Vitamin D is reported to have anti-inflammatory properties; however the effects of vitamin D supplementation on inflammation in patients with heart failure (HF) have not been established. We performed a systematic review and meta-analysis examining effects of vitamin D supplementation on inflammatory markers in patients with HF. MEDLINE, CINAHL, EMBASE, All EBM, and Clinical Trials registries were systematically searched for RCTs from inception to 25 January 2017. Two independent reviewers screened all full text articles (no date or language limits) for RCTs reporting effects of vitamin D supplementation (any form, route, duration, and co-supplementation) compared with placebo or usual care on inflammatory markers in patients with heart failure. Two reviewers assessed risk of bias and quality using the grading of recommendations, assessment, development, and evaluation approach. Seven studies met inclusion criteria and six had data available for pooling (n = 1012). In meta-analyses, vitamin D-supplemented groups had lower concentrations of tumor necrosis factor-alpha (TNF-α) at follow-up compared with controls (n = 380; p = 0.04). There were no differences in C-reactive protein (n = 231), interleukin (IL)-10 (n = 247) or IL-6 (n = 154) between vitamin D and control groups (all p > 0.05). Our findings suggest that vitamin D supplementation may have specific, but modest effects on inflammatory markers in HF.

The adipocytokines leptin and adiponectin have been variously associated with diabetic microvascular complications. No comprehensive clinical data exist examining the association between adipocytokines and the presence of these complications. This is a systematic review of cross-sectional studies comparing circulating adipocytokines in patients with type 2 diabetes mellitus (T2DM), with and without microvascular complications. Studies were retrieved from MEDLINE, EMBASE, Scopus and Cochrane databases. Study quality was evaluated using a modified Newcastle-Ottawa Scale. Meta-analysis was performed using an inverse-variance model, providing standardised mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity was determined by I(2) statistic. Amongst 554 identified studies, 28 were included in the review. Study quality range was 3.5-9 (maximum 11). Higher leptin levels were associated with microalbuminuria (SMD=0.41; 95% CI=0.14-0.67; n=901; p=0.0003), macroalbuminuria (SMD=0.68; 95% CI=0.30-1.06; n=406; p=0.0004), and neuropathy (SMD=0.26; 95% CI=0.07-0.44; n=609; p=0.008). Higher adiponectin levels were associated with microalbuminuria (SMD=0.55; 95% CI=0.29-0.81, n=274; p<0.001), macroalbuminuria (SMD=1.37; 95% CI=0.78-1.97, n=246; p<0.00001), neuropathy (SMD=0.25; 95% CI=0.14-0.36; n=1516; p<0.00001), and retinopathy (SMD=0.38; 95% CI=0.25-0.51; n=1306; p<0.00001). Meta-regression suggested no influence of body mass index and duration of diabetes on effect size, and a weak trend in terms of age on effect size. Our meta-analysis suggests leptin and adiponectin levels are higher in T2DM patients with microvascular complications. Studies were limited by cross-sectional design. Large prospective analyses are required to validate these findings.

Background: Peripheral artery disease ( PAD ) is associated with impaired mobility and a high rate of mortality. The aim of this systematic review was to investigate whether reduced lower extremity performance was associated with an increased incidence of cardiovascular and all‐cause mortality in people with PAD . Methods and Results: A systematic search of the MEDLINE , EMBASE , SCOPUS , Web of Science, and Cochrane Library databases was conducted. Studies assessing the association between measures of lower extremity performance and cardiovascular or all‐cause mortality in PAD patients were included. A meta‐analysis was conducted combining data from commonly assessed performance tests. The 10 identified studies assessed lower extremity performance by strength tests, treadmill walking performance, 6‐minute walk, walking velocity, and walking impairment questionnaire ( WIQ ). A meta‐analysis revealed that shorter maximum walking distance was associated with increased 5‐year cardiovascular (unadjusted RR =2.54, 95% CI 1.86 to 3.47, P <10 ⁻⁵ , n=1577, fixed effects) and all‐cause mortality (unadjusted RR =2.23 95% CI 1.85 to 2.69, P <10 ⁻⁵ , n=1710, fixed effects). Slower 4‐metre walking velocity, a lower WIQ stair‐climbing score, and poor hip extension, knee flexion, and plantar flexion strength were also associated with increased mortality. No significant associations were found for hip flexion strength, WIQ distance score, or WIQ speed score with mortality. Conclusions: A number of lower extremity performance measures are prognostic markers for mortality in PAD and may be useful clinical tools for identifying patients at higher risk of death. Further studies are needed to determine whether interventions that improve measures of lower extremity performance reduce mortality.

Background: Abdominal aortic calcification (AAC) has been inconsistently associated with skeletal health. We aimed to investigate the association of AAC with bone mineral density (BMD) and fracture risk by pooling the findings of observational studies. Methods: MEDLINE, EMBASE, Web of Science, and Google Scholar were searched (August 2021). All clinical studies that assessed the association between AAC and BMD or fracture were included. AAC was categorized into any/advanced (all higher reported groups) versus no/less advanced (lowest reported group). Pooled standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CI) were determined for BMD and fracture, respectively, using random-effects models. Results: Of 2 192 articles screened, 86 (61 553 participants) were included in the review, while 42 provided data for meta-analysis. AAC was associated with lower BMD at the total hip (SMD = −1.05 [95%CI: −1.47 to −0.63]; 16 studies), femoral neck (−0.25 [−0.46 to−0.04]; 10), and lumbar spine (−0.67 [−1.21 to −0.12]; 20). AAC was associated with a greater risk of any fracture (RR = 1.73 [95%CI: 1.48–2.02]; 27). AAC was also associated with vertebral, non-vertebral, and hip fractures. In dose–response analysis, the highest AAC group had greater risks of any, vertebral and non-vertebral fractures. Conclusions: AAC is associated with lower BMD and increased fracture risk at multiple sites, underscoring the potential importance of vascular disease on skeletal health. Detection of AAC at the time of BMD testing may provide clinicians with prognostic information about bone health to enhance osteoporosis screening programs and fracture risk prediction.

The cardiovascular safety of denosumab has not yet been evaluated in a systematic review. This systematic review and meta‐analysis sought to quantify the number of randomized controlled trials (RCTs) of denosumab (against comparators) reporting cardiovascular adverse events (CAEs) and examine the balance of CAEs between treatment arms. MEDLINE, Embase and clinicaltrials.gov were searched from inception to 26^th October 2019 for RCTs of denosumab versus comparators for any indication. Included trials were randomized, enrolled ≥100 participants and reported bone‐related outcomes. Primary outcome for analysis was all CAEs; a composite endpoint representing summation of all CAEs as reported by included trials. Secondary outcomes included Major Adverse Cardiovascular Events (MACE). Data were pooled using a fixed effects model to determine relative risk (RR) and 95% confidence interval (95%CI). Risk of bias was assessed using the Cochrane risk‐of‐bias tool. Of 554 records screened, 49 were included, while 36 reported CAEs. Twenty‐seven included trials (twelve eligible for meta‐analysis) were conducted in 13,202 post‐menopausal women. Compared with bisphosphonates, there was a 46% (95% CI: 1.05 to 2.02) increase in CAEs [85/2136 events in denosumab‐treated vs. 58/2131 events in bisphosphonate‐treated); seven trials]. There was a similar imbalance in a five‐point (stroke, myocardial infarction, cardiovascular death, heart failure, atrial fibrillation) MACE endpoint [28/2053 vs. 12/2050; RR=2.33(1.19, 4.56)]. Compared with placebo‐treated women, there was no imbalance in total CAEs [439/4725 events in denosumab vs. 399/4467 in placebo; RR=0.79 (0.41 to 1.52); seven trials]. No imbalance in total AEs [versus bisphosphonates: 0.98 (0.92 to 1.04); versus placebo: 0.99 (0.98 to 1.01)] occurred. Other indications showed no statistically significant results. The excess CAEs in post‐menopausal women treated with denosumab compared with bisphosphonates, but not placebo, indirectly supports claims that bisphosphonates may suppress CAEs. Future trials should use standardized CAE reporting to better describe cardiovascular effects of bone active medications. (PROSPERO: CRD42019135414.)