The relationship of fatty acids to ischaemic heart disease and lifespan in men and women using Mendelian randomization.

BACKGROUND: Observationally, polyunsaturated fatty acids (PUFAs) have health benefits compared with saturated fatty acids (SFAs); randomized controlled trials suggest fewer benefits. We used uni- and multi-variable Mendelian randomization to assess the association of major fatty acids and their sub-species with ischaemic heart disease (IHD) overall and sex-specifically and with lifespan sex-specifically, given differing lifespan by sex. METHODS: We obtained strong (P <5x10-8), independent (r2<0.001) genetic predictors of fatty acids from genome-wide association studies (GWAS) in a random subset of 114 999 UK Biobank participants. We applied these genetic predictors to the Cardiogram IHD GWAS (cases = 60 801, controls = 123 504) and to the Finngen consortium GWAS (cases = 31 640, controls = 187 152) for replication and to the UK Biobank for sex-specific IHD and for lifespan based on parental attained age (fathers = 415 311, mothers = 412 937). We used sensitivity analysis and assessed sex differences where applicable. RESULTS: PUFAs were associated with IHD [odds ratio 1.23, 95% confidence interval (CI) 1.05 to 1.44] and lifespan in men (-0.76 years, 95% CI -1.34 to -0.17) but not women (0.20, 95% CI -0.32 to 0.70). Findings were similar for omega-6 fatty acids and linoleic acid. Independent associations of SFAs, mono-unsaturated fatty acids or omega-3 fatty acids with IHD overall or lifespan in men and women were limited. CONCLUSIONS: PUFAs, via specific subspecies, may contribute to disparities in lifespan by sex. Sex-specific dietary advice might be a start towards personalized public health and addressing inequities.

Overall and Sex-Specific Effect of Berberine for the Treatment of Dyslipidemia in Adults: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: Berberine is a nutraceutical that can improve lipid metabolism. Berberine may also affect sex hormones and exert sex-specific lipid-modifying effects, which have been overlooked. This study aimed to comprehensively review the efficacy and safety of berberine in adults for the treatment of dyslipidemia with consideration of potential sex disparity. Data Sources We searched Medline, Embase, Wanfang, CNKI, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform from inception to 13 December 2022. No language restrictions were applied. This study was registered in PROSPERO (CRD42021293218) prior to completing the literature search. Study Selection Two blinded reviewers assessed studies for inclusion. Eligible studies were randomized controlled trials in adults that compared berberine versus placebo, and measured blood lipids or lipoproteins. Data Extraction and Synthesis Data extraction was performed by two blinded reviewers using a structured form in Covidence. Risk of bias was assessed using the Cochrane risk of bias tool for randomized trials. Mean differences (MD) were estimated using inverse variance weighting with random effects models for lipid outcomes using R. Adverse events (AEs) were described narratively. Main Outcomes Primary outcomes were low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein B. Secondary outcomes were gastrointestinal and muscle-related AEs. RESULTS: Eighteen studies (n = 1788 participants), conducted mainly in mainland China and Hong Kong (15 studies [83%]), were included with treatment durations ranging from 4 to 24 weeks. Berberine reduced LDL cholesterol (- 0.46 mmol/L, 95% CI - 0.62 to - 0.30, 14 studies, n = 1447), total cholesterol (- 0.48 mmol/L, 95% CI - 0.63 to - 0.33, 17 studies, n = 1637), triglycerides (- 0.34 mmol/L, 95% CI - 0.46 to - 0.23, 18 studies, n = 1661) and apolipoprotein B (- 0.25 g/L, 95% CI - 0.40 to - 0.11, 2 studies, n = 127). Berberine increased HDL cholesterol by 0.06 mmol/L (95% CI 0.00 to 0.11, 15 studies, n = 1471). Notably, the effect on HDL cholesterol was different in women (0.11 mmol/L, 95% CI 0.09 to 0.13) from that in men (- 0.07 mmol/L, 95% CI - 0.16 to 0.02). Among 16 studies that reported AEs, no serious AEs were reported for berberine. Gastrointestinal AEs were reported in 12 studies and tended to be more frequent in participants allocated to berberine versus placebo (2-23% vs 2-15%). CONCLUSIONS: Berberine produces small reductions in LDL cholesterol, triglycerides, and apolipoprotein B, with potential sex-specific effects on HDL cholesterol. Large-scale trials that consider sex disparity and assess clinical outcomes are required.

Berberine is found naturally in barberry and goldenthread, plants which have long been used in traditional herbal medicine in Asia. Nowadays berberine is used as a purified product and is easy to purchase as a nutraceutical supplement or non-prescription drug. People with dyslipidemia, a medical condition often known as 'high cholesterol', may prefer treatment with a nutraceutical such as berberine to reduce blood cholesterol. In recent years, many studies have contrasted the effects of taking berberine with an inactive placebo. This study aimed to combine all the available randomized controlled trials that assessed berberine's effects on blood lipids and lipoproteins. We included 18 studies that used berberine doses of 900­1500 mg/day, the majority of which were conducted in mainland China and Hong Kong. We found that on average berberine can modestly reduce low-density lipoprotein (LDL) cholesterol by 0.5 mmol/L (18 mg/dL) and triglycerides by 0.3 mmol/L (30 mg/dL). Berberine also increases high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (2 mg/dL). Interestingly, women may obtain a greater increase in HDL cholesterol than men. The short-term use of berberine appears to be safe. No study participants treated with berberine experienced a serious adverse event. However, berberine may occasionally cause constipation, diarrhea, or nausea. Larger high-quality studies are still needed to determine the long-term effects of berberine for dyslipidemia.

Effect of Berberine on Cardiovascular Disease Risk Factors: A Mechanistic Randomized Controlled Trial.

Cardiovascular disease (CVD) is a major contributor to the global burden of disease. Berberine, a long-standing, widely used, traditional Chinese medicine, is thought to have beneficial effects on CVD risk factors and in women with polycystic ovary syndrome. The mechanisms and effects, specifically in men, possibly via testosterone, have not been examined previously. To assess the effect of berberine on CVD risk factors and any potential pathway via testosterone in men, we conducted a randomized, double-blind, placebo-controlled, parallel trial in Hong Kong. In total, 84 eligible Chinese men with hyperlipidemia were randomized to berberine (500 mg orally, twice a day) or placebo for 12 weeks. CVD risk factors (lipids, thromboxane A2, blood pressure, body mass index and waist-hip ratio) and testosterone were assessed at baseline, and 8 and 12 weeks after intervention. We compared changes in CVD risk factors and testosterone after 12 weeks of intervention using analysis of variance, and after 8 and 12 weeks using generalized estimating equations (GEE). Of the 84 men randomized, 80 men completed the trial. Men randomized to berberine had larger reductions in total cholesterol (-0.39 mmol/L, 95% confidence interval (CI) -0.70 to -0.08) and high-density lipoprotein cholesterol (-0.07 mmol/L, 95% CI -0.13 to -0.01) after 12 weeks. Considering changes after 8 and 12 weeks together, berberine lowered total cholesterol and possibly low-density lipoprotein-cholesterol (LDL-c), and possibly increased testosterone. Changes in triglycerides, thromboxane A2, blood pressure, body mass index and waist-hip ratio after the intervention did not differ between the berberine and placebo groups. No serious adverse event was reported. Berberine is a promising treatment for lowering cholesterol. Berberine did not lower testosterone but instead may increase testosterone in men, suggesting sex-specific effects of berberine. Exploring other pathways and assessing sex differences would be worthwhile, with relevance to drug repositioning and healthcare.

Effect of glutamate and aspartate on ischemic heart disease, blood pressure, and diabetes: a Mendelian randomization study.

BACKGROUND: Evolutionary biology suggests reproduction trades off against longevity. Genetic selection in favor of fertility and ischemic heart disease (IHD) exists in humans. Observationally, soy protects against IHD. Soy amino acids, glutamate and aspartate, may lower androgens. No large randomized controlled trials testing their health effects exist. OBJECTIVE: Using Mendelian randomization, we assessed how genetically predicted glutamate and aspartate affected IHD, blood pressure, and diabetes. METHODS: A separate sample instrumental variable analysis with genetic instruments was used to obtain unconfounded estimates using genetic variants strongly (P < 5 × 10(-8)) and solely associated with glutamate or aspartate applied to an IHD case (n ≤76,014)-control (n ≤ 264,785) study (based on a meta-analysis of CARDIoGRAMplusC4D 1000 Genomes, UK Biobank CAD SOFT GWAS and Myocardial Infarction Genetics and CARDIoGRAM Exome), blood pressure from the UK Biobank (n ≤ 361,194), and the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)-control (n = 132,532) study. A weighted median and MR-Egger were used for a sensitivity analysis. RESULTS: Glutamate was not associated with IHD, blood pressure, or diabetes after correction for multiple comparisons. Aspartate was inversely associated with IHD (odds ratio (OR) 0.92 per log-transformed standard deviation (SD); 95% confidence interval (CI) 0.88, 0.96) and diastolic blood pressure (-0.03; 95% CI -0.04, -0.02) using inverse variance weighting, but not diabetes (OR 1.00; 95% CI 0.91, 1.09). Associations were robust to the sensitivity analysis. CONCLUSIONS: Our findings suggest aspartate may play a role in IHD and blood pressure, potentially underlying cardiovascular benefits of soy. Clarifying the mechanisms would be valuable for IHD prevention and for defining a healthy diet.

The effects of folate supplementation on glucose metabolism and risk of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Observationally, homocysteine is associated with higher risk of diabetes. Folate, which reduces homocysteine, is promising for the prevention and treatment of diabetes. Previous meta-analysis of three trials suggested folate might lower hemoglobin A1c (HbA1c). METHODS: An updated systematic review and meta-analysis of placebo-controlled randomized trials was conducted. We searched PubMed using ("folate" or "folic acid") and trial and ("glucose" or "diabetes" or "insulin" or "hemoglobin A1c" or "HbA1c") in any field until February 3, 2017. We also conducted a bibliographic search of selected studies and relevant reviews. Relative risk of diabetes and mean differences in indicators of glucose metabolism between folate and placebo were summarized in a meta-analysis using inverse variance weighting with random effects. Heterogeneity, publication bias, and risk of bias were also assessed. RESULTS: Eighteen trials of 21,081 people with/without diabetes were identified. Folate decreased fasting glucose (-0.15 mmol/L, 95% confidence interval [CI] -0.29 to -0.01), homeostatic model assessment-insulin resistance (-0.83, 95% CI -1.31 to -0.34), and insulin (-1.94 µIU/mL, 95% CI -3.28 to -0.61) but had no clear effect on diabetes or HbA1c. CONCLUSIONS: Our study suggests a potential benefit of folate on insulin resistance and glycemic control; the latter requires examination in more high-quality trials.