Impact of weight loss and weight gain trajectories on body composition in a population at high risk of type 2 diabetes: A prospective cohort analysis.

AIM: In a primary care population at high risk of type 2 diabetes, 24-month weight change trajectories were used to investigate the impact of weight cycling on fat mass (FM) and fat-free mass (FFM). MATERIALS AND METHODS: Cohort data from the Walking Away from Type 2 Diabetes trial was used, which recruited adults at-risk of type 2 diabetes from primary care in 2009/10. Annual weight change trajectories based on weight loss/gain of ≥5% were assessed over two 24-month periods. Body composition was measured by bioelectrical impedance analysis. Repeated measures were analysed using generalized estimating equations with participants contributing up to two 24-month observation periods. RESULTS: In total, 622 participants were included (average age = 63.6 years, body mass index = 32.0 kg/m2 , 35.4% women), contributing 1163 observations. Most observations (69.2%) were from those that maintained their body weight, with no change to FM or FFM. A minority (4.6% of observations) lost over 5% of body weight between baseline and 12 months, which was then regained between 12 and 24 months. These individuals regained FM to baseline levels, but lost 1.50 (0.66, 2.35) kg FFM, adjusted for confounders. In contrast, those that gained weight between baseline and 12 months but lost weight between 12 and 24 months (5.5% of observations) had a net gain in FM of 1.70 (0.27, 3.12) kg with no change to FFM. CONCLUSION: Weight cycling may be associated with a progressive loss in FFM and/or gain in FM in those with overweight and obesity at-risk of type 2 diabetes.

Patient-reported outcomes after 10-year follow-up of intensive, multifactorial treatment in individuals with screen-detected type 2 diabetes: the ADDITION-Europe trial.

AIMS: To present the longer-term impact of multifactorial treatment of type 2 diabetes on self-reported health status, diabetes-specific quality of life, and diabetes treatment satisfaction at 10-year follow up of the ADDITION-Europe trial. METHODS: The ADDITION-Europe trial enrolled 3057 individuals with screen-detected type 2 diabetes from four centres [Denmark, the UK (Cambridge and Leicester) and the Netherlands], between 2001 and 2006. Participants were randomized at general practice level to intensive treatment or to routine care . The trial ended in 2009 and a 10-year follow-up was performed at the end of 2014. We measured self-reported health status (36-item Short-Form Health Survey and EQ-5D), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life questionnaire), and diabetes treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire) at different time points during the study period. A mixed-effects model was applied to estimate the effect of intensive treatment (intention-to-treat analyses) on patient-reported outcome measures for each centre. Centre-specific estimates were pooled using a fixed effects meta-analysis. RESULTS: There was no difference in patient-reported outcome measures between the routine care and intensive treatment arms in this 10-year follow-up study [EQ-5D: -0.01 (95% CI -0.03, 0.01); Physical Composite Score (36-item Short-Form Health Survey): -0.27 (95% CI -1.11, 0.57), Audit of Diabetes-Dependent Quality of Life questionnaire: -0.01 (95% CI -0.11, 0.10); and Diabetes Treatment Satisfaction Questionnaire: -0.20 (95% CI -0.70, 0.29)]. CONCLUSIONS: Intensive, multifactorial treatment of individuals with screen-detected type 2 diabetes did not affect self-reported health status, diabetes-specific quality of life, or diabetes treatment satisfaction at 10-year follow-up compared to routine care.

Selectivity of beta-blockers, cardiovascular and all-cause mortality in people with hypoglycaemia: An observational study.

BACKGROUND AND AIMS: The association of beta-blockers and their selectivity with mortality and cardiovascular events in patients with and without hypoglycaemia is unknown. METHODS AND RESULTS: Insulin-treated patients with diabetes were identified within the UK CPRD database. All-cause deaths, cardiovascular events, and hypoglycaemic episodes were captured to assess the interaction between beta-blocker therapy and selectivity with hypoglycaemia. 13,682 patients, of which 2036 (14.9%) with at least one hypoglycaemic episode, were included; 3148 deaths and 1235 cardiovascular events were recorded during a median of 2.3 and 4.7 years in patients with and without incident hypoglycaemia, respectively. Treatment with any beta-blocker was not associated with risk of death in both patients with and without hypoglycaemia, without significant interaction. Compared to no therapy, non-selective beta-blockers were associated with higher risk of death in patients without hypoglycaemia (hazard ratio (HR) 2.93 [1.26-6.83] in the fully adjusted model) but not in those with hypoglycaemia; interactions was not significant. For beta1-selective beta-blockers, there was no association with mortality in both patients with and without hypoglycaemia, without significant interaction. After missing data imputation, results were consistent for non-selective beta-blockers (HR in patients without hypoglycaemia 1.59 [1.22-2.08]) while indicated a reduced risk of death for beta1-selective beta-blockers in patients with hypoglycaemia (HR 0.76 [0.61-0.94]). Due to few cardiovascular events, complete-case analysis compared only any vs no beta-blocker therapy and indicated no associations with therapy or interaction by hypoglycaemia. CONCLUSION: In patients with hypoglycaemic episodes, treatment with beta1-selective beta-blockers may potentially reduce the risk of death. These explorative findings and the potential role of confounding by indication need to be evaluated in other studies.

Cardiovascular risk factors and incident albuminuria in screen-detected type 2 diabetes.

BACKGROUND: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria 5 years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management. METHODS: In 1826 participants with newly diagnosed, screen-detected diabetes without albuminuria, we explored associations between risk of new albuminuria (≥2.5 mg mmol-1 for males and ≥3.5 mg mmol-1 for females) and (1) baseline cardio-metabolic risk factors and (2) changes from baseline to 1 year in systolic blood pressure (ΔSBP) and glycated haemoglobin (ΔHbA1c ) using logistic regression. RESULTS: Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in 5 years after detection of diabetes. In a model adjusted for age, gender, baseline HbA1c and blood pressure, a 1% decrease in HbA1c and 5-mm Hg decrease in SBP during the first year were independently associated with lower risks of albuminuria (odds ratio), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively. Further adjustment did not materially change these estimates. There was no interaction between ΔSBP and ΔHbA1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease. CONCLUSIONS: Baseline measurements and changes in HbA1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria 4 years later. Established multifactorial treatment for diabetes applies to cases identified through screening.

Incident Type 2 diabetes and the effect of early regression to normoglycaemia in a population with impaired glucose regulation.

AIMS: To report contemporary regression rates from impaired glucose regulation to normal glucose tolerance, identify modifiable factors associated with early regression, and establish whether it affects subsequent diabetes risk in a population-based cohort. METHODS: Participants with impaired glucose regulation (impaired fasting glucose and/or impaired glucose tolerance on a 75-g oral glucose tolerance test) at baseline in the UK-based ADDITION-Leicester study had annual Type 2 diabetes re-screens for 5 years or until diabetes diagnosis. Logistic regression models investigated modifiable risk factors for regression to normal glucose tolerance at 1 year (n = 817). Cox regression models estimated subsequent diabetes risk (n = 630). RESULTS: At 1 year, 54% of participants had regressed to normal glucose tolerance, and 6% had progressed to diabetes. Regression to normal glucose tolerance was associated with weight loss of 0.1-3% [adjusted odds ratio 1.81 (95% CI 1.08, 3.03) compared with maintaining or gaining weight] and a waist circumference reduction of > 3 cm [adjusted odds ratio 1.78 (95% CI 1.03, 3.06) compared with maintaining or increasing waist circumference]. Those with normal glucose tolerance at 1 year subsequently had lower diabetes risk than those who remained with impaired glucose regulation [adjusted hazard ratio 0.19 (95% CI 0.10, 0.37)]. CONCLUSIONS: Early regression to normal glucose tolerance was associated with reduced diabetes incidence, and might be induced by small reductions in weight or waist circumference. If confirmed in experimental research, this could be a clear and achievable target for individuals diagnosed with impaired glucose regulation.

Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis.

AIM: To assess the comparative efficacy and safety of sodium-glucose co-transporter-2 (SGLT2) inhibitors in adults with type 2 diabetes. METHODS: We electronically searched randomized controlled trials (≥24 weeks) including canagliflozin, dapagliflozin or empagliflozin that were published up to 3 November 2015. Data were collected on cardiometabolic and safety outcomes and synthesized using network meta-analyses. RESULTS: A total of 38 trials (23 997 participants) were included. Compared with placebo, all SGLT2 inhibitors reduced glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and blood pressure, and slightly increased HDL cholesterol. Canagliflozin 300 mg reduced HbA1c, FPG and systolic blood pressure and increased LDL cholesterol to a greater extent compared with other inhibitors at any dose. At their highest doses, canagliflozin 300 mg reduced: HbA1c by 0.2% [95% confidence interval (CI) 0.1-0.3] versus both dapagliflozin 10 mg and empagliflozin 25 mg; FPG by 0.6 mmol/l (95% CI 0.3-0.9) and 0.5 mmol/l (95% CI 0.1-0.8) versus dapagliflozin and empagliflozin, respectively; and systolic blood pressure by 2 mmHg (95% CI 1.0-3.0) versus dapagliflozin; and increased LDL cholesterol by 0.13 mmol/l (95% CI 0.03-0.23) and 0.15 mmol/l (95% CI 0.06-0.23) versus dapagliflozin and empagliflozin, respectively. The highest doses of inhibitors had similar effects on body weight reduction. Canagliflozin 300 and 100 mg increased the risk of hypoglycaemia versus placebo, dapagliflozin 10 mg and empagliflozin 10 mg [odds ratios (ORs) 1.4-1.6]. Dapagliflozin 10 mg increased the risk of urinary tract infection versus placebo and empagliflozin 25 mg (ORs 1.4). All inhibitors similarly increased the risk of genital infection (ORs 4-6 versus placebo). CONCLUSIONS: Although they increase the risk of genital infection, SGLT2 inhibitors are effective in improving cardiometabolic markers in type 2 diabetes, with canagliflozin 300 mg performing better in this respect than other inhibitors. Further studies will clarify whether these differences are likely to translate into differing long-term outcomes.

Association between direct measurement of active serum calcium and risk of type 2 diabetes mellitus: A prospective study.

BACKGROUND AND AIMS: Previous prospective studies showing a positive association between serum calcium and incidence of type 2 diabetes mellitus (T2DM) have relied on total calcium or an indirect estimate of active, ionized calcium (iCa). We aimed to assess this relationship using a direct measurement of iCa. METHODS AND RESULTS: iCa and cardiometabolic risk factors were measured in a population-based sample of 2350 men without a known history of T2DM at baseline. Associations between iCa levels and incident cases of T2DM (self-reported, ascertained with a glucose tolerance test, or determined by record linkage to national registers) were estimated using Cox regression analyses adjusted for potential confounders. At baseline, mean (standard deviation) age was 53 (5) years and mean iCa 1.18 (0.05) mmol/L. During a median follow-up of 23.1 years, 140 new cases of T2DM were recorded. In a multivariable analysis adjusted for age, body mass index, systolic blood pressure, serum HDL-cholesterol, and family history of T2DM, there was no association comparing second (hazard ratio 0.84; 95% confidence interval 0.59-1.18), third (0.77; 0.52-1.14), or fourth (0.98; 0.69-1.39) vs first quartile of iCa (p for trend 0.538); further adjustment for C-reactive protein, physical activity level, and triglycerides did not change the estimates (p for trend 0.389). CONCLUSION: In this study, we did not find evidence of an association between direct measurement of active calcium and risk of T2DM. Further studies are needed to confirm our findings and define the relationship between factors influencing indirect calcium estimation and incident T2DM.

Detection of impaired glucose regulation and/or type 2 diabetes mellitus, using primary care electronic data, in a multiethnic UK community setting.

AIMS/HYPOTHESIS: The aim of this study was to develop and validate a score for detecting the glycaemic categories of impaired glucose regulation (IGR) and type 2 diabetes using the WHO 2011 diagnostic criteria. METHODS: We used data from 6,390 individuals aged 40-75 years from a multiethnic population based screening study. We developed a logistic regression model for predicting IGR and type 2 diabetes (diagnosed using OGTT or HbA(1c) ≥ 6.5% [48 mmol/mol]) from data which are routinely stored in primary care. We developed the score by summing the ß coefficients. We externally validated the score using data from 3,225 participants aged 40-75 years screened as part of another study. RESULTS: The score includes age, ethnicity, sex, family history of diabetes, antihypertensive therapy and BMI. Fifty per cent of a population would need to be invited for testing to detect type 2 diabetes mellitus on OGTT with 80% sensitivity; this is slightly raised to 54% that need to be invited if using HbA(1c). Inviting the top 10% for testing, 9% of these would have type 2 diabetes mellitus using an OGTT (positive predictive value [PPV] 8.9% [95% CI 5.8%,12.8%]), 26% would have IGR (PPV 25.9% [95% CI 20.9%, 31.4%]). Using HbA(1c) increases the PPV to 19% for type 2 diabetes mellitus (PPV 18.6% [95% CI 14.2%, 23.7%]) and 28% for an HbA(1c) between 6.0% and 6.4% (PPV 28.3% [95% CI 23.1%, 34.0%]). CONCLUSIONS: The score can be used to reliably identify those with undiagnosed IGR and type 2 diabetes in multiethnic populations. This is the first score developed taking into account HbA(1c) in the diagnosis of type 2 diabetes.

Intensive multifactorial intervention improves modelled coronary heart disease risk in screen-detected Type 2 diabetes mellitus: a cluster randomized controlled trial.

AIMS: To compare the effects of intensive multifactorial cardiovascular risk intervention with standard care in screen-detected Type 2 diabetes. METHODS: Twenty general practices randomly invited 30 950 adults without diagnosed diabetes for screening (World Health Organization, 1999). In a cluster randomized controlled trial, screen-detected cases were assigned by practice allocation to receive intensive protocol-driven cardiovascular risk management (n = 146) or standard care (n = 199) according to local guidelines. Intensive intervention was designed to achieve an HbA(1c) of 48 mmol/mol (6.5%), blood pressure < 130/80 mmHg and total cholesterol < 3.5 mmol/l. Primary outcome was modelled 5-year coronary heart disease risk (UKPDS-CHD). Analysis was via intention to treat. RESULTS: After 1.1 years 339 (98%) individuals were still participating. There were significant reductions in HbA(1c) , blood pressure and total cholesterol from baseline in both groups [mean change for total study population -27.7 mmol/mol (-0.62%), -11.64/10.01 mmHg, -1.11 mmol/l]. After adjustment for baseline and clustering, significant inter-group differences were observed in mean changes from baseline for HbA(1c) {-28.5 mmol/mol [-0.7% (1.4)] vs. -27.5 mmol/mol [-0.6% (1.6)], P = 0.001}, blood pressure [systolic -16.2 (19.6) vs. -8.4 (18.6) mmHg, P < 0.001], total cholesterol [-1.3 (1.3) vs. -1.0 (1.2) mmol/l, P < 0.001] and weight [-3.8 (5.5) vs. -2.2 (5.5) kg, P = 0.01] in favour of intensive treatment. UKPDS 5-year coronary heart disease risk was reduced by 3.2% and 2.3%, respectively (P < 0.0001). Intensive intervention was associated with more lipid-lowering and anti-hypertensive but not hypoglycaemic medication use [odds ratios 2.5 (1.4-4.4), 5.5 (2.4-11.5), 1.6 (0.8-2.3); compared with standard care, P < 0.001, P = 0.003, P = 0.65]. Treatment satisfaction responses were superior with intensive intervention, with no increase in self-reported hypoglycaemia. CONCLUSION: Intensive intervention in patients with diabetes identified through systematic non-risk-factor-based screening significantly reduces modelled coronary heart disease risk. This is achieved predominantly with lipid-lowering and anti-hypertensive treatments with no adverse effect on quality of life or hypoglycaemia.

Screening for diabetes using an oral glucose tolerance test within a western multi-ethnic population identifies modifiable cardiovascular risk: the ADDITION-Leicester study.

AIMS/HYPOTHESIS: The aim of this study was to determine the frequency of undiagnosed glucose abnormalities and the burden of cardiovascular disease (CVD) risk among south Asians and white Europeans attending a systematic screening programme for type 2 diabetes (ADDITION-Leicester) and to estimate the achievable risk reduction in individuals identified with glucose disorders. METHODS: Random samples of individuals (n = 66,320) from 20 general practices were invited for a 75 g OGTT and CVD risk assessment. Ten-year CVD risk among screen-detected people with diabetes or impaired glucose regulation (IGR) (impaired fasting glycaemia and/or impaired glucose tolerance [IGT]) was computed using the Framingham-based ETHRISK engine and achievable risk reduction was predicted using relative reductions for treatments extracted from published trials. RESULTS: A total of 6,041 participants (48% male, 22% south Asian) aged 40-75 years inclusive were included. Undiagnosed glucose disorders occurred more frequently in south Asians than white Europeans; age and sex adjusted odds ratios were 1.74 (95% CI 1.42-2.13) and 2.30 (95% CI 1.68-3.16) for IGT and diabetes respectively. Prevalence of any undetected glucose disorder was 17.5% in the whole cohort. Adjusted 10-year risk was similar in screen-detected people with IGR and diabetes (18.3% vs 21.6%), and was higher in south Asians across the glucose spectrum. Absolute CVD risk reductions of up to 13% in those with screen-detected type 2 diabetes and 6% in IGR are achievable using existing cardioprotective therapies. CONCLUSIONS/INTERPRETATION: Population screening with an OGTT identifies a significant burden of modifiable CVD risk, especially within south Asian groups. Strategies enticing this population to consider screening programmes are urgently needed as significant risk reduction is possible once a glucose abnormality is identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT00318032. FUNDING: The project is funded for support and treatment costs by NHS Department of Health Support for Science and project grants.

The association between anxiety and measures of glycaemia in a population-based diabetes screening programme.

AIM: To investigate associations between anxiety and measures of glycaemia in a White European and South Asian population attending community-based diabetes screening. METHODS: In total, 4688 White European and 1353 South Asian participants (aged 40-75 years) without a previous diagnosis of Type 2 diabetes underwent an oral glucose tolerance test and HbA(1c) measurement, detailed history, anthropometric measurements and completed the short-form Spielberger State Trait Anxiety Inventory. RESULTS: Anxiety was significantly higher in South Asian participants (mean 34.1; sd 0.37) compared with White European participants (mean 29.8; sd 0.13). Significant correlations were not identified between anxiety and fasting (r = -0.01, P = 0.75), 2-h glucose (r = -0.10, P = 0.24) or HbA(1c) (r = 0.01, P = 0.40). CONCLUSIONS: Anxiety levels at screening were greater among South Asian people. Fasting, 2-h plasma glucose and HbA(1c) are not affected by anxiety during screening tests for diabetes. Current and proposed screening methods for diagnosis of diabetes are not affected by anxiety at screening.

Impact of metabolic indices on central artery stiffness: independent association of insulin resistance and glucose with aortic pulse wave velocity.

AIMS/HYPOTHESIS: Non-invasive measures of aortic stiffness reflect vascular senescence and predict outcome in diabetes. Glucose-mediated elastic artery sclerosis may play an integral role in the development of macrovascular complications. We used carotid-femoral pulse wave velocity ((cf)PWV) to quantify independent associations of fasting glucose, post-challenge glucose and derived insulin resistance (HOMA-IR) with aortic stiffness. METHODS: (cf)PWV was measured using a 4 MHz continuous wave Doppler ultrasound probe within groups with newly identified age- and sex-matched normal glucose metabolism (NGM), impaired glucose regulation (IGR) and diabetes mellitus populations (n = 570, mean age 59.1, 56% male). RESULTS: After multivariate adjustment, IGR and diabetes were associated with significant aortic stiffening compared with NGM (adjusted (cf)PWV+/-SE: NGM, 9.15 +/- 0.12 m/s; IGR 9.76 +/- 0.11 m/s, p < 0.001; diabetes, 9.89 +/- 0.12 m/s, p < 0.001). IGR stratification indicated that impaired fasting glucose (IFG; 9.71 +/- 0.12 m/s) and post-challenge (impaired glucose tolerance; 9.82 +/- 0.24 m/s) categories had similar (cf)PWV (p = 0.83). Modelled predictors of (cf)PWV were used to assess independent metabolic associations with arterial stiffness. Fasting glucose concentration (beta = 0.10; 95% CI 0.05, 0.18; p = 0.003), 2 h post-challenge glucose (beta = 0.14; 95% CI 0.02, 0.23; p < 0.001) and HOMA-IR (beta = 0.20, 95% CI 0.05, 0.53; p < 0.001) were independently related to (cf)PWV after adjustment for age, sex, mean arterial pressure, heart rate, body mass index, renal function and antihypertensive medication. CONCLUSIONS/INTERPRETATION: IGR characterised by fasting or post-challenge hyperglycaemia is associated with significant vascular stiffening. Post-challenge glucose and HOMA-IR are the most powerful metabolic predictors of arterial stiffness, implying hyperglycaemic excursion and insulin resistance play important roles in the pathogenesis of arteriosclerosis.

Purification and characterization of an L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT)-specific suppressor factor from genetic responder mice.

A hybridoma-derived, GAT-specific suppressor T cell factor (GAT-TsFR) from responder C57BL/10 mice has been purified to apparent chemical homogeneity using reversed phase HPLC techniques. 40 l of starting material yielded approximately 880 micrograms protein with a specific activity of 28.4 X 10(3) S50 U/ng protein representing a purification factor of 4.2 X 10(6). Purified GAT-TsFR is a hydrophobic protein with a minimum molecular weight of 18,000 that is capable of forming biologically active aggregates with molecular weights of 28,000, 64,000 and approximately 84,000 and has a pI of 6.4. GAT-TsFR is a glycoprotein that binds GAT and GT, but not GA, and bears determinants encoded by the I-J subregion of the H-2 complex. This GAT-TsFR derived from an H-2b responder haplotype to GAT is compared with GAT-TsF derived from the nonresponder H-2q haplotype on the basis of biochemical and some serological properties.

The Leicester Risk Assessment score for detecting undiagnosed Type 2 diabetes and impaired glucose regulation for use in a multiethnic UK setting.

AIMS: Risk assessment scores identify those at high risk of impaired glucose regulation and Type 2 diabetes mellitus. To date no risk assessment scores that can be completed by a lay person have been developed and validated specifically for multiethnic populations in the UK. METHODS: We used data on 6186 subjects aged 40-75 years from a multiethnic UK screening study (73% white European, 22% South Asian). All participants were given a 75 g oral glucose tolerance test. We developed logistic regression models for predicting current impaired glucose regulation (impaired fasting glycaemia/impaired glucose tolerance) or Type 2 diabetes mellitus using data from anthropometric measurements and self-reported questionnaires. Using the best-fitting model, we developed the Leicester Risk Assessment score. We externally validated the score using data from 3171 subjects aged 40-75 years from a separate screening study. RESULTS: The components of the final model are age, ethnicity [white European vs. other (predominantly South Asian)], sex, first degree family history of diabetes, antihypertensive therapy or history of hypertension, waist circumference and body mass index. The score ranges from 0 to 47. Validating this model using the data from the second screening study gave an area under the receiver operator characteristic curve of 72% (95% confidence interval, 69-74%). A cut point of 16 had a sensitivity of 81% and a specificity of 45%. CONCLUSIONS: The Leicester Risk Assessment score can be used to identify those at high risk of impaired glucose regulation and Type 2 diabetes mellitus in UK multiethnic populations. The score is simple (seven questions) and non-invasive.

Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones.

INTRODUCTION: Recent meta-analyses cast doubt over purported beneficial effects of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-gamma) receptor agonists. Thiazolidinedione (TZD) trials using surrogate outcomes to postulate an antiatherogenic paradigm have been criticised as misinformative. We conducted an independent systematic review and meta-analysis of controlled TZD studies incorporating carotid intima-media thickness (CIMT) or pulse wave velocity (PWV) as primary outcome measures. The aim was to provide an evidence-based overview of TZD intervention studies using markers prospectively linked to vascular outcome in type 2 diabetes. METHODS: Systematic search of known databases for TZD intervention trials using mean thickness CIMT(n = 9) and ankle-brachial PWV(n = 6) as primary outcome measures was performed. CIMT and PWV pooled weighted mean difference was calculated using a random effects model accounting for heterogeneity and publication bias. An indirect meta-analysis provided a comparison of rosiglitazone and pioglitazone effects. RESULTS: A composite of combined placebo and comparator controlled trials demonstrated a significant weighted mean difference of-0.06 mm for CIMT (95% CI-0.09 to-0.02, p = 0.001) and-0.72 ms(-1) for PWV (95% CI-1.28 to-0.16, p = 0.011) in favour of thiazolidiendione treatment. No TZD intraclass variation in CIMT (p = 0.96) or PWV (p = 0.33) change was observed. CONCLUSION: TZDs exhibit significant beneficial effects on aorto-carotid atherosclerosis when assessed using prospectively validated non-invasive techniques. Inferring clinical benefit in the absence of confirmatory outcome trials is questionable and caution should be exercised when interpreting intervention data with surrogate endpoints. TZD-induced congestive cardiac failure or other unknown PPAR-gamma adverse effects are plausible explanations for the conflicting results of intervention trials using markers of atherosclerosis and clinical event outcomes.

Moderate increases in daily step count are associated with reduced IL6 and CRP in women with PCOS.

Aims Physical activity has been proposed to be an effective non-pharmacological method of reducing systemic inflammation and therefore may prove particularly efficacious for women with polycystic ovary syndrome (PCOS) who have been shown to have high levels of inflammation and an increased risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Therefore, the aim of the present study was to assess whether modest changes in daily step count could significantly reduce levels of inflammatory markers in women with PCOS. Subjects and Methods Sixty-five women with PCOS were assessed at baseline and again at 6 months. All had been provided with an accelerometer and encouraged to increase activity levels. Multivariate linear regression analyses (adjusted for age, ethnicity, baseline step count, change in BMI and change in accelerometer wear-time) were used to assess changes in daily step count against clinical and research biomarkers of inflammation, CVD and T2DM. Results Mean step count/day at baseline was 6337 (±270). An increase in step count (by 1000 steps) was associated with a 13% reduction in IL6 (ß: -0.81 ng/L; 95% CI, -1.37, -0.25, P = 0.005) and a 13% reduction in CRP (ß: -0.68 mg/L; 95% CI, -1.30, -0.06, P = 0.033). Additionally, there was a modest decrease in BMI (ß: 0.20 kg/m2; 95% CI, -0.38, -0.01, P = 0.038). Clinical markers of T2DM and CVD were not affected by increased step count. Conclusions Modest increases in step count/day can reduce levels of inflammatory markers in women with PCOS, which may reduce the future risk of T2DM and CVD.

Pulmonary abnormalities in intermediate alpha-1-antitrypsin deficiency.

Pulmonary function studies were carried out in a group of asymptomatic nonsmoking adults with intermediate alpha-1-antitrypsin deficiency who were attending an early disease detection unit in Rochester, N. Y. All subjects were identified by specific protease inhibitor (Pi) typing. Fifteen MZ and 14 MS subjects who had never smoked cigarettes were matched by sex and age to MM controls. Spirometry, static lung volumes, and single breath-diffusing capacity were identical in all Pi type groups with no statistically significant differences noted. Maximal expiratory flow volume curves were obtained in all subjects. MZ subjects demonstrated statistically impaired maximal flow rates at 75%, 50%, and 25% of vital capacity compared to their MM controls. Total pulmonary resistance by the oscillometric method was measured at 3, 5, 7, and 9 cycle/s in the same subjects. Increased frequency dependence of resistance (defined as the difference between total pulmonary resistance at 3 cycle/s and 9 cycle/s) was observed in MZ subjects compared to MM controls. No differences were noted by this method in MS-MM pairs. The data suggest that detectable mechanical abnormalities are present in subjects with the MZ phenotype, even in the absence of established risk factors such as cigarette smoking and high air pollution.

Association between undiagnosed hypertension and microalbuminuria in South Asians without known diabetes.

Data suggest increased rates of chronic kidney disease (CKD) in those with undiagnosed hypertension (HTN). Our study aimed to determine the prevalence of CKD in undiagnosed hypertensives in a previously unreported subgroup of individuals of South Asian ethnicity. We analysed data from subjects in the ADDITION-Leicester study, a UK based multiethnic, community diabetes screening study. Standard definitions included: HTN-mean recorded BP of ⩾140/90 mm Hg, CKD stage 3 and above-estimated glomerular filtration rate (eGFR) <60 ml min(-1) per 1.73 m2 and microalbuminuria as albumin creatinine ratio ⩾3 mg mmol(-1). Logistic regression was performed with age, gender and body mass index (kg m(-2)) as co-variates. 6082 individuals (52.5% female, mean age, 57.2 years; White European, 77.8% and South Asian, 22.0%), 31.1% had undiagnosed HTN. Overall, individuals with undiagnosed HTN compared with normotensives had an odds ratio for microalbuminuria of 2.24 (95% confidence interval (CI): 1.72-2.94). For South Asians, the odds ratio was 3.81. (95% CI: 2.24-6.47) for microalbuminuria with a trend towards an eGFR<60 ml min(-1) per 1.73 m2. Future studies should consider intensified screening for HTN to refine the population suitable for CKD screening, particularly in the South Asian ethnic group.

Management of children with slightly elevated blood lead levels.

OBJECTIVE: To determine whether counseling of parents reduced blood lead levels in their young children. PARTICIPANTS AND METHODS: A lead exposure study was conducted in the vicinity of a defunct lead smelter. A total of 827 volunteers including 490 children younger than 6 years participated in the study. The mean venous blood lead level in the 490 children was 0.33 mumol/L (6.9 micrograms/dL), with a range of 0.03 to 1.94 mumol/L (0.7 to 40.2 micrograms/dL). A total of 78 (16%) children had blood lead levels > or = 0.48 mumol/L (10 micrograms/dL). However, only 5 (1%) of the children had blood lead levels of > or = 1.21 mumol/L (25 micrograms/dL). The blood lead levels in this community were much lower than levels reported in earlier studies in many areas of the United States, when lead levels in air and in food were higher. Most houses in the study community were built before 1920 and had high lead paint levels. High levels of lead were also found in many house dust and soil samples. Intervention consisted of home visits and counseling of parents of children with blood lead levels of > or = 0.48 mumol/L (10 micrograms/dL). RESULTS: In children with initial blood lead levels of > or = 0.48 mumol/L (10 micrograms/dL) the blood lead test was repeated 4 months later. The arithmetic mean blood lead level 4 months later showed a decrease from 0.72 mumol/L (15 micrograms/dL) to 0.38 mumol/L (7.8 micrograms/dL). An additional blood sample was taken 1 year after the first sample in a subset of 30 children. These children showed a mean blood lead level of 0.43 mumol/L (9 micrograms/dL) at the 1-year follow-up, whereas their mean blood lead level at the 4-month follow-up had been 0.38 mumol/L (8 micrograms/dL). CONCLUSION: Educating parents proved a very effective tool. Further studies are needed in larger populations to evaluate the effectiveness of this approach.