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Here’s a very quick summary of some randomized controlled trials (RCTs) and meta-analyses of RCTs that were published in January through February of 2020 and didn’t find evidence of an effect. This is known as a null effect.

Keep these things in mind when interpreting a null effect:

  • While one study can provide evidence that something doesn’t work, it doesn’t prove it. Similar, repeatable results from multiple studies make for stronger evidence, whether the finding is positive or negative.

  • Not all null effects are the same. A meta-analysis of low-quality studies or a small clinical trial usually won’t provide strong evidence, whether the finding is positive or negative.

  • The population matters. For instance, the lack of an effect in healthy young people doesn’t necessarily mean that an intervention wouldn’t work in people who are older and have a specific health condition.

Autoimmune disease, allergies, & asthma

Higher dose vitamin D supplementation during pregnancy does not reduce asthma in children[1]
  • What was studied? The rate of asthma and recurrent wheezing in children at 6 years of age who were born to mothers who supplemented with either 4,000 IU (100 mcg) vitamin D3 daily on top of a multivitamin containing 400 IU (10 mcg) during pregnancy, compared to those who supplemented 400 IU via the multivitamin.

  • Why study it? Vitamin D plays an important role in lung development during gestation, and animal models have suggested that vitamin D deficiency can lead to impaired airway development.

  • What was(n’t) found? No effect on recurrent wheezing or asthma rate was found when adding 4,000 IU vitamin D3 to the multivitamin.

  • How null was it? This study’s 3-year results found a significant effect on asthma reduction. However, this effect did not last through mid-childhood. The fact that this a large (over 800 participants), long-term study, coupled with the fact that similar results were found in a separate Danish study, suggests these results are reliable.

  • Anything else? Recurrent wheezing prevention was of borderline statistical insignificance. Also, supplementation was not given to the children postnatally (i.e., after birth), and there’s preliminary evidence suggesting that this could provide added benefit.

Cancer

Vitamin D supplementation didn’t affect colorectal cancer precursors either way in VITAL[2]
  • What was studied? This was a secondary analysis of the VITamin D and OmegA-3 TriaL (VITAL) examining the rate of either colorectal adenomas or serrated polyps (two precursors to full-blown colorectal cancer) in 25,871 people over 5 years in people who were randomized to take either placebo or 2,000 IU (50 mcg) vitamin D3 daily. The population was not necessarily vitamin D deficient, nor particularly at risk for colorectal cancer.

  • Why study it? While observational studies have found an association between vitamin D levels and colorectal cancer, randomized controlled trial data has been mixed.

  • What was(n’t) found? There was no association between supplementation and the rate of occurrence for either colorectal cancer precursor, nor their size, shape, or number.

  • How null was it? While this study was not designed to specifically study colorectal cancer’s precursors, its size and length provide moderate evidence for a lack of large effect against precursor development in the general population. However, the confidence intervals were wide enough to suggest room for a smaller effect.

  • Anything else? The study found preliminary evidence suggesting that vitamin D supplementation may benefit people with lower starting levels of vitamin D. Specifically, for people with levels below 30 ng/dL (<12 ng/mL), the rate of adenoma development trended lower (but was not statistically significant). Also, supplementation and serum level was associated with the rate of more advanced adenomas.

Diabetes & blood sugar

Four cups of instant coffee per day did not influence insulin sensitivity in people without diabetes but with mild insulin resistance[3]
  • What was studied? The effect of 4 cups of instant coffee daily for 26 weeks versus placebo on insulin sensitivity in people without diabetes, and who drank at least one cup of coffee daily habitually and with a baseline HOMA-IR over 1.3.

  • Why study it? Observational studies have found that insulin sensitivity is greater in coffee drinkers, but trials have tended to be short, small, and equivocal.

  • What was(n’t) found? There was no difference between groups in the primary outcome of glucose metabolized per unit bodyweight as measured through a hyperinsulinemic euglycemic clamp. Secondary glycemic-related indices didn’t differ between groups, either.

  • How null was it? This study is one of the stronger trials to date examining the effect of coffee on glycemic control due to its length, rigor, and use of a gold standard technique in measuring its primary outcome. However, it’s possible that people who didn’t drink coffee habitually would have seen a benefit; the authors selected coffee drinkers in order to boost compliance. Also, while the authors attempted to blind participants, the majority of people were able to tell what group they were in, which may have influenced other factors related to glycemic control. Finally, the population consisted of Malay, Chinese, and Asian-Indian people over 35 years old, leaving open the possibility that younger people or people of different ethnicities may have seen an effect.

Diets & foods

Egg consumption doesn’t seem to affect blood pressure[4]
  • What was studied? 15 randomized controlled trials involving 748 participants were meta-analyzed to see if egg consumption affected blood pressure.

  • Why study it? Observational evidence has suggested egg consumption may be associated with reduced blood pressure, while randomized controlled trials have been inconsistent.

  • What was(n’t) found? Egg consumption neither reduced nor increased systolic or diastolic blood pressure in a wide range of study participants, ranging from healthy people to those with diseases like type 2 diabetes and coronary artery disease.

  • How null was it? This isn’t strong evidence for several reasons. First, the longest studies included in the meta-analysis was 12 weeks, leaving open the possibility that longer trials may reveal differences. Second, most of the trials didn’t focus on blood pressure as a primary outcome, so they may have been underpowered to detect blood pressure differences. Third, the sample sizes for different populations were too small to explore subgroups, leaving open the possibility that different populations’ blood pressure could react differently to egg consumption. Finally, the authors found the study quality to be low to fair, leaving room for better quality evidence examining this issue.

Gut health

A Lactobacillus casei-based probiotic did not seem to influence the rate of antibiotic-associated diarrhea[5]
  • What was studied? The effect of 1010colony-forming units (CFUs) daily of L.casei DN114001 mixed with two common yogurt strains (L. delbrueckii subspecies bulgaricus and S. thermophilus at 108 CFUs) on the rate of antibiotic-associated diarrhea in 1,127 people over 55 years old in the UK who were prescribed antibiotics for at least 72 hours.

  • Why study it? While antibiotic-associated diarrhea is a major health concern in older patients, the efficacy of probiotics in reducing its rate is open to question.

  • What was(n’t) found? The probiotic had no clear benefit on diarrhea rate compared to placebo after two weeks of follow-up.

  • How null was it? The rate of diarrhea and drop-out rate were both much lower than the researchers anticipated, which may very well have contributed to the null result. The lower rate was possibly due to modifications in nationwide awareness and changes in practices in the UK that occurred around the time the trial was conducted. The authors suggest that future research into the matter controls for these factors.

Healthy aging & longevity

Walnuts don’t help cognition in older adults[6]
  • What was studied? How consuming walnuts (~15% of daily energy needs) impacted cognition over two years in women between the ages of 63 and 79, compared to abstaining from walnuts entirely.

  • Why study it? Walnuts are high in alpha-linoleic acid and polyphenols, both of which could prevent cognitive decline with age.

  • What was(n’t) found? Walnut consumption had no effect on global cognition compared to abstaining from walnuts.

  • How null was it? Quite null. This was a preregistered, well-powered study with close to 700 participants recruited. However, while 2 years is a long time as far as trials go, it’s possible that differences could manifest over a longer period of time, and the trial simply wasn’t long enough to see this.

Protein supplementation didn’t improve physical performance in older people with sarcopenia[7]
  • What was studied? 218 people older than 74 with sarcopenia were trained in a light physical activity regimen and randomized to either 40 grams of whey protein, an isocaloric placebo, or no supplementation at all for 12 months. Physical performance was assessed.

  • Why study it? Age-related muscle loss (sarcopenia) is associated with poorer health and wellbeing outcomes, but it’s unclear how preventable it is through protein supplementation.

  • What was(n’t) found? No effect was found on the primary outcome of physical performance as measured by the Short Physical Performance Battery (SPPB). Hand grip strength declined in all groups to a roughly equal extent.

  • How null was it? The authors powered the study to detect the smallest clinically relevant difference in the SPPB, so if an effect existed in this population, it probably isn’t clinically significant. That being said, only 50% of the population was found to adhere to the supplementation and exercise protocol consisting of 10–30 minutes light exercise (e.g., walking, getting out of chairs) twice daily, suggesting that adherence may not have been large enough to see a clear difference. Also, baseline protein intakes were already around 1 gram per kilogram bodyweight, so it’s possible that this population was already protein sufficient.

  • Anything else? Both placebo and protein supplementation groups had an increased rate of gastrointestinal upset, and experienced a slight average increase in weight.

Memory, focus, & cognition

Grape seed polyphenol extract has no effect on cognitive function in healthy young adults[8]
  • What was studied? How supplementing 400 mg grape seed polyphenol extract for 12 weeks affects cognitive function in healthy young adults.

  • Why study it? Epidemiological evidence suggests an association between polyphenol-rich food intake and cognitive function, and brain-derived neurotrophic factor increases after one month of grape juice consumption.

  • What was(n’t) found? There were no consistent cognitive benefits for supplementation compared to placebo.

  • How null was it? This isn’t very strong evidence against grape seed extract since, while a power calculation was performed, no clear, single primary outcome was declared. Instead, multiple measurements were taken. This, coupled with a small sample size of 60 participants, means that some effects could have been easily missed.

  • Anything else? People who took grape seed extract did show acute improvements in reaction time and chronic improvements in psychomotor skills (cognitive function as it relates to physical skills, e.g. reaction time), finger coordination,. However, since multiple outcomes were measured, and the placebo group also showed some improvements in other skills, it’s likely that these improvements were the result of chance, and are not strong evidence of grape seed extract’s effectiveness.

Muscle gain & exercise

Beetroot juice didn’t clearly help with tennis performance[9]
  • What was studied? Thirteen high-level tennis players (four of whom had professional-level rankings) were given either 70 mL (2.4 oz) commercial beetroot juice (Beet IT) or placebo in a crossover fashion, and strength, agility, serve speed, and sprint tests were performed 3 hours after ingestion.

  • Why study it? While some evidence suggests that nitrate-containing supplements like beetroot juice could improve performance by increasing blood flow to the muscles and improving recovery, no study has directly tested the ergogenic effects of beetroot juice on tennis players in particular.

  • What was(n’t) found? No statistically significant effect in any performance measure was found.

  • How null was it? This isn’t strong evidence against an effect. The study was powered to detect an 8% difference in countermovement jump, so a smaller difference may have occurred. It’s also quite possible that the dose was too low, and since the researchers didn’t measure plasma levels of NO3- and NO2-, dosing issues can’t be ruled out. Also, it’s possible that the sample size was too small to detect differences in tennis-specific secondary outcomes like serving velocity.

Acute ketone supplementation doesn’t improve exercise performance[10]
  • What was studied? Thirteen randomized controlled trials involving 148 mostly male participants looking at acute ketone supplementation’s effect on various aspects of exercise performance.

  • Why study it? Ketone supplementation could spare glucose as an efficient source of fuel during exercise, but trials examining its acute effects on measures of performance have been mixed.

  • What was(n’t) found? No statistically significant effect on exercise performance was found for ketones supplemented acutely in ester or salt form for exercise ranging from sprints to bouts lasting up to 50 minutes.

  • How null was it? Given the relatively small number of participants, this study couldn’t rule out possible very small effects which may matter to highly competitive athletes. That being said, the evidence to date isn’t consistent with larger benefits. Also, this meta-analysis only looked at ketones supplemented right before performance bouts lasting up to 50 minutes, so it can’t speak to the effects of chronic supplementation or for exercise bouts lasting longer than 50 minutes.

  • Anything else? The authors note that while their research doesn’t speak to chronic ketone supplementation, there’s reason to suspect that longer-term supplementation could have safety issues, and that more research is needed to explore this possibility.

Pain, joints, & bones

Vitamin D supplementation didn’t clearly improve bone density in a subset of VITAL participants[11]
  • What was studied? A subset of 771 men over 50 or women over 55 in the VITamin D and OmegA-3 TriaL (VITAL) who weren’t taking bone-modifying medications were studied to see if 2,000 IU (50 mcg) daily of vitamin D3 over two years affected bone density.

  • Why study it? Vitamin D, especially when coupled with calcium, has been a mainstay of maintaining bone density with age. However, recent trial data have been inconsistent.

  • What was(n’t) found? Supplementation had no effect on spine, femoral neck, or whole-body bone density, nor did it affect other measures of bone structure. However, in people with free vitamin D levels below the median, supplementation led to a slight increase in spine bone density and slowed hip bone density loss, too.

  • How null was it? This was a substudy of the main VITAL study, so it should be interpreted cautiously. Also, the population was not selected for vitamin D deficiency but found mild evidence that lower baseline free vitamin D may be associated with stronger supplementation effects, which warrants further study.

Women's health

A Lactobacillus-based probiotic did not prevent bacterial vaginosis in pregnant women[12]
  • What was studied? The effects of a probiotic containing 2.5 ⨉ 109 colony-forming units each of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on the rate of bacterial vaginosis in pregnant women who started taking the probiotic sometime between 9 and 14 weeks gestation.

  • Why study it? Bacterial vaginosis during pregnancy is associated with poorer pregnancy outcomes like preterm birth, and there’s evidence that Lactobacillus-based probiotics can reduce the rate of bacterial vaginosis.

  • What was(n’t) found? There was no effect found on the rates of bacterial vaginosis compared to placebo. Vaginal bacterial diversity and colonization was also not affected.

  • How null was it? This trial is weak evidence against this specific probiotics’ efficacy for two reasons: the rate of bacterial vaginosis was lower than the researchers anticipated when powering the study, and they weren’t able to recruit as many women as they aimed for. These two facts combined suggest that the study may have been underpowered to detect a difference if one exists.

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See other articles with similar topics: Vitamin D, Asthma, Children, Cancer, Caffeine, Diabetes, Insulin Sensitivity, Eggs, Blood Pressure, Probiotics, Diarrhea, Walnuts, Omega 3, Cognitive Decline, Polyphenols, Sarcopenia, Protein, Supplementation, Grape Seed, Beetroot, Exercise Performance, Ketone, Bone Health, Bacterial Vaginosis, Nulls.

See other articles in Issue #67 (May 2020) of Study Deep Dives.

Other Articles in Issue #67 (May 2020)

References

  1. ^ Litonjua AA, et al. Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction. N Engl J Med. (2020)
  2. ^ Song M, et al. No Association Between Vitamin D Supplementation and Risk of Colorectal Adenomas or Serrated Polyps in a Randomized Trial. Clin Gastroenterol Hepatol. (2020)
  3. ^ Alperet DJ, et al. The effect of coffee consumption on insulin sensitivity and other biological risk factors for type 2 diabetes: a randomized placebo-controlled trial. Am J Clin Nutr. (2020)
  4. ^ Kolahdouz-Mohammadi R, et al. Effect of Egg Consumption on Blood Pressure: a Systematic Review and Meta-analysis of Randomized Clinical Trials. Curr Hypertens Rep. (2020)
  5. ^ Rajkumar C, et al. Do probiotics prevent antibiotic-associated diarrhoea? Results of a multicentre randomized placebo-controlled trial. J Hosp Infect. (2020)
  6. ^ Sala-Vila A, et al. Effect of a 2-year diet intervention with walnuts on cognitive decline. The Walnuts And Healthy Aging (WAHA) study: a randomized controlled trial. Am J Clin Nutr. (2020)
  7. ^ Björkman MP, et al. Effect of Protein Supplementation on Physical Performance in Older People With Sarcopenia-A Randomized Controlled Trial. J Am Med Dir Assoc. (2020)
  8. ^ Bell L, et al. Grape seed polyphenol extract and cognitive function in healthy young adults: a randomised, placebo-controlled, parallel-groups acute-on-chronic trial. Nutr Neurosci. (2020)
  9. ^ López-Samanes Á, et al. Effects of Beetroot Juice Ingestion on Physical Performance in Highly Competitive Tennis Players. Nutrients. (2020)
  10. ^ Valenzuela PL, et al. Acute Ketone Supplementation and Exercise Performance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Sports Physiol Perform. (2020)
  11. ^ LeBoff MS, et al. Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL). J Bone Miner Res. (2020)
  12. ^ Husain S, et al. Effects of oral probiotic supplements on vaginal microbiota during pregnancy: a randomised, double-blind, placebo-controlled trial with microbiome analysis. BJOG. (2020)