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Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial.
Katayoshi, T, Uehata, S, Nakashima, N, Nakajo, T, Kitajima, N, Kageyama, M, Tsuji-Naito, K
Scientific reports. 2023;13(1):2786
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Nicotinamide adenine dinucleotide (NAD+) is a coenzyme that plays a crucial role in energy metabolism and different biological processes. Sirtuins (SIRT1) are NAD+-dependent deacetylases, an enzyme that plays a key role in enhancing metabolic efficiency. Nicotinamide mononucleotide (NMN) is a precursor to NAD+. NMN supplementation may help to reduce the risk of developing metabolic diseases and cardiovascular diseases. This randomised, double-blinded, and placebo-controlled, parallel trial investigated the effects of 12 weeks of 125 mg NMN supplementation on metabolic health parameters, including CVD risk factors, blood NAD+ metabolites level, and SIRT1 expression in middle-aged men and women. Serum nicotinamide was significantly higher and arterial stiffness was lower in the NMN test group of middle-aged men and women after 12 weeks of NMN supplementation. The results of the study indicate that the administration of 250mg of nicotinamide mononucleotide (NMN) daily for an extended period is considered safe and well-tolerated. Healthcare professionals can use this finding to understand the significant implications of the use of NMN as a potential therapeutic agent in individuals seeking to improve their metabolic and cardiovascular health. Further robust studies are required to evaluate the effects of NMN supplementation due to the limitations and high baseline variability between the participants of this study.
Expert Review
Conflicts of interest:
None
Take Home Message:
- As we age, NAM levels decline, which could have a negative effect on cardiovascular health.
- Middle-aged adults may like to consider NMN supplementation to improve NAM metabolism and arterial stiffness.
- However, without data on CVD events, it is difficult to determine actual risk reductions.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
- Nicotinamide adenine dinucleotide (NAD+) is a coenzyme involved in metabolism. When we age, NAD+ levels decline resulting in poorer metabolism and age-related disease such as cardiovascular disease (CVD). Nicotinamide mononucleotide (NMN) is a precursor in the biosynthesis of NAD+.
- This double-blind, randomised control trial aimed to determine the effect of supplementing NMN on NAD+ levels, CVD risk factors and sirtuin 1 (SIRT1) expression, which relies on NAD+ for adequate functioning.
Methods
- 36 healthy male and female individuals aged between 40-65 years of age were assigned to either NMN (125mg/day) or placebo for 12 weeks.
- One capsule was taken twice per day after meals.
- Serum nicotinamide (NAM), NAD+, NMN, advanced glycation end products (AGES), 8-hydroxydeoxyguanosine (8-OHdG) and SIRT1 mRNA expression were measured.
- The condition of blood vessels (arterial stiffness) was also assessed using the ankle brachial index (ABI).
- In a sub-analysis, individuals with hypertension, above average body mass index (BMI), or blood glucose level were also assessed for blood vessel condition using the ABI.
Results
- The results showed that from baseline serum NAM decreased in the placebo group (P=0.014), whereas it increased in the NMN group (P=0.006). This resulted in an increase in the NMN group compared to placebo (P=0.037).
- Interestingly serum NAM was lower in the NMN group compared to placebo at baseline (P=0.001).
- There was no statistically significant difference in ABI with NMN supplementation.
- Amongst those with hypertension there was also no change in ABI. However, those with high BMI or blood glucose, there was an improvement in vascular condition compared to placebo (P=<0.007 and P=0.019 respectively).
- 8-OHdG, SIRT1 mRNA and AGEs remained unchanged by NMN supplementation
Conclusion
- NMN supplementation enhanced NAD+ metabolism in middle-aged adults.
- It also relieved arterial stiffness and reduced CVD risk factors.
Clinical practice applications:
- Apparently healthy middle-aged adults who would like to activate NAD metabolism and decrease their risk for CVD, should consider 12-week supplementation with NMN (125mg/day).
- ABI should be monitored to ensure desired effects.
- It is unclear as to the effects of NMN supplementation after 12-weeks.
Considerations for future research:
- Future research should consider longer supplementation duration and/or adding in a follow-up period to determine duration of effect.
- Different supplemental doses should also be researched to determine an optimal dose.
Abstract
Many animal studies have shown that oral administration of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) prevents the reduction of NAD+ levels in organs and tissues, helping alleviate aging-related diseases. However, there are very few clinical reports of NMN supplementation in humans. Thus, this study aimed to investigate the influence of a 12-week NMN oral supplementation on biochemical and metabolic health parameters. A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD+ metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness.
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A Randomised Placebo-Controlled Study of Purified Anthocyanins on Cognition in Individuals at Increased Risk for Dementia.
Aarsland, D, Khalifa, K, Bergland, AK, Soennesyn, H, Oppedal, K, Holteng, LBA, Oesterhus, R, Nakling, A, Jarholm, JA, de Lucia, C, et al
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2023;31(2):141-151
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A growing body of evidence suggests that some modifiable factors, including cardiometabolic disorders such as hypertension, diabetes and hypercholesterolemia, as well as lifestyle factors such as physical exercise and diet, are associated with an increased risk of developing dementia. Anthocyanins, a flavonoid subclass found in dark berries and fruits, are among the dietary factors that may have positive effects on the pathogenesis of Alzheimer’s disease. The aim of this study was to assess whether anthocyanins can improve cognition and reduce the risk of dementia. This study is a 24-week randomised, double-blind, placebo-controlled Phase II study. Two-hundred and six participants were randomly assigned to one of the two groups: anthocyanins (n=106) or placebo (n=100). Results show that there wasn’t any significant group difference at the end of the study (24 weeks) in episodic memory (primary analysis) or for the secondary cognitive outcomes. However, there was a significant difference in slopes during weeks 8−24 where the anthocyanin group improved while the placebo group worsened. Furthermore, anthocyanin capsules were well-tolerated and safe to use. Authors conclude that future studies need to explore the potential mechanisms leading to cognitive improvement, how they relate to bioavailability of anthocyanins and metabolites, the optimal dosage, and the duration of treatment.
Abstract
IMPORTANCE Identifying nutritional compounds which can reduce cognitive decline in older people is a hugely important topic. OBJECTIVE To study the safety and effect of anthocyanins in maintaining cognitive functioning in people at increased risk for dementia. DESIGN, SETTING, AND PARTICIPANTS Participants (206 individuals, aged 60-80 years) diagnosed with either mild cognitive impairment (MCI) or two or more cardiometabolic disorders (i.e., diabetes, hypertension, obesity) were enrolled at three different centres in Norway. INTERVENTION Participants were randomly assigned to four capsules with a total of 320 mg/d of naturally purified anthocyanins or placebo 1:1 for 24 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the Quality of Episodic Memory composite measure (0-100) from an online cognitive test battery CogTrack, which was administered at baseline and monthly for the next 24 weeks. Secondary outcomes included other cognitive scores from the CogTrack battery. We applied mixed effects models with a baseline test score, group, time and their interaction as fixed effects, as well as other predefined baseline covariates. The primary comparison was the group difference at week 24 based on a modified intention-to-treat principle. RESULTS The primary analysis did not show a significant group difference at 24 weeks (78.2 versus 76.8; adjusted mean difference 1.4 (95% confidence interval -0.9-3.7); effect size 0.15; p = 0.23). However, there was a significant difference in slopes during weeks 8-24 (p = 0.007); the anthocyanin group improved while the placebo group worsened. No differences were found for the secondary cognitive outcomes. Anthocyanin capsules were well-tolerated and safe to use. CONCLUSION Anthocyanin supplementation for 24 weeks was safe and well tolerated in people with MCI or cardiometabolic disorders. We found no significant group difference in episodic memory at the end of the study but statistically significant differences in slopes. Further studies are warranted to explore whether anthocyanins supplementation can reduce cognitive decline in people at increased risk of dementia. TRIAL REGISTRATION ClinicalTrials.gov, (Identifier NCT03419039). http://www. CLINICALTRIALS gov/, NCT03419039.
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Nuts and seeds consumption and risk of cardiovascular disease, type 2 diabetes and their risk factors: a systematic review and meta-analysis.
Arnesen, EK, Thorisdottir, B, Bärebring, L, Söderlund, F, Nwaru, BI, Spielau, U, Dierkes, J, Ramel, A, Lamberg-Allardt, C, Åkesson, A
Food & nutrition research. 2023;67
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Nuts and seeds consumption is associated with a reduced risk of coronary heart disease (CHD) and cardiovascular disease (CVD). Nuts and seeds contain beneficial components to reduce the risk of CVD and CHD; hence dietary addition may benefit heart health. This systematic review and meta-analysis included sixty studies to analyse the effects of the consumption of nuts and seeds on the incidence of mortality from type 2 diabetes (T2D) and CVD and intermediate cardiometabolic risk factors. High nuts and seed consumption showed a 19% reduction in CVD risk and a 23% reduction in CVD mortality. In addition, high consumption lowered the risk of CHD by 25%. Increased nut consumption up to 30 g/day showed a dose-dependent relationship with reduced risk of CVD. Healthcare professionals can use the results of this study to understand the association between nuts and seeds consumption and CHD, CVD and blood lipid levels. However, further robust studies are required to evaluate the effect of specific nuts and seeds on CHD and CVD risk reduction.
Abstract
OBJECTIVES We aimed to systematically review studies and evaluate the strength of the evidence on nuts/seeds consumption and cardiometabolic diseases and their risk factors among adults. METHODS A protocol was pre-registered in PROSPERO (CRD42021270554). We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Scopus up to September 20, 2021 for prospective cohort studies and ≥12-week randomized controlled trials (RCTs). Main outcomes were cardiovascular disease (CVD), coronary heart disease (CHD), stroke and type 2 diabetes (T2D), secondary total-/low density lipoprotein (LDL)-cholesterol, blood pressure and glycaemic markers. Data extraction and risk of bias (RoB) assessments (using RoB 2.0 and RoB-NObS) were performed in duplicate. Effect sizes were pooled using random-effects meta-analyses and expressed as relative risk (RR) or weighted mean differences with 95% confidence intervals (CI); heterogeneity quantified as I 2. One-stage dose-response analyses assessed the linear and non-linear associations with CVD, CHD, stroke and T2D. The strength of evidence was classified per the World Cancer Research Fund criteria. RESULTS After screening 23,244 references, we included 42 papers from cohort studies (28 unique cohorts, 1,890,573 participants) and 18 RCTs (2,266 participants). In the cohorts, mainly populations with low consumption, high versus low total nuts/seeds consumption was inversely associated with total CVD (RR 0.81; 95% CI 0.75, 0.86; I 2 = 67%), CVD mortality (0.77; 0.72, 0.82; I 2 = 59.3%), CHD (0.82; 0.76, 0.89; I 2 = 64%), CHD mortality (0.75; 0.65, 0.87; I 2 = 66.9%) and non-fatal CHD (0.85; 0.75, 0.96; I 2 = 62.2%). According to the non-linear dose-response analyses, consumption of 30 g/day of total nuts/seeds was associated with RRs of similar magnitude. For stroke and T2D the summary RR for high versus low intake was 0.91 (95% CI 0.85, 0.97; I 2 = 24.8%) and 0.95 (0.75, 1.21; I 2 = 82.2%). Intake of nuts (median ~50 g/day) lowered total (-0.15 mmol/L; -0.22, -0.08; I 2 = 31.2%) and LDL-cholesterol (-0.13 mmol/L; -0.21, -0.05; I 2 = 68.6%), but not blood pressure. Findings on fasting glucose, HbA1c and insulin resistance were conflicting. The results were robust to sensitivity and subgroup analyses. We rated the associations between nuts/seeds and both CVD and CHD as probable. There was limited but suggestive evidence for no association with stroke. No conclusion could be made for T2D. CONCLUSION There is a probable relationship between consumption of nuts/seeds and lower risk of CVD, mostly driven by CHD, possibly in part through effects on blood lipids. More research on stroke and T2D may affect the conclusions. The evidence of specific nuts should be further investigated.
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The potential prolonged effect at one-year follow-up after 18-month randomized controlled trial of a 90 g/day low-carbohydrate diet in patients with type 2 diabetes.
Chen, CY, Huang, WS, Ho, MH, Chang, CH, Lee, LT, Chen, HS, Kang, YD, Chie, WC, Jan, CF, Wang, WD, et al
Nutrition & diabetes. 2022;12(1):17
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A low carbohydrate diet (LCD) could be an effective dietary strategy for managing Type 2 Diabetes and body weight. This follow-up of a randomised controlled study evaluated the effect of moderate LCD after 18 months of 90 g/day LCD in 85 poorly controlled Type 2 Diabetic patients and compared it with Traditional Diabetic Diet (TDD). Those who followed the LCD diet ate significantly fewer carbohydrates and more protein and fat at the follow up between 18 and 30 months compared to those who followed the TDD group. The LCD group also showed significant improvements in serum HbA1C, two-hour serum glucose, serum alanine aminotransferase and Medication Effect Score in comparison with the TDD group. However, the level of triglycerides increased, and HDL levels decreased significantly in the LCD group from 18 to 30 months. There was however no significant difference between the groups in the improvement of HbA1C, fasting serum glucose, 2 h serum glucose, as well as serum cholesterol, triglycerides, low-density lipoprotein, ALT, creatinine, and urine microalbumin. To confirm the benefits of LCD on glycaemic control, further robust studies are needed. Results of this study can help healthcare professionals gain a better understanding of the prolonged effects of LCD on glycaemic control, liver function, and medication effect scores.
Abstract
OBJECTIVES To evaluate the effect at a one-year follow-up after an 18-month randomized controlled trial (RCT) of 90 gm/day low-carbohydrate diet (LCD) in type 2 diabetes. RESEARCH DESIGN AND METHODS Eighty-five poorly controlled type 2 diabetic patients with an initial HbA1c ≥ 7.5% who have completed an 18-month randomized controlled trial (RCT) on 90 g/day low-carbohydrate diet (LCD) were recruited and followed for one year. A three-day weighted food record, relevant laboratory tests, and medication effect score (MES) were obtained at the end of the previous trial and one year after for a total of 30 months period on specific diet. RESULTS 71 (83.5%) patients completed the study, 35 were in TDD group and 36 were in LCD group. Although the mean of percentage changes in daily carbohydrate intake was significantly lower for those in TDD group than those in LCD group (30.51 ± 11.06% vs. 55.16 ± 21.79%, p = 0.0455) in the period between 18 months and 30 months, patients in LCD group consumed significantly less amount of daily carbohydrate than patients in TDD group (131.8 ± 53.9 g vs. 195.1 ± 50.2 g, p < 0.001). The serum HbA1C, two-hour serum glucose, serum alanine aminotransferase (ALT), and MES were also significantly lower for the LCD group patients than those in the TDD group (p = 0.017, p < 0.001, p = 0.017, and p = 0.008 respectively). The mean of percentage changes of HbA1C, fasting serum glucose, 2 h serum glucose, as well as serum cholesterol, triglyceride, low-density lipoprotein, ALT, creatinine, and urine microalbumin, however, were not significantly different between the two groups (p > 0.05). CONCLUSIONS The one-year follow-up for patients on 90 g/d LCD showed potential prolonged and better outcome on glycaemic control, liver function and MES than those on TDD for poorly controlled diabetic patients.
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No Effect of Isolated Anthocyanins from Bilberry Fruit and Black Rice on LDL Cholesterol or other Biomarkers of Cardiovascular Disease in Adults with Elevated Cholesterol: A Randomized, Placebo-Controlled, Cross-Over Trial.
Aboufarrag, H, Hollands, WJ, Percival, J, Philo, M, Savva, GM, Kroon, PA
Molecular nutrition & food research. 2022;66(21):e2101157
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Elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides contribute significantly to the development of atherosclerosis, an underlying pathophysiological cause of cardiovascular disease (CVD). Conversely, elevated levels of circulating high-density lipoprotein cholesterol (HDL-C) provide protection against the development of atherosclerosis and is inversely correlated with the incidence of CVD. The main aim of this study was to determine the effects of two major types of anthocyanins on LDL-C and other cardiometabolic markers for CVD risk in hyperlipidaemic individuals. This study is a randomised, placebo-controlled, double-blind, three arm crossover design. The three treatments were: (i) a bilberry extract delivering 320mg of mostly delphinidin/trihydroxy type anthocyanins, (ii) a black rice extract delivering 320mg of mostly cyanidin/dihydroxy type anthocyanins, and (iii) a placebo control. A total of fifty-five participants were randomly assigned to one of the three treatments. Results show that ingestion of 320mg day of delphinidin or cyanidin type anthocyanins for 28-day did not reduce LDL-C in a study population with elevated cholesterol levels. Additionally, neither did consumption of delphinidin or cyanidin type anthocyanins beneficially alter other biomarkers related to vascular function, glycaemic control or biomarkers of HDL function. Authors conclude that the lack of positive effects in their study may be due to the short duration of the treatments. Thus, future research should conduct studies based on longer time periods (≥12 weeks duration).
Abstract
SCOPE Some dietary interventions with berry fruits, berry fruit extracts, and purified anthocyanins have been reported to beneficially alter lipoprotein profiles in hyperlipidemic participants. The major anthocyanins in human diets are glycosides of cyanidin and delphinidin, and structure can influence both absorption and bioactivity. The aim of this study is to determine the effects of two major types of anthocyanins on low-density lipoprotein cholesterol and other cardiometabolic markers for cardiovascular disease (CVD) risk in hyperlipidemic individuals. METHODS AND RESULTS Fifty-two hyperlipidemic participants complete this randomized, placebo-controlled, double-blind, three arm crossover trial. Participants ingest capsules containing 320 mg of anthocyanins (bilberry trihydroxy-type or black rice dihydroxy-type) or placebo once daily for 28 days. Biomarkers of CVD risk are measured before and after the intervention period. Compared to the placebo, neither anthocyanin treatment significantly (p < 0.05) changes circulating levels of lipoproteins (total-/high-density lipoprotein (HDL)-/low-density lipoprotein (LDL)-cholesterol, triglycerides, Apolipoprotein B (ApoB)), biomarkers of glycemic control (fasting glucose, fructosamine), biomarkers of HDL function (ApoA1, HDL3, paraoxonase-1 (PON1) arylesterase, and lactonase activities), or plasma bile acids. CONCLUSIONS These data do not support the notion that regular consumption of anthocyanins beneficially affects glycemic control or lipoprotein profiles or functions. It is possible the no effect observation is due to the relatively short duration of treatments.
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The Effect of Curcumin on Lipid Profile and Glycemic Status of Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.
Tian, J, Feng, B, Tian, Z
Evidence-based complementary and alternative medicine : eCAM. 2022;2022:8278744
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Dyslipidaemia is a common comorbidity of type 2 diabetes mellitus (T2DM), which is characterised by elevated triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) level, and/or decreased high-density lipoprotein cholesterol (HDL-c) concentrate serum. Dyslipidaemia and dysglycemia interact with each other, and they are the main risk factors of macro- and microvascular diseases in T2DM. The aim of this study was to outline curcumin’s efficacy and possible uses in clinical practice. This study is a meta-analysis of nine randomised controlled trials (RCTs). A total of 604 participants (284 in the curcumin group and 281 in the control group) were included in the selected studies. The design of all trials was parallel; seven of them were double-blind RCTs, and the other two were open label RCTs. Results show that curcumin significantly decreased TG, TC, fasting blood glucose, and haemoglobin A1C levels and also led to a reduction in LDL-c and an elevation in HDL-c concentration, although with no statistical difference. Authors conclude that curcumin has promising effects on the lipid profile and glycaemic status in patients with T2DM. It indicated that curcumin might be a favourable therapeutic option for T2DM patients with mixed dyslipidaemia.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Dyslipidemia and dysglycemia interact with each other, and are risk factors of macro- and microvascular diseases in T2DM.
Although effective intervention strategies exist for improving glycemic status of T2DM patients, they often need lipid-lowering drugs simultaneously to prevent CVD.
- Novel therapeutic interventions are needed to manage dyslipidemia and dysglycemia in diabetic patients, when statin therapy to treat dyslipidemia, may increase the risk of new-onset diabetes and myopathy.
- Other clinical studies have highlighted the benefits of curcumin supplementation on lipid profile and glycemic status. Clarifying its effects is important for assessing its potential as an alternative and complementary medicine on improving the metabolic status of T2DM patients.
- Overall there is limited evidence and further research is required.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This meta-analysis aimed to evaluate the effects of curcumin on lipid profile in patients with type 2 diabetes mellitus (T2DM), including: serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL-c), and/or high-density lipoprotein cholesterol (HDL-c). Fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) were also assessed.
Methods
A search was performed on Pubmed, Embase, Web of Sciences, and the Cochrane Library up to March 2022. Quality assessment of all included studies was performed.
Results
9 studies were included in the review, with a total of 604 participants (284 in the curcumin group and 281 in the control group) of mean age from 41 to 60.95 years. Curcumin forms varied among the studies including, turmeric, curcuminoids, and curcumin. The dosage of curcumin in the intervention group ranged from 80 to 2100 mg/day. The duration of intervention was between 4 weeks and 3 months in different studies.
- Effect of Curcumin on TG: A difference was observed between curcumin supplementation and control (p = 0.03), indicating curcumin could reduce serum TG.
- Effect of Curcumin on TC: The mean difference in net changes of TC between intervention and control groups was −8.91mg/dL (p = 0.001), suggesting that curcumin could decrease serum TC.
- Effect of Curcumin on LDL-C: No difference in the net change of LDL-c between intervention and control groups (p = 0.26).
- Effect of Curcumin on HDL-C: No difference in HDL-c between intervention and control groups (p = 0.56).
- Effect of Curcumin on FBG: Curcumin reduced blood glucose levels compared with control treatment (p = 0.002). The effect was greater in trials with the treatment duration >8w (p = 0.037), curcumin dose >100mg/day (p = 0.004), and with the participants receiving the other therapy (p = 0.002).
- Effect of Curcumin on HbA1c: HbA1c (%) decreased in the intervention group compared with the control group (p ≤ 0.001).
Conclusion
Curcumin has promising effects on the lipid profile and glycemic status of T2DM patients and might be a therapeutic option for T2DM patients with mixed dyslipidemia.
Clinical practice applications:
- Limitations were the small number of included studies, mostly with small sample sizes. In some studies, treatment duration was short (<2 months) and may be insufficient to see a difference in some metabolic parameters.
- The reduction of FBG and HbA1c after treatment with curcumin suggested that it improved the glycemic metabolism in the T2DM patients studied.
- Studies have shown that curcumin could promote insulin release through inducing β-cell electrical activity and lower serum glucose level via decreasing the production of hepatic glucose and increasing glucose uptake. While changes of LDL-c and HDL-c was not statistically significant, the authors note the effect of curcumin on LDL-c/HDL-c and its potential clinical significance could not be neglected.
- The reduction of dyslipidemia by curcumin supplementation could improve the glucose metabolic status of T2DM patients, and multiple molecular targets including PPAR-c, cholesteryl ester transfer protein, and lipoprotein lipase contribute to the beneficial effects of curcumin.
Considerations for future research:
- While significant heterogeneity was found in pooled analyses of TG, LDL-c, FBG, and Hb1Ac, a random-effects model revealed that trial duration, curcumin dosage, and other therapy may contribute to the variation in pooled effects, and these aspects could be discussed in future studies.
- The study found that a higher dose of curcumin was more powerful in reducing plasma TG and FBG concentrations, but further large-scale multicenter RCTs are required to confirm the clinical improvement of curcumin.
Abstract
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder, some natural compounds are thought to be beneficial in improving the metabolic status of patients with T2DM. Curcumin is the main bioactive agent of turmeric, the impact of curcumin on T2DM is still controversial. This meta-analysis aimed to evaluate the effects of curcumin on lipids profile and glucose status in patients with T2DM. Randomized controlled trials (RCTs) examining the effects of curcumin on lipids profile and glycemic control of T2DM patients were searched in PubMed, Embase, Web of Science and Cochrane Library. Pooled estimates of weighted mean difference (WMD) were calculated between intervention and control groups using random-effects or fixed-effects model. Subgroup and sensitivity analyses were conducted to assess the effects. Nine eligible RCT with 604 subjects were included. The estimated pooled mean changes with curcumin were -18.97 mg/dL (95% CI: -36.47 to -1.47; P=0.03) for triglyceride (TG), -8.91 mg/dL (95% CI: -14.18 to -3.63, P=0.001) for total cholesterol (TC), -4.01 mg/dL (95% CI: -10.96 to 2.95, P=0.259) for low density lipoprotein cholesterol (LDL-c), 0.32 mg/dL (95% CI: -0.74 to 1.37, P=0.557) for high density lipoprotein cholesterol (HDL-c), -8.85 mg/dL (95% CI: -14.4 to -3.29, P=0.002) for fasting blood glucose (FBG), -0.54 (95% CI: -0.81 to -0.27, P ≤ 0.001) for glycated hemoglobin (HbA1c) (%) compared with controls. There was a significant heterogeneity for the influence of curcumin on TG, LDL-c, FBG and HbA1c. Subgroup analysis revealed that the heterogeneity mainly attributed to trial period, curcumin dosage and other therapy. The results of this study showed that curcumin supplementation had beneficial effects on glycemic status and some lipid parameters in patients with T2DM. Further studies with large-scale are still needed to confirm the results.
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The Gut Microbiota (Microbiome) in Cardiovascular Disease and Its Therapeutic Regulation.
Rahman, MM, Islam, F, -Or-Rashid, MH, Mamun, AA, Rahaman, MS, Islam, MM, Meem, AFK, Sutradhar, PR, Mitra, S, Mimi, AA, et al
Frontiers in cellular and infection microbiology. 2022;12:903570
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Cardiovascular disease (CVD) accounts for 31% of all-cause mortality worldwide. Irregularities in the composition of intestinal microbial composition, genetic factors, nutrition, metabolic irregularities, and smoking are among the potential causes of CVD. Intestinal permeability and translocation of endotoxins and bacterial metabolites to systemic circulation may trigger an immune response and inflammation, which may increase the risk of CVD. Synthesis of bacterial metabolites such as trimethylamine N-oxide (TMAO) by choline-inducing gut bacteria and reduced consumption of dietary TMAO precursors may elevate the CVD risk. This review explores the latest research on the role of gut microbiota in the development of atherosclerosis and CVD, as well as potential strategies to prevent CVD by targeting TMAO-producing gut bacteria. Elevated levels of TMAO in the bloodstream can lead to the buildup of cholesterol and ultimately result in atherosclerosis. However, consuming probiotics and fibre-rich foods can help regulate gut bacteria, reduce inflammation, and improve lipid profiles, all of which contribute to better cardiovascular health. More future robust studies are required to examine the mechanistic insights and confirm whether TMAO can serve as a biomarker for preventing CVD through the therapeutic modulation of intestinal bacteria.
Abstract
In the last two decades, considerable interest has been shown in understanding the development of the gut microbiota and its internal and external effects on the intestine, as well as the risk factors for cardiovascular diseases (CVDs) such as metabolic syndrome. The intestinal microbiota plays a pivotal role in human health and disease. Recent studies revealed that the gut microbiota can affect the host body. CVDs are a leading cause of morbidity and mortality, and patients favor death over chronic kidney disease. For the function of gut microbiota in the host, molecules have to penetrate the intestinal epithelium or the surface cells of the host. Gut microbiota can utilize trimethylamine, N-oxide, short-chain fatty acids, and primary and secondary bile acid pathways. By affecting these living cells, the gut microbiota can cause heart failure, atherosclerosis, hypertension, myocardial fibrosis, myocardial infarction, and coronary artery disease. Previous studies of the gut microbiota and its relation to stroke pathogenesis and its consequences can provide new therapeutic prospects. This review highlights the interplay between the microbiota and its metabolites and addresses related interventions for the treatment of CVDs.
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Evidence for the Benefits of Melatonin in Cardiovascular Disease.
Tobeiha, M, Jafari, A, Fadaei, S, Mirazimi, SMA, Dashti, F, Amiri, A, Khan, H, Asemi, Z, Reiter, RJ, Hamblin, MR, et al
Frontiers in cardiovascular medicine. 2022;9:888319
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Cardiovascular disease (CVD) encompasses a group of disorders involving blood vessels or the heart. The beneficial effects of melatonin [hormone] in treating various human diseases have been broadly investigated. Melatonin is an indoleamine-derived molecule, which is synthesised at night. The aim of this review was to point out therapeutic potentials of melatonin in the treatment of CVDs with an emphasis on the molecular mechanisms of action. This review shows that: - nearly all the studies have reported positive effects of melatonin on cardiovascular physiology, and the prevention of damage to the myocardium after heart attack, reperfusion injury, or sepsis. - melatonin can help blood pressure and heart arrhythmia. - some clinical trials indicated that the utilization of melatonin in CVDs is associated with more inconsistencies regarding its cardioprotective effects. Authors conclude that further preclinical and clinical studies are required to better delineate the cardiovascular benefits of melatonin.
Abstract
The pineal gland is a neuroendocrine gland which produces melatonin, a neuroendocrine hormone with critical physiological roles in the circadian rhythm and sleep-wake cycle. Melatonin has been shown to possess anti-oxidant activity and neuroprotective properties. Numerous studies have shown that melatonin has significant functions in cardiovascular disease, and may have anti-aging properties. The ability of melatonin to decrease primary hypertension needs to be more extensively evaluated. Melatonin has shown significant benefits in reducing cardiac pathology, and preventing the death of cardiac muscle in response to ischemia-reperfusion in rodent species. Moreover, melatonin may also prevent the hypertrophy of the heart muscle under some circumstances, which in turn would lessen the development of heart failure. Several currently used conventional drugs show cardiotoxicity as an adverse effect. Recent rodent studies have shown that melatonin acts as an anti-oxidant and is effective in suppressing heart damage mediated by pharmacologic drugs. Therefore, melatonin has been shown to have cardioprotective activity in multiple animal and human studies. Herein, we summarize the most established benefits of melatonin in the cardiovascular system with a focus on the molecular mechanisms of action.
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Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.
O'Donoghue, ML, Rosenson, RS, Gencer, B, López, JAG, Lepor, NE, Baum, SJ, Stout, E, Gaudet, D, Knusel, B, Kuder, JF, et al
The New England journal of medicine. 2022;387(20):1855-1864
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Numerous epidemiologic studies over the past three decades have shown an association between higher circulating lipoprotein(a) concentrations and an increased risk of atherosclerotic cardiovascular disease. The aim of this study was to evaluate the efficacy and safety of repeated administration of a small interfering RNA designed to lower the body's production of apolipoprotein(a). This study is a multicentre, randomised, double-blind, placebo-controlled, dose-finding trial. Patients were randomly assigned in a 1:1:1:1:1 ratio to receive one of four doses of small interfering RNA (n= 281) (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. Results show that treatment with small interfering RNA markedly reduced the concentration of lipoprotein(a) in a dose-dependent manner and appeared to be safe. At higher doses, the treatment reduced the lipoprotein(a) concentration by more than 95%, as compared with placebo, with nearly all patients who received the treatment with small interfering RNA having a lipoprotein(a) concentration of less than 125 nmol per litre. Authors conclude that further large-scale interventions are needed to confirm a causal role for lipoprotein(a) in atherosclerotic cardiovascular disease.
Abstract
BACKGROUND Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
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Treatment With a Marine Oil Supplement Alters Lipid Mediators and Leukocyte Phenotype in Healthy Patients and Those With Peripheral Artery Disease.
Schaller, MS, Chen, M, Colas, RA, Sorrentino, TA, Lazar, AA, Grenon, SM, Dalli, J, Conte, MS
Journal of the American Heart Association. 2020;9(15):e016113
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Peripheral artery disease (PAD) is one of the most advanced forms of atherosclerosis. This disease state begins from an inflammatory lesion. The aim of this study was to investigate the impact of a short-course, oral, enriched marine oil supplement on circulating leukocytes and biochemical mediators in patients with symptomatic PAD and healthy controls. This study is a prospective, open-label, nonblinded study. Twenty participants completed the study: ten with PAD and 10 healthy individuals. Results show: - a shift in the leukocyte profiling towards a less inflammatory and more pro-resolving phenotype, most notably within the PAD cohort. - that supplementation led to an increase in phagocytic [a type of immune cell] activity of peripheral blood monocytes and neutrophils. - that circulating monocyte phenotyping demonstrated reduced expression of multiple proinflammatory markers. - that gene expression patterns in mono-derived macrophage from patients with PAD displayed a less inflammatory (type 1 macrophage) and greater reparative (type 2 macrophage) phenotype after supplementation. Authors conclude that their findings provide a foundation for characterising biochemical and cellular biomarkers of inflammation and resolution in PAD.
Abstract
Background Peripheral artery disease (PAD) is an advanced form of atherosclerosis characterized by chronic inflammation. Resolution of inflammation is a highly coordinated process driven by specialized pro-resolving lipid mediators endogenously derived from omega-3 fatty acids. We investigated the impact of a short-course, oral, enriched marine oil supplement on leukocyte phenotype and biochemical mediators in patients with symptomatic PAD and healthy volunteers. Methods and Results This was a prospective, open-label study of 5-day oral administration of an enriched marine oil supplement, assessing 3 escalating doses in 10 healthy volunteers and 10 patients with PAD. Over the course of the study, there was a significant increase in the plasma level of several lipid mediator families, total specialized pro-resolving lipid mediators, and specialized pro-resolving lipid mediator:prostaglandin ratio. Supplementation was associated with an increase in phagocytic activity of peripheral blood monocytes and neutrophils. Circulating monocyte phenotyping demonstrated reduced expression of multiple proinflammatory markers (cluster of differentiation 18, 163, 54, and 36, and chemokine receptor 2). Similarly, transcriptional profiling of monocyte-derived macrophages displayed polarization toward a reparative phenotype postsupplementation. The most notable cellular and biochemical changes over the study occurred in patients with PAD. There were strong correlations between integrated biochemical measures of lipid mediators (specialized pro-resolving lipid mediators:prostaglandin ratio) and phenotypic changes in circulating leukocytes in both healthy individuals and patients with PAD. Conclusions These data suggest that short-term enriched marine oil supplementation dramatically remodels downstream lipid mediator pathways and induces a less inflammatory and more pro-resolution phenotype in circulating leukocytes and monocyte-derived macrophages. Further studies are required to determine the potential clinical relevance of these findings in patients with PAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02719665.