Fish Oil and Heart Disease

Patients (n = 13,078; mean age, 62.5 years) from 22 countries who were at high risk for cardiovascular disease were randomly assigned to receive, in double-blind fashion, 4 g per day of EPANOVA (AstraZeneca) or placebo (corn oil). Each EPANOVA capsule contains 1 g of fish oil-derived free fatty acids, with at least 850 mg of polyunsaturated fatty acids (mostly eicosapentaenoic acid and docosahexaenoic acid). To be included in the study, the patients had to be receiving a statin drug, have a triglyceride level of 180-500 mg/dl, and have a low HDL-cholesterol level (<42 mg/dl for men, <47 mg/dl for women).

The trial was halted early, after a median duration of 3.5 years, because an interim analysis concluded there was a low probability the treatment would demonstrate a clinical benefit. The primary endpoint (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization) occurred in 12.0% of patients treated with omega-3 fatty acids and 12.2% of those given corn oil (p = 0.84). The mean triglyceride level in the fish oil group decreased from 239 mg/dl at baseline to 191 mg/dl after 12 months (19% decrease; p < 0.001 compared with the change in the placebo group). The authors concluded that these findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.

Comment: Many studies have investigated the effects of fish oil or the omega-3 fatty acids present in fish oil for the primary or secondary prevention of cardiovascular disease. Many studies have shown benefit, but many others (including the present study) did not. One possible reason for the negative results in the present study is that all of the patients were taking a statin drug and 71% were also taking a platelet inhibitor. These drugs mimic some of the effects of fish oil. Like statin drugs, fish oil has an anti-inflammatory effect and, like platelet inhibiting drugs, fish oil inhibits platelet aggregation. Therefore, the use of these drugs may have “stolen fish oil’s thunder” (in a manner of speaking) and left little room for further improvement from omega-3 fatty acids.

Nicholls SJ, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA. 2020;324:2268-2280.

Iron Deficiency and Heart Failure

One thousand one hundred ten patients (mean age 71 years) in Europe, South America, and Singapore, who were stabilized after being hospitalized for acute heart failure and who had iron deficiency, were randomly assigned to receive, in double-blind fashion, intravenous iron (ferric carboxymaltose) or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. The patients were followed up for a total of 52 weeks. During the follow-up period, the proportion of patients who had to be readmitted to the hospital for heart failure was 24% lower in the iron group than in the placebo group (p = 0.013). The mortality rate did not differ between groups.

Comment: Iron deficiency is a common and often overlooked factor in patients with heart failure. Iron is a component of hemoglobin, which delivers oxygen to the tissues. In addition, iron is a cofactor for the enzyme cytochrome oxidase, which plays a role in mitochondrial ATP production via the electron-transport chain. ATP is essential for the pumping action of the heart; therefore, iron deficiency could exacerbate heart failure whether or not the patient is anemic. In previous studies, correction of iron deficiency improved functional status and decreased the frequency of hospitalizations in patients with heart failure. The present large-scale multicenter clinical trial confirmed the importance of identifying and treating iron deficiency in heart failure patients. As I have noted previously in the Townsend Letter, despite the growing body of evidence regarding iron and heart failure, most patients hospitalized for heart failure are still not being properly assessed or treated for iron deficiency.¹ Hopefully, the publication of this large-scale study in a major medical journal will help correct this epidemic of substandard medical care.

Ponikowski P, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396:1895-1904.

Blueberries Improve Metabolic Parameters

Fifty-two male US veterans (mean age, 67 years; mean body mass index, 34 kg/m²) with type 2 diabetes were randomly assigned to consume, in double-blind fashion, 11 g of freeze-dried blueberries or placebo twice a day (morning and evening with meals) for eight weeks. The total daily dose of freeze-dried blueberries was equivalent to 1 cup of blueberries. The placebo was matched with blueberries for energy and carbohydrate content. At the end of the treatment period, mean concentrations of hemoglobin A1c (7.1% vs. 7.5%; p = 0.03), fructosamine (276 vs. 292 µmol/L; p = 0.04), triglycerides (180 vs. 200 mg/dl; p = 0.03), aspartate aminotransferase (23 vs. 31 units/L; p = 0.02), and alanine aminotransferase (36 vs. 48 units/L; p = 0.0003) were significantly lower in the blueberry group than in the placebo group.

Comment: In this study, consumption of 22 g per day of freeze-dried blueberries improved glycemic control and certain measures of cardiovascular risk and liver function in men with type 2 diabetes. Certain compounds present in blueberries may also improve visual function, capillary integrity, and cognitive function. Blueberries are an excellent choice to include as part of a healthful diet. Blueberries are among the list of fruits and vegetables (along with apples, strawberries, grapes, and others) that may contain significant concentrations of pesticide residues, so it is preferable to consume organic blueberries.

Stote KS, et al. Effect of blueberry consumption on cardiometabolic health parameters in men with type 2 diabetes: an 8-week, double-blind, randomized, placebo-controlled trial. Curr Dev Nutr. 2020;4:nzaa030.

Eggs, Trimethylamine Oxide, and Cardiovascular Disease

Twenty overweight or obese postmenopausal women (aged 48-70 years) consumed an egg-free diet for two weeks and were then randomly assigned to consume two whole eggs per day at breakfast or the equivalent amount of yolk-free eggs for four weeks. After a four-week washout period with no egg consumption, each woman consumed the alternate diet for an additional four weeks. Morning blood samples were obtained after an overnight fast at the beginning and end of each intervention period. Compared with baseline, consumption of whole eggs significantly increased mean plasma choline and betaine concentrations, whereas consumption of yolk-free eggs had no significant effect on these levels. Neither diet had a significant effect on plasma trimethylamine N-oxide (TMAO) levels.

Comment: Dietary choline and betaine can be converted by intestinal bacteria to trimethylamine, which is then converted to TMAO in the liver. There is some evidence that TMAO is atherogenic, although other research suggests that TMAO is only a marker, rather than a cause, of increased cardiovascular disease risk. Because egg yolks contain relatively large amounts of choline, it has been hypothesized that eating eggs could increase TMAO levels. In the present study, consumption of 2 eggs per day increased plasma concentrations of choline and betaine (choline is converted in part to betaine), but it did not increase TMAO levels. In most observational studies, egg consumption was not associated with an increased risk of developing cardiovascular disease in non-diabetics, although it was associated with increased risk in diabetics. If eating eggs does increase heart disease risk to some extent, the mechanism is more likely related to the formation of atherogenic cholesterol oxides during cooking than to any effect on TMAO levels. Cholesterol oxides are less likely to form when the yolk remains intact during cooking (as in boiling or poaching of eggs).

Zhu C, et al. Whole egg consumption increases plasma choline and betaine without affecting TMAO levels or gut microbiome in overweight postmenopausal women. Nutr Res. 2020;78:36-41.

N-Acetylcysteine for Ulcerative Colitis, or More Iranian Research Fraud?

One hundred sixty-eight Iranian patients with severe acute ulcerative colitis, who had gone into remission after treatment with prednisolone (1 mg per kg of body weight per day) and oral mesalamine (4 g per day) for four weeks, were randomly assigned to receive, in double-blind fashion, 400 mg of N-acetylcysteine (NAC) twice a day or placebo for 16 weeks, and were then followed for an additional six weeks. At the start of NAC or placebo treatment, prednisolone was gradually tapered and discontinued. During 22 weeks of follow-up, 25 patients experienced a relapse: six in the NAC group and 19 in the placebo group. The relapse-free period was significantly longer (p = 0.007), and the proportion of patients who had an endoscopic relapse was significantly lower (p < 0.001) in the NAC group than in the placebo group.

Comment: As readers of the Townsend Letter know, I have been concerned that a large proportion of the nutrition research coming from Iran appears to be fraudulent. My reading of the present paper identified so many holes in it that (as the Beatles might have said) it could fill the Albert Hall.

1. Issue related to the submission date: According to the Iranian Registry of Clinical Trials document, patients were recruited from July 23, 2019, through April 20, 2020. The study included four weeks of high-dose prednisolone, followed by 16 weeks of NAC or placebo, followed by six weeks of observation. Thus, the earliest date the study could have been completed would have been October 19, 2020. Presumably, it would take at least several months for the data to be analyzed, the paper to be written, and the journal to accept and publish the paper. However, the paper appeared in print on October 14, 2020, even before it was possible to have completed the study.

2. The number of study subjects seems implausibly large: Patients were ineligible if they did not have pancolitis (which excludes about 80% of ulcerative colitis patients) or if they had been treated in the past six months with a tumor necrosis factor inhibitor or azathioprine (both of which are common treatments for ulcerative colitis). In addition, patients were eligible only if they were treated with a specific drug regimen (high-dose prednisolone plus mesalamine) and if they went into clinical remission from that treatment. Moreover, eligible patients had to agree to visit the clinic every two weeks for 16 weeks to have their blood drawn and to donate a stool sample. It is likely that many patients would not be willing to enroll in such a tedious study. Considering these various obstacles to enrollment, the researchers would likely have had to treat many thousands of acute severe flare-ups at a single clinic over a nine-month period in order to enroll 168 patients.

3. Implausible diagnostic testing: The paper stated that pancolitis was verified endoscopically in all enrolled patients just before the study. However, the paper also stated that all patients had been diagnosed previously, based on standard diagnostic criteria including endoscopy. It is not plausible that every patient who presented with an acute flare-up of a previously diagnosed disease would immediately be given another colonoscopy.

4. Implausible treatment regimen: The paper stated that every patient was started on prednisolone at a dosage of 1 mg per kg of body weight per day for four weeks. Prednisolone was then tapered by 5 mg per day every week until a dosage of 20 mg per day was reached, after which the dosage was tapered by 2.5 mg per day every week until it was discontinued. For a 70-kg person, it would take 10 weeks to taper to 20 mg per day, and an additional four weeks to taper to 10 mg per day (a total of 14 weeks to reach 10 mg per day). However, the paper also stated that the dosage was reduced to less than 10 mg per day in the third month (“in,” not “after” the third month). “In the third month” would be around weeks 9 to 13. It would be impossible to have decreased the dosage to less than 10 mg per day in weeks 9 to 13, if it took 14 weeks to taper to 10 mg per day.

5. Illogical diagnostic criterion: Clinical remission was defined in part as having at least three non-bloody stools per day. While cessation of bleeding is a logical criterion for remission, it is likely that many patients in remission would not have three or more bowel movements per day.

6. Ethical issue regarding the treatment: By the time the patients had tapered prednisolone to less than 10 mg per day, 13% had suffered a relapse. However, all patients were required to continue tapering prednisolone and then to discontinue it. Despite the risks of long-term glucocorticoid therapy, it would seem that at least some of the patients who suffered a relapse should have been advised to continue low-dose prednisolone for a longer period of time.

7. Funding issue: Double-blind studies are expensive, so it is unusual to conduct a double-blind study when there has been no prior evidence from case reports or uncontrolled trials that the treatment being tested is effective. This study was particularly expensive, because it included more than 300 colonoscopies and more than 6,000 laboratory tests. Conducting lab tests on every patient every two weeks for 16 weeks seems excessive and a waste of money. One wonders why anyone would have funded this study.

8. Issue related to the lead author: The lead author of this study published an earlier double-blind study of vitamin A supplementation for ulcerative colitis. I reviewed that paper in an editorial in the July 2019 issue of the Townsend Letter, and I pointed out many issues that raised concerns the research was fraudulent.

Masnadi Shirazi K, et al. Effect of N-acetylcysteine on remission maintenance in patients with ulcerative colitis: A randomized, double-blind controlled clinical trial. Clin Res Hepatol Gastroenterol. 2020 Oct 14 [Online ahead of print].

B Vitamins for Diabetic Foot Ulcers

A retrospective study was conducted on 29 US veterans with non-healing, early-stage diabetic foot ulcers who were treated daily with 5 mg of folic acid, 4 mg of cyanocobalamin, and 50 mg of pyridoxine for up to six months. Approximately 70% of the patients had hyperhomocysteinemia. Twenty-six of the patients (90%) had complete healing of the ulcer. Data were available for nine patients regarding the rate of wound healing in the four weeks before and the four weeks after B-vitamin therapy was started. The rate of healing was determined by calculating the absolute decrease in wound area (cm²). In those nine patients, the mean reduction in wound area was significantly greater during B-vitamin treatment than before such treatment.

Comment: These results suggest that supplementing with folic acid, vitamin B12, and vitamin B6 can accelerate the healing of early-stage diabetic foot ulcers. Possible mechanisms of action include lowering homocysteine levels (hyperhomocysteinemia appears to be a risk factor for impaired healing of diabetic foot ulcers) and improvement of endothelial dysfunction. It should be noted that a previous study found that B-vitamin supplementation accelerated disease progression in patients with diabetic nephropathy. Circumstantial evidence suggests that this adverse effect may be preventable by supplementing with magnesium along with the B vitamins.²

Boykin JV Jr, et al. High-dose folic acid and its effect on early stage diabetic foot ulcer wound healing. Wound Repair Regen. 2020;28:517-525.

Selenium, Cardiovascular Disease, and Mortality

A meta-analysis was conducted on 43 randomized controlled trials that examined the effect of selenium alone and antioxidant supplement mixtures (with or without selenium) on risk of cardiovascular disease and mortality. In the pooled analysis, neither selenium alone nor antioxidant mixtures had any significant effects. However, when selenium was included in the antioxidant mixture, there was a significant 23% decrease in cardiovascular disease mortality and a significant 10% decrease in all-cause mortality. In contrast, no reduction in risk was seen when selenium was not included in the antioxidant mixture.

Comment: In this meta-analysis of randomized controlled trials, selenium when given by itself, and antioxidant mixtures that did not contain selenium did not have a beneficial effect. In contrast, when selenium was included as part of an antioxidant mixture, reductions were seen in cardiovascular disease mortality and all-cause mortality. These findings should remind us that nutrients work in the body as a team, and that achieving the best results often requires the presence of adequate amounts of all nutrients.

Jenkins DJ, et al. Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2020;112:1642-1652.

Nitrate Supplementation for COPD

One hundred sixty-five patients (median age, 69 years) in the United Kingdom with chronic obstructive pulmonary disease (COPD) underwent a supervised exercise program twice a week for eight weeks. During this time they were also instructed in a home exercise program that included aerobic and strength training. The patients were randomly assigned to receive, in double-blind fashion, 140 ml of beetroot juice (containing 0.8 g of nitrate) or placebo (the same beverage that had been run through an ion exchange column to remove the nitrate). The beverages were consumed twice a week, three hours before each supervised exercise session. The primary outcome measure was the change in the incremental shuttle walk test (ISWT) distance. In this test, the subject walks at progressively increasing speed until they are either unable to continue or are unable to keep up with the required walking speed. Compared with baseline, the median ISWT distance increased by 60 meters in the beetroot juice group and by 30 meters in the placebo group (p < 0.03 for the difference in the change between groups). No serious adverse effects were reported.

Comment: In this study, supplementation with nitrate in the form of beetroot juice was well tolerated and enhanced the beneficial effect of exercise training in patients with COPD. The beneficial effects of nitrate are thought to be due to its conversion to nitric oxide. Nitric oxide functions as a vasodilator (and thereby enhances blood flow) and improves mitochondrial efficiency by decreasing the amount of oxygen required to synthesize ATP.

Pavitt MJ, et al. Oral nitrate supplementation to enhance pulmonary rehabilitation in COPD: ON-EPIC a multicentre, double-blind, placebo-controlled, randomised parallel group study. Thorax. 2020;75:547-555.