The Effects of Nutritional Supplements and Dietary Interventions on All-Cause Mortality and Cardiovascular Outcomes

The Effects of Nutritional Supplements and Dietary Interventions on All-Cause Mortality and Cardiovascular Outcomes

By Aly Becraft, MS and Kevin C Maki, PhD


Despite scientific uncertainty surrounding the benefits of dietary supplements, many U.S. adults use them, along with various dietary interventions, with the belief that they will improve their overall health (1).  Khan et al. (2) recently published a systematic review to assess the effect of various nutritional supplements and dietary interventions on cardiovascular outcomes.  The criteria for inclusion were randomized controlled trials (RCTs) and meta-analyses of RCTs that assessed the effect of nutritional supplements (vitamins, minerals, dietary supplements) or dietary interventions on all-cause mortality and cardiovascular outcomes in adults and written in English.  The main outcome of interest was all-cause mortality and secondary outcomes included cardiovascular mortality, myocardial infarction (MI), stroke, and coronary heart disease (CHD).  From these criteria, 942 articles were identified, and after initial title and abstract screening, 140 full-text articles remained to be reviewed for eligibility.  Ultimately, 9 systematic reviews and 4 new RCTs were included, comprising a total of 105 meta-analyses, 24 interventions (16 types of nutritional supplements and 8 dietary interventions), 277 RCTs and 922,129 participants.  A list of these interventions is shown in Table 1 and the significant findings from the present analysis are summarized in Table 2.


Table 1. List of interventions analyzed in Khan et al. (2)

Nutritional Supplements

Dietary Interventions


Mediterranean diet

Vitamin B6

Reduced dietary fat

Vitamin B3 or niacin

Modified dietary fat

Vitamin B complex

Reduced saturated fat


Reduced salt (hypertensive)


Reduced salt (normotensive)

Vitamin E

Increased omega-3 α-linolenic acid

Vitamin A

Increased omega-6 PUFA

Vitamin C


Vitamin D


Calcium and calcium plus vitamin D


Folic acid




Omega-3 long-chain PUFA




Abbreviation: PUFA, polyunsaturated fatty acids




Table 2. Summary of statistically significant findings from Khan et al. (2)



RR (95% CI)



All-cause mortality

Reduced salt intake in normotensive patients

0.90 (0.85 to 0.95)



Cardiovascular mortality

Reduced salt intake in hypertensive patients

0.67 (0.46 to 0.99)




Omega-3 LC-PUFA

0.92 (0.85 to 0.99)




Omega-3 LC-PUFA

0.93 (0.89 to 0.98)




Folic acid

0.80 (0.67 to 0.96)




Calcium plus vitamin D

1.17 (1.05 to 1.30)



Abbreviations: CHD, coronary heart disease; CI, confidence interval; LC-PUFA, long-chain polyunsaturated fatty acids; MI, myocardial infarction; RR, risk ratio


Comment.  Overall, the researchers found little evidence for nutritional supplements or dietary interventions to significantly reduce risk for all-cause mortality or cardiovascular outcomes, with some exceptions as outlined in Table 2.  Interventions associated with lower risks included reduced salt intake and lower total (normotensives) or cardiovascular mortality (hypertensives), omega-3 fatty acid supplementation and reduced risks for CHD and MI, and folic acid supplementation associated with lower risk for stroke. 


Of note, calcium plus vitamin D intake was associated with increased risk for stroke.  This finding could be related to hypercalcemia-mediated vascular calcification and/or effects on coagulation, although additional research is needed to more firmly establish causality and mechanistic explanations (3-5).


Certainty of evidence from this systematic review was low for most interventions due to low precision of estimates, qualitative and quantitative heterogeneity, and publication bias.  Regardless, these findings can be a useful resource for healthcare professionals who would like to recommend evidence-based nutritional interventions and provide a basis for future studies to explore the gaps in the currently available evidence base. 



  1. Gahche JJ, Bailey RL, Potischman N, et al. Dietary supplement use was very high among older adults in the United States in 2011-2014. J Nutr. 2017;147:1968-76.
  2. Khan SU, Khan MU, Riaz H, et al. Effects of nutritional supplements and dietary interventions on cardiovascular outcomes: an umbrella review and evidence map. Ann Intern. 2019;E-pub ahead of print
  3. Chin K, Appel LJ, Michos ED. Vitamin D, calcium, and cardiovascular disease: A”D”vantageous or “D”etrimental? An era of uncertainty. Curr Atheroscler Rep. 2017;19(1):5.
  4. Anderson JJ, Kruszka B, Delaney JA, et al. Calcium intake from diet and supplements and the risk of coronary artery calcification and its progression among older adults: 10-year follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc. 2016;5(10).
  5. Heaney RP, Kopecky S, Maki KC, Hathcock J, MacKay D, Wallace TC. A review of calcium supplements and cardiovascular disease risk. Adv Nutr. 2012;3:763-771.


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Meta-regression Characterizes the Relationships Between Changes in Dietary Cholesterol Intake and Plasma Low-density and High-density Lipoprotein Cholesterol Changes

Meta-regression Characterizes the Relationships Between Changes in Dietary Cholesterol Intake and Plasma Low-density and High-density Lipoprotein Cholesterol Changes

By Kevin C Maki, PhD and Orsolya M Palacios, PhD


Our group recently collaborated with scientists from the University of Cincinnati to conduct meta-regression analyses that investigated the dose-response relationships between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol levels.  The results from these analyses were presented in June at the American Society for Nutrition’s annual Nutrition 2018 meetings,1,2 and have also recently been accepted for publication in the American Journal of Clinical Nutrition.This summary is also available in the Fall 2018 Newsletter of MB Clinical Research.


Elevated low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, and there is a strong inverse association between high-density lipoprotein cholesterol (HDL-C) concentration and cardiovascular risk.4  Dietary guidance generally recommends reducing intakes of saturated fatty acids (SFA) and trans fatty acids (TFA) to reduce LDL-C levels, but in recent years there has been a step back from making specific quantitative recommendations with regard to limiting dietary cholesterol intake.5,6  A key recommendation from the 2010 Dietary Guidelines was to limit consumption of dietary cholesterol to <300 mg/day, but this was not included in the 2015-2020 Dietary Guidelines, although they did explain that “this change does not suggest that dietary cholesterol is no longer important to consider when building healthy eating patterns.”6  The 2015 guidelines stated “Strong evidence from mostly prospective cohort studies but also randomized controlled trials has shown that eating patterns that include lower intake of dietary cholesterol are associated with reduced risk of CVD…”.6  However, the committee concluded that “More research is needed regarding the dose-response relationship between dietary cholesterol and blood cholesterol levels.  Adequate evidence is not available for a quantitative limit for dietary cholesterol specific to the Dietary Guidelines.” 6  The 2013 American Heart Association/American College of Cardiology Lifestyle Management Guideline also concluded “There is insufficient evidence to determine whether lowering dietary cholesterol reduces LDL-C.”5  One problem with the available evidence is that there are limited data examining how much of an impact on lipoprotein lipid levels is attributable to dietary cholesterol after controlling for intakes of dietary fatty acids (i.e., SFA, TFA, polyunsaturated fatty acids [PUFA] and monounsaturated fatty acids [MUFA]).


Therefore, the goal of these meta-regression analyses was to examine the impacts of changes in dietary cholesterol on lipoprotein cholesterol levels, after accounting for dietary fatty acids.1,2  This meta-regression examined results from 55 randomized controlled dietary intervention trials (n = 2652 subjects) using a Bayesian approach (with Markov chain Monte Carlo techniques) and adjustment for dietary fatty acids to determine the best fitting mathematical models to the data.7  No significant associations were observed between change in dietary cholesterol intake and change in triglyceride or very low density lipoprotein cholesterol level.


For LDL-C, the meta-regression results indicated a positive correlation using a linear model and two non-linear models (Michaelis-Menten and Hill models), even after accounting for intakes of SFA, PUFA, MUFA and, where possible, TFA.  The relationship was best characterized by the non-linear models across the full range of cholesterol changes (0-1500 mg/day).  A 100 mg/day dietary cholesterol change was predicted to be associated with an increase in LDL-C of ~ 4.5 mg/dL in LDL-C.  Baseline cholesterol intake was not a significant predictor of the LDL-C response to a change in dietary cholesterol.  The relationship between baseline LDL-C and LDL-C response was unclear, and needs further exploration.  For HDL-C, the meta-regression analyses did not indicate a clear relationship between the change in dietary cholesterol intake and the change in HDL-C levels when both men and women were included.  However, when analyzed according to sex, the linear model and the Michaelis-Menten non-linear model demonstrated an inverse relationship in men, and a positive relationship in women.  This suggests a possible interaction between sex and HDL-C response to dietary cholesterol.


Using the Mensink et al. equation, which is designed to calculate the effects of changes in carbohydrate and fatty acid intakes on serum lipid and lipoprotein levels, each 1% increase in SFA in exchange for carbohydrate is predicted to increase LDL-C by 1.23 mg/dL.8  These findings suggest that increasing dietary cholesterol by 100 mg/day or 200 mg/day would have effects comparable to increasing dietary SFA by 3.7% and 5.5%, respectively.


These results suggest that there is a clinically meaningful effect of dietary cholesterol on LDL-C concentration.  This finding from a pooled analysis of results from 55 studies aligns with those from the best-controlled individual studies, such as two published by Ginsberg et al.9,10  This dose-response analysis provides reference for clinicians and nutrition scientists on how changes in dietary cholesterol intake may impact plasma cholesterol levels, although considerable interindividual variability should be expected.9-11  The clinical implications of changes in HDL-C associated with increased dietary cholesterol intake remain uncertain.



  1. Vincent MJ, Allen B, Maki KC, Palacios OM, Haber LT. Non-linear models best characterize the relationship between dietary cholesterol intake and circulating low-density lipoprotein cholesterol levels. Presented at American Society of Nutrition’s Nutrition 2018 meetings, June 9-12, 2018, Boston MA.
  2. Palacios OM, Vincent MJ, Allen B, Haber LT, Maki KC. The effect of dietary cholesterol on high-density lipoprotein cholesterol levels in men and women: a meta-analysis of randomized controlled trials. Presented at American Society of Nutrition’s Nutrition 2018 meetings, June 9-12, 2018, Boston MA.
  3. Vincent MJ, Allen B, Palacios OM, Haber LT, Maki KC. Meta-regression analysis of the effects of dietary cholesterol intake on low- and high-density lipoprotein cholesterol. Am J Clin Nutr. 2018; In Press.
  4. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, Wilson DP, Brown WV. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8:473-488.
  5. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr., Svetkey LP, Wadden TA, Yanovski SZ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle managemnet to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2960-2984.
  6. U.S. Department of Health and Human Services and U.S Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th edition. December 2015. Available at
  7. The Stan Development Team. RStan: the R interface to Stan. R package version 2.16.2. 2017. Available at
  8. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77:1146-1155.
  9. Ginsberg HN, Karmally W, Siddiqui M, Holleran S, Tall AR, Rumsey SC, Deckelbaum RJ, Blaner WS, Ramakrishnan R. A dose-response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men. Arterioscler Thromb. 1994;14:576-586.
  10. Ginsberg HN, Karmally W, Siddiqui M, Holleran S, Tall AR, Blaner WS, Ramakrishnan R. Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women. Arterioscler Thromb Vasc Biol. 1995;15:169- 178.
  11. Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, La Forge R, Daniels SR, Wilson DP, Morris PB, Wild RA, Grundy SM, Daviglus M, Ferdinand KC, Vijayaraghavan K, Deedwania PC, Aberg JA, Liao KP, McKenney JM, Ross JL, Braun LT, Ito MK, Bays HE, Brown WV, Underberg JA, NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2. J Clin Lipidol. 2015;9(6 Suppl):S1-S122.
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Results from A Study of Cardiovascular Events in Diabetes (ASCEND): Taking a Closer Look at the Potential Benefit of Omega-3 Fatty Acids for Preventing Cardiac Death

Results from A Study of Cardiovascular Events in Diabetes (ASCEND): Taking a Closer Look at the Potential Benefit of Omega-3 Fatty Acids for Preventing Cardiac Death

By Kevin C Maki, PhD; Mary R Dicklin, PhD


Results from A Study of Cardiovascular Events in Diabetes (ASCEND) were recently presented at the European Society of Cardiology (ESC) Congress 2018 held in Munich, Germany, along with their simultaneous publication in the New England Journal of Medicine.1,2  ASCEND was designed to evaluate whether daily aspirin safely prevented cardiovascular disease (CVD) and cancer in patients with diabetes, but without known CVD.3  The study also assessed whether supplementation with 1 g/d omega-3 fatty acids prevented CVD.  Persons with diabetes (n = 15,480) were randomly assigned to receive 100 mg/d aspirin or placebo and, in a factorial design, 1 g/d omega-3 fatty acid capsules, containing 460 mg eicosapentaenoic acid (EPA) and 380 mg docosahexaenoic acid (DHA), or placebo (olive oil).  The primary outcome was a first serious vascular event, which was defined as a composite of nonfatal myocardial infarction or stroke (excluding confirmed intracranial hemorrhage), transient ischemic attack, or vascular death.  The secondary outcome was a composite of any serious vascular event or any arterial revascularization procedure. 


The results for the omega-3 fatty acid portion of the trial showed no benefit from omega-3 vs. placebo for the primary or secondary composite outcomes.  During a mean follow-up of 7.4 years, a serious vascular event occurred in 8.9% and 9.2% of patients in the omega-3 and placebo groups, respectively, with a rate ratio of 0.97, 95% confidence interval (CI) 0.87 to 1.08, p = 0.55.  The composite outcome of any serious vascular event or revascularization occurred in 11.4% and 11.5% of patients in the omega-3 and placebo groups, respectively, with a rate ratio of 1.00, 95% CI 0.91 to 1.09.  The lack of a significant benefit of omega-3 fatty acids on the pre-specified primary outcome in ASCEND was consistent with results from recent meta-analyses of randomized controlled trials (RCTs) of long-chain omega-3 polyunsaturated fatty acids (compared to control or no treatment) on coronary heart disease (CHD) events.4  In a meta-analysis of 10 RCTs (n = 77,917) Aung et al. reported a risk ratio (95% CI) for a CHD event of 0.96 (0.90 to 1.01).5  Similarly, in a meta-analysis of 18 RCTs (n = 93,633) Alexander et al. reported a risk ratio of 0.94 (0.85 to 1.06).6  Abdelhamid et al. reported a risk ratio of 0.93 (0.88 to 0.97) in a meta-analysis of 28 RCTs (n = 84,301).7


Although the balance of the evidence from the RCTs conducted to date is supportive of the conclusion that omega-3 long-chain polyunsaturated fatty acid supplementation does not reduce risk for CHD events, there is promising evidence to suggest that omega-3 fatty acids may be beneficial for preventing fatal CHD or cardiac death.4,8  A meta-analysis of the effects of omega-3 fatty acids on cardiac death (defined as deaths from CHD, cardiac arrhythmia or heart failure) in 14 RCTs (n = 71,899) showed a risk ratio of 0.92 (0.86 to 0.98), p = 0.015.8  Aung et al. also reported a marginally significant reduction in CHD death 0.93 (0.85-1.00).5  In ASCEND, there was a near-significant difference in coronary deaths (incidence rate ratio = 0.79, 95% CI 0.61 to 1.02).1  In addition, there were significantly fewer vascular deaths (which represented 28% of all deaths) in the fatty acid group than in the placebo group (incidence rate ratio = 0.82, 95% CI 0.68 to 0.98).  Vascular deaths included coronary, sudden, stroke, and pulmonary embolism mortality. 


The ASCEND investigators suggested the possibility that if their results were to be combined with the studies reported in the meta-analysis by Aung et al., that a small benefit for fatal CHD might be detected.1,5  To assess this possibility, we have added the events reported in ASCEND to the events reported by Aung et al., and there was, in fact, a significant reduction in CHD/coronary death.


CHD deaths were as follows:

  • Aung meta-analysis5: 1301 of 39017 participants for omega-3 and 1394 of 38900 participants for control
  • ASCEND1: 100 of 7740 participants for omega-3 and 127 of 7740 participants for control
  • When combined, this is 3.00% of 46757 participants for omega-3 and 3.26% of 46640 participants for control
  • The relative risk is 0.919 (95% CI 0.855 to 0.987, p = 0.021)



Although it is important to not over-interpret findings from post-hoc subset analyses, these results show promise for the prevention of cardiac death with omega-3 fatty acid supplementation through mechanisms that we outlined in our recent editorial comment in Nutrients.4  Unfortunately, the dosages used in most RCTs of omega-3 fatty acids conducted to date have been small (most employed 1 g/d Omacor/Lovaza, which contains 840 mg of EPA + DHA).  Pooled results from observational studies with omega-3 biomarker measurements suggest that each 1-standard deviation (SD) increase in omega-3 status is associated with a 12-16% reduction in risk for CHD death.9  Based on the same observational study dataset, Harris et al. estimated that a 1-SD increase in omega-3 index (erythrocyte fatty acid EPA + DHA content), or 2.1% from the 10 cohorts included in the analysis, was associated with a 15% (95% CI 9% to 20%) reduction in risk for fatal CHD.10


A subset of 152 of the ASCEND participants had omega-3 index measurements completed.  There was no material change in the placebo group (6.6% at baseline and 6.5% at follow-up), whereas the index increased from 7.1% to 9.1% in the omega-3 fatty acid group, resulting in a net difference of 2.1% in the change from baseline, and a difference between groups of 2.6% at the end of the trial.  If the Harris et al. estimate of a 15% reduction in fatal CHD risk per 2.1% (1-SD) omega-3 index difference is applied to the ASCEND data, the predicted risk reduction would be 15%, or 18% if the difference between groups during follow-up of 2.6% (1.24-SDs) is used.10  These estimates are close to the observed difference of 21% in coronary death. 


At lower dosages, it is our opinion that there is no compelling evidence to suggest benefits regarding non-fatal myocardial infarction or stroke, but that there is promising evidence for prevention of cardiac death.  Of the three large-scale trials that have been recently completed or are underway, including the Vitamin D and Omega-3 Trial (VITAL),11 the Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH)12 and the Reduction of Cardiovascular Events with EPA – Intervention Trial (REDUCE-IT),13 only the latter two trials are using a higher EPA+DHA dosage (≥3000 mg/d).  Future investigation should focus on higher dosages than have generally been employed to date.


Our view is that the potential for omega-3 fatty acid supplementation to reduce cardiac death clearly deserves additional study.  Further details about why we hold this view may be found in our recent commentary in Nutrients.4  Also, we agree with the recent recommendation from the American Heart Association that it is reasonable to consider an omega-3 fatty acid supplement for patients with atherosclerotic CVD or heart failure.  The message to patients can be as follows:

  1. There is little or no risk associated with taking an omega-3 fatty acid (EPA + DHA) supplementation;
  2. The available evidence does not support a benefit of EPA + DHA supplements for reducing risk of heart attack or stroke;
  3. However, if a heart attack or heart failure should occur, those who take an omega-3 supplement might be less likely to die as a result.




  1. The ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].


  1. The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].


  1. Bowman L, Mafham M, Stevens W, et al. ASCEND: A study of cardiovascular events in diabetes: characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144.


  1. Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10:864.


  1. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77,917 individuals. JAMA Cardiol. 2018;3:224-234.


  1. Alexander DD, Miller PE, Van Elswyk ME, et al. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017;29:15-29.


  1. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.


  1. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. 2017;11:1152-1160.


  1. Del Gobbo LC, Imamura F, Aslibekyan S, et al. n-3 polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Intern Med. 2016;176:1155-1166.


  1. Harris WS, Del Gobbo L, Tintle NL. The omega-3 index and relative risk for coronary heart disease mortality: estimation from 10 cohort studies. Atherosclerosis. 2017;262:51-54.


  1. Manson JE, Bassuk SS, Lee IM, et al. The Vitamin D and Omega-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159-171.


  1. NIH. U.S. National Library of Medicine. Outcomes study to assess statin residual risk reduction with Epanova in high CV risk patients with hypertriglyceridemia (STRENGTH). NCT02104817.


  1. Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: Reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin Cardiol. 2017;40:138-148.


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