Insights into the Progression of Labile Hb A1c to Stable Hb A1c via a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process.

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A1c (the conjugate acid of the Schiff base). Labile Hb A1c can then undergo slow, largely irreversible, formation of stable Hb A1c (the Amadori product). Stable Hb A1c is measured to assess diabetic progression after labile Hb A1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A1c and the slow rate of NEG.

Modelling incremental benefits on complications rates when targeting lower HbA1c levels in people with Type 2 diabetes and cardiovascular disease.

AIM: Glucose-lowering interventions in Type 2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA1c reductions might reduce risk is unclear. METHODS: Participant-level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type 2 diabetes-specific simulation model to quantify the likely impact of different HbA1c decrements on complication rates. Ten-year micro- and macrovascular rates were estimated with HbA1c levels fixed at 86, 75, 64, 53 and 42 mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA1c decrement. RESULTS: Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd) age of 66.2 (7.9) years, systolic blood pressure 134 (16.9) mmHg, LDL-cholesterol 2.3 (0.9) mmol/l, HDL-cholesterol 1.13 (0.3) mmol/l and median Type 2 diabetes duration 9.6 (5.1-15.6) years. Ten-year cumulative relative risk reductions for modelled HbA1c values of 75, 64, 53 and 42 mmol/mol, relative to 86 mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes-related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single-eye blindness. CONCLUSIONS: These simulated complication rates might help inform the degree to which complications might be reduced by targeting particular HbA1c reductions in Type 2 diabetes.

Do glycoalbumin levels preferentially reflect changes in postprandial glucose excursions?

AIMS: To evaluate whether plasma glycated albumin, which provides an integrated measure of plasma glucose levels over the preceding 2-4 weeks, better reflects changes in postprandial glucose excursions than HbA1c . METHODS: People with suboptimum glycaemic control on dual oral therapy were enrolled in the Treating-to-Target-in-Type 2 diabetes (4-T) trial, in which participants were randomized to the addition of once-daily basal insulin, twice-daily biphasic insulin or thrice-daily prandial insulin. Glycated albumin levels were assayed enzymatically from baseline and 1-year fasting plasma samples. We evaluated robust correlations of glycated albumin and HbA1c both with fasting and postprandial glucose levels at these two time points, and with insulin-induced changes in the postprandial excursion. RESULTS: Requisite data were available for 625 of the participants in the 4-T trial. Their mean (±sd) age was 62 ± 10 years and body weight was 85.8 ± 15.9 kg, and their median (interquartile range) diabetes duration was 9 (6, 13) years. Partial correlations at baseline and 1 year between postprandial glucose excursions and glycated albumin/HbA1c , after adjusting for fasting glucose, were 0.27/0.15 and 0.22/0.18, respectively. Glycated albumin, compared with HbA1c , explained 66% more of the variation in postprandial glucose excursions at baseline. At 1 year, postprandial glucose excursions on basal, biphasic and prandial and insulin therapy were reduced by 0.43, 0.78 and 1.88 mmol/l, respectively. These reductions were associated with changes in both glycated albumin and HbA1c (P < 0.01), with a stronger association for glycated albumin. CONCLUSION: Changes in glycated albumin and HbA1c reflect changes in postprandial glucose excursions to a similar extent.

Low incidence of the immune reconstitution inflammatory syndrome among HIV-infected patients starting antiretroviral therapy in Gabon: a prospective cohort study.

There is a paucity of data on the immune reconstitution inflammatory syndrome (IRIS) in the Central African region. We followed ART-naive HIV-infected patients initiating antiretroviral therapy in an HIV clinic in Gabon, for 6 months. Among 101 patients, IRIS was diagnosed in five. All IRIS cases were mucocutaneous manifestations. There were no cases of tuberculosis (TB) IRIS, but active TB (n = 20) was associated with developing other forms of IRIS (p = 0.02). Six patients died. The incidence of IRIS is low in Gabon, with mild, mucocutaneous manifestations.

Effect of metformin therapy on circulating amino acids in a randomized trial: the CAMERA study.

AIMS: To investigate whether metformin therapy alters circulating aromatic and branched-chain amino acid concentrations, increased levels amino acid concentrations, increased levels of which have been found to predict Type 2 diabetes. METHODS: In the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) study (NCT00723307), 173 individuals without Type 2 diabetes, but with coronary disease, were randomized to metformin (n=86) or placebo (n=87) for 18 months. Plasma samples, taken every 6 months, were analysed using quantitative nuclear magnetic resonance spectroscopy. Ten metabolites consisting of eight amino acids [three branched-chain (isoleucine, leucine, valine), three aromatic (tyrosine, phenylalanine, histidine) and two other amino acids (alanine, glutamine)], lactate and pyruvate were quantified and analysed using repeated-measures models. On-treatment analyses were conducted to investigate whether amino acid changes were dependent on changes in weight, fat mass or insulin resistance estimated using homeostasis model assessment (HOMA-IR). RESULTS: Tyrosine decreased [-6.1 µmol/l (95% CI -8.5, -3.7); P<0.0001], while alanine [42 umol/l (95% CI 25, 59); P<0.0001] increased in the metformin-treated group compared with the placebo-treated group. Decreases in phenylalanine [-2.0 µmol/l (95% CI -3.6, -0.3); P=0.018] and increases in histidine [2.3 µmol/l (95% CI 0.1, 4.6); P=0.045] were also observed in the metformin group, although these changes were less statistically robust. Changes in these four amino acids were not accounted for by changes in weight, fat mass or HOMA-IR values. Levels of branched-chain amino acids, glutamine, pyruvate and lactate were not altered by metformin therapy. CONCLUSIONS: Metformin therapy results in a sustained and specific pattern of changes in aromatic amino acid and alanine concentrations. These changes are independent of any effects on weight and insulin sensitivity. Any causal link to metformin's unexplained cardiometabolic benefit requires further study.

Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily aspirin in people with Type 2 diabetes.

AIMS: Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively. METHODS: Participants with Type 2 diabetes (n = 24) but without known cardiovascular disease were randomized in a three-way crossover design to 2-week treatment periods with aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily. The primary outcome was platelet reactivity, assessed using the VerifyNow(™) ASA method. Relationships between platelet reactivity and aspirin dosing were examined using generalized linear mixed models with random subject effects. RESULTS: Platelet reactivity decreased from baseline with all doses of aspirin. Modelled platelet reactivity was more effectively reduced with aspirin 100 mg twice daily vs. 100 mg once daily, but not vs. 200 mg once daily. Aspirin 200 mg once daily did not differ from 100 mg once daily. Aspirin 100 mg twice daily was also more effective than once daily as measured by collagen/epinephrine-stimulated platelet aggregation and urinary thromboxane levels, with a similar trend measured by serum thromboxane levels. No episodes of bleeding occurred. CONCLUSIONS: In Type 2 diabetes, aspirin 100 mg twice daily reduced platelet reactivity more effectively than 100 mg once daily, and numerically more than 200 mg once daily. Clinical outcome trials evaluating primary cardiovascular disease prevention with aspirin in Type 2 diabetes may need to consider using a more frequent dosing schedule.

Early intervention leads to long-term developmental improvements in very preterm infants, especially infants with bronchopulmonary dysplasia.

AIM: Various early intervention programmes have been developed in response to the high rate of neurodevelopmental problems in very preterm infants. We investigated longitudinal effects of the Infant Behavioral Assessment and Intervention Program on cognitive and motor development of very preterm infants at the corrected ages of six months to five and a half years. METHODS: This randomised controlled trial divided 176 infants with a gestational age <32 weeks or birthweight <1500 g into intervention (n = 86) and control (n = 90) groups. Cognitive development and motor development were assessed with the Bayley Scales of Infant Development at the CAs of six, 12 and 24 months and at five and a half years with the Wechsler Preschool and Primary Scale of Intelligence and the Movement Assessment Battery for Children. RESULTS: We found significant longitudinal intervention effects (0.4 SD, p = 0.006) on motor development, but no significant impact on cognitive development (p = 0.063). Infants with bronchopulmonary dysplasia showed significant longitudinal intervention effects for cognitive (0.7 SD; p = 0.019) and motor (0.9 SD; p = 0.026) outcomes. Maternal education had little effect on intervention effects over time. CONCLUSION: The Infant Behavioral Assessment and Intervention Program led to long-term developmental improvements in the intervention group, especially in infants with BPD.

Spinodal instabilities and super-Planckian excursions in natural inflation.

Models such as Natural Inflation that use pseudo-Nambu-Goldstone bosons as the inflaton are attractive for many reasons. However, they typically require trans-Planckian field excursions ΔΦ>MPl, due to the need for an axion decay constant f>MPl to have both a sufficient number of e-folds and values of ns,r consistent with data. Such excursions would in general require the addition of all other higher dimension operators consistent with symmetries, thus disrupting the required flatness of the potential and rendering the theory nonpredictive. We show that in the case of Natural Inflation, the existence of spinodal instabilities (modes with tachyonic masses) can modify the inflaton equations of motion to the point that versions of the model with f

The impact of diabetes-related complications on healthcare costs: new results from the UKPDS (UKPDS 84).

AIMS: To estimate the immediate and long-term inpatient and non-inpatient costs for Type 2 diabetes-related complications. METHODS: The costs of all consultations, visits, admissions and procedures associated with diabetes-related complications during UK Prospective Diabetes Study post-trial monitoring in the period 1997-2007 were estimated using hospitalization records for 2791 patients in England and resource use questionnaires that were administered to 3589 patients across the UK. RESULTS: The estimated (95% CI) inpatient care costs (in 2012 pounds sterling) in the event year for the example of a 60-year-old man were: non-fatal ischaemic heart disease £9767 (£7038-£12 696); amputation £9546 (£6416-£13 463); non-fatal stroke £6805 (£3856-£10 278); non-fatal myocardial infarction £6379 (£4290-£8339); fatal stroke £3954 (£2012-£6428); fatal ischaemic heart disease £3766 (£746-£5512); heart failure £3191 (£1678-4903); fatal myocardial infarction £1521 (£647-£2670); and blindness in one eye £1355 (£415-£2655). In subsequent years, estimated (95% CI) costs ranged from £1792 (£1060-£2943) for amputations to £453 (£315-£691) for blindness in one eye. Costs of non-inpatient healthcare in the event year were: amputation £2699 (£1409-£4126); blindness in one eye £1790 (£878-£3056); non-fatal stroke £1019 (£770-£1499); nonfatal myocardial infarction £1963 (£794-£1157); heart failure £979 (£708-£1344); non-fatal ischaemic heart disease £864 (£718-£1014); and cataract extraction £700 (£619-£780). In each subsequent year, non-inpatient costs ranged from £1611 (£1193-£2116) for amputations to £654 (£572-£799) for ischaemic heart disease. CONCLUSIONS: Diabetic complications are associated with substantial immediate and long-term healthcare costs. Our comprehensive new estimates of these costs, derived from detailed recent UK Prospective Diabetes Study post-trial data, should aid researchers and health policy analyses.

Physical activity as a determinant of fasting and 2-h post-challenge glucose: a prospective cohort analysis of the NAVIGATOR trial.

AIM: To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. METHODS: Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2 ) and 1 year (t-1 ) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. RESULTS: The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2)  = 0.3473 vs. 0.3468). There was no association with fasting glucose. CONCLUSIONS: In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.

Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).

AIMS: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. METHODS: TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. RESULTS: Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. CONCLUSION: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.

Ethnicity and long-term vascular outcomes in Type 2 diabetes: a prospective observational study (UKPDS 83).

AIMS: Evidence of ethnic differences in vascular complications of diabetes has been inconsistent. The aim of this study was to examine the relationship between ethnicity and long-term outcome in a large sample of individuals with newly diagnosed Type 2 diabetes. METHODS: In a prospective observational study of 4273 UK Prospective Diabetes Study participants followed for a median of 18 years, 3543 (83%) were White Caucasian, 312 (7%) Afro-Caribbean and 418 (10%) Asian Indian. Relative risks for predefined outcomes were assessed comparing Afro-Caribbean and Asian Indian with White Caucasian using accelerated failure time models, with adjustment for cardiovascular risk factors and other potentially confounding variables. RESULTS: During follow-up, 2468 (58%) participants had any diabetes-related end point, 1037 (24%) a myocardial infarction and 401 (9%) a stroke, and 1782 (42%) died. Asian Indian were at greater risk (relative risk, 95% confidence interval) for any diabetes-related end point (1.18, 1.07-1.29), but at lower risk of all-cause mortality (0.89, 0.80-0.97) and peripheral vascular disease (0.43, 0.23-0.82), vs. White Caucasian. Afro-Caribbean participants were at lower risk for all-cause mortality (0.84, 0.76-0.93), diabetes-related death (0.75, 0.64-0.88), myocardial infarction (0.55, 0.43-0.71) and peripheral vascular disease (0.55, 0.33-0.93) vs. White Caucasian. No ethnicity-related associations were found for stroke or microangiopathy. CONCLUSIONS: Asian Indian ethnicity is associated with the greatest burden of disease, but not with an increased risk of major vascular complications or death. Afro-Caribbean ethnicity is associated with reduced risk of all-cause and diabetes-related death, myocardial infarction and peripheral vascular disease, suggesting an ethnicity-specific protective mechanism.

Change in levels of physical activity after diagnosis of type 2 diabetes: an observational analysis from the NAVIGATOR study.

Increased physical activity is known to be beneficial in people with type 2 diabetes mellitus (T2DM), but it is not known whether individuals change their activity levels after T2DM diagnosis. The present Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2816 participants with the requisite data. Participants were relatively inactive at baseline, taking a median (interquartile range) of 5488 (3258-8361) steps/day, which decreased after T2DM diagnosis by a mean (s.e.) of 258 (64) steps/day (p < 0.0001); however, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged [mean (s.e.) of 103 (87) fewer steps/day; p = 0.23]. Awareness of T2DM diagnosis had no impact on the trajectory of activity established before the diagnosis.

UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82.

AIMS/HYPOTHESIS: The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient-level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus. METHODS: Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models. RESULTS: Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS-OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model. CONCLUSIONS/INTERPRETATION: The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus.

High incidence of intermittent care in HIV-1-infected patients in Curaçao before and after starting cART.

Retention in care is one of the major challenges to scaling up and maximizing the effectiveness of combination antiretroviral therapy (cART). High attrition rates have been reported in the Caribbean region, varying from 6% to 23%. We studied the incidence of and risk factors for intermittent care in a cohort of adult HIV-1-positive patients, who entered into care in Curaçao between January 2005 and July 2009. A total of 214 therapy-naïve HIV-1-infected patients aged 15 years or older, entered HIV care between January 2005 and July 2009. Intermittent care was defined as at least one period of 365 days or longer in which there was no HIV care contact in Curaçao. Cox regression models were used to identify characteristics associated with time to intermittent care. In all, 203 (95%) patients could be classified as having intermittent or continuous care. The incidence of intermittent care before starting cART was 25.4 per 100 person years observation (PYO), whilst it was 6.1 per 100 PYO after starting cART. Being born outside Curaçao was associated with intermittent care before and after starting cART. Time from diagnosis to entry into care was an independent predictor for intermittent care before starting cART. Younger age was independently associated with intermittent care after starting cART. Half of the patients returned to care after intermitting care. Upon returning to care, median CD4 count was 264 cells/mm(3) (IQR, 189-401) for those who intermitted care before starting cART, and 146 cells/mm(3) (IQR, 73-436) in those who intermitted care after starting cART. In conclusion, the incidence of intermitting care is high in Curaçao, especially before starting cART, and intermitting care before starting cART is an independent predictor for starting cART late.

Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial.

AIMS/OBJECTIVE: Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality. METHODS: A large multicentre 3 × 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥ 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n = 541), rosiglitazone 4-8 mg/day (n = 399) or pioglitazone 30-45 mg/day (n = 392); 1,221 participants were randomised to placebo (n = 614) or vitamin D 1,000 IU/day (n = 607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis. RESULTS: From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups. CONCLUSIONS/INTERPRETATION: Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.

Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials.

AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.

A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.

Impact of personalized cardiovascular disease risk estimates on physical activity-a randomized controlled trial.

AIM: Informing a person of their individual risk of developing a disease in the future may be sufficient to provide the person with the impetus to adopt risk reducing behaviours. The aim of this study was to determine if a personalised 10-year cardiovascular disease (CVD) risk estimate can increase physical activity and other risk reduction behaviours in adults at high risk of CVD. METHODS: Pilot 2 × 2 factorial randomised controlled trial conducted in Oxfordshire, UK including 194 adults at increased CVD risk (10-year CVD risk ≥ 20%) recruited from four general practices. Main outcome measure at one month was physical activity measured by accelerometer. RESULTS: Median (IQR) age was 62.3 (54.9, 66.1) years, 67% were men and 19% had known diabetes. Mean (SD) total accelerometer counts per day was 297 × 10(-3) (110 × 10(-3) ) and activity of moderate or greater intensity was undertaken for 53 (22) minutes per day. In the 185 (95%) participants attending follow-up an increase in physical activity was not seen. There was a non-significant 0.5% (p = 0.56) greater increase in accelerometer counts in those receiving personalised CVD risk estimates. No significant within or between group changes were seen at one month in estimated 10-year CVD risk. A net 7% decrease in mean LDL cholesterol (p = 0.004) was seen in the intervention group despite similar increases in new prescriptions for lipid lowering therapies. CONCLUSION: In adults at increased risk of CVD provision of personalised 10-year CVD risk estimates did not appear to increase physical activity or estimated CVD risk over a one-month period.

Participants' experiences of intensifying insulin therapy during the Treating to Target in Type 2 Diabetes (4-T) trial: qualitative interview study.

AIM: To explore participants' experiences of intensifying insulin therapy during the Treating to Target in Type 2 Diabetes (4-T) trial. METHODS: In-depth interviews were conducted with 41 trial participants who had had their insulin therapy intensified during this trial. Data were analysed using an inductive, thematic approach. RESULTS: The vast majority of participants were receptive towards intensifying treatment. Whilst some were happy simply to follow health professionals' recommendations, others saw taking two types of insulin as a more effective way of controlling their diabetes. Post-intensification, participants sought to remember to take their additional injections by developing injection-related strategies and daily routines. The need to inject insulin whilst in public often arose more frequently following intensification and was a consistent source of anxiety. Those who were worried about injecting in public sought to avoid having to do so; for example, by injecting in toilets or by advancing or delaying the timing of their injections. CONCLUSIONS: IT was not increasing the number of daily injections per se which was problematic for the participants who had agreed to have their insulin therapies intensified, but the increased likelihood of having to inject insulin in public. Addressing concerns about injecting in public places may help promote adherence to intensified insulin regimens.