The effect of vitamin K1 on arterial calcification activity in subjects with diabetes mellitus: a post hoc analysis of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET). OBJECTIVES: We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus. METHODS: This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score > 10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10 mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta. RESULTS: In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P = 0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P = 0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P = 0.002). CONCLUSIONS: In individuals with diabetes mellitus, supplementation with 10 mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448.

A Comprehensive Cardiovascular-Renal-Metabolic Risk Reduction Approach to Patients with Type 2 Diabetes Mellitus.

Despite decades of research into risk-reduction strategies, cardiovascular disease and renal disease remain leading causes of morbidity and mortality among patients with type 2 diabetes mellitus. Given the tight clustering of cardiovascular and renal disease with the metabolic abnormalities of type 2 diabetes mellitus, we can think of these conditions together as cardiovascular-renal-metabolic disease states. A holistic view of cardiovascular-renal-metabolic disease states is critical to provide integrated patient-centered care to individuals with these disease states. Here, we explore the cardiovascular and renal risks associated with type 2 diabetes mellitus and highlight the importance of reducing cardiovascular-renal-metabolic disease risk in a comprehensive manner. We advocate a cross-disciplinary, team-based model to manage cardiovascular-renal-metabolic disease risk among patients with type 2 diabetes mellitus.

Keap1-Nrf2 signaling activation by Bardoxolone-methyl ameliorates high glucose-induced oxidative injury in human umbilical vein endothelial cells.

In cultured human umbilical vein endothelial cells (HUVECs) high glucose (HG) stimulation will lead to significant cell death. Bardoxolone-methyl (BARD) is a NF-E2 p45-related factor 2 (Nrf2) agonist. In this study we show that BARD, at only nM concentrations, activated Nrf2 signaling in HUVECs. BARD induced Keap1-Nrf2 disassociation, Nrf2 protein stabilization and nuclear translocation, increasing expression of antioxidant response element (ARE) genes. BARD pretreatment in HUVECs inhibited HG-induced reactive oxygen species production, oxidative injury and cell apoptosis. Nrf2 shRNA or knockout (using a CRISPR/Cas9 construct) reversed BARD-induced cytoprotection in HG-stimulated HUVECs. Conversely, forced activation of Nrf2 cascade by Keap1 shRNA mimicked BARD's activity and protected HUVECs from HG. Importantly, BARD failed to offer further cytoprotection against HG in the Keap1-silened HUVECs. Taken together, Keap1-Nrf2 cascade activation by BARD protects HUVECs from HG-induced oxidative injury.

Cinnamaldehyde Ameliorates Vascular Dysfunction in Diabetic Mice by Activating Nrf2.

BACKGROUND: Oxidative stress is known to be associated with the development of diabetes. Cinnamaldehyde (CA) is a spice compound in cinnamon that enhances the antioxidant defense against reactive oxygen species (ROS) by activating nuclear factor erythroid-related factor 2 (Nrf2), which has been shown to have a cardioprotection effect. However, the relationship between CA and Nrf2 in diabetic vascular complications remains unclear. METHODS: Leptin receptor-deficient (db/db) mice were fed normal chow or diet containing 0.02% CA for 12 weeks. The vascular tone, blood pressure, superoxide level, nitric oxide (NO) production, renal morphology, and function were measured in each group. RESULTS: CA remarkably inhibited ROS generation, preserved NO production, increased phosphorylated endothelial nitric oxide synthase (p-eNOS), attenuated the upregulation of nitrotyrosine, P22 and P47 in aortas of db/db mice, and apparently ameliorated the elevation of type IV collagen, TGF-ß1, P22, and P47 in kidney of db/db mice. Feeding with CA improved endothelium-dependent relaxation of aortas and mesenteric arteries, and alleviated the remodeling of mesenteric arteries in db/db mice. Additionally, dietary CA ameliorated glomerular fibrosis and renal dysfunction in diabetic mice. Nrf2 and its targeted genes heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1) were slightly increased in db/db mice and further upregulated by CA. However, these protective effects of CA were reversed in Nrf2 downregulation mice. CONCLUSIONS: A prolonged diet of CA protects against diabetic vascular dysfunction by inhibiting oxidative stress through activating of Nrf2 signaling pathway in db/db mice.

Aqueous extract of Salvia miltiorrhiza Bunge-Radix Puerariae herb pair ameliorates diabetic vascular injury by inhibiting oxidative stress in streptozotocin-induced diabetic rats.

Vascular diabetic complications are the leading cause of mortality and morbidity for diabetes. The present study was designed to investigate the protective effect of herb pair Salvia miltiorrhiza Bunge-Radix Puerariae (DG) on diabetic vascular injury induced by streptozotocin. The protective effect of DG was determined by oral administration of DG (50 and 200 mg/kg) in rats and on high glucose (HG)-induced endothelial injury. DG showed no effect on body weight, fasting blood glucose (FBG) but decreased the serum levels of insulin, nitric oxide (NO), hydrogen peroxide (H2O2), malondialdehyde (MDA), soluble intercellular cell adhesion molecule-1 (s-ICAM-1) and vascular cell adhesion molecule-1 (s-VCAM-1), and increased superoxide dismutase (SOD) and catalase (CAT) levels. The pathological alterations of aorta was improved by DG. Furthermore, the increased expression of ICAM-1,VCAM-1, NOX2, and NOX4 in aorta were inhibited by DG. HG-induced endothelial ROS formation, ICAM-1,VCAM-1, NOX4 expression and monocyte-endothelial adhesion were dramatically suppressed by DG as well. In addition, both GKT137831, a NOX4 inhibitor, and PDTC, a NF-κB inhibitor, could significantly inhibited HG-induced ICAM-1, VCAM-1 expression and monocyte-endothelial adhesion. These results suggested that DG improved diabetic vascular injury possibly by reducing oxidative stress, which provides scientific evidence for the application of DG for diabetic vascular therapy.

Involvement of RBP4 in Diabetic Atherosclerosis and the Role of Vitamin D Intervention.

The purposes of this study were to evaluate the expression of retinol-binding protein 4 (RBP4) in diabetic rats with atherosclerosis and to investigate the role of vitamin D intervention. Male Wistar rats were randomly divided into 4 groups, including the control group (NC), the diabetic rats (DM1), the untreated diabetic atherosclerosis rats (DM2), and the vitamin D-treated diabetic atherosclerosis rats (DM3). The levels of serum and adipose RBP4, fasting insulin (FINS), fasting plasma glucose (FPG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), 25-hydroxyvitamin D [25(OH)D], C-reactive protein (CRP), and systolic blood pressure (SBP) were measured. Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment ß-cell function index (HOMA-ß), and atherogenic indexes (AI) were calculated. Compared with group NC, the levels of RBP4, TG, LDL-c, FPG, FINS, CRP, AI1, AI2, SBP, and HOMA-IR increased, while the levels of HDL-c, 25(OH)D, and HOMA-ß decreased in groups DM1 and DM2. After 8 weeks of vitamin D supplementation in group DM3, the levels of 25(OH)D and HOMA-ß increased and the levels of LDL-c, TC, HOMA-IR, FINS, CRP, RBP4, AI1, AI2, and SBP decreased significantly when compared with group DM2 (P < 0.05); Pearson analysis showed that serum RBP4 was positively correlated with TG, FINS, HOMA-IR, SBP, CRP, and AI and negatively correlated with 25(OH)D. In addition, multivariable logistic regression analysis showed that serum RBP4, SBP, and HDL-c were predictors for the presence of diabetic atherosclerosis. These findings suggested that RBP4 could involve in the improvement of diabetic atherosclerosis; vitamin D had the ability to decrease the level of RBP4 and eventually played an important role in preventing atherosclerosis in diabetes.

Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care: A Matched Cohort Study.

Background: Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes. Objective: To investigate the relationship between bariatric surgery and incident microvascular complications of T2DM. Design: Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015. Setting: 4 integrated health systems in the United States. Participants: Patients aged 19 to 79 years with T2DM who had bariatric surgery (n = 4024) were matched on age, sex, body mass index, hemoglobin A1c level, insulin use, diabetes duration, and intensity of health care use up to 3 nonsurgical participants (n = 11 059). Intervention: Bariatric procedures (76% gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) compared with usual care. Measurements: Adjusted Cox regression analysis investigated time to incident microvascular disease, defined as first occurrence of diabetic retinopathy, neuropathy, or nephropathy. Results: Median follow-up was 4.3 years for both surgical and nonsurgical patients. Bariatric surgery was associated with significantly lower risk for incident microvascular disease at 5 years (16.9% for surgical vs. 34.7% for nonsurgical patients; adjusted hazard ratio [HR], 0.41 [95% CI, 0.34 to 0.48]). Bariatric surgery was associated with lower cumulative incidence at 5 years of diabetic neuropathy (7.2% for surgical vs. 21.4% for nonsurgical patients; HR, 0.37 [CI, 0.30 to 0.47]), nephropathy (4.9% for surgical vs. 10.0% for nonsurgical patients; HR, 0.41 [CI, 0.29 to 0.58]), and retinopathy (7.2% for surgical vs. 11.2% for nonsurgical patients; HR, 0.55 [CI, 0.42 to 0.73]). Limitation: Electronic health record databases could misclassify microvascular disease status for some patients. Conclusion: In this large, multicenter study of adults with T2DM, bariatric surgery was associated with lower overall incidence of microvascular disease (including lower risk for neuropathy, nephropathy, and retinopathy) than usual care. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases.

l-Citrulline Supplementation: Impact on Cardiometabolic Health.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

The protean role of haptoglobin and haptoglobin genotypes on vascular complications in diabetes mellitus.

Introduction and background Haptoglobin (Hp) is considered to be an antioxidant and protective against cardiovascular complications. Polymorphisms in the Hp gene interact with diabetes mellitus to affect the risk of vascular complications. Methods We review the updated literature about the protean role of Hp and Hp genotypes spanning genomics, molecular, translational and clinical studies. We searched Pubmed, SCOPUS and Google Scholar for all articles using the keywords: haptoglobin and/or haptoglobin polymorphism and diabetes. We review the diverse Hp genotypes, phenotypes and the impact on diabetes complications, including lessons from animal models and in vitro models. We describe the clinical studies on the associations of Hp genotypes with vascular complications in type 1 and type 2 diabetes comprehensively. We review the studies looking at vitamin E supplementation in a personalized manner in Hp2-2 diabetes individuals. Results and conclusion Hp genotypes have evolved as a result of deletions in the traditional Hp genes. The Hp genotypes have been associated with microvascular and macrovascular complications in type 1 diabetes mellitus but the association in type 2 diabetes is more consistent with cardiovascular complications. A preferential benefit of vitamin E and other antioxidants in the Hp2-2 genotype for cardiovascular complications in type 2 diabetes has been seen presumably secondary to interaction with high-density lipoprotein function. Hence, the Hp genotype can be used to personalize antioxidant therapeutics in diabetes patients. These results need to be corroborated in large, global, pragmatic, prospective, cardiovascular outcome trials in type 2 diabetes patients.

Cardiovascular benefits of combined interval training and post-exercise nutrition in type 2 diabetes.

AIM: The purpose of this study was to examine whether the combination of high-intensity interval training (HIIT) and post-exercise protein supplementation would improve cardiovascular outcomes in individuals with T2D. METHODS: In a double-blind controlled trial, fifty-three adults with T2D (free of CVD and not on exogenous insulin) were randomized to 12weeks of cardio and resistance-based HIIT (4-10×1min at 90% maximal heart rate) with post-exercise milk, milk-protein, or placebo supplementation, thrice weekly. Before and after, carotid and femoral artery intima media thickness (IMT) and femoral flow profiles were assessed using high-resolution ultrasound. Central and peripheral arterial stiffness were assessed by pulse wave velocity (PWV), and resting and maximal heart rate rates were measured. RESULTS: After 12weeks of HIIT femoral IMT (Pre: 0.84±0.21mm vs. Post: 0.81±0.16mm, p=0.03), carotid-femoral PWV (Pre: 10.1±3.2m/s vs. Post: 8.6±1.8m/s, p<0.01) and resting heart rate (Pre: 70.4±10.8bpm vs. Post: 67.8±8.6 bpm, p=0.01) were all significantly lower. There were no differences between nutrition groups (all significant main effects of time) for all outcomes. CONCLUSION: HIIT reduces femoral IMT, arterial stiffness and resting heart rate in individuals with T2D. The addition of post-exercise milk or protein to HIIT did not have additive effects for improving cardiovascular outcomes in the present study. Taken together, HIIT alone may be an effective means to reduce the burden of cardiovascular complications in T2D.

Improvements in peripheral vascular function with vitamin D treatment in deficient adolescents with type 1 diabetes.

BACKGROUND: Vitamin D (VitD) deficiency is prevalent in adolescents with type 1 diabetes (T1D) and is associated with diabetes-related vascular complications in adulthood. The objective of this clinical trial was to assess VitD treatment on endothelial function (EF) and markers of renal inflammation, in this patient group. METHODS: Adolescents with T1D with suboptimal levels of VitD (<37.5 nmol/L) were treated for 12 to 24 weeks with a VitD analog (VitD3 ) at doses of 1000 or 2000 IU daily. The primary end-point assessed the change in reactive hyperemia index (lnRHI), a measure of EF. Secondary end-points included changes in blood pressure, lipid profile, HbA1c and albumin creatinine ratio (ACR). Urinary cytokine/chemokine inflammatory profile was also assessed in a subset of subjects posttreatment. RESULTS: Two hundred and seventy-one subjects were screened for VitD status and 31 VitD deficient subjects with a mean age of 15.7 ± 1.4 years were enrolled and completed the study. Mean 25-OH-VitD levels significantly increased (33.0 ± 12.8 vs 67.0 ± 23.2 nmol/L, P < .01) with a significant improvement in EF following VitD supplementation (lnRHI 0.58 ± 0.20 vs 0.68 ± 0.21, P = .03). VitD supplementation did not significantly impact systolic blood pressure/diastolic blood pressure (SBP/DBP), lipids, HbA1c and ACR and no adverse effects were seen. Several urinary inflammatory cytokines/chemokines: MCP-3 (P < .01), epidermal growth factor (EGF) (P < .01) tumor necrosis factor ß (TNFß) (P = .01), interleukin-10 (IL-10) (P = .01), also significantly decreased post-VitD-treatment. CONCLUSIONS: Treatment with VitD was associated with an improvement in EF and reduced expression of urinary inflammatory markers in adolescents with T1D. This data is suggestive of an additional benefit of VitD supplementation on early markers of microvascular complications.

Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus.

Diabetes mellitus is a growing in exponential proportions. If the current growth trend continues, it may result in every third adult in the United States having diabetes mellitus by 2050, and every 10th adult worldwide. Type 2 diabetes mellitus (T2DM) confers a 2- to 3-fold increased risk of cardiovascular (CV) events compared with non-diabetic patients, and CV mortality is responsible for around 80% mortality in this population. Patients with T2DM can have other features of insulin resistance-metabolic syndrome like hypertension, lipid abnormalities, and obesity which are all associated with increased CV disease and stroke risk even in the absence of T2DM. The management of a T2DM calls for employing a holistic risk factor control approach. Metformin is the first line therapy for T2DM and has been shown to have cardiovascular beneficial effects. Intense debate regarding the risk of myocardial infarction with rosiglitazone led to regulatory agencies necessitating cardiovascular outcome trials with upcoming anti-diabetic medications. Glucagon like peptide-1 agonists and sodium glucose co-transporter-2 inhibitors have shown promising CV safety and additional CV benefit in recent clinical trials. These drugs have favorable effects on traditional CV risk factors. The findings from these studies further support that fact that CV risk factor control plays an important role in reducing morbidity and mortality in T2DM patients. This review article will discuss briefly the cardiovascular safety and benefits of the oral medications which are currently being used for T2DM and will then discuss in detail about the newer medications being investigated for the treatment of T2DM.

Effect of intensive glucose control on microvascular events in people with type 2 diabetes.

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Association of glucagon-like peptide-1 receptor agonist use and rates of acute myocardial infarction, stroke and overall mortality in patients with type 2 diabetes mellitus in a large integrated health system.

AIMS: To assess the potential impact of glucagon-like peptide-1 receptor agonist (GLP-1RA) exposure on cardiovascular disease (CVD) and mortality outcomes in patients with type 2 diabetes (T2D), using a large retrospective cohort. RESEARCH DESIGN AND METHODS: Patients who had T2D between 2005 and 2014 (N = 105 862) were identified from the electronic health record system at Cleveland Clinic using a validated electronic phenotype. A time-dependent, Cox, multiple regression analysis was used to assess the association between GLP-1RA exposure and risk of acute myocardial infarction (AMI), stroke/cerebrovascular accident (CVA), and overall mortality, as well as the composite of all three outcomes. The findings were further evaluated by assessing the effect of GLP-1RAs on the same variables in patients with and without prior CVD. The model adjusted for differences in demographic information, hypertension, laboratory/vital signs, history of outcomes, and T2D medications. RESULTS: There were significantly lower rates of AMI (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.65 to 0.99; P = .045), CVA (HR 0.82, 95% CI 0.74 to 0.91, P < .001), overall mortality (HR 0.48, 95% CI 0.41 to 0.57; P < .001), and the composite outcome (HR 0.82, 95% CI 0.74 to 0.91; P < .002) during the consolidated time that patients were exposed to GLP-1RAs compared to corresponding rates during intervals without GLP-1RA exposure. GLP-1RA treatment was associated with a significant decrease in CVA, mortality, and the composite outcome in patients with and without established CVD, not significantly affecting AMI in these subgroups. CONCLUSIONS: GLP-1RA exposure was found to be associated with a reduction in the risk of cardiovascular events observed and overall mortality among patients with T2D with and without established CVD, after adjusting for potential confounders.

Effect of rivaroxaban on preventing deep vein thrombosis in aged diabetics with femoral neck fractures after hip replacement.

The present study estimates the effect of rivaroxaban on preventing deep vein thrombosis (DVT) in aged diabetics with femoral neck fractures after hip replacement. Our study consisted of 236 aged diabetics with femoral neck fractures, which were divided into the rivaroxaban and control groups. Reaction time (R time), clot formation time (K time), α angle (α), maximum amplitude (MA), clot elasticity (G) and coagulation index (CI), prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured. DVT was diagnosed by color duplex Doppler ultrasound (CDDU). The risk factors of DVT were analysed by logistic regression analysis. Compared with the control group, in the rivaroxaban group, R time and K time were extended and α, MA and G decreased 1 day before operation. One day after operation, the rivaroxaban group had less PT and APPT and lower incidence of DVT than the control group. In the two groups, preoperative and postoperative PT and APPT significantly differed. Body mass index (BMI) ≥25, abnormal coagulation indicators, use of cemented femoral hip prosthesis, high haemoglobin content and non-ankle pump exercise after operation were the risk factors for DVT. Rivaroxaban could prevent DVT in aged diabetics with femoral neck fractures after hip replacement.

The vascular protective effects of Anoectochilus roxburghii polysaccharose under high glucose conditions.

ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus roxburghii has been used as a health food and a herb for treatment diabetes in China for hundreds years. Anoectochilus roxburghii polysaccharose (ARP) is the major active component of the plant. AIM OF THE STUDY: The present study investigated the vascular protection of ARP in vivo and in vitro experiments. MATERIALS AND METHODS: Hypoglycemic activity of ARP was examined in diabetic mice. Moreover, the further vascular protective effects in vitro were investigated in human umbilical vein endothelial cells (HUVECs) stimulated by high glucose (HG, 35mM). RESULTS: Compared with untreated diabetic mice, ARP (100 or 300mg/kg) caused a significant decrease in blood glucose levels. Histological examination showed that ARP ameliorated endothelial damage to some extent, especially ARP at dosage of 300mg/kg. In vitro assay, pretreatment with ARP (10, 20 and 30µg/mL) markedly inhibited generations of reactive oxygen species (ROS), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) in HG-induced HUVECs. ARP pretreatment not only suppressed HG-induced matrix metalloproteinases (MMPs) activity via increasing the expression of the tissue inhibitors of MMPs (TIMPs), but also adjusted the MMPs/TIMPs balance to maintain homeostasis of vascular structure. Moreover, pretreatment with ARP could significantly reduce p-NF-κB p65, p-p38 MAPK expression levels in HG-induced HUVECs. CONCLUSIONS: The vascular protective effects of ARP might be associated with NF-κB and p38 MAPK pathway. ARP might be used as useful substance in the treatment of vasculopathy in diabetic patients.

No increased risk of cardiovascular events in older adults initiating dipeptidyl peptidase-4 inhibitors vs therapeutic alternatives.

AIM: To compare the cardiovascular (CV) risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors relative to sulphonylureas (SUs) and thiazolidinediones (TZDs). METHODS: During 2007 to 2013, using Medicare data for beneficiaries aged >65 years, we identified the following 2 cohorts of new-users, who had not been exposed to the drugs being compared in the 6 months before initiation: (1) DPP-4 inhibitor vs SU initiators and (2) DPP-4 inhibitor vs TZD initiators. Using propensity-score-adjusted Cox models accounting for competing risk by death, we estimated the hazard ratios (HRs), risk differences and 95% confidence intervals (CIs) for myocardial infarction (MI), stroke, hospitalization for heart failure (HF), and a combined outcome (MI, stroke, all-cause mortality). RESULTS: In the DPP-4 inhibitor vs SU comparison, there were 30 130 DPP-4 inhibitor initiators and 68 382 SU initiators. Their mean age was 75 years, 41% were men and 55% had a baseline CV condition. The HR for the composite outcome was 0.75 (95% CI 0.72-0.79) over a median treatment duration of 1 year, but the 1-year risks of MI were 1.00 (95% CI 0.89-1.12) and 1.47 (95% CI 1.38-1.56) per 100 patients for DPP-4 inhibitors and SUs, respectively, and the corresponding stroke risks were 0.98 (95% CI 0.87-1.10) and 1.09 (95% CI 1.01-1.17). For the DPP-4 inhibitor vs TZD comparison, there were 20 596 DPP-4 inhibitor initiators and 13 526 TZD initiators without previous HF. Their mean age was 74 years, 42% were men and 30% had a baseline CV event. The composite outcome HR was 0.94 (95% CI 0.86-1.02) over a median treatment duration of 1 year. The 1-year risk for MI was ~0.90 and for stroke it was ~0.80 per 100 patients in both DPP-4 inhibitor and TZD initiators. CONCLUSION: Although limited by the short treatment period, the present study suggests there is no increased short-term risk of MI, stroke or HF with DPP-4 inhibitors vs SUs/TZDs.

Longitudinal association between fasting blood glucose concentrations and first stroke in hypertensive adults in China: effect of folic acid intervention.

Background: Diabetes is a known risk factor for stroke, but data on its prospective association with first stroke are limited. Folic acid supplementation has been shown to protect against first stroke, but its role in preventing first stroke in diabetes is unknown.Objectives: This post hoc analysis of the China Stroke Primary Prevention Trial tested the hypotheses that the fasting blood glucose (FBG) concentration is positively associated with first stroke risk and that folic acid treatment can reduce stroke risk associated with elevated fasting glucose concentrations.Design: This analysis included 20,327 hypertensive adults without a history of stroke or myocardial infarction, who were randomly assigned to a double-blind daily treatment with 10 mg enalapril and 0.8 mg folic acid (n = 10,160) or 10 mg enalapril alone (n = 10,167). Kaplan-Meier survival analysis and Cox proportionate hazard models were used to test the hypotheses with adjustment for pertinent covariables.Results: During a median treatment duration of 4.5 y, 616 participants developed a first stroke (497 ischemic strokes). A high FBG concentration (≥7.0 mmol/L) or diabetes, compared with a low FBG concentration (<5.0 mmol/L), was associated with an increased risk of first stroke (6.0% compared with 2.6%, respectively; HR: 1.9; 95% CI: 1.3, 2.8; P < 0.001). Folic acid treatment reduced the risk of stroke across a wide range of FBG concentrations ≥5.0 mmol/L, but risk reduction was greatest in subjects with FBG concentrations ≥7.0 mmol/L or with diabetes (HR: 0.66; 95% CI: 0.46, 0.97; P < 0.05). There was a significant interactive effect of FBG and folic acid treatment on first stroke (P = 0.01).Conclusions: In Chinese hypertensive adults, an FBG concentration ≥7.0 mmol/L or diabetes is associated with an increased risk of first stroke; this increased risk is reduced by 34% with folic acid treatment. These findings warrant additional investigation. This trial was registered at clinicaltrials.gov as NCT00794885.