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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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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
- 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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Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials.
Wang, T, Zhang, X, Zhou, N, Shen, Y, Li, B, Chen, BE, Li, X
Journal of the American Heart Association. 2023;12(11):e029512
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Dyslipidaemia is considered to be a risk factor for cardiovascular disease (CVD) and the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are thought to confer benefits for both dyslipidaemia and CVD, although results from clinical trials and meta-analyses (studies pooling data from smaller studies to increase statistical power) are mixed. The aim of this meta-analysis, using a particular statistical method, was to evaluate whether dose-response relationships may be non-linear. This meta-analysis included 90 randomised controlled trials with 72,598 participants overall. Lipids evaluated were triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and non-HDL cholesterol. A near linear relationship was seen between intake of combined EPA and DHA and a decrease in TG and non-HDL, both overall and for the subgroups of patients with and without hyperlipidaemia and overweight. For LDL and HDL, J-shaped relationships were seen, with an increase followed by a decrease with increasing EPA + DHA intake, both overall and in the subgroups with and without hyperlipidaemia. The authors also pooled data from studies which used the red blood cell omega index (a measure of omega-3 status) and found that with increasing omega-3 status, TG and non-HDL declined whilst HDL increased in a near linear fashion, whilst there was still a J-shaped curve for LDL. The authors consider that a medium dose of EPA + DHA may be needed for the management of dyslipidaemia, and a high dose for people at high risk of developing CVD.
Abstract
Background Previous results provide supportive but not conclusive evidence for the use of omega-3 fatty acids to reduce blood lipids and prevent events of atherosclerotic cardiovascular disease, but the strength and shape of dose-response relationships remain elusive. Methods and Results This study included 90 randomized controlled trials, reported an overall sample size of 72 598 participants, and examined the association between omega-3 fatty acid (docosahexaenoic acid, eicosapentaenoic acid, or both) intake and blood lipid changes. Random-effects 1-stage cubic spline regression models were used to study the mean dose-response association between daily omega-3 fatty acid intake and changes in blood lipids. Nonlinear associations were found in general and in most subgroups, depicted as J-shaped dose-response curves for low-/high-density lipoprotein cholesterol. However, we found evidence of an approximately linear dose-response relationship for triglyceride and non-high-density lipoprotein cholesterol among the general population and more evidently in populations with hyperlipidemia and overweight/obesity who were given medium to high doses (>2 g/d). Conclusions This dose-response meta-analysis demonstrates that combined intake of omega-3 fatty acids near linearly lowers triglyceride and non-high-density lipoprotein cholesterol. Triglyceride-lowering effects might provide supportive evidence for omega-3 fatty acid intake to prevent cardiovascular events.
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Effects of Diet on 10-Year Atherosclerotic Cardiovascular Disease Risk (from the DASH Trial).
Jeong, SY, Wee, CC, Kovell, LC, Plante, TB, Miller, ER, Appel, LJ, Mukamal, KJ, Juraschek, SP
The American journal of cardiology. 2023;187:10-17
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Determining the 10-year risk of heart disease can be used as tool to determine appropriate treatment plans. This study of 459 adults aged 22-75 years with obesity aimed to compare the effects on the 10-year risk for the development heart disease of an 8-week dietary approaches to stop hypertension (DASH) diet, with the standard American diet (AD) and a diet high in fruits and vegetables (F/V). The results showed that the DASH diet significantly improved risk factors such as systolic blood pressure and total cholesterol. However, the F/V diet had an improvement in good cholesterol, which the DASH diet did not. This equated to a similar 10% reduction in the 10-year heart disease risk compared to the AD. It was concluded that compared to a typical AD, DASH and F/V diets reduced the risk for heart disease over a 10-year period. However, the actual risk reduction was only small and individuals with obesity may need to reduce their risk further with other therapies. This study could be used by healthcare professionals to recommend a DASH diet or a diet high in fruits and vegetables to reduce the long-term risk for heart disease alongside other proven therapies or methods to reduce risk.
Expert Review
Conflicts of interest:
None
Take Home Message:
- DASH and F/V diets may be of benefit to obese individuals to decrease their risk for ASCVD
- The DASH diet did reduce HDL cholesterol and recommendations should be made to limit this effect (e.g. exercise and more fruit and vegetables in the diet).
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 study aimed to determine the effect of the Dietary Approaches to Stop Hypertension (DASH) diet compared to a standard American diet (AD) and a diet emphasising fruits and vegetables (F/V) on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and how adopting these diets affect specific risk factors (e.g systolic blood pressure (SBP), diastolic blood pressure (DBP) and blood lipids).
Methods
- Secondary analysis from the DASH trial which ran for 8 weeks in 459 adults aged 22-75 years with obesity
- All meals were provided and dietary intake was adjusted to prevent weight loss
- The primary outcome was an absolute and relative difference in 10-year ASCVD risk from baseline.
Participants were randomised to one of three diets:
1) DASH diet
2) F/V diet, similar to AD but with more fruits and vegetables and higher potassium and magnesium
3) Standard AD.
Results
- DASH significantly lowered SBP, total cholesterol, and HDL cholesterol compared to F/V (absolute difference SBP: -2.8, (95% confidence interval [CI]-4.5, -1.2), total cholesterol: 9.3 (-14.7, 3.9), and HDL cholesterol: -3.5 (-5.0, -2.1) P=<0.05 for all)
- DASH significantly lowered SBP, total cholesterol, and HDL cholesterol compared to AD (absolute difference SBP: -5.3 (-7.0, -3.7), total cholesterol: -13.1 (-18.5, -7.7), and HDL cholesterol: -3.8 (-5.2, -2.4) P=<0.05 for all)
- Compared to AD, DASH and F/V diets reduced 10-year ASCVD relative risk by -10.3%
( −14.4 to −5.9) and −9.9% ( −14.0 to −5.5) respectively
- This translated into low actual risk reductions of -0.21% for the F/V diet and -0.17% for the DASH diet
- Although DASH improved SBP, and total cholesterol compared to F/V, no differences in ASCVD risk between DASH and F/V were apparent. This was attributable to the detrimental effect of the DASH diet on HDL cholesterol, which was not seen in the F/V diet
- The effects of the DASH diet were more pronounced in black participants and in women.
Conclusion
Compared to the AD, DASH and F/V reduced 10-year ASCVD risk by approximately 10% over 8-weeks. The DASH diet was more effective for women and black adults.
Clinical practice applications:
- DASH and F/V diets decrease risk factors and an individual’s risk of ASCVD, and should be encouraged in individuals with obesity, especially women and black adults
- However, these diets do still leave obese individuals at risk for ASCVD.
Considerations for future research:
- Research on these diets in combination with weight loss regimes may give more pronounced results
- It may also be interesting to understand the mechanisms behind why the DASH diet reduces HDL cholesterol.
Abstract
Although modern risk estimators, such as the American College of Cardiology/American Heart Association Pooled Cohort Equation, play a central role in the decisions of patients to start pharmacologic therapy to prevent atherosclerotic cardiovascular disease (ASCVD), there is limited evidence to inform expectations for 10-year ASCVD risk reduction from established lifestyle interventions. Using data from the original DASH (Dietary Approaches to Stop Hypertension) trial, we determined the effects of adopting the DASH diet on 10-year ASCVD risk compared with adopting a control or a fruits and vegetables (F/V) diet. The DASH trial included 459 adults aged 22 to 75 years without CVD and not taking antihypertensive or diabetes mellitus medications, who were randomized to controlled feeding of a control diet, an F/V diet, or the DASH diet for 8 weeks. We determined 10-year ASCVD risk with the American College of Cardiology/American Heart Association Pooled Cohort Equation based on blood pressure and lipids measured before and after the 8-week intervention. Compared with the control diet, the DASH and F/V diets changed 10-year ASCVD risk by -10.3% (95% confidence interval [CI] -14.4 to -5.9) and -9.9% (95% CI -14.0 to -5.5) respectively; these effects were more pronounced in women and Black adults. There was no difference between the DASH and F/V diets (-0.4%, 95% CI -6.9 to 6.5). ASCVD reductions attributable to the difference in systolic blood pressure alone were -14.6% (-17.3 to -11.7) with the DASH diet and -7.9% (-10.9 to -4.8) with the F/V diet, a net relative advantage of 7.2% greater relative reduction from DASH compared with F/V. This was offset by the effects on high-density lipoprotein of the DASH diet, which increased 10-year ASCVD by 8.8% (5.5 to 12.3) compared with the more neutral effect of the F/V diet of -1.9% (-5.0 to 1.2). In conclusion, compared with a typical American diet, the DASH and F/V diets reduced 10-year ASCVD risk scores by about 10% over 8 weeks. These findings are informative for counseling patients on both choices of diet and expectations for 10-year ASCVD risk reduction.
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Comparative effects of vitamin and mineral supplements in the management of type 2 diabetes in primary care: A systematic review and network meta-analysis of randomized controlled trials.
Xia, J, Yu, J, Xu, H, Zhou, Y, Li, H, Yin, S, Xu, D, Wang, Y, Xia, H, Liao, W, et al
Pharmacological research. 2023;188:106647
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Type 2 diabetes mellitus (T2DM), characterised by sustained hyperglycaemia and insulin resistance, remains a severe driver of chronic metabolic diseases such as cardiovascular diseases. The aim of this study was to investigate and compare the efficacy of vitamin and mineral supplements in the management of glycaemic control and lipid metabolism for type 2 diabetic patients to inform clinical practice. This study is a systematic review and meta-analysis of one hundred and seventy articles with a total of 4223 adults with T2DM. Participants were randomised to either the placebo/no treatment group (n= 6345) or to the treatment group (n= 7878). Results show that: - chromium was the most effective micronutrient for decreasing fasting blood glucose and insulin resistance. - vitamin K was the top-ranked micronutrient in reducing haemoglobin A1C and fasting insulin levels. - vanadium was the top-ranked micronutrient in total cholesterol reductions. - niacin was ranked as the most effective in triglycerides reductions and increasing high-density lipoprotein cholesterol levels. - vitamin E was the top-ranked micronutrient in low-density lipoprotein cholesterol reductions. Authors conclude that micronutrient supplements especially chromium, vitamin E, vitamin K, vanadium, and niacin supplements, may be more effective in the management of T2DM compared with other micronutrients.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Clinicians could consider the adjunctive effect of micronutrients supplements, such as chromium, vitamin E, vitamin K, vanadium, and niacin supplements in a nutrition protocol to manage T2DM and slow or prevent its complications.
- The study authors state that the vitamin and mineral supplements under review had a statistically significant improvement, however they did not reach the study threshold for clinical significance. Therefore they advise caution in utilising micronutrient supplements in the management of glucose and lipid metabolism for T2DM.
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:
Objectives
The aim of this systematic review was to evaluate the comparative effects of vitamin and mineral supplements on managing glycemic control and lipid metabolism for type 2 diabetes mellitus (T2DM).
Methodology
This systematic review is registered with PROSPERO and adhered to PRISMA-2020 guidelines for network meta-analysis
The Cochrane Collaboration’s risk-of-bias tool was used to assess eligible randomised trials
8 prespecified markers identified and assessed in this study : 1) HbA1c (%), 2) fasting blood glucose (mmol/L), 3) total cholesterol (mmol/L), 4) triglycerides (mmol/L), 5) fasting insulin (μIU/mL), 6) HOMA-IR, 7) LDL-c (mmol/L), and 8) HDL-c (mmol/L).
Results
- 170 RCT trials of 14223 participants with T2DM treated with vitamin supplements, mineral supplements, or placebo/no treatment were included
- Low to very low certainty evidence established chromium supplements as the most effective in reducing fasting blood glucose levels and homeostasis model assessment of insulin resistance (SUCRAs: 90.4% and 78.3%, respectively)
- Vitamin K supplements ranked best in reducing glycated haemoglobin A1c and fasting insulin levels (SUCRAs: 97.0% and 82.3%, respectively), with moderate to very low certainty evidence
- Vanadium supplements ranked best in lowering total cholesterol levels with very low evidence certainty (SUCRAs:100%)
- Niacin supplements ranked best in triglyceride reductions and increasing high-density lipo-protein cholesterol levels with low to very low evidence certainty (SUCRAs:93.7% and 94.6%, respectively)
- Vitamin E supplements ranked best in reducing low-density lipoprotein cholesterol levels with very low evidence certainty (SUCRAs:80.0%).
Conclusion
- Micronutrient supplements, such as chromium, vitamin E, vitamin K, vanadium, and niacin supplements, may be efficacious in managing T2DM
- It should be noted that the evidence certainty for all was low.
Clinical practice applications:
- Chromium plays an important role in carbohydrate and lipid metabolism and was the most effective micronutrient for decreasing fasting blood glucose, HbA1c, fasting insulin, and HOMA-IR reductions. More pronounced effects were seen for chromium than vitamin E, vitamin C, niacin, selenium, and magnesium supplements
- Vitamin K was the top-ranked micronutrient in reducing HbA1c and fasting insulin levels. The mechanism through which Vitamin K affects glucose metabolism is proposed as activation of the AMP-activated protein kinase/sirtuin 1, that in turn increases phosphocreatine 3-kinase and glucose transporter 2 to decrease insulin resistance and fasting glucose.
- Vanadium was the top-ranked micronutrient in total cholesterol (TC) reductions, where supplementation dosage should be carefully considered, as vanadium compounds can be moderately or highly toxic. Vanadium supplementation is only recommended in cases of vanadium deficiency or diabetes, hyperlipidemia, and hypertension, where the intake of vanadium from food should be enhanced in preference to supplementation
- Niacin was ranked as the most effective in triglyceride (TG) reductions and increasing HDL cholesterol levels. The dose of niacin could not be determined
- Vitamin E was the top-ranked micronutrient in low-density lipo- protein (LDL) cholesterol reductions.
Considerations for future research:
- Considering the clinical importance of these findings, new research is needed to get better insight into the efficacy of micronutrient supplements in managing T2DM
- Selenium homeostasis, selenoprotein, insulin signaling/secretion, and carbohydrate/lipid metabolism are linked in multiple and complex ways but the authors could not explain why chromium supplementation would lower blood glucose more effectively than selenium supplementation, and suggest more research is needed to clarify this
- While vitamin K status could be an emerging treatment target in T2DM prevention and management, it remains to be determined whether vitamin K supplementation has an advantage over other nutrients in terms of hypoglycemic effect, and further research is necessary
- The beneficial effect of vitamin E and niacin supplements regarding lipid metabolism warrant investigation through more rigorous comparative studies.
Abstract
Medical nutrition treatment can manage diabetes and slow or prevent its complications. The comparative effects of micronutrient supplements, however, have not yet been well established. We aimed at evaluating the comparative effects of vitamin and mineral supplements on managing glycemic control and lipid metabolism for type 2 diabetes mellitus (T2DM) to inform clinical practice. Electronic and hand searches for randomized controlled trials (RCTs) were performed until June 1, 2022. We selected RCTs enrolling patients with T2DM who were treated with vitamin supplements, mineral supplements, or placebo/no treatment. Data were pooled via frequentist random-effects network meta-analyses. A total of 170 eligible trials and 14223 participants were included. Low to very low certainty evidence established chromium supplements as the most effective in reducing fasting blood glucose levels and homeostasis model assessment of insulin resistance (SUCRAs: 90.4% and 78.3%, respectively). Vitamin K supplements ranked best in reducing glycated hemoglobin A1c and fasting insulin levels (SUCRAs: 97.0% and 82.3%, respectively), with moderate to very low certainty evidence. Vanadium supplements ranked best in lowering total cholesterol levels with very low evidence certainty (SUCRAs:100%). Niacin supplements ranked best in triglyceride reductions and increasing high-density lipoprotein cholesterol levels with low to very low evidence certainty (SUCRAs:93.7% and 94.6%, respectively). Vitamin E supplements ranked best in reducing low-density lipoprotein cholesterol levels with very low evidence certainty (SUCRAs:80.0%). Our analyses indicated that micronutrient supplements, especially chromium, vitamin E, vitamin K, vanadium, and niacin supplements, may be more efficacious in managing T2DM than other micronutrients. Considering the clinical importance of these findings, new research is needed to get better insight into this issue.
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Distribution of energy intake across the day and weight loss: A systematic review and meta-analysis.
Young, IE, Poobalan, A, Steinbeck, K, O'Connor, HT, Parker, HM
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2023;24(3):e13537
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Obesity increases an individual's risk of metabolic disease, such as diabetes and cardiovascular disease, musculoskeletal disorders such as osteoarthritis, and some cancers. “Chrononutrition” relates to the timing of meals and distribution of total energy intake across the day. Evidence is building chrononutrition as a potential target in both weight loss and metabolic disease interventions. The aim of this study was to examine the impact of earlier versus later distribution of total daily energy intake on weight loss, and to evaluate the potential for utilizing altered energy distribution as a tool in weight loss interventions. This study is a systematic review and meta-analysis of nine clinical studies. Total number of participants was 485 (earlier distributed total energy intakes: n = 244, later distributed total energy intakes; n = 241). Results show that energy intakes with a focus on earlier distribution resulted in significantly greater weight loss when compared with similarly energy-restricted diets with individuals consuming a larger proportion of their total energy intake later in the day and into the evening. Authors conclude that earlier energy intakes may be a promising tool to be used in conjunction with other weight loss strategies such as energy restriction to enhance weight loss. However, further research is required to elucidate the additional positive impacts that earlier distributed total energy intakes may have on weight and metabolic health.
Expert Review
Conflicts of interest:
None
Take Home Message:
Implementing a dietary strategy where a higher proportion of energy is consumed earlier in the day may offer additional benefits to an energy restricted diet for weight loss, blood glucose, improve markers of insulin resistance, increase satiety and improve hunger management. Based on the findings, earlier distribution of energy intake may serve as an effective component of a weight loss protocol.
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:
Background
Chrononutrition refers to the timing and distribution of total daily energy intake across the day. It has been proposed that consuming a greater proportion of total daily energy intake earlier in the day as opposed to the evening may be beneficial for weight loss and metabolic health.
Aims
This systematic review and meta-analysis aimed to assess the impact of earlier versus later distribution of total daily energy intake on weight loss.
Results
A total of 9 randomised controlled trials involving 485 participants were included in this analysis. The study durations ranged from 5-16 weeks. All of the studies included in this analysis applied energy-restricted diets to both intervention arms. The mean percentages of energy intake in 8 of the 9 studies per meal were:
- Earlier distributed intakes: breakfast: 34% ± 16%, lunch: 38% ± 7%, dinner: 20% ± 6%.
- Later distributed intakes: breakfast: 19% ± 6%, lunch: 30% ± 10%, dinner; 40% ± 11%.
One of the studies advised percentage of energy intakes as either:
- Earlier: 70% for breakfast, morning tea and lunch and 30% for afternoon tea and dinner
- Late: 55% for breakfast, morning tea and lunch and 45% for afternoon tea and dinner.
The earlier distributed energy intake groups demonstrated significantly greater weight loss when compared with later distributed energy intake groups ( Mean Difference (MD) −1.23 kg; 95% CI −2.40, −0.06, p = 0.04;
I2 = 98%).
The earlier energy intake groups also displayed lower fasting and bedtime glucose levels (fasting: −0.83 vs. −0.27 mmol/L, p = 0.001; before sleep: −1.70 vs. −0.28 mmol/L, p = 0.009).
A random-effects model demonstrated that the earlier intake groups displayed greater reductions in LDL (MD: −0.11 mmol/L; 95% CI −0.14, −0.07, p < 0.01), fasting glucose (MD: 0.15 mmol/L, 95% CI −0.23, −0.06, p < 0.001) and HOMA-IR (MD: −0.38; 95% CI −0.64, −0.11, p = 0.005).
One study reported that earlier distribution energy intake also led to a greater reduction in medications following the intervention for type 2 diabetics (31% vs. 0%, P=0.002).
Two of the studies assessed both appetite and hunger and identified that earlier distribution of energy led to improvements in their urge to eat, preoccupation with food and cravings for sweets and fats.
Clinical practice applications:
Earlier distribution of energy intake may be beneficial for:
- Weight loss
- Improve fasting insulin, HOMA-IR, fasting glucose and HbA1c
- Reducing LDL
- Improving satiety and hunger management
- Supporting the reduction of medications for individuals with type 2 diabetes
- Improving regularity of sleep and waking times
Considerations for future research:
As the included studies only ranged from 5-16 weeks, longer duration studies would be useful to identify the effect of earlier distribution of energy intake on body weight, metabolic health and appetite over a longer period of time. There was a high degree of heterogeneity between the studies and a lack of uniformity in the distributions of energy intake across the day. Further studies with more uniformity of energy distribution would be needed to identify the optimal distribution of energy across the day to improve body weight and metabolic health.
Abstract
Consuming a greater proportion of total energy intake earlier in the day rather than in the evening is proposed to positively influence weight loss and health, potentially due to greater synchronization of human body circadian rhythms. This systematic review provides an update on existing evidence regarding earlier distributed eating patterns in weight loss interventions. Using a robust search strategy in five electronic databases, nine randomized controlled trials investigating the impact of energy intake distribution on weight loss were identified. Following critical appraisal, a random-effects meta-analyses found that, in the context of an energy-reduced diet, distributing energy intake with a focus on earlier intake resulted in significantly greater weight loss (-1.23 kg; 95% CI 2.40, -0.06, p = 0.04). Improvements in HOMA-IR, fasting glucose, and LDL cholesterol were also seen. The current study provides a timely update on the evidence linking distribution of total daily energy intake and health, showing that a focus on earlier intakes can result in greater short-term weight loss compared with later intakes. Future studies are needed to elucidate the impact that earlier intakes may have on weight management and metabolic health.
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Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial.
Thomsen, MN, Skytte, MJ, Samkani, A, Carl, MH, Weber, P, Astrup, A, Chabanova, E, Fenger, M, Frystyk, J, Hartmann, B, et al
Diabetologia. 2022;65(3):506-517
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The carbohydrate restricted diet has been shown to be beneficial for Type 2 diabetes (T2D) management and reducing cardiovascular disease risk. This open-label, parallel randomised controlled trial involved Type 2 diabetic patients taking antidiabetic medications who restricted their energy intake by following either a carbohydrate-reduced high protein diet or a conventional diabetic diet. Participants in both groups had a 5.9% reduction in body weight, similar changes in fasting NEFA, apoB, apoA-1, total cholesterol, LDL-cholesterol, HDL-cholesterol, and non-HDL cholesterol, and a significant reduction in fasting glucose, insulin, C-peptide, and HOMA2-IR after 6 weeks of intervention. Carbohydrate-reduced high protein diet group showed a greater reduction in HbA1c and diurnal mean glucose, glycaemic variability, fasting triacylglycerol concentration and liver fat content. Carbohydrate-reduced high protein diet caused an adverse reaction in some patients, and those following a carbohydrate-reduced high protein diet excreted more urea than those eating a conventional diabetic diet. To confirm the results of this study, long-term robust studies are needed. This study can assist healthcare professionals in understanding the benefits of following a carbohydrate-reduced high protein diet in improving glycaemic control, triglyceride levels, and reducing body weight in Type 2 diabetes patients.
Abstract
AIMS/HYPOTHESIS Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes. METHODS This open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), BMI >25 kg/m2, eGFR >30 ml min-1 [1.73 m]-2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev). RESULTS Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol [-0.18 (-0.32, -0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] -0.8 [-1.2, -0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] -4.1 [-5.9, -2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] -18 [-29, -6]%, p < 0.01) and liver fat content (by mean [95% CI] -26 [-45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets. CONCLUSIONS/INTERPRETATION Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies. TRIAL REGISTRATION ClinicalTrials.gov NCT03814694. FUNDING The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.
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Time-restricted eating and exercise training improve HbA1c and body composition in women with overweight/obesity: A randomized controlled trial.
Haganes, KL, Silva, CP, Eyjólfsdóttir, SK, Steen, S, Grindberg, M, Lydersen, S, Hawley, JA, Moholdt, T
Cell metabolism. 2022;34(10):1457-1471.e4
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A healthy diet and regular physical activity are primary lifestyle strategies for the prevention and treatment of obesity and its associated conditions. However, poor adherence rates to these strategies limit their effectiveness. Time-restricted eating (TRE) is a popular dietary strategy that emphasises the timing of meals in alignment with diurnal circadian rhythms, permitting ad libitum energy intake during a restricted eating window (8–10 h between the first and last energy intake of the day). The aim of this study was to investigate the isolated and combined effects of TRE and high-intensity interval training (HIIT) on glycaemic control and cardiometabolic health outcomes in women with overweight/obesity. This study is a 7-week randomised controlled trial with four parallel groups: TRE (energy intake limited to a %10-h eating window every day), HIIT (three supervised treadmill exercise sessions per week), a combination (TREHIIT), and a control group (CON, no intervention). Participants (n=131) were randomly assigned to one of the four groups. . Results show that 7 weeks of TRE, HIIT, or a combination failed to improve glycaemic control in reproductive-aged women with overweight/obesity. However, the combination of TRE and HIIT significantly reduced glycated haemoglobin levels compared with CON and induced greater losses in body weight, fat mass, and visceral fat area compared with either intervention alone. Isolated TRE resulted in lower nocturnal glucose concentrations compared with CON. Authors conclude that combining TRE with HIIT can rapidly induce several health benefits and decrease metabolic disease risk in women with overweight/obesity. In fact, the high rates of compliance and adherence shown in their findings, highlight the potential of these diet-exercise (TRE and HIIT) protocols to be implemented in clinical practice for treatment and primary prevention of overweight/ obesity.
Abstract
Diet modification and exercise training are primary lifestyle strategies for obesity management, but poor adherence rates limit their effectiveness. Time-restricted eating (TRE) and high-intensity interval training (HIIT) improve cardiometabolic health in at-risk individuals, but whether these two interventions combined induce superior improvements in glycemic control than each individual intervention is not known. In this four-armed randomized controlled trial (ClinicalTrials.gov NCT04019860), we determined the isolated and combined effects of 7 weeks of TRE (≤10-h daily eating window, with ad libitum energy intake) and HIIT (three exercise sessions per week), compared with a non-intervention control group, on glycemic control and secondary cardiometabolic outcomes in 131 women (36.2 ± 6.2 years) with overweight/obesity. There were no statistically significant effects after isolated TRE, HIIT, or a combination (TREHIIT) on glucose area under the curve during an oral glucose tolerance test (the primary outcome) compared with the control group (TRE, -26.3 mmol/L; 95% confidence interval [CI], -82.3 to 29.7, p = 0.36; HIIT, -53.8 mmol/L; 95% CI, -109.2 to 1.6, p = 0.057; TREHIIT, -41.3 mmol/L; 95% CI, -96.4 to 13.8, p = 0.14). However, TREHIIT improved HbA1c and induced superior reductions in total and visceral fat mass compared with TRE and HIIT alone. High participant adherence rates suggest that TRE, HIIT, and a combination thereof may be realistic diet-exercise strategies for improving markers of metabolic health in women at risk of cardiometabolic disease.
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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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Impact of Replacement of Individual Dietary SFAs on Circulating Lipids and Other Biomarkers of Cardiometabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Humans.
Sellem, L, Flourakis, M, Jackson, KG, Joris, PJ, Lumley, J, Lohner, S, Mensink, RP, Soedamah-Muthu, SS, Lovegrove, JA
Advances in nutrition (Bethesda, Md.). 2022;13(4):1200-1225
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Cardiovascular disease is one of the leading causes of mortality worldwide, and metabolic disorders such as diabetes, hyperlipidaemia, and hypertension contribute to this risk. Cardiometabolic disease (CMD) can be reduced by reducing saturated fatty acids (SFAs) and replacing them with unsaturated fatty acids (UFAs). Dietary SFA's are classified as a whole group in general dietary guidelines. However, blood lipid levels and other biomarkers of CMD may be affected differently by individual dietary SFAs. In this systematic review and meta-analysis, 44 randomised controlled trials were included that investigated the effects of replacing SFAs with individual dietary SFAs or UFAs on markers of CMD. CMD markers like Total cholesterol (TC), LDL cholesterol, and apoB concentrations were significantly reduced by replacing 1.5%TE of palmitic acid with oleic acid or UFAs for 14 days. The research also showed associations between apoB and LDL-cholesterol and apoA-I and HDL-cholesterol concentrations. Dietary palmitic acid substituted with UFAs significantly reduced fasting LDL-cholesterol and total cholesterol. The majority of studies included in this study focused on dietary palmitic acid and not much on stearic acid, myristic acid, or lauric acid. Therefore, further robust studies are required to assess the effect of individual dietary SFAs on the markers of CMD, including markers of inflammation, hemostasis, glycemic control, or metabolic hormones. Healthcare professionals can use this study to understand the benefits of substituting SFAs with UFAs on CMD markers.
Abstract
Little is known of the impact of individual SFAs and their isoenergetic substitution with other SFAs or unsaturated fatty acids (UFAs) on the prevention of cardiometabolic disease (CMD). This systematic literature review assessed the impact of such dietary substitutions on a range of fasting CMD risk markers, including lipid profile, markers of glycemic control and inflammation, and metabolic hormone concentrations. Eligible randomized controlled trials (RCTs) investigated the effect of isoenergetic replacements of individual dietary SFAs for ≥14 d on ≥1 CMD risk markers in humans. Searches of the PubMed, Embase, Scopus, and Cochrane CENTRAL databases on 14 February, 2021 identified 44 RCTs conducted in participants with a mean ± SD age of 39.9 ± 15.2 y. Studies' risk of bias was assessed using the Cochrane Risk of Bias tool 2.0 for RCTs. Random-effect meta-analyses assessed the effect of ≥3 similar dietary substitutions on the same CMD risk marker. Other dietary interventions were described in qualitative syntheses. We observed reductions in LDL-cholesterol concentrations after the replacement of palmitic acid (16:0) with UFAs (-0.36 mmol/L; 95% CI: -0.50, -0.21 mmol/L; I2 = 96.0%, n = 18 RCTs) or oleic acid (18:1n-9) (-0.16 mmol/L; 95% CI: -0.28, -0.03 mmol/L; I2 = 89.6%, n = 9 RCTs), with a similar impact on total cholesterol and apoB concentrations. No effects on other CMD risk markers, including HDL-cholesterol, triacylglycerol, glucose, insulin, or C-reactive protein concentrations, were evident. Similarly, we found no evidence of a benefit from replacing dietary stearic acid (18:0) with UFAs on CMD risk markers (n = 4 RCTs). In conclusion, the impact of replacing dietary palmitic acid with UFAs on lipid biomarkers is aligned with current public health recommendations. However, owing to the high heterogeneity and limited studies, relations between all individual SFAs and biomarkers of cardiometabolic health need further confirmation from RCTs. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42020084241.
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Effect of a multi-domain lifestyle intervention on cardiovascular risk in older people: the FINGER trial.
Lehtisalo, J, Rusanen, M, Solomon, A, Antikainen, R, Laatikainen, T, Peltonen, M, Strandberg, T, Tuomilehto, J, Soininen, H, Kivipelto, M, et al
European heart journal. 2022;43(21):2054-2061
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Older people are at high risk of cardiovascular disease, and 90% of the risk factors can be modified, including an unhealthy diet, poor physical activity, obesity, smoking, and obesity-related comorbidities. This randomised controlled trial examined a multifactorial approach combining several lifestyle modifications in 1259 older adults between 60 and 77 years of age to reduce the risk of cardiovascular disease. Participants were randomly assigned to intensive multi-domain lifestyle intervention or regular health advice control groups. The multifactorial lifestyle intervention incorporated dietary counselling, exercise training, cognitive training, and managing CVD and metabolic risk factors. Dietary interventions included tailored strategies that considered increased consumption of fruits, berries, vegetables, whole grains, margarine, oil, and fish. Physical exercise interventions included strength training, balance exercises, and aerobic exercises. Cognitive interventions and intensive strategies to manage metabolic factors were also implemented. In the multifactorial lifestyle intervention group, cerebrovascular events were lower after two years than in the control group. In addition, cardiovascular disease and stroke incidence were lower in the elderly with a history of cardiovascular disease. Healthcare professionals can use the results from this study to understand the benefits of multifactorial lifestyle interventions on cardiovascular disease. However, there is a need for longer-term robust studies since the evidence is sparse.
Abstract
AIMS: Joint prevention of cardiovascular disease (CVD) and dementia could reduce the burden of both conditions. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) demonstrated a beneficial effect on cognition (primary outcome) and we assessed the effect of this lifestyle intervention on incident CVD (pre-specified secondary outcome). METHODS AND RESULTS FINGER enrolled 1259 individuals aged 60-77 years (ClinicalTrials.gov NCT01041989). They were randomized (1:1) to a 2-year multi-domain intervention with diet, physical and cognitive activity, and vascular monitoring (n = 631), or general health advice (n = 628). National registries provided data on CVD including stroke, transient ischaemic attack (TIA), or coronary heart event. During an average of 7.4 years, 229 participants (18%) had at least one CVD diagnosis: 107 in the intervention group and 122 in the control group. The incidence of cerebrovascular events was lower in the intervention than the control group: hazard ratio (HR) for combined stroke/TIA was 0.71 [95% confidence interval (CI): 0.51-0.99] after adjusting for background characteristics. Hazard ratio for coronary events was 0.84 (CI: 0.56-1.26) and total CVD events 0.80 (95% CI: 0.61-1.04). Among those with history of CVD (n = 145), the incidence of both total CVD events (HR: 0.50, 95% CI: 0.28-0.90) and stroke/TIA (HR: 0.40, 95% CI: 0.20-0.81) was lower in the intervention than the control group. CONCLUSION A 2-year multi-domain lifestyle intervention among older adults was effective in preventing cerebrovascular events and also total CVD events among those who had history of CVD.