Nutrition & Supplements: February 2020

Effects of Nutritional Supplements and Dietary Interventions on Cardiovascular Outcomes: An Umbrella Review and Evidence Map

Safi U. Khan, MD; Muhammad U. Khan, MD; Haris Riaz, MD; Shahul Valavoor, MD; Di Zhao, PhD; Lauren Vaughan, MD; Victor Okunrintemi, MD, MPH; Irbaz Bin Riaz, MD, MS; Muhammad Shahzeb Khan, MD; Edo Kaluski, MD; M. Hassan Murad, MD; Michael J. Blaha, MD, MPH; Eliseo Guallar, MD, DrPH; Erin D. Michos, MD, MHS

Aug. 6, 2019 – Annals of Internal Medicine

Abstract

Background:

The role of nutritional supplements and dietary interventions in preventing mortality and cardiovascular disease (CVD) outcomes is unclear.

Purpose:

To examine evidence about the effects of nutritional supplements and dietary interventions on mortality and cardiovascular outcomes in adults.

Data Sources:

PubMed, CINAHL, and the Cochrane Library from inception until March 2019; ClinicalTrials.gov (10 March 2019); journal Web sites; and reference lists.

Study Selection:

English-language, randomized controlled trials (RCTs) and meta-analyses of RCTs that assessed the effects of nutritional supplements or dietary interventions on all-cause mortality or cardiovascular outcomes, such as death, myocardial infarction, stroke, and coronary heart disease.

Data Extraction:

Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence.

Data Synthesis:

Nine systematic reviews and 4 new RCTs were selected that encompassed a total of 277 trials, 24 interventions, and 992 129 participants. A total of 105 meta-analyses were generated. Low-certainty evidence showed that omega-3 long-chain polyunsaturated fatty acid (LC-PUFA) was associated with reduced risk for myocardial infarction (RR, 0.92 [CI, 0.85 to 0.99]) and coronary heart disease (RR, 0.93 [CI, 0.89 to 0.98]). Folic acid was associated with lower risk for stroke (RR, 0.80 [CI, 0.67 to 0.96]; low certainty), whereas calcium plus vitamin D increased the risk for stroke (RR, 1.17 [CI, 1.05 to 1.30]; moderate certainty). Other nutritional supplements, such as vitamin B6, vitamin A, multivitamins, antioxidants, and iron and dietary interventions, such as reduced fat intake, had no significant effect on mortality or cardiovascular disease outcomes (very low– to moderate-certainty evidence).

Limitations:

Suboptimal quality and certainty of evidence.

Conclusion:

Use of omega-3 LC-PUFA and folate supplementation could reduce risk for some cardiovascular outcomes in adults. Combined calcium plus vitamin D might increase risk for stroke.

Primary Funding Source:

None.

Current U.S. dietary guidelines recommend several healthy eating patterns, including U.S., Mediterranean, and vegetarian diets (1). Although the guidelines recognize the occasional need for nutritional supplementation or food fortification for specific nutrients that may be consumed in inadequate amounts, they do not recommend routine use of any dietary supplement to reduce risk for cardiovascular disease (CVD) or other chronic diseases. Despite these recommendations, most U.S. adults use supplements to enhance their diets, with uncertain health benefits (2, 3). From 1999 to 2012, the NHANES (National Health and Nutrition Examination Survey) reported that 52% of participants used at least 1 and 10% used at least 4 dietary supplements (4). From 2011 to 2014, the NHANES reported that among participants aged 60 years or older, 70% used at least 1 and 29% used at least 4 supplements, and 41% of supplement takers reported that they did so to improve their overall health (5).
 
In 2013, the U.S. Preventive Services Task Force conducted a systematic review of the utility of vitamin and mineral supplements for CVD prevention and found little evidence to support use (6). More recently, Jenkins and colleagues published a meta-analysis of randomized controlled trials (RCTs) of dietary supplements published through October 2017 (7). They found some stroke benefit conferred by folate; no CVD benefit for multivitamins, vitamin C, vitamin D, or calcium; and evidence for mortality harm for niacin and antioxidants. Since then, several landmark RCTs evaluating the efficacy of fish oils (8–10) and vitamin D (11, 12) for CVD prevention have been published, which add to the evidence level. In addition, the quality of the evidence base of these various nutritional supplements and dietary interventions still needs to be evaluated to ascertain the confidence in their efficacy. Thus, we performed a systematic review of existing meta-analyses of RCTs and generated an evidence map for efficacy of nutritional supplements and dietary interventions for CVD prevention.
 
Cardiovascular Mortality
 
Twenty-one interventions assessed the risk for cardiovascular mortality. Reduced salt intake in hypertensive participants reduced risk (RR, 0.67 [CI, 0.46 to 0.99]; P = 0.04; I2 = 0%; moderate certainty) (Figure 3). Other nutritional supplements or dietary interventions were not associated with risk for this outcome.
 
MI
 
Twenty-one interventions assessed risk for MI. Use of omega-3 LC-PUFA was associated with reduced risk (RR, 0.92 [CI, 0.85 to 0.99]; P = 0.03; I2 = 1%; low certainty) (Supplement Figure 1). Other nutritional supplements or dietary interventions had no association with risk for this outcome. The Egger regression test was consistent with publication bias for meta-analyses of vitamin E (P = 0.01) (Supplement Table 7).
 
Stroke
 
Twenty interventions assessed the risk for stroke. Folic acid was associated with lower risk (RR, 0.80 [CI, 0.67 to 0.96]; P = 0.02; I2 = 0%; low certainty), whereas combined calcium plus vitamin D intake was associated with increased risk (RR, 1.17 [CI, 1.05 to 1.30]; P = 0.01; I2 = 0%; moderate certainty) (Supplement Figure 2). Other nutritional supplements or dietary interventions had no association with risk for this outcome. The Egger regression test was consistent with publication bias for meta-analyses of vitamin E (P = 0.08) (Supplement Table 7).
 
CHD
 
Nineteen interventions assessed the risk for CHD. Use of omega-3 LC-PUFA was associated with reduced risk (RR, 0.93 [CI, 0.89 to 0.98]; P = 0.01; I2 = 2%; low certainty) (Supplement Figure 3). There was no association between other nutritional supplements or dietary interventions with risk for CHD.
 
Discussion
 
In this overview of 24 nutritional supplements and dietary interventions evaluating data from RCTs and meta-analyses of RCTs, we found some evidence that reduced salt intake was protective for all-cause mortality in normotensive participants and cardiovascular mortality in hypertensive participants, that omega-3 LC-PUFA was protective for MI and CHD, and folic acid was protective for stroke. Conversely, combined calcium plus vitamin D intake increased the risk for stroke. Other supplements, such as multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, folic acid, and iron, or such dietary interventions as the Mediterranean diet, reduced saturated fat intake, modified fat intake, reduced dietary fat intake, and increased intake of omega-3 ALA or omega-6 PUFA, did not seem to have a significant effect on mortality or CVD outcomes (with very low– to moderate-certainty evidence).
 
The beneficial effects of reduced salt intake on mortality and CVD risk reduction remain a debatable issue. Although some data support lower salt intake to reduce CVD risk (31, 32), other studies have shown a U-shaped relationship between sodium intake and death (33–35). Recently, 2 studies explored the relationship between measures of sodium intake, estimated from urinary sodium excretion and death (29, 32). A patient-level study of 4 prospective studies (133 118 participants) concluded that reduced intake of sodium should be confined to hypertensive patients only who also consume high sodium (29). However, Cook and colleagues reported a higher risk for all-cause mortality with increased sodium intake in participants of the TOHP (Trials of Hypertension Prevention) and showed the benefit of reduced sodium intake on death during a period of 20 years (32).
 
The mechanism behind the benefit of reduced salt intake on death is most likely related to reduced blood pressure. Hypertension is a known risk factor for CVD, and scientific evidence exists of a direct relationship between dietary salt intake and blood pressure (36–38). A meta-analysis of 34 trials (3230 participants) showed that reduction in salt intake (an average of 4.4 g/d) was associated with reduced systolic and diastolic blood pressures in both hypertensive and normotensive patients, regardless of sex or ethnicity (36). This benefit can potentially translate into cardiovascular risk reduction. It was estimated that lowering salt intake to 6 g per day would be associated with a reduction in systolic blood pressure by about 7 mm Hg and a reduction in diastolic blood pressure by about 4 mm Hg in hypertensive patients and approximately 4 and 2 mm Hg, respectively, in normotensive patients; in turn, this could predict reduction in stroke rates by 24% and CHD by 18% (36, 39).
 
Clinical trials of omega-3 LC-PUFA have shown conflicting results regarding reduction of cardiovascular outcomes. However, recent randomized data have shown cardiovascular benefits (8–10). Although VITAL (Vitamin D and Omega-3 Trial) (8) and ASCEND (A Study of Cardiovascular Events iN Diabetes) (10) did not find convincing evidence of protective effects of omega-3 LC-PUFA for overall cardiovascular benefits (primary outcomes), VITAL did show a benefit of omega-3 LC-PUFA at 1 g per day for the reduction of MI, a secondary outcome (8). Moreover, VITAL showed a 19% reduction in major CVD outcomes among the subgroup of participants with low dietary fish intake (8).
 
Even more notable was the recent publication of the landmark REDUCE-IT, that found, compared with placebo, a remarkable 25% reduction in cardiovascular end points with the use of icosapent ethyl, a modified and highly purified form of EPA (9). This trial studied a much higher dose of EPA (4 g/d) than previous studies and included high-risk participants (those with known atherosclerotic CVD or diabetes mellitus and at least 1 additional vascular risk factor) who had controlled low-density lipoprotein cholesterol while receiving statin therapy but had elevated triglyceride levels (135 to 499 mg/dL) (9). As the cardiovascular risk reduction seen with icosapent ethyl exceeded the anticipated benefits from triglyceride reduction alone, other potential beneficial mechanisms, such as anti-inflammatory or antithrombotic effects, have been speculated. Icosapent ethyl is proprietary and is available only by prescription. It is unclear whether the effects observed in REDUCE-IT are specific for icosapent ethyl or reflect use of the higher dose of omega-3 LC-PUFA. The results should thus not be generalized to dietary supplement formulations of omega-3 LC-PUFA, which are unregulated and have variable composition (typically EPA plus docosahexaenoic acid).
 
Folate supplementation was associated with a lower risk for stroke, but this was largely driven by the results of the CSPPT (China Stroke Primary Prevention Trial), which evaluated the efficacy of folic acid therapy for primary prevention of stroke among hypertensive adults in China (40). This benefit might be due to the lack of folate fortification of foods in China (7), and whether these results can be generalized to a population, such as the United States, which has folate fortification, remains unclear.
 
On the other hand, we found that combined calcium plus vitamin D supplementation resulted in a higher risk for stroke. In a reanalysis of the WHI CaD Study (Women’s Health Initiative Calcium/Vitamin D Supplementation Study), risk for cardiovascular events, including stroke, was higher in women allocated to calcium plus vitamin D administration who were not taking personal calcium supplements (41). Potential biological explanations are hypercalcemia-mediated vascular calcifications, triggering of atherosclerosis, and hypercoagulability (42, 43). Of note, a recent observational analysis from NHANES found that use of calcium supplements was associated with an increased risk for death from cancer (2). Another analysis found an association with increased risk for MI (44). These findings, along with our findings from RCTs regarding stroke risk, raise concerns about harms from calcium supplement use. Regarding vitamin D alone (without calcium), despite new RCT data from the VITAL (11) and ViDA (Vitamin D Assessment Study) (12) trials, there was no evidence found for benefit or harm for vitamin D supplementation and CVD risk reduction.
 
Regarding multivitamins, our review was consistent with a previous meta-analysis (3) and supports the statements by the U.S. Preventive Services Task Force in 2014 regarding the lack of adequate evidence to support the benefit of multivitamin supplementation for CVD or death (6, 45). The lack of benefit of dietary supplements on death was also seen in a recent observational study from NHANES (2).
 
Regarding dietary recommendations from food sources, the American Heart Association (46) and the 2015 to 2020 U.S. dietary guidelines suggest limiting saturated fats and trans fats as a “key recommendation” for promoting a healthy lifestyle. The Mediterranean diet has been shown to be effective in reducing cardiovascular risk (23), but concerns have been raised regarding the methodological validity of some of the RCT studies. For instance, the Indo-Mediterranean study generated considerable controversy because of the lack of trained professionals required to run a trial of scientific validity (47). Similarly, the PREDIMED (Prevención con Dieta Mediterránea) (48) study was retracted and republished after errors in random assignment were found, although the conclusions were largely unchanged in the reanalysis. In our analysis, the Mediterranean diet, modified dietary fat, reduced dietary fat, reduced saturated fat intake, omega-6 PUFA, or omega-3 ALA PUFA did not reduce the risk for mortality or cardiovascular outcomes.
 
We compared our results with previous meta-analyses identified in our searches. Graudal and colleagues (274 683 patients) concluded that both low and high salt intake were associated with higher risk for all-cause mortality (35). However, their results were predominantly based on observational studies (23 cohort studies and 2 follow-up studies of RCTs). Conversely, Adler and colleagues showed little evidence for cardiovascular mortality reduction with lowered salt intake among hypertensive patients (RR, 0.67 [CI, 0.45 to 1.01]), which did not achieve statistical significance (22). We included the same clinical trials, but the discrepancy in results may be due to the different analytic approach used in the meta-analyses. Adler and colleagues used a fixed-effects model to analyze the results, whereas our meta-analysis was conducted using a more robust Paule–Mandel estimator with Hartung–Knapp adjustments (15). The same explanation applies to differences in results related to multivitamins and minerals from a recent meta-analysis by Jenkins and colleagues (7), except for folic acid, where we are in accord with Jenkins and colleagues’ findings. Abdelhamid and colleagues suggested benefit of omega-3 LC-PUFA in reducing CHD risk (RR, 0.93 [CI, 0.88 to 0.97]) but found no statistically significant effect on MI (24). Another meta-analysis by Aung and colleagues (10 RCTs, 77 917 participants) showed that omega-3 LC-PUFA supplementation was not associated with prevention of fatal CHD or CVD events (49). Our analysis is updated with recent data through March 2019, which explains the difference in results for omega-3 LC-PUFA compared with earlier reviews (8, 10, 24, 49). Regarding the higher risk for stroke due to combined calcium plus vitamin D, our results are consistent with a previous meta-analysis (41).
 
Our study’s strengths included using data only from RCTs and their meta-analyses, considering both dietary interventions and dietary supplements, and incorporating new trial data published in 2018 and 2019 after prior meta-analyses. The U.S. Department of Health and Human Services and the U.S. Department of Agriculture have been criticized for the paucity of sound scientific background behind their dietary recommendations (50). Similarly, the U.S. Preventive Services Task Force report has not been updated since 2014 (45). Our review provides a direct quantitative comparison of various nutritional and dietary interventions for cardiovascular outcomes. Because our generated evidence map is derived from RCTs, this report can assist to cover the “evidence-free zone” in this field (50).
 
Nevertheless, our findings need to be considered in the context of certain limitations. There are inherent limitations secondary to the shortcomings of included meta-analyses and RCTs (that is, heterogeneity of baseline characteristics of the participants, including age, sex, health and socioeconomic status, and interventions; lack of dose–response analyses; and variable duration of follow-up). Because the focus of our study was to provide broad-based evidence for various nutritional supplements and dietary interventions using existing meta-analyses and trial-level information, we could not analyze interventions according to important subgroups, such as sex, body mass index, lipid values, blood pressure thresholds, diabetes, and history of CVD. Various meta-analyses pooled a smaller number of trials, leading to the risk for small-study effects (51), and were limited by trials that were not double blind, lacked robust methods of pooling estimates, and had publication bias. Using the GRADE system, we found that the certainty of evidence was generally low or very low. Issues related to precision of the estimates, indirectness, quantitative and qualitative heterogeneity, and publication bias resulted in generally low-quality evidence.
 
In summary, this overview of the efficacy of nutritional supplements and dietary interventions on mortality and cardiovascular outcomes found evidence that supports reduced salt intake, omega-3 LC-PUFA intake, and folate supplementation for CVD risk reduction. Conversely, combined calcium plus vitamin D showed an increased risk for stroke. Other vitamins, minerals, dietary supplements, and dietary interventions were not associated with survival or cardiovascular benefits. Overall, these findings are limited by suboptimal quality of the evidence. This study can help those who create professional cardiovascular and dietary guidelines modify their recommendations, provide the evidence base for clinicians to discuss dietary supplements with their patients, and guide new studies to fulfill the evidence gap.

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