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Nulls: May–June 2021

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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 May and June of 2021 that didn’t find evidence of an effect. This is known as a null effect.

Keep the following 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.

Diabetes & blood sugar

Oral capsaicin doesn’t seem to affect glycemic control, but more evidence is needed[1]

What was studied? Researchers meta-analyzed 14 controlled trials using oral capsaicin supplementation to evaluate how glucose control measures were affected. The doses ranged from 400 mcg to 135 mg daily for 1 to 13 weeks. The studies mostly involved relatively healthy participants with BMIs ranging from normal to obese. Only one study focused on people with glucose control problems, specifically gestational diabetes.

Why study it? Animal studies have found that capsaicin can lower blood sugar and increase insulin sensitivity, but human clinical studies have produced mixed results, suggesting that meta-analysis could help shed light on the topic.

What was(n’t) found? No statistically significant effect was found for fasting blood glucose, two-hour postprandial blood glucose, or insulin. Dose didn’t seem to make a difference, either.

How null was it? Not very. For one, the large majority of the trials didn’t involve people with glucose control problems, so these results may not extend to that population. Also, there was very high heterogeneity that couldn’t be explained by subgroup analysis. This raises the question of whether the pooled results make much sense. Finally, the included studies didn’t account for possible differences in the participants that could have modified capsaicin’s efficacy, especially genetic differences in its main target: TRPV1.

Healthy aging & longevity

High protein didn’t help postmenopausal women retain fat-free mass during weight loss[2]

What was studied? Researchers investigated how normal (1.5 g/kg of body weight) and high-protein (1.5 g/kg of body weight) hypocaloric diets compare in terms of helping postmenopausal women with overweight or obesity retain fat-free mass during weight loss. The 12-week diet phase of this study involved a daily caloric deficit of around 750 kcal, with two meals per day being supplied by meal replacement shakes with different whey protein levels and the third daily meal being suggested by a dietitian.

Why study it? Low muscle mass and strength can pose issues for many older women, and losing fat-free mass can be exacerbated by weight loss. Thus, finding ways to mitigate the fat-free mass loss while losing weight would be especially useful for this population.

What was(n’t) found? Both the high- and normal-protein groups lost around 5 kg of weight, with no difference in the amounts of fat-free mass lost or resting energy expenditure.

How null was it? The study was specifically powered to detect a medium-sized difference in fat-free mass loss between groups, so smaller differences cannot be ruled out. More importantly, there was a large loss to follow-up of about 46%, so these results should be taken as preliminary.

Anything else? The high-protein group did seem to have better grip strength outcomes than the normal-protein group, possibly suggesting that higher protein may be able to help with strength maintenance in this population.

Leucine-enriched protein with or without n3 PUFAs had no effect on lean mass or strength in older adults at risk for sarcopenia [3]

What was studied? This study was designed to evaluate whether 10 grams of whey protein with an additional 3 grams of leucine supplemented twice daily for 24 weeks improved lean mass or strength in people over 65 years of age with low muscle mass or strength. Some participants also received 0.8 grams of EPA and 1.1 grams of DHA in addition to the leucine-rich protein.

Why study it? Previous research has suggested that leucine-enriched protein and n3 fatty acids could both improve muscle mass or function in older adults on their own. However, the effects of combining them haven’t been studied previously.

What was(n’t) found? Leucine-enriched protein, with or without n3 fatty acids, had no clear effect on fat-free soft tissue volume of the limbs as measured by DEXA, measures of strength or physical performance, or myofibrillar protein synthesis.

How null was it? Pretty null, since this study was powered to detect small differences in its primary outcome of fat-free soft tissue volume in the arms and legs, and the secondary outcomes were pretty consistent with the lack of effect seen for the primary outcome.

Supplementing with NAD± precursors didn’t seem to affect mitochondrial or muscle function in older adults with impaired physical function [4]

What was studied? Researchers examined whether a daily mix of NAD+ precursors (210 mg of L-tryptophan, 4 mg of nicotinic acid, and 200 mg of nicotinamide for 32 days) improved mitochondrial or muscle function. The participants were over 65 years old, had BMIs between 20 and 30, and were generally healthy except that they had trouble walking as quickly on a flat surface as other people in their age group, which was taken to be a sign of pre-frailty.

Why study it? Muscle function declines with age, which seems to be driven in part by reduced mitochondrial function. This, in turn, may be driven by the bioavailability of reduced activity of the SIRT protein family, which regulates mitochondrial metabolism and is dependent on NAD+. However, NAD+ bioavailability decreases with age, raising the possibility that supplementing NAD+ precursors could improve older people’s muscle function.

What was(n’t) found? The primary outcomes of mitochondrial function and energy expenditure during submaximal exercise were not improved by NAD+ precursor supplementation.

How null was it? The study was designed to detect a 10% change in mitochondrial function, which the authors state is physiologically relevant and realistic, given that past research has found that resveratrol supplementation yielded this effect size in a similar time frame. However, the authors state that this population may not have been very physically impaired. Also, the fact that the researchers measured impairment via a walking test and energy expenditure while cycling may have confounded the results.

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See other articles with similar topics: Nulls, Diabetes, Aging.

See other articles in Issue #82 (August 2021) of Study Deep Dives.

Other Articles in Issue #82 (August 2021)