Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91).

BACKGROUND: The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control. 10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects. We aimed to determine whether these effects would wane by extending follow-up for another 14 years. METHODS: 5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years. Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan-Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837. FINDINGS: Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3-26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2-17; p=0·015) for death from any cause, 17% (6-26; p=0·002) for myocardial infarction, and 26% (14-36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively. Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5-32; p=0·010) for death from any cause and 31% (12-46; p=0·003) for myocardial infarction. Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy. INTERPRETATION: Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible. FUNDING: University of Oxford Nuffield Department of Population Health Pump Priming.

Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. METHODS: EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03332212.

Estimated glomerular filtration rate slope and risk of primary and secondary major adverse cardiovascular events and heart failure hospitalization in people with type 2 diabetes: An analysis of the EXSCEL trial.

AIM: The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. MATERIALS AND METHODS: Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). RESULTS: Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. CONCLUSIONS: eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.

Joint longitudinal and time-to-event modelling compared with standard Cox modelling in patients with type 2 diabetes with and without established cardiovascular disease: An analysis of the EXSCEL trial.

AIM: To demonstrate the gain in predictive performance when cardiovascular disease (CVD) risk prediction tools (RPTs) incorporate repeated rather than only single measurements of risk factors. MATERIALS AND METHODS: We used data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to compare the quality of predictions of future major adverse cardiovascular events (MACE) with the Cox proportional hazards model (using single values of risk factors) compared to the Bayesian joint model (using repeated measures of risk factors). The risk of MACE was calculated in patients with type 2 diabetes with and without established CVD. We assessed the predictive ability of the following cardiovascular risk factors: glycated haemoglobin, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, estimated glomerular filtration rate, low-density lipoprotein cholesterol (LDL-C), total cholesterol, and systolic blood pressure (SBP) using the time-dependent area under the receiver-operating characteristic curve (aROC) for discrimination and the time-dependent Brier score for calibration. RESULTS: In participants without history of CVD, the aROC of SBP increased from 0.62 to 0.69 when repeated rather than only single measurements of SBP were incorporated into the predictive model. Similarly, the aROC increased from 0.67 to 0.80 when repeated rather than only single measurements of both SBP and LDL-C were incorporated into the predictive model. For all other investigated cardiovascular risk factors, the measures of discrimination and calibration both improved when using the joint model as compared to the Cox proportional hazards model. The improvement was evident in participants with and without history of CVD but was more pronounced in the latter group. CONCLUSIONS: The analysis demonstrates that the joint modelling approach, considering trajectories of cardiovascular risk factors, provides superior predictive performance compared to standard RPTs that use only a single timepoint.

Gamified Problem Gambling and Psychological Distress: The Mediated-Moderated Roles of Cognitive and Economic Motives.

Economic and non-economic motives for gambling may amplify anxiety and depression among young adults. On the grounds that online gambling is highly addictive, it is imperative to assess significant contributory factors in gambling that aggravate financial harm and psychological distress. The study examines gamified problem gambling and psychological distress among young adults in Ghanaian universities. The study further explores the mediating role of cognitive biases and heuristics as well as financial motive for gambling between gamified problem gambling and psychological distress. Through a cross-sectional design and convenience sampling technique, the study employed (n = 678) respondents who took part in different forms of gambling events in the last 2 years. Instruments for construct assessment include problem gambling severity, cognitive biases and heuristics, financial motive for gambling and psychological distress scales. Control variables include gender, age, income source and type of gambling patronized in the last 2 years. Using hierarchical regression, gamified problem gambling was found to have a positive effect on psychological distress. Also, cognitive biases & heuristics partially mediates between gamified problem gambling and psychological distress. Finally, financial motive for gambling moderates between gamified problem gambling and psychological distress. The outcomes bring to bear economic and non-economic motives that exacerbate psychological distress among young adults. Based on the vulnerability of problem gamblers in developing countries, the researchers recommend a need for stricter regulations to somewhat control online gambling frequency among young adults.

Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease: An Individual Participant Meta-Analysis.

Importance: There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension. Objective: To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension. Data Sources: Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022. Study Selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with orthostatic hypotension assessments. Data Extraction and Synthesis: Individual participant data meta-analysis extracted following PRISMA guidelines. Effects were determined using Cox proportional hazard models using a single-stage approach. Main Outcomes and Measures: Main outcomes were CVD or all-cause mortality. Orthostatic hypotension was defined as a decrease in systolic BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg after changing position from sitting to standing. Standing hypotension was defined as a standing systolic BP of 110 mm Hg or less or standing diastolic BP of 60 mm Hg or less. Results: The 9 trials included 29 235 participants followed up for a median of 4 years (mean age, 69.0 [SD, 10.9] years; 48% women). There were 9% with orthostatic hypotension and 5% with standing hypotension at baseline. More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline orthostatic hypotension (hazard ratio [HR], 0.81; 95% CI, 0.76-0.86) similarly to those with baseline orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00; P = .68 for interaction of treatment with baseline orthostatic hypotension). More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and nonsignificantly among those with baseline standing hypotension (HR, 0.94; 95% CI, 0.75-1.18). Effects did not differ by baseline standing hypotension (P = .16 for interaction of treatment with baseline standing hypotension). Conclusions and Relevance: In this population of hypertension trial participants, intensive therapy reduced risk of CVD or all-cause mortality regardless of orthostatic hypotension without evidence for different effects among those with standing hypotension.

Risk prediction models for incident type 2 diabetes in Chinese people with intermediate hyperglycemia: a systematic literature review and external validation study.

BACKGROUND: People with intermediate hyperglycemia (IH), including impaired fasting glucose and/or impaired glucose tolerance, are at higher risk of developing type 2 diabetes (T2D) than those with normoglycemia. We aimed to evaluate the performance of published T2D risk prediction models in Chinese people with IH to inform them about the choice of primary diabetes prevention measures. METHODS: A systematic literature search was conducted to identify Asian-derived T2D risk prediction models, which were eligible if they were built on a prospective cohort of Asian adults without diabetes at baseline and utilized routinely-available variables to predict future risk of T2D. These Asian-derived and five prespecified non-Asian derived T2D risk prediction models were divided into BASIC (clinical variables only) and EXTENDED (plus laboratory variables) versions, with validation performed on them in three prospective Chinese IH cohorts: ACE (n = 3241), Luzhou (n = 1333), and TCLSIH (n = 1702). Model performance was assessed in terms of discrimination (C-statistic) and calibration (Hosmer-Lemeshow test). RESULTS: Forty-four Asian and five non-Asian studies comprising 21 BASIC and 46 EXTENDED T2D risk prediction models for validation were identified. The majority were at high (n = 43, 87.8%) or unclear (n = 3, 6.1%) risk of bias, while only three studies (6.1%) were scored at low risk of bias. BASIC models showed poor-to-moderate discrimination with C-statistics 0.52-0.60, 0.50-0.59, and 0.50-0.64 in the ACE, Luzhou, and TCLSIH cohorts respectively. EXTENDED models showed poor-to-acceptable discrimination with C-statistics 0.54-0.73, 0.52-0.67, and 0.59-0.78 respectively. Fifteen BASIC and 40 EXTENDED models showed poor calibration (P < 0.05), overpredicting or underestimating the observed diabetes risk. Most recalibrated models showed improved calibration but modestly-to-severely overestimated diabetes risk in the three cohorts. The NAVIGATOR model showed the best discrimination in the three cohorts but had poor calibration (P < 0.05). CONCLUSIONS: In Chinese people with IH, previously published BASIC models to predict T2D did not exhibit good discrimination or calibration. Several EXTENDED models performed better, but a robust Chinese T2D risk prediction tool in people with IH remains a major unmet need.

Effects of Intensive Blood Pressure Treatment on Orthostatic Hypotension : A Systematic Review and Individual Participant-based Meta-analysis.

BACKGROUND: Although intensive blood pressure (BP)-lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH). PURPOSE: To examine the effects of intensive BP-lowering treatment on OH in hypertensive adults. DATA SOURCES: MEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions. STUDY SELECTION: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing. DATA EXTRACTION: 2 investigators independently abstracted articles and rated risk of bias. DATA SYNTHESIS: 5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH (P for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged. LIMITATIONS: Assessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available. CONCLUSION: Intensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753).

Can the cardiovascular risk reductions observed with empagliflozin in the EMPA-REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels?

AIM: To perform post-hoc analyses of the EMPA-REG OUTCOME trial examining the degree to which empagliflozin-induced changes in conventional cardiovascular (CV) risk factors might explain the observed CV benefits. MATERIALS AND METHODS: We estimated 3-year EMPA-REG OUTCOME CV event rates using a type 2 diabetes-specific clinical outcomes simulation model applied to annual patient-level data. Variables included were atrial fibrillation, smoking, albuminuria, HDL cholesterol, LDL cholesterol, systolic blood pressure, glycated haemoglobin, heart rate, white cell count, haemoglobin, estimated glomerular filtration rate, and histories of ischaemic heart disease, heart failure, amputation, blindness, renal failure, stroke, myocardial infarction or diabetic ulcer. Multiple simulations were performed for each participant to minimize uncertainty and optimize confidence interval precision around CV risk point estimates. Observed and simulated cardiovascular relative risk reductions were compared. RESULTS: Model-predicted relative risk reductions were smaller than those observed in the trial, with empagliflozin-associated changes in conventional CV risk factor values appearing to explain only 12% of the observed relative risk reduction for all-cause death (4% of 32%), 7% for CV death (3% of 39%) and 15% for heart failure (4% of 29%). CONCLUSIONS: Empagliflozin-associated changes in conventional CV risk factors in EMPA-REG OUTCOME appear to explain only a small proportion of the CV and all-cause death reductions observed. Alternative risk-reduction mechanisms need to be explored to determine if the observed CV risk changes can be explained by other factors, or possibly by a direct drug-specific effect.

Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.

BACKGROUND: Alpha-glucosidase inhibitors (AGIs) have been shown to reduce incident type 2 diabetes but their impact on cardiovascular (CV) disease remains controversial. We sought to identify the overall impact of AGIs with respect to incident type 2 diabetes in individuals with impaired glucose tolerance (IGT), and CV outcomes in those with IGT or type 2 diabetes. METHODS: We used PubMed and SCOPUS to identify randomized controlled trials reporting the incidence of type 2 diabetes and/or CV outcomes that had compared AGIs with placebo in populations with IGT or type 2 diabetes, with or without established CV disease. Eligible studies were required to have ≥ 500 participants and/or ≥ 100 endpoints of interest. Meta-analyses of available trial data were performed using random effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and CV outcomes. RESULTS: Of ten trials identified, three met our inclusion criteria for incident type 2 diabetes and four were eligible for CV outcomes. The overall HR (95% CI) comparing AGI with placebo for incident type 2 diabetes was 0.77 (0.67-0.88), p < 0.0001, and for CV outcomes was 0.98 (0.89-1.10), p = 0.85. There was little to no heterogeneity between studies, with I2 values of 0.03% (p = 0.43) and 0% (p = 0.79) for the two outcomes respectively. CONCLUSIONS: Allocation of people with IGT to an AGI significantly reduced their risk of incident type 2 diabetes by 23%, whereas in those with IGT or type 2 diabetes the impact on CV outcomes was neutral.

Long-term risk of cardiovascular disease in individuals with latent autoimmune diabetes in adults (UKPDS 85).

AIMS: Latent autoimmune diabetes in adults (LADA) is diagnosed in up to 12% of adults with clinically diagnosed type 2 diabetes (T2D). LADA tends to have healthier cardiovascular (CV) risk profiles than T2D, but it remains uncertain whether the risk of CV events differs between the two. We examined the risk of CV events in patients enrolled in the United Kingdom Prospective Diabetes Study (UKPDS) according to LADA status. MATERIALS AND METHODS: Diabetes autoantibodies (AAb) were measured in 5062 UKPDS participants. The incidence of major adverse CV events (MACE), defined as CV death, non-fatal myocardial infarction or non-fatal stroke, was compared in those with LADA (≥1 AAb test positive) and those without LADA (AAb negative). RESULTS: There were 567 participants (11.2%) with LADA. Compared with participants with T2D, they were younger, with higher mean HbA1c and HDL-cholesterol values, and with lower body mass index and total cholesterol and systolic blood pressure values (all P < 0.01). After a median (25th, 75th percentile) 17.3 (12.6-20.7) years of follow-up, MACE occurred in 157 (17.4 per 1000 person-years) participants with LADA and in 1544 (23.5 per 1000 person-years) participants with T2D (HR, 0.73; 95% confidence interval [CI], 0.62-0.86; P < 0.001). However, after adjustment for confounders, this difference was no longer significant (HRadj , 0.90; 95% CI, 0.76-1.07; P = 0.22). CONCLUSIONS: In adults thought to have newly diagnosed T2D, the long-term risk of MACE was lower in those with LADA. However, this did not differ after adjustment for traditional CV risk factors, suggesting that measurement of AAb in addition to traditional CV risk factors will not aid in stratification of CV risk in clinically diagnosed T2D.

Comparison of nine platelet function tests used to determine responses to different aspirin dosages in people with type 2 diabetes.

The antiplatelet efficacy of aspirin (ASA) is reduced in type 2 diabetes (T2D). As the best ex vivo method of measuring ASA efficacy remains uncertain, we compared nine platelet function tests to assess responsiveness to three ASA dosing regimens in 24 T2D patients randomized in a three-treatment crossover design to ASA 100 mg/day, 200 mg/day, or 100 mg twice daily for 2-week treatment periods. Platelet function tests compared were as follows: light transmission aggregometry (LTA)-0.5 mg/mL of arachidonic acid (AA) and 10 µM adenosine diphosphate (ADP); multiplate whole blood aggregometry (WBA)-0.5 mM AA and 6.5 µM ADP; platelet function analyzer (PFA)-100™-collagen and ADP (CADP) and collagen and epinephrine (CEPI); VerifyNow™-ASA; and urinary 11-dehydro-thromboxane B2 (TxB2) and serum TxB2. All cyclo-oxygenase (COX-1)-dependent tests and some COX-1-independent tests (PFA-CEPI, LTA-ADP) demonstrated significant reductions in platelet reactivity with all ASA doses. Two COX-1-independent tests (WBA-ADP and PFA-CADP) showed no overall reduction in platelet reactivity. Overall classifications for detecting all ASA doses, compared to baseline, were as follows: very good-LTA-AA (k = 0.95) and VerifyNow™-ASA (k = 0.85); good-serum TxB2 (k = 0.79); moderate-LTA-ADP (k = 0.59), PFA-100™-CEPI (k = 0.56), urinary TxB2 (k = 0.55), WBA-AA (k = 0.47); and poor-PFA-100™-CADP (k = -0.02) and WBA-ADP (k = -0.07). No significant kappa statistic differences were seen for each test for each ASA dose. Correlations for each test with serum TxB2 measurements were as follows: very good-VerifyNow™-ASA (k = 0.81, R2 = 0.56) and LTA-AA (k = 0.85, R2 = 0.65); good-PFA-100TM-CEPI (k = 0.62, R2 = 0.30); moderate-urinary TxB2 (k = 0.57, R2 = 0.51) and LTA-ADP (k = 0.47, R2 = 0.56); fair-WBA-AA (k = 0.31, R2 = 0.31); and poor-PFA-100™-CADP (k = 0.04, R2 = 0.003) and WBA-ADP (k = -0.04, R2 = 0.0005). The platelet function tests we assessed were not equally effective in measuring the antiplatelet effect of ASA and correlated poorly amongst themselves, but COX-1-dependent tests performed better than non-COX-1-dependent tests.

Prognostic significance of silent myocardial infarction in newly diagnosed type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 79.

BACKGROUND: We aimed to determine the prevalence of silent myocardial infarction (SMI) in people with newly diagnosed type 2 diabetes mellitus and its relationships to future myocardial infarction (MI) and all-cause mortality. METHODS AND RESULTS: We examined data from the 5102 patients in the 30-year UK Prospective Diabetes Study (UKPDS) and used Cox proportional hazards regression to examine outcomes by SMI status. Of 1967 patients with complete baseline data, 326 (16.6%) had ECG evidence of SMI (Minnesota codes 1.1 or 1.2) at enrollment. Those with SMI were more likely to be older, female, sedentary, and nonsmokers compared with those without SMI. Their mean blood pressure was greater despite more intensive antihypertensive treatment; they were more likely to be taking aspirin and lipid-lowering therapy; and they had a greater prevalence of microangiopathy. Fully adjusted hazard ratios for those with versus those without SMI in multivariate models that included UKPDS Risk Engine variables were 1.58 (95% confidence interval, 1.22-2.05) for fatal MI and 1.31 (95% confidence interval, 1.10-1.56) for all-cause mortality. Hazard ratios for first fatal or nonfatal MI and for first nonfatal MI were nonsignificant. The net reclassification index showed no improvement when SMI was added to these models, and the integrated discrimination index showed that SMI marginally improved the prediction of fatal MI and all-cause mortality. CONCLUSIONS: About 1 in 6 UKPDS patients with newly diagnosed type 2 diabetes mellitus had evidence of SMI, which was independently associated with an increased risk of fatal MI and all-cause mortality. However, identification of SMI does not add substantively to current UKPDS Risk Engine predictive variables. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Identifier: ISRCTN number 75451837.

Younger-onset compared with later-onset type 2 diabetes: an analysis of the UK Prospective Diabetes Study (UKPDS) with up to 30 years of follow-up (UKPDS 92).

BACKGROUND: Younger-onset type 2 diabetes is associated with accelerated complications. We assessed whether complications and mortality rates differed for younger age compared with older age at diagnosis over 30 years of follow-up. METHODS: In this study, we used data from the UKPDS, collected between 1977 and 2007, of participants aged 25-65 years with newly diagnosed type 2 diabetes with younger-onset (younger than 40 years) or later-onset (40 years or older), and without diabetes autoantibodies. We analysed standardised mortality ratios (SMR) using UK general population data, and incidence rates of prespecified outcomes by 10-year age intervals at diagnosis. FINDINGS: Of 4550 participants testing negative to all measured autoantibodies, 429 (9·4%) had younger-onset type 2 diabetes. 2704 (59·4%) were male, and mean HbA1c was 76 mmol/mol (SD 24·6). The median follow-up was 17·5 years (IQR 12·7-20·8). SMR for younger-onset type 2 diabetes was higher (3·72 [95% CI 2·98-4·64]) compared with later-onset type 2 diabetes (1·54 [1·47-1·61]). The incidence rate was higher for all outcomes in later-onset type 2 diabetes, except for microvascular disease (younger-onset 14·5 (11·9-17·7) vs later-onset 12·1 (11·3-13·0) per 1000 person-years). However, at any given age, the 5-year incidence of any diabetes-related endpoint, all-cause mortality, microvascular disease, and myocardial infarction was higher with younger age at diagnosis. Annual mean HbA1c was higher in the first 20 years in younger-onset compared with later-onset type 2 diabetes. Among participants randomised to intensive versus conventional glycaemic control, we observed no interactions by subgroup of younger-onset versus later-onset type 2 diabetes for any outcome. INTERPRETATION: The risk of dying relative to the general population is even greater for people diagnosed with type 2 diabetes at younger ages. The increased risk of complications and poorer glycaemic control in younger-onset type 2 diabetes calls for the development of services to identify and manage these individuals. FUNDING: National Institute of Health and Care Research's Biomedical Research Centre.

Comparison of medical resources and costs among patients with coronary heart disease and impaired glucose tolerance in the Acarbose Cardiovascular Evaluation trial.

BACKGROUND: The Acarbose Cardiovascular Evaluation (ACE) trial (ISRCTN91899513) evaluated the alpha-glucosidase inhibitor acarbose, compared with placebo, in 6522 patients with coronary heart disease and impaired glucose tolerance in China and showed a reduced incidence of diabetes. We assessed the within-trial medical resource use and costs, and quality-adjusted life years (QALYs). METHODS: Resource use data were collected prospectively within the ACE trial. Hospitalizations, medications, and outpatient visits were valued using Chinese unit costs. Medication use was measured in drug days, with cardiovascular and diabetes drugs summed across the trial by participant. Health-related quality of life was captured using the EuroQol-5 Dimension-3 Level questionnaire. Regression analyses were used to compare resource use, costs, and QALYs, accounting for regional variation. Costs and QALYs were discounted at 3% yearly. RESULTS: Hospitalizations were 6% higher in the acarbose arm during the trial (rate ratio 1.06, p = .009), but there were no significant differences in total inpatient days (rate ratio 1.04, p = .30). Total costs per participant, including study drug, were significantly higher for acarbose (¥ [Yuan] 56 480, £6213), compared with placebo (¥48 079, £5289; mean ratio 1.18, p < 0.001). QALYs reported by participants in the acarbose arm (3.96 QALYs) were marginally higher than in the placebo arm (3.95 QALYs), but the difference was not statistically significant (0.01 QALYs; p = .58). CONCLUSIONS: Acarbose, compared with placebo, participants cost more due to study drug costs and reported no statistically significant difference in QALYs. These higher within-trial costs could potentially be offset in future by savings from the acarbose-related lower incidence of diabetes.

Computer modeling of diabetes and its complications: a report on the Fifth Mount Hood challenge meeting.

OBJECTIVES: The Mount Hood Challenge meetings provide a forum for computer modelers of diabetes to discuss and compare models, to assess predictions against data from clinical trials and other studies, and to identify key future developments in the field. This article reports the proceedings of the Fifth Mount Hood Challenge in 2010. METHODS: Eight modeling groups participated. Each group was given four modeling challenges to perform (in type 2 diabetes): to simulate a trial of a lipid-lowering intervention (The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus [ASPEN]), to simulate a trial of a blood glucose-lowering intervention (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE]), to simulate a trial of a blood pressure-lowering intervention (Cardiovascular Risk in Diabetes [ACCORD]), and (optional) to simulate a second trial of blood glucose-lowering therapy (ACCORD). Model outcomes for each challenge were compared with the published findings of the respective trials. RESULTS: The results of the models varied from each other and, in some cases, from the published trial data in important ways. In general, the models performed well in terms of predicting the relative benefit of interventions, but performed less well in terms of quantifying the absolute risk of complications in patients with type 2 diabetes. Methodological challenges were highlighted including matching trial end-point definitions, the importance of assumptions concerning the progression of risk factors over time, and accurately matching the patient characteristics from each trial. CONCLUSIONS: The Fifth Mount Hood Challenge allowed modelers, through systematic comparison and validation exercises, to identify important differences between models, address key methodological challenges, and discuss avenues of research to improve future diabetes models.

Bubble-PAPR: a phase 1 clinical evaluation of the comfort and perception of a prototype powered air-purifying respirator for use by healthcare workers in an acute hospital setting.

OBJECTIVES: We aimed to design and produce a low-cost, ergonomic, hood-integrated powered air-purifying respirator (Bubble-PAPR) for pandemic healthcare use, offering optimal and equitable protection to all staff. We hypothesised that participants would rate Bubble-PAPR more highly than current filtering face piece (FFP3) face mask respiratory protective equipment (RPE) in the domains of comfort, perceived safety and communication. DESIGN: Rapid design and evaluation cycles occurred based on the identified user needs. We conducted diary card and focus group exercises to identify relevant tasks requiring RPE. Lab-based safety standards established against British Standard BS-EN-12941 and EU2016/425 covering materials; inward particulate leakage; breathing resistance; clean air filtration and supply; carbon dioxide elimination; exhalation means and electrical safety. Questionnaire-based usability data from participating front-line healthcare staff before (usual RPE) and after using Bubble-PAPR. SETTING: Overseen by a trial safety committee, evaluation progressed sequentially through laboratory, simulated, low-risk, then high-risk clinical environments of a single tertiary National Health Service hospital. PARTICIPANTS: 15 staff completed diary cards and focus groups. 91 staff from a range of clinical and non-clinical roles completed the study, wearing Bubble-PAPR for a median of 45 min (IQR 30-80 (15-120)). Participants self-reported a range of heights (mean 1.7 m (SD 0.1, range 1.5-2.0)), weights (72.4 kg (16.0, 47-127)) and body mass indices (25.3 (4.7, 16.7-42.9)). OUTCOME MEASURES: Preuse particulometer 'fit testing' and evaluation against standards by an independent biomedical engineer.Primary:Perceived comfort (Likert scale).Secondary: Perceived safety, communication. RESULTS: Mean fit factor 16 961 (10 participants). Bubble-PAPR mean comfort score 5.64 (SD 1.55) vs usual FFP3 2.96 (1.44) (mean difference 2.68 (95% CI 2.23 to 3.14, p<0.001). Secondary outcomes, Bubble-PAPR mean (SD) versus FFP3 mean (SD), (mean difference (95% CI)) were: how safe do you feel? 6.2 (0.9) vs 5.4 (1.0), (0.73 (0.45 to 0.99)); speaking to other staff 7.5 (2.4) vs 5.1 (2.4), (2.38 (1.66 to 3.11)); heard by other staff 7.1 (2.3) vs 4.9 (2.3), (2.16 (1.45 to 2.88)); speaking to patients 7.8 (2.1) vs 4.8 (2.4), (2.99 (2.36 to 3.62)); heard by patients 7.4 (2.4) vs 4.7 (2.5), (2.7 (1.97 to 3.43)); all p<0.01. CONCLUSIONS: Bubble-PAPR achieved its primary purpose of keeping staff safe from airborne particulate material while improving comfort and the user experience when compared with usual FFP3 masks. The design and development of Bubble-PAPR were conducted using a careful evaluation strategy addressing key regulatory and safety steps. TRIAL REGISTRATION NUMBER: NCT04681365.

11ß-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial.

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates active glucocorticoid, we investigated whether 11ß-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.