Gliflozins for the prevention of stroke in diabetes and cardiorenal diseases: A meta-analysis of cardiovascular outcome trials

Background:Individual randomized trials are not powered to assess the relationship between use of sodium–glucose transporter 2 inhibitors and risk of stroke. We sought to explore this issue by a meta-analysis incorporating relevant trials including several latest trials.Methods:Cardiovascular outcome trials of gliflozins were included. Primary outcome was stroke, while secondary outcome was major adverse cardiovascular events (MACE), which was a composite of stroke, myocardial infarction, or cardiovascular death. Meta-analysis was conducted stratified by with/without chronic kidney disease (CKD), with/without heart failure (HF), and with/without atherosclerotic cardiovascular disease (ASCVD), and stratified by different gliflozins.Results:We included 9 trials in this meta-analysis. Compared with placebo, gliflozins significantly lowered stroke (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.55–0.84) and MACE (HR 0.77, 95% CI 0.69–0.86) in type 2 diabetes (T2D) patients with CKD, but did not significantly affect stroke (HR 1.00, 95% CI 0.86–1.16) and MACE (HR 0.94, 95% CI 0.86–1.02) in T2D patients without CKD. Gliflozins had no significant effects on the stroke risk (HR 0.94, 95% CI 0.82–1.07) in T2D patients regardless of HF status (P_subgroup = .684) and ASCVD status (P_subgroup = .915), but significantly lowered MACE (HR 0.89, 95% CI 0.83–0.96) in T2D patients regardless of HF status (P_subgroup = .428) and ASCVD status (P_subgroup = .423). Canagliflozin (HR 0.84, 95% CI 0.69–1.01) showed the trend of a reduction in the stroke risk versus placebo, and sotagliflozin (HR 0.73, 95% CI 0.54–0.98) significantly lowered the stroke risk; whereas the other 3 gliflozins did not significantly affect that risk. Ertugliflozin (HR 0.97, 95% CI 0.85–1.11) had no significant effects on the MACE risk, whereas the other 4 gliflozins significantly lowered that risk.Conclusions:Gliflozins, especially canagliflozin and sotagliflozin, should be recommended in T2D patients with CKD to prevent stroke. Most gliflozins lower the risk of MACE in T2D patients regardless of HF status and ASCVD status, whereas ertugliflozin is not observed to lower that risk.     

Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study

AimsNon-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD.MethodsCross-sectional associations of indices of NAFLD with glycemia and vitamin D status were assessed in 3972 individuals screened for the D2d study. In those with prediabetes randomized to vitamin D or placebo (n = 2423), we examined longitudinal associations of NAFLD indices with incident T2D. We used validated non-invasive scores to assess steatosis [(hepatic steatosis index (HSI); NAFLD-liver fat score (NAFLD-LFS)] and advanced fibrosis [fibrosis-4 (FIB-4) index; AST to Platelet Ratio Index (APRI)].ResultsEighty-five percent of screened participants had likely steatosis by HSI and 71 % by NAFLD-LFS; 3 % were likely to have advanced fibrosis by FIB-4 and 1.2 % by APRI. FIB-4 indicated that 20.4 % of individuals require further follow up to assess liver health. Steatosis and fibrosis scores were higher among participants with worse glycemia. The NAFLD-LFS and APRI predicted development of diabetes (hazard ratios [95%CI] 1.35 [1.07, 1.70]; P = 0.012) and 2.36 (1.23, 4.54; P = 0.010), respectively). The effect of vitamin D on diabetes risk was not modified by baseline NAFLD indices. Individuals with likely steatosis had a smaller increase in serum 25-hydroxyvitamin D level in response to vitamin D than those without steatosis.ConclusionsThe predicted high prevalence of steatosis, the need for further fibrosis workup, and the relationship between liver health and incident T2D suggest that routine screening with clinically accessible scores may be an important strategy to reduce disease burden.     

Vitamin D supplementation and adverse skeletal and non-skeletal outcomes in individuals at increased cardiovascular risk: Results from the International Polycap Study (TIPS)-3 randomized controlled trial

Background and aimsVitamin D has mostly been tested in Western populations. We examined the effect of high dose vitamin D in a population drawn predominantly from outside of Western countries.Methods and resultsThis randomized trial tested vitamin D 60,000 IU monthly in 5670 participants without vascular disease but at increased CV risk. The primary outcome was fracture. The secondary outcome was the composite of CV death, myocardial infarction stroke, cancer, fracture or fall. Death was a pre-specified outcome. Mean age was 63.9 years, and 3005 (53.0%) were female. 3034 (53.5%) participants resided in South Asia, 1904 (33.6%) in South East Asia, 480 (8.5%) in South America, and 252 (4.4%) in other regions. Mean follow-up was 4.6 years. A fracture occurred in 20 participants (0.2 per 100 person years) assigned to vitamin D, and 19 (0.1 per 100 person years) assigned to placebo (HR 1.06, 95% CI 0.57–1.99, p-value = 0.86). The secondary outcome occurred in 222 participants (1.8 per 100 person years) assigned to vitamin D, and 198 (1.6 per 100 person years) assigned to placebo (HR 1.13, 95% CI 0.93–1.37, p = 0.22). 172 (1.3 per 100 person years) participants assigned to vitamin D died, compared with 135 (1.0 per 100 person years) assigned to placebo (HR 1.29, 95% CI 1.03–1.61, p = 0.03).ConclusionIn a population predominantly from South Asia, South East Asia and South America, high-dose vitamin D did not reduce adverse skeletal or non-skeletal outcomes. Higher mortality was observed in the vitamin D group.Registration numberNCT01646437.     

The bidirectional relationship between NAFLD and type 2 diabetes: A prospective population-based cohort study

Background and aimsTo explore the bidirectional relationship between NAFLD and type 2 diabetes and the possible directions of the main effect.Methods and results30 633 participants from the Jinchang cohort were enrolled. Firstly, cox proportional hazards regression model was used to assess the unidirectional causality between NAFLD and prediabetes and type 2 diabetes. Secondly, cross-lag path analysis model was conducted to estimate the bidirectional relationship between NAFLD and prediabetes and type 2 diabetes, and to determine the direction of the main effects. Finally, potential effect modifications were also considered by age, sex, hyperlipidemia, and overweight/obesity. We found that NAFLD increased the risk of prediabetes and type 2 diabetes with adjusted HR (95%CI) of 1.355(95%CI: 1.255–1.462) and 1.898(95%CI: 1.415–2.545), respectively. Prediabetes and type 2 diabetes also increased the risk of NAFLD, with adjusted HR (95%CI) of 1.245(95%CI: 1.115–1.392) and 1.592(95%CI: 1.373–1.846), respectively. Cross-lag path analysis showed that NAFLD significantly affected the incidence of prediabetes (β = 0.285, P < 0.001), while the effect on type 2 diabetes was not statistically significant. The effect of prediabetes and type 2 diabetes on the risk of NAFLD was weak, and the path coefficients were 0.076 and 0.037, respectively. Stratified analyses showed similar results.ConclusionThis study provides evidence that there was a bidirectional causal association between NAFLD and type 2 diabetes, and the progression from NAFLD through prediabetes to type 2 diabetes may be the main pathway.     

The dietary and lifestyle indices of insulin resistance are associated with increased risk of cardiovascular diseases: A prospective study among an Iranian adult population

Background and aimsPrevious studies have introduced insulin resistance (IR) as a major risk factor for poor cardiovascular diseases (CVDs) outcomes. Diet, body weight, and physical activity are three key pillars of lifestyle that can significantly impact the IR status. We aimed to assess the possible link between the empirical dietary index for IR (EDIR) and the empirical lifestyle index for IR (ELIR) with the risk of chronic heart disease (CHD) and CVDs.Methods and resultsThis study was conducted on 4980 participants aged ≥30 years (follow-up rate: 99.85%). Dietary intake data was collected using a validated food frequency questionnaire. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence intervals (HRs and 95% CIs) of CVDs and CHD across tertiles of EDIR and ELIR scores. In the final model, after adjusting for all potential confounding variables, participants in the highest tertile of EDIR had a higher risk of CVD (HR:1.36, 95%CI:1.03–1.80, P-trend = 0.016) and CHD (HR:1.36, 95% CI:1.01–1.83, P-trend = 0.023) compared to the lowest tertile. Also, participants with a higher score of ELIR had a higher risk of CVD (HR: 1.64, 95%CI:1.24–2.16, P-trend=<0.001) and CHD (HR: 1.72, 95%CI:1.28–2.32, P-trend=<0.001).ConclusionA greater adherence to the lifestyle and diet with a higher EDIR and ELIR may be associated with an increased risk of CVD and CHD outcomes in the adult population.     

Advanced glycation end products via skin autofluorescence as a new biomarker for major adverse cardiovascular events: A meta-analysis of prospective studies

AimsThis meta-analysis aimed to systematically evaluate the prospective association between advanced glycation end products (AGEs) and major adverse cardiovascular events (MACE).Data synthesisProspective studies that reported the association of AGEs (measured by skin autofluorescence) with MACE were searched in PubMed and EMBASE from inception up to July 2021. Multivariable-adjusted hazard ratios (HRs) and their respective 95% confidence intervals (CIs) reflecting the risk of MACE associated with AGEs were determined using random-effects meta-analysis. Fourteen articles with sixteen items involving 79,389 participants were included. A significant association was found between AGEs and MACE (pooled HR: 1.54, 95% CI: 1.31–1.81, I² = 68%). Moreover, AGEs were associated with a significant increase in fatal cardiovascular disease (CVD) (HR: 1.88, 95% CI: 1.30–2.70) and nonfatal CVD (HR: 1.40, 95% CI: 1.12–1.74). The association between AGEs and MACE was also significant in patients with diabetes (HR: 1.88, 95% CI: 1.31–2.69) and kidney disease (HR: 1.50, 95% CI: 1.16–1.94).ConclusionsThis meta-analysis indicates that higher levels of AGEs measured by skin autofluorescence are significantly correlated with a higher pooled risk of MACE, and AGEs are closely related to both nonfatal and fatal cardiovascular events. AGEs are a valuable biomarker for predicting the occurrence of MACE.The PROSPERO registration numberCRD42021279714.     

Circulating 25-hydroxy-vitamin D and the risk of cardiovascular diseases. Systematic review and meta-analysis of prospective cohort studies

AimsCirculating vitamin D is linked with the risk of cardiovascular disease (CVD). A meta-analysis has yet to explicitly explore correlation between vitamin D and the risk of CVD incidence and recurrent CVD. This meta-analysis examines the association between 25-hydroxy-vitamin D (25(OH)D) and the risk of CVD incidence (fatal, non-fatal, fatal and non-fatal combined events) and the risk of recurrent CVD (fatal, recurrent, and fatal and recurrent combined events). PROSPERO registration-CRD42021251483.Data synthesisA total of 79 studies (46 713 CVD cases in 1 397 831 participants) were included in the meta-analysis, of which 61 studies examined the risk of CVD incidence events, and 18 studies examined risk of recurrent CVD events. The risk of CVD incidence events (RR = 1.34, 95% CI: 1.26–1.43, p < 0.001) and recurrent CVD events (RR = 1.86, 95% CI: 1.46–2.36, p < 0.001) was higher in the lowest than the highest category of circulating 25(OH)D. Dose–response analysis reported a linear association for every 10 ng/ml increment of 25(OH)D and non-fatal CVD incidence events (RR = 0.94; 95% CI = 0.89–0.98, p = 0.005), lower fatal recurrent CVD events (RR = 0.45; 95% CI = 0.32–0.62, p < 0.001) and lower combined recurrent CVD events (RR = 0.80; 95% CI = 0.65–0.97, p = 0.023). A non-linear association was observed between higher 25(OH)D and lower fatal CVD incidence events (P-nonlinear<0.001), lower combined CVD incidence events (P-nonlinear = 0.001), and lower non-fatal recurrent CVD events (P-nonlinear = 0.044).ConclusionsThe lowest category of circulating 25(OH)D was associated with a higher risk of CVD incidence events and recurrent CVD events.     

Elevated depressive symptoms and risk of all-cause and cardiovascular mortality among adults with and without diabetes: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study

AimsTo examine the association of elevated depressive symptoms with all-cause and cardiovascular disease (CVD) mortality and determine whether these associations differ for those with and without diabetes.MethodsWe included 22,807 black and white men and women aged 45–98 years at baseline (2003–2007) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. Elevated depressive symptoms were defined as a score ≥ 4 on the 4-item Centers for Epidemiologic Studies of Depression Scale. Participants were classified as having diabetes, prediabetes, or no prediabetes/diabetes based on glucose levels and diabetes medication use. All-cause mortality events were available through 2018 and adjudicated CVD mortality events were available through 2015.ResultsDuring follow-up, there were 5383 all-cause deaths, of which 1585 were adjudicated CVD deaths. The mean survival time was lower for participants with elevated depressive symptoms than those without elevated depressive symptoms for those with diabetes, prediabetes, and no prediabetes/diabetes. In multivariable adjusted models, elevated depressive symptoms increased the risk of all-cause mortality for those with diabetes (HR = 1.15; 95% CI = 1.00–1.32), prediabetes (HR = 1.56; 95% CI = 1.28–1.91), and neither prediabetes/diabetes (HR = 1.34; 95% CI = 1.19–1.50) (p for interaction = 0.0342). Findings were similar for CVD mortality.ConclusionElevated depressive symptoms increased the risk of all-cause and CVD mortality among individuals with and without diabetes, with a stronger magnitude of association observed among those with prediabetes. This underscores the need for assessing depressive symptoms across the glycemic spectrum, including those with prediabetes.     

Do GLP-1RAs and SGLT-2is reduce cardiovascular events in women with type 2 diabetes? A systematic review and meta-analysis

AimsThe risk of cardiovascular disease is often underestimated in women. This leads to a delay in controlling the risk factors for cardiovascular disease and even delays in prescribing medications with cardiovascular benefit. Our aim was to explore if glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 inhibitor (SGLT-2i) medications would reduce cardiovascular events in women with type 2 diabetes when atherosclerotic cardiovascular disease (ASCVD) predominates.Materials and methodsWe searched for randomized trials comparing GLP-1RA or SGLT-2i to placebo in people with type 2 diabetes and had a primary outcome exploring major adverse cardiovascular events (MACE). Data concerning women were then extracted. A sensitivity and subgroup analyses were performed according to the class of diabetes medication.ResultsA total of 9 trials (GLP-1RA in 6 trials and SGLT-2i in 3) were included. Of the 84,258 participants enrolled, 30,784 (37%) participants were women. Pooled results showed a statistically significant lower incidence of MACE favouring diabetes medications (GLP-1RA or SGLT-2i) compared to placebo (RR [95%CI] = 0.87 [0.80, 0.94]). On restricting the analysis to GLP-1RA then to SGLT-2i, results remained significant with GLP-1RA but not SGLT-2i.ConclusionsIn women with type 2 diabetes who either have increased cardiovascular risk or established cardiovascular disease and ASCVD predominates, GLP-1RA significantly reduce the incidence of MACE while SGLT-2i result in a non-significant reduction. SGLT-2i may have comparable effect when examined in more studies. GLP-1RA and SGLT-2i should be considered without delay in women with type 2 diabetes and increased risk for cardiovascular disease.     

Effects of a digital diabetes prevention program on cardiovascular risk among individuals with prediabetes

ObjectiveTo examine changes in cardiovascular disease (CVD) risk outcomes of overweight/obese adults with prediabetes.MethodsUsing data from a randomized control trial of digital diabetes prevention program (d‐DPP) with 599 participants. We applied the atherosclerotic CVD (ASCVD) risk calculator to predict 10-year CVD risk for d‐DPP and small education (comparison) groups. Between-group risk changes at 4 and 12 months were compared using a repeated measures linear mixed-effect model. We examined within-group differences in proportion of participants over time for specific CVD risk factors using generalized estimating equations.ResultsWe found no differences between baseline 10-year ASCVD risk. Relative to the comparison group, the d‐DPP group experienced greater reductions in predicted 10-year ASCVD risk at each follow-up visit and a significant group difference at 4 months (−0.96%; 95% confidence interval: −1.58%, −0.34%) (but not at 12 months). Additionally, we observed that the d‐DPP group experienced a decreased proportion of individuals with hyperlipidemia (18% and 16% from baseline to 4 and 12 months), high-risk total cholesterol (8% from baseline to 12 months), and being insufficiently active (26% and 22% from baseline to 4 and 12 months at follow-up time points.ConclusionsOur findings suggest that a digitally adapted DPP may promote the prevention of cardiometabolic disease among overweight/obese individuals with prediabetes. However, given the lack of maintenance of effect on ASCVD risk at 12 months, there may also be a need for additional interventions to sustain the effect detected at 4 months.     

Future directions in vitamin D and cardiovascular research

AimsEvidence is accumulating that vitamin D status may influence the risk of cardiovascular disease (CVD). Final confirmation for a causal relationship between vitamin D and CVD is however still lacking. The present viewpoint article outlines several future research directions to close this gap.Data synthesisFuture directions include the need of performing large randomised controlled supplementation trials with vitamin D in specific risk groups. In addition, large register sets of data on vitamin D supplementation can be used, provided that adequate statistical methods such as propensity score modelled analysis are applied. To better understand vitamin D-mediated effects on CVD risk, the routine measurement of circulating levels of the hormonal vitamin D form, 1,25-dihydroxyvitamin D, is also necessary, in addition to the determination of its precursor 25-hydroxyvitamin D. Further, genetic association studies may help in clarifying the contribution of vitamin D to the development of CVD. Finally, the interrelationship of vitamin D with physical activity should be considered when studying CVD risk.ConclusionsOverall, it can be expected that the next 10–15 years will provide an increased clarity concerning the role of vitamin D in CVD.     

Serum and dietary vitamin D and cardiovascular disease risk in elderly men: a prospective cohort study

Background and aimRecent research suggests that low vitamin D may be associated with cardiovascular disease (CVD).Methods and resultsWe prospectively evaluated the association of dietary plus supplemental vitamin D intake and serum 25(OH) vitamin D with CVD incidence in the Osteoporotic Fractures in Men (MrOS) Study. Vitamin D intake was measured using a food frequency questionnaire and self-reported supplemental intake in 3094 men (mean age 76.4 years). From a subset of this population, we measured 25(OH) vitamin D in 813 men. Median 25(OH) vitamin D was 25.3 ng/mL. During a median follow-up of 4.4 years, there were 472 CVD cases, including 371 from coronary heart disease (CHD) and 101 from cerebrovascular attack (CVA). In the 25(OH) vitamin D sub-cohort, there were 140 cases of CVD including 115 from CHD and 25 from CVA. We used a Cox proportional hazards regression to calculate hazard ratios (HR) for CVD by vitamin D quartile. After adjusting for age, season, and standard CVD risk factors, the lowest quartile of 25(OH) vitamin D (HR, 1.18; 95% CI, 0.69–2.03) and vitamin D intake (HR, 0.76; 95% CI, 0.56–1.04) were not significantly associated with CVD incidence, compared to the highest vitamin D quartiles. When 25(OH) vitamin D was further analyzed by sufficiency (≥30 ng/mL), insufficiency (≥15–29.9 ng/mL), and deficiency (<15 ng/mL), vitamin D deficiency was not significantly associated with CVD incidence compared to sufficiency (HR 1.34; 95% CI 0.65–2.77).ConclusionVitamin D intake and serum 25(OH) vitamin D were not associated with CVD risk.     

Coronary Atherosclerosis,Cardiac Troponin,and Interleukin-6 in Patients With Chest Pain: The PROMISE Trial Results

BackgroundIncreased inflammation and myocardial injury can be observed in the absence of myocardial infarction or obstructive coronary artery disease (CAD).ObjectivesThe authors determined whether biomarkers of inflammation and myocardial injury—interleukin (IL)-6 and high-sensitivity cardiac troponin (hs-cTn)—were associated with the presence and extent of CAD and were independent predictors of major adverse cardiovascular events (MACEs) in stable chest pain.MethodsUsing participants from the PROMISE trial, the authors measured hs-cTn I and IL-6 concentrations and analyzed computed tomography angiography (CTA) images in the core laboratory for CAD characteristics: significant stenosis (≥70%), high-risk plaque (HRP), Coronary Artery Disease Reporting and Data System (CAD-RADS) categories, segment involvement score (SIS), and coronary artery calcium (CAC) score. The primary endpoint was a composite MACE (death, myocardial infarction, or unstable angina).ResultsThe authors included 1,796 participants (age 60.2 ± 8.0 years; 47.5% men, median follow-up 25 months). In multivariable linear regression adjusted for atherosclerotic cardiovascular disease (ASCVD) risk, hs-cTn was associated with HRP, stenosis, CAD-RADS, and SIS. IL-6 was only associated with stenosis and CAD-RADS. hs-cTn above median (1.5 ng/L) was associated with MACEs in univariable analysis (HR: 2.1 [95% CI: 1.3-3.6]; P = 0.006), but not in multivariable analysis adjusted for ASCVD and CAD. IL-6 above median (1.8 ng/L) was associated with MACEs in multivariable analysis adjusted for ASCVD and HRP (HR: 1.9 [95% CI: 1.1-3.3]; P = 0.03), CAC (HR: 1.9 [95% CI: 1.0-3.4]; P = 0.04), and SIS (HR: 1.8 [95% CI: 1.0-3.2]; P = 0.04), but not for stenosis or CAD-RADS. In participants with nonobstructive CAD (stenosis 1%-69%), the presence of both hs-cTn and IL-6 above median was strongly associated with MACEs (HR: 2.5-2.7 after adjustment for CAD characteristics).ConclusionsConcentrations of hs-cTn and IL-6 were associated with CAD characteristics and MACEs, indicating that myocardial injury and inflammation may each contribute to pathways in CAD pathophysiology. This association was most pronounced among participants with nonobstructive CAD representing an opportunity to tailor treatment in this at-risk group. (PROspective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550)     

Vitamin D and histologic severity of nonalcoholic fatty liver disease: A systematic review and meta-analysis

BackgroundNAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several risk factors. Recent studies investigating the relationship between vitamin D levels and severity of NAFLD showed conflicting results. Thus we conducted a systematic review and meta-analysis to evaluate association between vitamin D and NAFLD histologic severity.MethodsA comprehensive search of the databases of the MEDLINE and EMBASE was performed from inception through November 2016. Observational studies compared serum vitamin D levels among NAFLD patients with high and low histologic severity, which was determined by NAFLD activity score (NAS) and fibrosis score. We calculated pooled mean difference (MD) of 25-hydroxyvitamin D levels with 95% confidence intervals (CI) using random-effects model.ResultsData were extracted from 6 studies involving 974 NAFLD patients. There was no difference in 25-hydroxyvitamin D levels among NAFLD patients with high NAS (score of ≥5) versus low NAS (pooled MD = −0.93, 95%CI −2.45 to 0.58, I² = 0%) and also high fibrosis score (score of ≥3) versus low fibrosis score (pooled MD = 0.88, 95%CI −2.65 to 4.42, I² = 64%).ConclusionsDespite evidence implicating vitamin D in NAFLD pathogenesis, serum 25-hydroxyvitamin D may not be associated with NAFLD histologic severity.     

Prognostic impact of Vitamin D deficiency in patients with coronary artery disease undergoing percutaneous coronary intervention

BackgroundWhether Vitamin D deficiency represents an independent predictor of mortality and major cardiovascular events or rather the mirror of a more advanced clinical condition with increased comorbidities is still debated. We aimed at assessing the impact of vitamin D levels on the long-term outcomes among patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention.MethodsConsecutive patients from a single centre were included. Vitamin D levels were measured at admission by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). Severe deficiency was defined for 25(OH)D < 10 ng/ml. The primary study endpoint was overall mortality. Secondary endpoints were cardiovascular mortality, recurrent acute coronary syndrome or major cardiovascular events (a composite of death, recurrent MI and target vessel revascularization) at the longest available follow-up.ResultsWe included a total of 705 patients, that were divided according to vitamin D tertiles (<12.7; 12.7-21.59; ≥21.6 ng/ml). Lower levels of Vitamin D were associated with renal failure (p=0.03), more severe coronary disease (p=0.001), diabetes mellitus and previous CABG (p<0.001), lower ejection fraction (p=0.02), acute presentation (p=0.04), use of statins (p=0.02), diuretics, nitrates and clopidogrel (p<0.001) and RASI (p=0.008). An inverse association was documented with BMI, glycemia, total cholesterol (p<0.001), creatinine and WBC (p=0.001). At a median follow-up of 996.5 [377-1552] days, 3.8% of the patients died. Vitamin D deficiency was significantly associated with overall mortality (7.6% vs 2.9% vs 0.4%, adjusted HR[95%CI]=3.6[1.43-8.9], p=0.006), MACE (adjusted HR[95%CI]=1.32[1.07-1.63], p=0.01) and the composite of death and MI (adjusted HR[95%CI]=1.3[1.03-1.65], p=0.03). A similarly increased risk was confirmed for all major higher-risk subsets of patients, with no significant interaction according to age, gender, diabetes mellitus or chronic kidney disease.ConclusionAmong patients undergoing percutaneous coronary interventions, lower levels of vitamin D are associated with an over 3-fold increased risk of mortality and major cardiovascular events. Future larger studies are certainly warranted in order to define the prognostic implications of cholecalciferol supplementation among high-risk patients with established coronary artery disease.     

Effects of SGLT2 inhibitors on cardiovascular and renal outcomes in type 2 diabetes: A meta-analysis with trial sequential analysis

Background:It is unclear whether there are false positive or negative results in the effects of sodium-glucose transporter 2 (SGLT2) inhibitors on various cardiovascular and renal outcomes in patients with type 2 diabetes. We aimed to explore this issue by a meta-analysis with trial sequential analysis.Methods:We included randomized trials evaluating the effects of SGLT2 inhibitors on cardiorenal endpoints in type 2 diabetic patients. Eight endpoints evaluated in the study were fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure (CVD or HHF), all-cause death (ACD), cardiovascular death (CVD), hospitalization for heart failure (HHF), and kidney function progression (KFP). Meta-analysis and trial sequential analysis was conducted for each endpoint.Results:Seven randomized trials of SGLT2 inhibitors were included for pooled analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the risk of MACE (HR 0.89, 95% confidence interval [CI] 0.84–0.94), MI (HR 0.91, 95% CI 0.84–0.99), CVD (HR 0.86, 95% CI 0.79–0.93), CVD or HHF (HR 0.77, 95% CI 0.73–0.82), HHF (HR 0.67, 95% CI 0.62–0.74), KFP (HR 0.63, 95% CI 0.56–0.70), and ACD (HR 0.88, 95% CI 0.83–0.94), whereas SGLT2 inhibitors did not have significant effects on stroke (HR 0.98, 95% CI 0.88–1.09). Trial sequential analyses for MI and stroke showed that cumulative Z curve did not cross trial sequential monitoring boundary and required information size, whereas those for the other 6 endpoints showed that cumulative Z curve crossed trial sequential monitoring boundary and/or required information size.Conclusions:Compared with placebo, SGLT2 inhibitors conclusively reduce the risk of MACE, CVD or HHF, ACD, CVD, HHF, and KFP in patients with type 2 diabetes, whereas the effects of SGLT2 inhibitors on MI and stroke are not conclusive and need to be further assessed in future studies with the adequate sample size to reject or accept the effect size.     

Association between estimated glomerular filtration rate and 10-year atherosclerotic cardiovascular disease risk among community residents in Shanghai,China

Background and aimsThe association between the estimated glomerular filtration rate (eGFR) and atherosclerotic cardiovascular disease (ASCVD) risk is unknown. We aimed to evaluate whether eGFR can be used as a predictor in ASCVD risk assessment.Methods and resultsUsing baseline data from 28,187 participants from Shanghai Suburban Adult Cohort and Biobank study, we adopted Pooled Cohort Equations (PCEs) and Prediction for ASCVD Risk in China (China-PAR) to estimate 10-year ASCVD risk. Multivariate logistic regression was used to analyze the relationship between 10-year ASCVD risk and eGFR. The receiver operating characteristic (ROC) curve was used to evaluate predictive value of eGFR for 10-year high ASCVD risk. Compared with normal eGFR, both men and women with reduced eGFR had a higher prevalence of ASCVD risk factors. With the decrease of eGFR level, the median of 10-year ASCVD risk gradually increased. For men, the adjusted odds ratios (95% confidence interval (CI)) of 10-year high ASCVD risk by PCEs associated with eGFR (60–74 and <60 mL/min/1.73 m²) were 1.52 (95%CI:1.17–1.99) and 2.51 (95%CI:1.27–4.97). The corresponding result was significant only for eGFR < 60 mL/min/1.73 m², OR of 1.57 (1.14–2.18) for women. Using China-PAR, the adjusted OR of 10-year high risk associated with eGFR < 60 mL/min/1.73 m² was 1.82 (1.40–2.38) in men. ROC indicated that eGFR has a good predictive value for 10-year high ASCVD risk.ConclusioneGFR may be an important risk factor in predicting and stratifying ASCVD risk. Consideration should be given to integrating eGFR into existing risk assessment tools to improve predictive performance.     

The Atrial fibrillation Better Care (ABC) pathway and cardiac complications in atrial fibrillation: a potential sex-based difference. The ATHERO-AF study

BackgroundAn integrated care approach is recommended to optimize management of patients with atrial fibrillation (AF). The impact of the Atrial fibrillation Better Care (ABC) pathway on major adverse cardiac events (MACE), which are the main causes of death in AF, has not been explored.Material and methodsWe investigated the association between ABC compliance and MACE incidence in 1157 (2690 patient-years) nonvalvular AF patients from the ATHERO-AF study. A subgroup analysis by sex and high cardiovascular risk patients as defined by a 2MACE score ≥3 was performed.ResultsOverall, 428 (37%) patients composed the ABC-compliant group. During a median follow up of 23 (IQR 12-37) months, 64 MACE occurred (2.38%/year). Kaplan Meier curve analysis showed a higher rate of MACE in ABC non-compliant group compared to the ABC-compliant (log-rank test p=0.006). The risk of MACE increased by the number of non-fulfilled ABC criteria. On multivariable Cox proportional hazard regression analysis, the ABC non-compliance was associated with an increased risk of MACE (Hazard ratio (HR) 2.244, 95% Confidence Interval (95%CI) 1.129-4.462). Men were more likely to have suboptimal anticoagulation control (group A), while uncontrolled symptoms were more frequent in women. The association between non-ABC and MACE was more evident in men than women (HR 3.647, 95%CI 1.294-10.277) and in patients with 2MACE score ≥3 (HR 1.728, 95%CI 1.209-2.472).ConclusionAn integrated care ABC approach is associated with a reduced risk of MACE in the AF population, especially in men and in patients at high risk of MACE.     

Association between the visceral adiposity index and risks of all-cause and cause-specific mortalities in a large cohort: Findings from the UK biobank

Background and aimsThe visceral adiposity index (VAI) has been recently established as a measure of visceral fat distribution and is shown to be associated with a wide range of adverse health events. However, the precise associations between the VAI score and all-cause and cause-specific mortalities in the general population remain undetermined.Methods and resultsIn this large-scale prospective epidemiological study, 357,457 participants (aged 38–73 years) were selected from the UK Biobank. We used Cox competing risk regression models to estimate the association between the VAI score and all-cause, cardiovascular disease (CVD), cancer, and other mortalities. The VAI score was significantly correlated with an increased risk of all-cause mortality (hazard ratio [HR], 1.200; 95% confidence interval [CI], 1.148–1.255; P < 0.0001), cancer mortality (HR, 1.224; 95% CI, 1.150–1.303; P < 0.0001), CVD mortality (HR, 1.459; 95% CI, 1.148–1.255; P < 0.0001), and other mortalities (HR, 1.200; 95% CI, 1.148–1.255; P < 0.0001) after adjusting for a series of confounders. In addition, the subgroup analyses showed that HRs were significantly higher in participants who were male, aged below 65 years, and body mass index less than 25.ConclusionIn summary, VAI was positively associated with an increased risk of all-cause and cause-specific mortalities in a nationwide, well-characterised population identified in a UK Biobank. The VAI score might be a complementary traditional predictive indicator for evaluating the risk of adverse health events in the population of Western adults aged 38 years and older.