Methotrexate can prevent cardiovascular events in patients with rheumatoid arthritis: An updated meta-analysis

Aims:The incidence of cardiovascular events (CVEs) in patients with rheumatoid arthritis (RA) is higher than that in people without RA. This may be because inflammation promotes the progression of atherosclerosis. Anti-inflammatory drugs might reduce the occurrence of CVEs in patients with RA. Methotrexate (MTX) is a conventional synthetic anti-rheumatic drug that is widely used in the treatment of RA. We performed a meta-analysis to determine whether MTX can prevent CVEs in RA patients. Then, we discussed the possibility of using MTX to prevent recurred CVEs in patients with coronary heart disease (CHD).Methods:We searched PubMed, Embase, Web of Science, and the Cochrane Library using the key words “methotrexate,” “cardiovascular,” “acute coronary syndrome,” “coronary heart disease,” “myocardial infarction,” “angina pectoris,” and “rheumatoid arthritis.” The efficacy outcome was defined as a composite of CVEs, including stable angina, acute coronary syndrome, stroke, heart failure, and cardiac death.Results:A total of 10 studies and 195,416 RA patients were included in our meta-analysis, and the effect size of relative risk (RR) was pooled using a fixed effect model. The results showed that MTX prevented CVEs in RA patients (RR: 0.798, 95% CI 0.726–0.876, P = .001, I² = 27. 9%).Conclusion:MTX can prevent CVEs in RA patients, but there is not sufficient evidence for using MTX to treat patients with CHD.     

The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism

The aim of our study was to assess the changes in serum lipid profiles after replacement therapy with L-T4 in patients with subclinical hypothyroidism (SCH), and to see whether there is an improvement in dyslipidemia based cardiovascular risk. Thirty non-smoker pre-menopausal women with newly diagnosed SCH (TSH between 4 and 10 microIU/ml) were involved in our study; twenty-six euthyroid healthy subjects were used as control group. TSH, free T3 (FT3), free T4 (FT4), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were measured before and after 6 months of L-T4 (50-100 microg/ day) therapy. TSH levels were targeted as < 2.0 microIU/ml. LDL-C was calculated using the Friedewald formula, while the cardiovascular risk was assessed with the TC/HDL-C ratio. Pre-treatment serum TC and LDL-C concentrations in SCH patients were significantly higher than those of euthyroid subjects (199.8 +/- 22.2 vs 181.5 +/- 24.6 mg/dl, p < 0.01; 146.3 +/- 26.1 vs 124.8 +/- 12 mg/dl, p < 0.001, respectively). TC, LDL-C levels and the TC/HDL-C ratio were reduced significantly after 6-month replacement therapy (-21.1 +/- 34.4 mg/dl or -10.5%, p < 0.01; -21.5 +/- 30.3 mg/dl or -14.7%, p < 0.001, respectively; and TC/HDL-C from 4.8 +/- 0.6 to 4.1 +/- 0.5 mg/dl, p < 0.01), while body mass index (BMI) values did not change. In conclusion, even mild elevations of TSH are associated with changes in lipid profile significant enough to raise the cardiovascular risk ratio, and these changes are corrected once the patients have been rendered euthyroid.     

Carotid intima-media thickness as a marker of cardiovascular risk in patients with subclinical hypothyroidism

Subclinical hypothyroidism (SH) has been associated with an increased risk for coronary disease. Carotid intima-media thickness (IMT), as assessed by ultrasonography, is a precise marker of atherosclerotic changes and can be used as an endpoint for cardiovascular events. Aims of this study were to determine carotid IMT in a group of patients with SH and its possible association with an increase in cardiovascular risk. There were no significant differences in mean carotid IMT between patients and controls. Results of both groups were, respectively: common carotid arteries, 0.573 +/- 0.070 mm and 0.576 +/- 0.068 mm (p= 0.904); carotid bifurcation, 0.602 +/- 0.079 mm and 0.617 +/- 0.102 mm (p= 0.714). Similar results were obtained when analyzing subgroups with serum TSH < or > 8 mIU/L and with positive or negative titers of TPOAb. The mean carotid IMT in these subgroups were: TSH 4-8 mIU/L: 0.579 +/- 0.070 mm and 0.586 +/- 0.063 mm; TSH > 8 mIU/L: 0.569 +/- 0.073 mm and 0.616 +/- 0.091 mm; TPOAb+: 0.585 +/- 0.070 mm and 0.621 +/- 0.085 mm; TPOAb-: 0.554 +/- 0.072 mm and 0.571 +/- 0.066 mm. No differences in the lipid profile and in the apoprotein B and lipoprotein (a) levels between the groups were found. These findings suggest that mild SH with no related metabolic changes is not associated with an increase in cardiovascular risk, as assessed by carotid IMT.     

Homocysteine: a risk factor for cardiovascular disease in subclinical hypothyroidism?

The role of homocysteine as a causal risk factor for cardiovascular disease remains controversial. Moderately elevated total plasma homocysteine levels have been reported in patients with overt hypothyroidism, a condition that is associated with an increased risk for cardiovascular disease. Recently, subclinical hypothyroidism has been identified as an independent risk factor for atherosclerosis and myocardial infarction in elderly women. Therefore, we measured prospectively total fasting plasma homocysteine levels in 37 consecutive subjects (6 males, 31 females, mean age 50 +/- 18 standard deviation [SD] years) with newly diagnosed subclinical hypothyroidism at baseline and after 3-4 months of levothyroxine supplementation. During levothyroxine treatment concentrations of thyrotropin (TSH) decreased from 10.1 +/- 5.8 (SD) to 1.5 +/- 1.8 mU/L. Fasting total plasma homocysteine levels were not elevated at baseline (9.9 +/- 2.9 micromol/L) and remained unchanged (9.6 +/- 3.5 micromol/L) after levothyroxine treatment. Serum folate or vitamin B(12) levels also remained unchanged. We conclude that subclinical hypothyroidism is not associated with hyperhomocysteinemia. Levothyroxine supplementation has no influence on total plasma homocysteine levels in subclinical hypothyroidism. Hence, total plasma homocysteine does not appear to contribute to the increased risk for atherosclerotic disease and myocardial infarction in patients with subclinical hypothyroidism.     

Plasma viscosity, an early cardiovascular risk factor in women with subclinical hypothyroidism

OBJECTIVE: It is controversial, if subclinical hypothyroidism increases cardiovascular risk. Plasma viscosity is a hemorheological parameter, which is accepted as an early cardiovascular risk factor. We investigated the alterations in plasma viscosity in women with subclinical hypothyroidism. DESIGN: 40 female patients with subclinical hypothyroidism and 31 age- and weight-matched healthy women were included. Free thyroxine (FT4), thyroid stimulating hormone (TSH), lipid parameters, fibrinogen, C-reactive protein (CRP) levels, hematocrit and plasma viscosity were measured in all subjects. MAIN OUTCOME: Plasma viscosity, total cholesterol and low density lipoprotein were significantly increased and high density lipoprotein was significantly decreased in patients with subclinical hypothyroidism. No significant correlation was found among the parameters. CONCLUSION: Increased plasma viscosity in patients' group suggests that cardiovascular risk might be increased in patients with subclinical hypothyroidism. As far as we could reach, this is the first study concerning plasma viscosity in subclinical hypothyroidism.     

Metabolic cardiovascular disease risk factors and their clustering in subclinical hypothyroidism

Objective A possible association between subclinical hypothyroidism and cardiovascular disease (CVD) has been reported. Monitoring of atomic‐bomb survivors for late effects of radiation exposure at the Radiation Effects Research Foundation has provided the opportunity to examine associations between subclinical hypothyroidism and metabolic CVD risk factors. The objective of the study was to evaluate associations between subclinical hypothyroidism and metabolic CVD risk factors, and a cluster of these factors. Design and participants This was a cross‐sectional study of 3549 subjects (mean age 70 years; 1221 men and 2328 women) between 2000 and 2003 comprising 306 subjects with subclinical hypothyroidism and 3243 control euthyroid subjects in Japan. Measurements We investigated associations between subclinical hypothyroidism and metabolic CVD risk factors such as hypertension, diabetes mellitus, dyslipidaemia and hyperuricaemia, and a cluster of these factors. Results Subclinical hypothyroidism was not significantly associated with either hypertension, diabetes mellitus or hyperuricaemia defined by taking into account the use of medications in both men and women, but in men it was associated with dyslipidaemia (P = 0·02). We observed a significantly increased odds ratio (OR) for the presence of three or more metabolic CVD risk factors in men with subclinical hypothyroidism after adjusting for age, body mass index (BMI), and smoking status [OR: 1·83, 95% confidence interval (CI): 1·13–2·94, P = 0·01]. The significant associations remained after an additional adjustment for atomic‐bomb radiation dose. Conclusions There appears to be a significant increase in a cluster of metabolic CVD risk factors among people with subclinical hypothyroidism.     

Restoration of euthyroidism does not improve cardiovascular risk factors in patients with subclinical hypothyroidism in the short term

Subclinical hypothyroidism (SH) is being accepted as a condition that is associated with increased risk of cardiovascular disease. Restoration of euthyroidism might be involved in prevention of cardiovascular disease. Thus, we evaluated biochemical risk factors of 75 patients with SH without evidence of any other diseases before and after restoration of euthyroidism and compared to 27 healthy controls. Before and a mean of 18.2+/-4.4 weeks after restoration of euthyroidism, serum total and LDL cholesterol, lipoprotein (Lp) (a), total homocysteine (t-Hyc) and highly sensitive C-reactive protein (hsCRP) levels were analyzed. Pre-treatment levels of TSH (10.04+/-5.36 vs 1.74+/-1.1 mIU/l, p<0.05), total cholesterol (204+/-68 vs 179+/-26 mg/dl, p<0.05) and LDL cholesterol (129+/-50 vs 106+/-16 mg/dl, p<0.05) were significantly higher than controls while Lp (a), t-Hyc, and hsCRP levels were not different. None of these biochemical risk factors have improved after euthyroidism in patients with SH with average dose of 85+/-30 microg/day, when compared to pre-treatment levels. Only in a subgroup of patients (no. 30) with higher TSH levels (>10 mIU/l), did serum LDL cholesterol levels decrease significantly (139+/-38 vs 112+/-35 mg/dl, p<0.05). Lp (a), t-Hyc and hsCRP levels were not significantly different after treatment with levothyroxine therapy even in this subgroup of patients. We conclude that clinical management of SH does not contribute to prevention of cardiovascular disease in the short term, and monitoring risk factors of cardiovascular disease does not offer additional benefits for treating patients with SH.     

Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials

AimsThe Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes.Data synthesisA MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH–OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n = 13 RCTs; MH–OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH–OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n = 2 RCTs; MH–OR 0.52 [0.37, 0.73]), p < 0.001. Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH–OR: 0.57 [0.42, 0.76]).ConclusionsThis updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs.     

An updated meta-analysis of TAVR in patients at intermediate risk for SAVR

Background

Transcatheter aortic valve replacement (TAVR) has been approved for use in patients with severe aortic stenosis at intermediate, high and extreme surgical risk. This meta-analysis was performed to assess the safety and efficacy of TAVR compared to surgical aortic valve replacement (SAVR) in intermediate risk patients.

Surrogate cardiovascular outcomes with sodium-glucose co-transporter-2 inhibitors in women: An updated meta-analysis

The burden of cardiovascular disease morbidity and mortality among women with type 2 diabetes mellitus remains high, despite the improvement in therapeutic management over the recent years. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have revolutionized treatment of cardiovascular disease in subjects with diabetes. However, previous meta-analyses of cardiovascular outcome trials failed to prove a significant effect on surrogate cardiovascular outcomes among female participants. Therefore, we sought to update these results, by incorporating data from the most recently published trials. We pooled available data from all available trials (EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS CV, DAPA-HF, EMPEROR-Reduced), except for the CANVAS trial. In the present updated meta-analysis we document that SGLT-2 inhibitors do not confer a significant decrease in the risk for major adverse cardiovascular events among women; however, they provide significant results in terms of reduction in the risk for cardiovascular death or hospitalization for heart failure, primarily driven by the results observed in the heart failure with reduced ejection fraction population. Better representation of women in future trials will provide further insights into the question whether there are true gender differences in the cardiovascular efficacy with this drug class.     

Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism

Subclinical hypothyroidism (SH) is a frequent condition that may be associated with increased cardiovascular risk. There is current interest in determining the effect, if any, of substitutive therapy with l-thyroxine (L-T4) on cardiovascular risk factors in SH and, particularly, on those associated with emerging cardiovacular risk, such as apolipoprotein (apo) B, lipoprotein (Lp) (a), total homocysteine (t-Hcy), and C-reactive protein (CRP). Thus, the aim of this study was to assess the impact of euthyroidism restoration on these emerging risk factors in SH. Forty-two patients diagnosed with SH were consecutively recruited before treatment. These patients were treated with L-T4 for 3 to 6 months with the dose necessary to restore euthyroidism. Lp(a), fasting and postmethionine (n = 28) t-Hcy, and CRP did not change with substitutive therapy, regardless of the respective baseline values, and the decrease in apo B paralleled that of low-density lipoprotein (LDL) cholesterol. Similarly, no treatment effect was observed on homocysteine or CRP in patients with thyrotropin-stimulating hormone (TSH) >10 mIU/L. Monitoring of emerging risk factors did not offer additional arguments for treating patients with SH and, thus, is not justified in their clinical management.     

亚临床甲状腺功能减退与心血管疾病的研究进展

亚临床甲状腺功能减退症(亚临床甲减)是一种常见、多发病,主要诊断依据是血清TSH水平增高,而游离甲状腺素(FT4)正常。其与心血管疾病的关系已成为当今研究的热点,目前认为亚临床甲减与高胆固醇血症、高血压、吸烟和糖尿病一样,构成动脉粥样硬化和心肌梗死的独立危险因素。本文综述了亚临床甲减与常见心血管疾病的关系及亚临床甲减的干预治疗等方面的进展。     

Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism.

Hypothyroidism has been associated with atherosclerosis. The mechanisms of atherosclerosis in patients with thyroid failure remain controversial. Hypofibrinolysis might be a risk factor for thromboembolic disease in subclinical hypothyroidism (SH). We measured fibrinolytic activity in patients with SH before and after levothyroxine (LT(4)) treatment and compared it to those of controls. We prospectively included 35 patients with SH and 30 healthy controls. We treated patients with LT(4) until almost 6 months after the euthyroid state has been achieved. We measured fibrinogen, D-dimer, antithrombin III (ATIII), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) activity, and factor VII. Clinical and anthropometric variables were recorded for both groups. We found increased levels of fibrinogen, PAI-1, and factor VII and decreased levels of ATIII activity in patients compared to control (p < 0.001 and p < 0.05). Decrease of tPA was not significant (p > 0.05). At the end of the LT(4) treatment, significant decreases were determined in PAI-1 and factor VII (p < 0.05). In conclusion, our data suggest an important role of hypofibrinolytic and hypercoagulable state on the development of atherosclerosis in patients with SH and beneficial effects of LT(4 )treatment for decreasing the risk of atherosclerosis.