonstrates that the progression of kidney disease in diabetic people without albuminuria is relatively benign compared with those with albuminuria.

Measuring clinical performance and outcomes from diabetes information systems: an observational study

Aims/hypothesis. To examine changes in diabetes care provision after the introduction of a district diabetes information system.¶Methods. All patients with diabetes registered on the system between 1993 and 1998 (n = 6544) were included in the analysis. Drop-out cohort analysis was used to handle population changes, logistic regression models with general estimating equations were used to examine changes in clinical performance over time.¶Results. After the introduction of the system, care processes improved appreciably, in both primary and secondary care. The proportion of patients receiving a preventative care review within the calendar year rose from 56 % in 1993 to 67 % in 1998. The proportion of these in whom each process was completed improved in all categories from 1993 to 1998: blood pressure 96 % to 98 %; glycaemic check 67 % to 93 %; lipid check 31 % to 68 %; renal check 46 % to 87 %; fundoscopy 79 % to 92 %; foot screen 87 % to 87 %. Similarly there was an increase in the proportion of patients achieving intermediate outcome treatment targets (HbA1 c≤ 9.0 % from 29 % to 43 %; cholesterol ≤ 5.5 mmol/l 5 % to 19 %; blood pressure ≤ 160/90 37 % to 46 %).¶Conclusion/interpretation. Our results suggest appreciable improvements in diabetes care between 1993 and 1998. These changes apply to an entire population of patients across primary and shared care. We believe that these improvements could, in part, be attributable to the way in which the district diabetes information system has facilitated the structured cascade of diabetes care. [Diabetologia (2000) 43: 836–843]