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

Associations between SARS-CoV-2 infection and incidence of new chronic condition diagnoses: a systematic review

ABSTRACTBecause of the large number of infected individuals, an estimate of the future burdens of the long-term consequences of SARS-CoV-2 infection is needed. This systematic review examined associations between SARS-CoV-2 infection and incidence of categories of and selected chronic conditions, by age and severity of infection (inpatient vs. outpatient/mixed care). MEDLINE and EMBASE were searched (1 January 2020 to 4 October 2022) and reference lists scanned. We included observational studies from high-income OECD countries with a control group adjusting for sex and comorbidities. Identified records underwent a two-stage screening process. Two reviewers screened 50% of titles/abstracts, after which DistillerAI acted as second reviewer. Two reviewers then screened the full texts of stage one selections. One reviewer extracted data and assessed risk of bias; results were verified by another. Random-effects meta-analysis estimated pooled hazard ratios (HR). GRADE assessed certainty of the evidence. Twenty-five studies were included. Among the outpatient/mixed SARS-CoV-2 care group, there is high certainty of a small-to-moderate increase (i.e. HR 1.26–1.99) among adults ≥65 years of any cardiovascular condition, and of little-to-no difference (i.e. HR 0.75–1.25) in anxiety disorders for individuals <18, 18–64, and ≥65 years old. Among 18–64 and ≥65 year-olds receiving outpatient/mixed care there are probably (moderate certainty) large increases (i.e. HR ≥2.0) in encephalopathy, interstitial lung disease, and respiratory failure. After SARS-CoV-2 infection, there is probably an increased risk of diagnoses for some chronic conditions; whether the magnitude of risk will remain stable into the future is uncertain

Older adults’ experiences and perceived impacts of the Aging, Community and Health Research Unit-Community Partnership Program (ACHRU-CPP) for diabetes self-management in Canada: a qualitative descriptive study

Objectives To assess the experiences and perceived impacts of the Aging, Community and Health Research Unit-Community Partnership Program (ACHRU-CPP) from the perspectives of older adults with diabetes and other chronic conditions. The ACHRU-CPP is a complex 6-month self-management evidence-based intervention for community-living older adults aged 65 years or older with type 1 or type 2 diabetes and at least one other chronic condition. It includes home and phone visits, care coordination, system navigation support, caregiver support and group wellness sessions delivered by a nurse, dietitian or nutritionist, and community programme coordinator.Design Qualitative descriptive design embedded within a randomised controlled trial was used.Setting Six trial sites offering primary care services from three Canadian provinces (ie, Ontario, Quebec and Prince Edward Island) were included.Participants The sample was 45 community-living older adults aged 65 years or older with diabetes and at least one other chronic condition.Methods Participants completed semistructured postintervention interviews by phone in English or French. The analytical process followed Braun and Clarke’s experiential thematic analysis framework. Patient partners informed study design and interpretation.Results The mean age of older adults was 71.7 years, and the mean length of time living with diabetes was 18.8 years. Older adults reported positive experiences with the ACHRU-CPP that supported diabetes self-management, such as improved knowledge in managing diabetes and other chronic conditions, enhanced physical activity and function, improved eating habits, and opportunities for socialisation. They reported being connected to community resources by the intervention team to address social determinants of health and support self-management.Conclusions Older adults perceived that a 6-month person-centred intervention collaboratively delivered by a team of health and social care providers helped support chronic disease self-management. There is a need for providers to help older adults connect with available health and social services in the community.Trial registration number ClinicalTrials.gov ID: NCT03664583; Results

CONCEPTT : Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol

Women with type 1 diabetes strive for optimal glycemic control before and during pregnancy to avoid adverse obstetric and perinatal outcomes. For most women, optimal glycemic control is challenging to achieve and maintain. The aim of this study is to determine whether the use of real-time continuous glucose monitoring (RT-CGM) will improve glycemic control in women with type 1 diabetes who are pregnant or planning pregnancy. A multi-center, open label, randomized, controlled trial of women with type 1 diabetes who are either planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤ 86 mmol/mol) or are in early pregnancy (<13 weeks 6 days) with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤ 86 mmol/mol). Participants will be randomized to either RT-CGM alongside conventional intermittent home glucose monitoring (HGM), or HGM alone. Eligible women will wear a CGM which does not display the glucose result for 6 days during the run-in phase. To be eligible for randomization, a minimum of 4 HGM measurements per day and a minimum of 96 hours total with 24 hours overnight (11 pm-7 am) of CGM glucose values are required. Those meeting these criteria are randomized to RT- CGM or HGM. A total of 324 women will be recruited (110 planning pregnancy, 214 pregnant). This takes into account 15 and 20 % attrition rates for the planning pregnancy and pregnant cohorts and will detect a clinically relevant 0.5 % difference between groups at 90 % power with 5 % significance. Randomization will stratify for type of insulin treatment (pump or multiple daily injections) and baseline HbA1c. Analyses will be performed according to intention to treat. The primary outcome is the change in glycemic control as measured by HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation during pregnancy. Secondary outcomes include maternal hypoglycemia, CGM time in, above and below target (3.5-7.8 mmol/l), glucose variability measures, maternal and neonatal outcomes. This will be the first international multicenter randomized controlled trial to evaluate the impact of RT- CGM before and during pregnancy in women with type 1 diabetes. NCT01788527 December 19, 2012

Characterization of Antiestrogenic Activity of the Chinese Herb, Prunella vulgaris, Using In Vitro and In Vivo (Mouse Xenograft) Models1

Prunella vulgaris (PV), a commonly used Chinese herb, also known as Self-heal, has a wide range of reported medicinal activities. By screening multiple herbs using the endometrial cancer cell line, ECC-1, and an alkaline phosphatase detection assay, we found that PV displayed significant antiestrogenic activity. We investigated the possible usefulness of antiestrogenic activity using both in vitro and in vivo models of endometrial function. Using the well-differentiated, hormone-responsive endometrial cell line, ECC-1, PV extract, at concentrations that were not toxic to the cells, significantly reduced alkaline phosphatase activity and cell proliferation in response to estrogen in a dose-dependent manner. The expression of CYR61, an estrogen-induced protein, was blocked in ECC-1 cells by both the antiestrogen ICI 182 780 and PV extract. Interestingly, PV extract did not appear to directly inhibit estrogen signaling. Rather, we found that its activities were probably related to an ability to function as an aryl hydrocarbon receptor (AHR) agonist in ECC-1 cells. In support of this hypothesis, we noted that PV induced CYP1A1, CYP1B1, and AHR repressor expression in a dose-dependent manner—responses that were blocked by small interfering RNA treatment to reduce AHR and specific AHR antagonists. Ovariectomized immunodeficient RAG-2/gamma(c) knockout mice implanted with human endometrial xenografts developed implants only when treated with estrogen. Mice treated with estrogen and PV tea in their drinking water had fewer and smaller xenograft implants compared with their estrogen-treated counterparts that drank only water (P < 0.05). Analysis of the resulting implants by immunohistochemistry demonstrated persistent estrogen receptor (ER), but reduced proliferation and CYR61 expression. Mouse uterine tissue weight in PV-treated mice was not different from controls, and cycle fecundity of intact C57 female mice was unaffected by PV tea treatment. PV, or Self-heal, exhibits significant antiestrogenic properties, both in vitro and in vivo. This activity is likely due to the ability of PV-activated AHR to interfere with estrogen. This herb may be useful as an adjunct for the treatment of estrogen-dependent processes like endometriosis and breast and uterine cancers. Full characterization of this herb will likely provide new insights into the crosstalk between AHR and ESR1, with potential for therapeutic applications in women