Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults.

Background: Recent studies have reported associations between high plasma high-density lipoprotein cholesterol (HDL-C) levels and risk of all-cause mortality, age-related macular degeneration, sepsis and fractures, but associations with dementia risk remain unclear. To determine whether high plasma HDL-C levels are associated with increased incident dementia risk in initially-healthy older people. Methods: We conducted a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial; a double-blind, randomized, placebo-controlled trial of daily low-dose aspirin in healthy older people. ASPREE recruited 16,703 participants aged ≥70 years (from Australia) and 2411 participants aged ≥65 years (from the US) between 2010 and 2014. Participants had no diagnosed cardiovascular disease, dementia, physical disability, or life-threatening illness at enrolment and were cognitively healthy (3MS score ≥78). All-cause dementia was a primary trial endpoint, and determined by DSM-IV criteria. Cox regression was used to examine hazard ratios between HDL-C categories <40 mg/dL, 40-60 mg/dL (reference category), 60-80 mg/dL, and >80 mg/dL and dementia. Restricted cubic spline curves were used to determine nonlinear associations. Data analysis was performed from October 2022 to January 2023. Findings: Of the 18,668 participants, 850 (4.6%) cases of incident dementia were recorded over 6.3 (SD 1.8) years. Participants with high HDL-C (>80 mg/dL) had a 27% higher risk of dementia (HR 1.27, 95% CI 1.03, 1.58). Age stratified analyses demonstrated that the risk of incident dementia was higher in participants ≥75 years compared to participants <75 years (HR 1.42, 95% CI 1.10, 1.83 vs HR 1.02, 95% CI 0.68, 1.51). Associations remained significant after adjusting for covariates including age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-PRS, and APOE genotype. Interpretation: In a population of initially-healthy older adults aged ≥75 years, high HDL-C levels were associated with increased risk of all-cause dementia. Funding: National Institutes of Health, USA; National Health and Medical Research Council Australia; Monash University (Melbourne, VIC, Australia); and the Victorian Cancer Agency (Australia).

Long-term blood pressure variability and frailty risk in older adults.

INTRODUCTION: In healthy older adults, the relationship between long-term, visit-to-visit variability in blood pressure (BP) and frailty is uncertain. METHODS: Secondary analysis of blood pressure variability (BPV) and incident frailty in >13 000 participants ≥65-70 years enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial and its observational follow-up (ASPREE-XT). Participants were without dementia, physical disability, or cardiovascular disease at baseline. BPV was estimated using standard deviation of mean BP from three annual visits (baseline through the second annual follow-up). Frailty was defined using Fried phenotype and a frailty deficit accumulation index (FDAI). Participants with frailty during the BPV estimation period were excluded from the main analysis. Adjusted Cox proportional hazards regression evaluated the association between BPV and incident frailty, and linear mixed models for change in frailty scores, through a maximum of 9 years of follow-up. RESULTS: Participants in the highest systolic BPV tertile were at higher risk of frailty compared to those in the lowest (referent) tertile of systolic BPV [Fried hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.04-1.31; FDAI HR 1.18, 95% CI 1.07-1.30]. Findings were consistent when adjusted for multiple covariates and when stratified by antihypertensive use. Linear mixed models showed that higher systolic BPV was associated with increasing frailty score over time. Diastolic BPV was not consistently associated. CONCLUSIONS: High systolic BPV, independent of mean BP, is associated with increased risk of frailty in healthy older adults. Variability of BP across visits, even in healthy older adults, can convey important risk information beyond mean BP. TRIAL REGISTRATION: ClinicalTrials.gov NCT01038583 and ISRCTN83772183.

Angiotensin Receptor Blockers and Cognition: a Scoping Review.

PURPOSE OF REVIEW: To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes. RECENT FINDINGS: ARBs have previously shown greater neuroprotection compared to other anti-hypertensive classes. The benefits are primarily attributed to the ARB's effect on modulating the renin-angiotensin system via inhibiting the Ang II/AT1R pathway and activating the Ang II/AT2R, Ang IV/AT4R, and Ang-(1-7)/MasR pathways. These interactions are associated with pleiotropic neurocognitive benefits, including reduced ß-amyloid accumulation and abnormal hyperphosphorylation of tau, ameliorated brain hypo-fusion, reduced neuroinflammation and synaptic dysfunction, better neurotoxin clearing, and blood-brain barrier function restoration. While ACEis also inhibit AT1R, they simultaneously lower Ang II and block the Ang II/AT2R and Ang IV/AT4R pathways that counterbalance the potential benefits. ARBs may be considered an adjunctive approach for neuroprotection. This preliminary evidence, coupled with their underlying mechanistic pathways, emphasizes the need for future long-term randomized trials to yield more definitive results.

Daily low-dose aspirin and incident type 2 diabetes in community-dwelling healthy older adults: a post-hoc analysis of efficacy and safety in the ASPREE randomised placebo-controlled trial.

BACKGROUND: Inflammation has been implicated in the pathogenesis of diabetes. This study investigated the randomised treatment effect of low-dose aspirin on incident type 2 diabetes and fasting plasma glucose (FPG) concentrations among older adults. METHODS: ASPREE was a double-blind, placebo-controlled trial of daily oral low-dose aspirin. The study population included community-dwelling individuals aged 70 years or older (≥65 years for US minority ethnic groups) in the USA and Australia who were free of cardiovascular disease, independence-limiting physical disability, or dementia. For the post-hoc analysis, we excluded participants with diabetes at baseline or with incomplete or missing incident diabetes data during follow-up. Participants were randomly assigned 1:1 to oral 100 mg daily enteric-coated aspirin or placebo. Incident diabetes was defined as self-reported diabetes, commencement of glucose-lowering medication, or a FPG concentration of 7·0 mmol/L or more assessed at annual follow-up visits among participants with no diabetes at baseline. We used Cox proportional hazards models and mixed-model repeated measures to assess the effect of aspirin on incident diabetes and FPG concentrations in the intention-to-treat population. We assessed major bleeding in participants who had taken at least one dose of study medication. FINDINGS: Between March 10, 2010, and Dec 24, 2014, a total of 16 209 participants were included (8086 [49·9%] randomly assigned to aspirin and 8123 [50·1%] randomly assigned to placebo). During a median follow-up of 4·7 years (IQR 3·6-5·7), 995 (in 6·1% individuals) incident cases of type 2 diabetes were recorded (459 in the aspirin group and 536 in the placebo group). Compared with placebo, the aspirin group had a 15% reduction in risk of incident diabetes (hazard ratio 0·85 [95% CI 0·75 to 0·97]; p=0·013) and a slower rate of increase in FPG concentration at year 5 (between-group difference estimate -0·048 mmol/L [95% CI -0·079 to -0·018]; p=0·0017). Major bleeding (major gastrointestinal bleeding, intracranial bleeding, and clinically significant bleeding at other sites) occurred in 510 (3·2%) of 16 104 participants (300 [3·7%] in the aspirin group and 210 [2·6%] in the placebo group). Compared with placebo, the aspirin group had a 44% increase in risk of major bleeding (hazard ratio 1·44 [95% CI 1·21 to 1·72]; p<0·0001). INTERPRETATION: Aspirin treatment reduced the incidence of type 2 diabetes and slowed the increase in FPG concentration but increased major bleeding among community-dwelling older adults. Given the increasing prevalence of type 2 diabetes among older adults, the potential for anti-inflammatory agents such as aspirin to prevent type 2 diabetes or improve glucose levels warrants further study with a comprehensive assessment of all potential safety events of interest. FUNDING: US National Institute on Aging, US National Cancer Institute, National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency.

Low-density-lipoprotein cholesterol and mortality outcomes among healthy older adults: A post-hoc analysis of ASPREE trial.

BACKGROUND: The prognostic implication of cholesterol levels in older adults remains uncertain. This study aimed to examine the relationship between low-density-lipoprotein-cholesterol (LDL-c) and mortality outcomes in older individuals. METHODS: This post-hoc analysis examined the associations of LDL-c levels with mortality risks from all-cause, CVD, cancer, and combined non-CVD/non-cancer conditions in a cohort of individuals aged ≥65 years from the ASPREE trial (NCT01038583). At baseline, participants had no diagnosed dementia, physical disability, or cardiovascular disease (CVD), and were not taking lipid-lowering agents. Outcome analyses were performed using multivariable Cox models. RESULTS: We analysed 12,334 participants (mean age:75.2 years). Over a median 7-year follow-up, 1250 died. Restricted cubic splines found a U-shaped relation for LDL-c and all-cause mortality, cancer mortality, and non-cancer/non-CVE mortality (nadir: 3.3-3.4 mmol/L); the risk of CVD mortality was similar at LDL-c below 3.3 mmol/L and increased above 3.3 mmol/L. The similar trends were observed in analyses modelling LDL-c by quartiles. When modelling LDL-c as a continuous variable, the risk of all-cause mortality, cancer mortality, and non-cancer/non-CVD mortality was decreased by 9%, 16% and 18% respectively per 1-mmol/L higher LDL-c, and the risk of CVD mortality was increased by 19% per 1-mmol/L higher LDL-c. Reduced all-cause and non-CVD/non-cancer mortality risks were only significant in males but not females (Pinteraction <0.05). CONCLUSIONS: There were U-shaped relationships between LDL-c and all-cause mortality, cancer mortality, and non-cancer/non-CVD mortality in healthy older adults. Higher LDL-c levels were associated with an increased risk of CVD mortality. Future studies are warranted to confirm our results.

Association Between Triglycerides and Risk of Dementia in Community-Dwelling Older Adults: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: It has been suggested that higher triglyceride levels were associated with a lower risk of Alzheimer disease. This study aimed to examine the association of triglycerides with dementia and cognition change in community-dwelling older adults. METHODS: This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial of adults aged 65 years or older without dementia or previous cardiovascular events at enrollment. The main outcome was incident dementia. Other outcomes included changes in composite cognition and domain-specific cognition (global cognition, memory, language and executive function, and psychomotor speed). The association between baseline triglycerides and dementia risk was estimated using Cox proportional hazard models adjusting for relevant risk factors. Linear mixed models were used to investigate cognitive change. The analysis was repeated in a subcohort of participants with available APOE-ε4 genetic data with additional adjustment for APOE-ε4 carrier status and an external cohort (UK Biobank) with similar selection criteria applied. RESULTS: This study included 18,294 ASPREE participants and 68,200 UK Biobank participants (mean age: 75.1 and 66.9 years; female: 56.3% and 52.7%; median [interquartile range] triglyceride: 106 [80-142] mg/dL and 139 [101-193] mg/dL), with dementia recorded in 823 and 2,778 individuals over a median follow-up of 6.4 and 12.5 years, respectively. Higher triglyceride levels were associated with lower dementia risk in the entire ASPREE cohort (hazard ratio [HR] with doubling of triglyceride: 0.82, 95% CI 0.72-0.94). Findings were similar in the subcohort of participants with APOE-ε4 genetic data (n = 13,976) and in the UK Biobank cohort (HR was 0.82 and 0.83, respectively, all p ≤ 0.01). Higher triglycerides were also associated with slower decline in composite cognition and memory over time (p ≤ 0.05). DISCUSSION: Older adults with higher triglyceride levels within the normal to high-normal range had a lower dementia risk and slower cognitive decline over time compared with individuals with lower triglyceride levels. Higher triglyceride levels may be reflective of better overall health and/or lifestyle behaviors that would protect against dementia development. Future studies are warranted to investigate whether specific components within the total circulating pool of plasma triglycerides may promote better cognitive function, with the hope of informing the development of new preventive strategies.

Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study.

BACKGROUND & AIMS: Prior studies have suggested that proton pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline. METHODS: We conducted a post hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults ≥65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria. Secondary endpoints include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models. RESULTS: Baseline PPI use vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72-1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92-1.09), or with changes in overall cognitive test scores over time (multivariable B, -0.002; standard error, 0.01; P = .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints. CONCLUSIONS: In adults ≥65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

The association of allopurinol with persistent physical disability and frailty in a large community based older cohort.

BACKGROUND: The protective effects of allopurinol on physical function in older adults are not well understood, despite its potential to improve functional gains and reduce sarcopenia. This study aims to determine the association between allopurinol, persistent physical disability, and frailty in older gout patients. METHODS: This analysis used data from a randomized trial in an older cohort, ASPirin in Reducing Events in the Elderly (ASPREE). ASPREE recruited 19,114 participants aged ≥65 years without prior cardiovascular events, dementia, or independence-limiting physical disability at trial enrolment. This analysis examined the association of baseline and time-varying allopurinol use with persistent physical disability and new-onset frailty in participants with gout at baseline (self-report or use of any anti-gout medications). Frailty was measured using the Fried frailty phenotype (score ≥3/5) and a deficit accumulation frailty index (FI) (score >0.21/1.0). Multivariable Cox proportional-hazards models were used for main analyses. RESULTS: This analysis included 1155 gout participants, with 630 taking allopurinol at baseline and 525 not. During a median follow-up of 5.7 years, 113 new allopurinol users were identified. Compared with nonusers, baseline allopurinol use was associated with a significant risk reduction of persistent physical disability (Adjusted HR 0.46, 95% CI 0.23-0.92, p = 0.03). The strength of the association was modestly attenuated in the time-varying analysis (Adjusted HR 0.56, 0.29-1.08, p = 0.08). No significant associations with frailty measures were observed for either baseline allopurinol use (Fried frailty: Adjusted HR 0.83, 0.62-1.12; FI: Adjusted HR 0.96, 0.74-1.24) or time-varying allopurinol use (Fried frailty: Adjusted HR 0.92, 0.69-1.24; FI: Adjusted HR 1.02, 0.78-1.33). CONCLUSIONS: Allopurinol use in older adults with gout is associated with a reduced risk of persistent physical disability but not associated with risk of frailty.

Longitudinal association between handgrip strength, gait speed and risk of serious falls in a community-dwelling older population.

OBJECTIVE: Both grip strength and gait speed can be used as markers of muscle function, however, no previous study has examined them in the same population with respect to risk of falls. METHODS: In this prospective cohort study, utilising data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and ASPREE-Fracture substudy, we analysed the association of grip strength and gait speed and serious falls in healthy older adults. Grip strength was measured using a handheld dynamometer and gait speed from 3-metre timed walks. Serious falls were confined to those involving hospital presentation. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations with falls. RESULTS: Over an average of 4.0±1.3 years, amongst 16,445 participants, 1,533 had at least one serious fall. After adjustment for age, sex, physical activity, body mass index, Short Form 12 (state of health), chronic kidney disease, polypharmacy and aspirin, each standard deviation (SD) lower grip strength was associated with 27% (HR 1.27, 95% CI 1.17-1.38) higher risk of falls. The results remained the same for males and females. There was a dose-response relationship in the association between grip strength and falls risk. The higher risk of falls was observed in males in all body mass index (BMI) categories, but only in obese females. The association between gait speed and falls risk was weaker than the association between grip strength and falls risk. CONCLUSIONS: All males and only obese females with low grip strength appear to be at the greatest risk of serious falls. These findings may assist in early identification of falls.

The association between frailty and incident cardiovascular disease events in community-dwelling healthy older adults.

Study objective: This study examined the association between frailty and incident cardiovascular disease (CVD) events, major adverse cardiovascular events (MACE), and CVD-related mortality. Design: Longitudinal cohort study. Setting: The ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial in Australia and the United States. Participants: 19,114 community-dwelling older adults (median age 74.0 years; 56.4 % females). Interventions: Pre-frailty and frailty were assessed using a modified Fried phenotype and a deficit accumulation Frailty Index (FI) at baseline. Main outcome measures: CVD was defined as a composite of CVD death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure; MACE included all except heart failure. Cox proportional hazards regression was used to analyze the association between frailty and CVD outcomes over a median follow-up of 4.7 years. Results: Baseline pre-frail and frail groups had a higher risk of incident CVD events (Hazard Ratio (HR): 1.31; 95 % Confidence Interval (CI): 1.14-1.50 for pre-frail and HR: 1.63; 95 % CI: 1.15-2.32 for frail) and MACE (pre-frail HR: 1.26; 95 % CI: 1.08-1.47 and frail HR: 1.51; 95 % CI: 1.00-2.29) than non-frail participants according to Fried phenotype after adjusting for traditional CVD risk factors. Effect sizes were similar or larger when frailty was assessed with FI; similar results for men and women. Conclusion: Frailty increases the likelihood of developing CVD, including MACE, in community-dwelling older men and women without prior CVD events. Screening for frailty using Fried or FI method could help identify community-dwelling older adults without prior CVD events who are more likely to develop CVD, including MACE, and may facilitate targeted preventive measures to reduce their risk.

Health Characteristics and Aspirin Use in Participants at the Baseline of the ASPirin in Reducing Events in the Elderly - eXTension (ASPREE-XT) Observational Study.

BACKGROUND: Aspirin as a primary preventative in healthy older adults did not prolong disability-free survival in the ASPREE randomized trial. Observational studies following randomized trials allow assessment of benefits and harms which may not appear during the trial. We describe health characteristics, physical function, and aspirin use in the ASPREE-eXTension (ASPREE-XT) observational study cohort. METHODS: Descriptive statistics compared health characteristics of those consented to ASPREE-XT at their first post-trial baseline (XT01) to corresponding ASPREE baseline values, and to those not consented. Likelihood of an indication for aspirin was assessed in participants reporting aspirin use at XT01. RESULTS: 16,317 (93%) of the remaining and eligible 17,546 ASPREE participants were consented into ASPREE-XT; 14,894 completed XT01. Mean participant age had increased from 74.9 to 80.6 years. Overall health and physical function declined from the original ASPREE baseline; more participants were living alone, there was higher prevalence of chronic kidney disease, diabetes, and frailty, grip strength was lower and gait speed slower. Those not consented into ASPREE-XT were slightly older, and had lower cognitive scores and higher prevalence of age-related conditions than those who continued. 1015/11,717 (8.7%) participants without an apparent indication for aspirin reported using aspirin at XT01. CONCLUSIONS: The ASPREE-XT cohort was slightly less healthy at the XT01 visit than at ASPREE trial initiation, and rates of aspirin use without indication were similar to ASPREE baseline. Participants will be followed long-term to investigate aspirin's potential legacy towards dementia and cancer prevention and explore determinants of healthy aging.

Potentially inappropriate medication use is associated with increased risk of incident disability in healthy older adults.

BACKGROUND: Efforts to minimize medication risks among older adults include avoidance of potentially inappropriate medications (PIMs). However, most PIMs research has focused on older people in aged or inpatient care, creating an evidence gap for community-dwelling older adults. To address this gap, we investigated the impact of PIMs use in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial cohort. METHODS: Analysis included 19,114 community-dwelling ASPREE participants aged 70+ years (65+ if US minorities) without major cardiovascular disease, cognitive impairment, or significant physical disability. PIMs were defined according to a modified 2019 AGS Beers Criteria. Cox proportional-hazards regression models were used to estimate the association between baseline PIMs exposure and disability-free survival, death, incident dementia, disability, and hospitalization, with adjustment for sex, age, country, years of education, frailty, average gait speed, and comorbidities. RESULTS: At baseline, 7396 (39% of the total) participants were prescribed at least one PIM. Compared with those unexposed, participants on a PIM at baseline were at an increased risk of persistent physical disability (adjusted hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.21, 1.80) and hospitalization (adjusted HR 1.26, 95% CI 1.20, 1.32), but had similar rates of disability-free survival (adjusted HR 1.02; 95% CI 0.93, 1.13) and death (adjusted HR 0.92, 95% CI 0.81, 1.05). These effects did not vary by polypharmacy status in interaction analyses. PIMs exposure was associated with higher risk of disability followed by hospitalization (adjusted HR 1.92, 95% CI 1.25, 2.96) as well as vice versa (adjusted HR 1.54, 95% CI 1.15, 2.05). PPIs, anti-psychotics and benzodiazepines, were associated with increased risk of disability. CONCLUSIONS: PIMs exposure is associated with subsequent increased risk of both incident disability and hospitalization. Increased risk of disability prior to hospitalization suggests that PIMs use may start the disability cascade in healthy older adults. Our findings emphasize the importance of caution when prescribing PIMs to older adults in otherwise good health.

Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults.

Importance: The association between weight change and subsequent cause-specific mortality among older adults is not well described. The significance of changes in waist circumference (WC) has also not been compared with weight change for this purpose. Objective: To examine the associations of changes in body weight and WC with all-cause and cause-specific mortality. Design, Setting, and Participants: This cohort study is a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial, which recruited participants between March 1, 2010, and December 31, 2014. The study included community-based older adults (16 703 Australian participants aged ≥70 years and 2411 US participants aged ≥65 years) without evident cardiovascular disease (CVD), dementia, physical disability, or life-limiting chronic illness. Data analysis was performed from April to September 2022. Exposures: Body weight and WC were measured at baseline and at annual visit 2. Analysis models were adjusted for baseline body mass index because height and weight were measured at baseline, allowing for calculation of body mass index and other variables. Both body weight and WC changes were categorized as change within 5% (stable), decrease by 5% to 10%, decrease by more than 10%, increase by 5% to 10%, and increase by more than 10%. Main Outcomes and Measures: All-cause, cancer-specific, CVD-specific, and noncancer non-CVD-specific mortality. Mortality events were adjudicated by an expert review panel. Cox proportional hazards regression and competing risk analyses were used to calculate hazard ratios (HRs) and 95% CIs. Results: Among 16 523 participants (mean [SD] age, 75.0 [4.3] years; 9193 women [55.6%]), 1256 deaths were observed over a mean (SD) of 4.4 (1.7) years. Compared with men with stable weight, those with a 5% to 10% weight loss had a 33% higher (HR, 1.33; 95% CI, 1.07-1.66) risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 289% higher (HR, 3.89; 95% CI, 2.93-5.18) risk. Compared with women with stable weight, those with a 5% to 10% weight loss had a 26% higher (HR, 1.26; 95% CI, 1.00-1.60) risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 114% higher (HR, 2.14; 95% CI, 1.58-2.91) risk. Weight loss was associated with a higher cancer-specific mortality (>10% decrease among men: HR, 3.49; 95% CI, 2.26-5.40; 5%-10% decrease among women: HR, 1.44; 95% CI, 1.46-2.04; >10% decrease among women: HR, 2.78; 95% CI, 1.82-4.26), CVD-specific mortality (>10% decrease among men: HR, 3.14; 95% CI, 1.63-6.04; >10% decrease among women: HR, 1.92; 95% CI, 1.05-3.51), and noncancer non-CVD-specific mortality (>10% decrease among men: HR, 4.98; 95% CI, 3.14-7.91). A decrease in WC was also associated with mortality. Conclusions and Relevance: This cohort study of healthy older adults suggests that weight loss was associated with an increase in all-cause and cause-specific mortality, including an increased risk of cancer, CVD, and other life-limiting conditions. Physicians should be aware of the significance of weight loss, especially among older men.

Prediabetes, diabetes and loss of disability-free survival in a community-based older cohort: a post-hoc analysis of the ASPirin in Reducing Events in the Elderly trial.

BACKGROUND: Evidence for the prognostic implications of hyperglycaemia in older adults is inconsistent. OBJECTIVE: To evaluate disability-free survival (DFS) in older individuals by glycaemic status. METHODS: This analysis used data from a randomised trial recruiting 19,114 community-based participants aged ≥70 years, who had no prior cardiovascular events, dementia and physical disability. Participants with sufficient information to ascertain their baseline diabetes status were categorised as having normoglycaemia (fasting plasma glucose [FPG] < 5.6 mmol/l, 64%), prediabetes (FPG 5.6 to <7.0 mmol/l, 26%) and diabetes (self-report or FPG ≥ 7.0 mmol/l or use of glucose-lowering agents, 11%). The primary outcome was loss of disability-free survival (DFS), a composite of all-cause mortality, persistent physical disability or dementia. Other outcomes included the three individual components of the DFS loss, as well as cognitive impairment-no dementia (CIND), major adverse cardiovascular events (MACE) and any cardiovascular event. Cox models were used for outcome analyses, with covariate adjustment using inverse-probability weighting. RESULTS: We included 18,816 participants (median follow-up: 6.9 years). Compared to normoglycaemia, participants with diabetes had greater risks of DFS loss (weighted HR: 1.39, 95% CI 1.21-1.60), all-cause mortality (1.45, 1.23-1.72), persistent physical disability (1.73, 1.35-2.22), CIND (1.22, 1.08-1.38), MACE (1.30, 1.04-1.63) and cardiovascular events (1.25, 1.02-1.54) but not dementia (1.13, 0.87-1.47). The prediabetes group did not have an excess risk for DFS loss (1.02, 0.93-1.12) or other outcomes. CONCLUSIONS: Among older people, diabetes was associated with reduced DFS, and higher risk of CIND and cardiovascular outcomes, whereas prediabetes was not. The impact of preventing or treating diabetes in this age group deserves closer attention.

The Association Between PCSK9 Inhibitor Use and Sepsis: A Systematic Review and Meta-Analysis of 20 Double-Blind, Randomized, Placebo-Controlled Trials.

OBJECTIVE: The aim of this study was to determine the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use on incident sepsis and other severe infections. METHODS: We searched PubMed, EMBASE, CENTRAL, and ClinicalTrial.gov up to September 14, 2021, for double-blind, placebo-controlled randomized trials of alirocumab, evolocumab, or inclisiran with >100 participants in each arm and report of serious adverse events related to infection. Data were synthesized with the fixed-effect Mantel-Haenszel model to generate risk ratios (RRs) with 95% confidence intervals (CIs) of each outcome for PCSK9 inhibitor versus placebo. Main outcome was sepsis. Other outcomes were total severe infections, severe bacterial and viral infections, and severe organ system-specific infections including respiratory tract, gastrointestinal, and genitourinary tract infections. RESULTS: A total of 20 studies of 64,984 participants were included (alirocumab: n = 7; evolocumab: n = 9; inclisiran: n = 4). Sepsis was reported in 292 (0.51%) participants from 11 trials (PCSK9 inhibitor 0.47%; placebo 0.56%). PCSK9 inhibitor use was not associated with risk of sepsis compared with placebo (Summary RR: 0.85, 95% CI: 0.67-1.07, P = .16); nor was it associated with any severe infection (0.96, 95% CI: 0.89-1.03), severe bacterial (0.96, 95% CI: 0.81-1.14) and viral infections (1.01, 95% CI: 0.77-1.33); nor with any severe organ system-specific infection (all P values >.05). The between-study heterogeneity in all analyses was small. CONCLUSION: There was neither a beneficial nor a harmful association between PCSK9 inhibitors and risk of sepsis or severe infections. These findings provide reassurance regarding the safety of PCSK9 inhibitors in patients who are concerned about potential drug side effects related to infections.

Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes.

BACKGROUND: Metformin and aspirin are commonly co-prescribed to people with diabetes. Metformin may prevent cancer, but in older people (over 70 years), aspirin has been found to increase cancer mortality. This study examined whether metformin reduces cancer mortality and incidence in older people with diabetes; it used randomization to 100 mg aspirin or placebo in the ASPirin in Reducing Events in the Elderly (ASPREE) trial to quantify aspirin's impact on metformin users. METHODS: Analysis included community-dwelling ASPREE participants (aged ≥70 years, or ≥65 years for members of US minority populations) with diabetes. Diabetes was defined as a fasting blood glucose level greater than 125 mg/dL, self-report of diabetes, or antidiabetic medication use. Cox proportional hazards regression models were used to analyze the association of metformin and a metformin-aspirin interaction with cancer incidence and mortality, with adjustment for confounders. RESULTS: Of 2045 participants with diabetes at enrollment, 965 were concurrently using metformin. Metformin was associated with a reduced cancer incidence risk (adjusted hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.51 to 0.90), but no conclusive benefit for cancer mortality (adjusted HR = 0.72, 95% CI = 0.43 to 1.19). Metformin users randomized to aspirin had greater risk of cancer mortality compared with placebo (HR = 2.53, 95% CI = 1.18 to 5.43), but no effect was seen for cancer incidence (HR = 1.11, 95% CI = 0.75 to 1.64). The possible effect modification of aspirin on cancer mortality, however, was not statistically significant (interaction P = .11). CONCLUSIONS: In community-dwelling older adults with diabetes, metformin use was associated with reduced cancer incidence. Increased cancer mortality risk in metformin users randomized to aspirin warrants further investigation. ASPREE TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01038583.

Associations of body size with all-cause and cause-specific mortality in healthy older adults.

In the general population, body mass index (BMI) and waist circumference are recognized risk factors for several chronic diseases and all-cause mortality. However, whether these associations are the same for older adults is less clear. The association of baseline BMI and waist circumference with all-cause and cause-specific mortality was investigated in 18,209 Australian and US participants (mean age: 75.1 ± 4.5 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) study, followed up for a median of 6.9 years (IQR: 5.7, 8.0). There were substantially different relationships observed in men and women. In men, the lowest risk of all-cause and cardiovascular mortality was observed with a BMI in the range 25.0-29.9 kg/m2 [HR25-29.9 vs 21-24.9 kg/m2: 0.85; 95% CI, 0.73-1.00] while the highest risk was in those who were underweight [HRBMI <21 kg/m2 vs BMI 21-24.9 kg/m2: 1.82; 95% CI 1.30-2.55], leading to a clear U-shaped relationship. In women, all-cause mortality was highest in those with the lowest BMI leading to a J-shaped relationship (HRBMI <21 kg/m2 vs BMI 21-24.9 kg/m2: 1.64; 95% CI 1.26-2.14). Waist circumference showed a weaker relationship with all-cause mortality in both men and women. There was little evidence of a relationship between either index of body size and subsequent cancer mortality in men or women, while non-cardiovascular non-cancer mortality was higher in underweight participants. For older men, being overweight was found to be associated with a lower risk of all-cause mortality, while among both men and women, a BMI in the underweight category was associated with a higher risk. Waist circumference alone had little association with all-cause or cause-specific mortality risk.Trial registration ASPREE https://ClinicalTrials.gov number NCT01038583.

GFR Variability, Survival, and Cardiovascular Events in Older Adults.

Rationale & Objective: Variability in estimated glomerular filtration rate (eGFR) over time is often observed, but it is unknown whether this variation is clinically important. We investigated the association between eGFR variability and survival free of dementia or persistent physical disability (disability-free survival) and cardiovascular disease (CVD) events (myocardial infarction, stroke, hospitalization for heart failure, or CVD death). Study Design: Post hoc analysis. Setting & Participants: 12,549 participants of the ASPirin in Reducing Events in the Elderly trial. Participants were without documented dementia, major physical disability, previous CVD, and major life-limiting illness at enrollment. Predictors: eGFR variability. Outcomes: Disability-free survival and CVD events. Analytical Approach: eGFR variability was estimated using the standard deviation of eGFR measurements obtained from participants' baseline, first, and second annual visits. Associations between tertiles of eGFR variability with disability-free survival and CVD events occurring after the eGFR variability estimation period were examined. Results: During median follow-up of 2.7 years after the second annual visit, 838 participants died, developed dementia, or acquired a persistent physical disability; 379 had a CVD event. The highest tertile of eGFR variability had an increased risk of death/dementia/disability (HR, 1.35; 95% CI, 1.14-1.59) and CVD events (HR, 1.37; 95% CI, 1.06-1.77) compared with the lowest tertile after covariate adjustment. These associations were present in patients with and without chronic kidney disease at baseline. Limitations: Limited representation of diverse demographics. Conclusions: In older, generally healthy adults, higher variability in eGFR over time predicts increased risk of future death/dementia/disability and CVD events.