Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Transgender Women’s Drug Use in the Dominican Republic

Purpose: Studies on drug use in transgender populations, particularly those in resource-limited settings, are scarce. Considering that drug use can be a coping mechanism to deal with stigma and traumatic experiences, we examined associations between stigma, trauma, and drug use in a national sample of transgender women from the Dominican Republic. Methods: Bivariate analyses examined differences between drug users and abstainers (n=287). Multivariate analyses reported odds ratios (OR) with general drug, marijuana, and cocaine use as outcomes (n=243). Results: A quarter of respondents (24.5%) experienced sexual abuse, 12.1% were tortured, and 20.1% experienced a murder attempt. More than a quarter reported using illegal drugs (26.1%). Drug users had lower socioeconomic status; 30.0% of drug users had a primary level of education or less (18.2% of abstainers) and 17.6% of drug users had higher income, defined as greater than 10,001 pesos (∼$210 United States Dollars, USD) per month (28.1% of abstainers). More than half of drug users experienced some form of trauma (51.4%) compared to 43.5% of abstainers, and 28.4% of drug users, compared to 17.1% of abstainers, experienced a murder attempt on her life. Independent sample t-tests found significant differences between drug users and abstainers. Transgender women who experienced sexual abuse had three times high odds of using cocaine. Drug users were more likely to have experienced sexual abuse and attempted suicide (p<0.05 for both). Respondents who attempted suicide had higher odds of using drugs generally and using marijuana specifically, compared to respondents who had not attempted suicide (OR=2.665 and 3.168, respectively). Higher scores on the stigma scale were associated with higher odds of any drug use and cocaine use (OR=1.132 and 1.325, respectively). Conclusions: Although some nations have implemented antidiscrimination policies protecting transgender citizens, these policies are not consistently enforced. Eliminating stigma and stigmatizing policies may reduce rates of drug use as a coping mechanism.University of Alabama at Birmingham (UAB) Sparkman Center for Global Healt

Influence of Hepatitis C Virus Sustained Virological Response on Immunosuppressive Tryptophan Catabolism in ART-Treated HIV/HCV Coinfected Patients

Background: We previously reported an association between tryptophan (Trp) catabolism and immune dysfunction in HIV monoinfection. Coinfection with HIV is associated with more rapid evolution of hepatitis C virus (HCV)-associated liver disease despite antiretroviral therapy (ART), possibly due to immune dysregulation. We hypothesized that liver fibrosis in HIV/HCV coinfection would be associated with immune dysfunction and alterations in Trp metabolism. Methods: Trp catabolism and inflammatory soluble markers were assessed in plasma samples from ART-treated HIV/HCV-coinfected patients (n = 90) compared with ART-treated HIV-monoinfected patients and noninfected subjects. Furthermore, 17 additional coinfected patients with sustained virological response (SVR) were assessed longitudinally 6 months after completion of interferon-alpha/ribavirin treatment. Results: HIV/HCV patients had higher Trp catabolism compared with HIV-monoinfected and healthy individuals. Elevated kynurenine levels in HIV/HCV patients with liver fibrosis correlated with the prognostic aspartate aminotransaminase to platelet ratio (APRI scores) and insulin levels. Furthermore, HIV/HCV patients had elevated levels of disease progression markers interleukin-6 and induced protein 10 and shared similar levels of markers of microbial translocation (intestinal fatty acid-binding protein, soluble CD14 and lipopolysaccharide-binding protein) compared with HIV-monoinfected and healthy individuals. Successful HCV treatment improved APRI score and markers of disease progression and microbial translocation although elevated Trp catabolism remained unchanged 6 months after SVR. Conclusion: ART-treated HIV/HCV-coinfected patients had elevated immunosuppressive Trp catabolism when compared with monoinfected HIV-treated patients, which did not normalize after SVR. These findings suggest that a necroinflammatory liver syndrome persists through inflammation by Trp catabolism after 6 month of SVR

The need for a consensus in the use of assessment tools for Alzheimer's disease: The Feasibility Study (assessment tools for dementia in Alzheimer Centres across Europe), a European Alzheimer's Disease Consortium's (EADC) survey

Aims To ensure that all Alzheimer centres across Europe are capable of using a similar method of data collection. Information about the patient assessment tools used by each participating centre was obtained and normal clinical practice in each EADC centre was documented by collecting data from routine new patient consultation. Methods Twenty new consecutive patients with objective memory impairment were recruited in each Alzheimer centre over 6 months. Each patient consultation was carried out according to routine clinical practice. Patient data were recorded using the anonymous patient protocol (demographic, diagnosis, MMSE score, patient assessment scales, and most prominent behavioural problem). Information about neuropsychological assessment tools used in each centre was take to account to harmonise research practice for future multicentre collaboration. Results Seven hundred and four patients from 36 memory clinics in 13 countries across Europe participated in the study. [M:F ratio 0.67. Mean age 75.4 SD 9.3 (51-102) Mean MMSE 21 SD 6 (0-30)] Five hundred and fifty-five patients had a clinical diagnosis of dementia [Alzheimer's disease (68.5%), vascular dementia (10.3%), frontal lobe dementia (5.6%), Lewy body dementia (4.1%), mixed dementia (5.6%)]. Duration of symptoms: 0-6 months 6.5%; 6-12 months 16.1%; 1-2 years 30.5%; 2-5 years 46.9%. Assessment scales used: Clinical Dementia Rating (CDR) 48.9%, Reisberg's Global Deterioration Scale (GDS) 38.6%, ADL/IADL (Lawton and Brody, 1969) 37.5%, Neuropsychological Inventory (NPI) 28.6%, Geriatric Depression Scale 22%, ADL (Katz et al., 1963) 19.2%, ADAS-Cog 14.9%, Cornell Scale for Depression 12.9%, Grober and Bushke Selective Reminding Test 11.5%, ADCS/ADL 7.7%. 64.8% of the patients experienced behavioural symptoms: apathy 13.6%; anxiety 12.8%; dysphoria 9.9%; irritability 7.8%; agitation 5.5%; hallucinations 3.6%; delusions 3.6%, sleep disorder 2.4%; desinhibition 2%. Conclusions The most common type of cognitive decline was Alzheimer's disease followed by mild cognitive impairment and vascular dementia. CDR, GDS Reisberg, and ADL/IADL were used widely (40-50%). The NPI, geriatric depression scale and ADL (Katz, 1963) were only used in 20% of the centres. We verified large differences in the tools use in the EADC centres to evaluate patients with dementia across Europe. There is a need for a consensus in the use of assessment tools for dementia in Alzheimer's centres in Europe. Copyright (c) 2005 John Wile

Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes

BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo