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A Serious Challenge To The 2012 Low-Carbohydrate Metabolic Wages Study

Warning: this postal service volition last a flake to a greater extent than wonkish than usual, because I demand to larn detailed to brand my points.  To read a summary, skip to the end.

In 2012, David Ludwig's grouping published an interesting RCT that suggested a substantial "metabolic advantage" resulting from a high-protein, very-low-carbohydrate diet (VLC) (2).

This finding has been used past times Ludwig, Gary Taubes, as well as others to back upward the carbohydrate-insulin hypothesis of obesity, although in that place is no bear witness that the lawsuit was mediated past times insulin, as well as also no bear witness that it was mediated past times reduced saccharide rather than increased poly peptide (3).

Since I published that post, my confidence inward the finding-- as well as specially the mutual interpretation of it that reducing saccharide intake to a really depression score increases REE as well as TEE-- has gradually been eroding.  This is partially because other studies remove hold mostly reported that the carbohydrate:fat ratio of the diet has fiddling or no lawsuit on REE, TEE, or fatty storage (4, 5, 6, 7, 8, 9, 10).

My confidence score dropped fifty-fifty to a greater extent than this week, when I saw a critical comment Kevin Hall added to the study inward PubMed Commons (11).  Ludwig as well as colleagues remove hold since responded (12).  Here's my perspective on the exchange, organized past times topic:

Inconsistency betwixt reported release energy expenditure as well as weight change

Hall pointed out that measured TEE was 200-500 kcal/day higher than reported release energy intake for all diets, amongst the largest gap inward the VLC diet.  In other words, 200-500 to a greater extent than kilocalories were going out than were going in.  Over a four-week period, if the information are correct, the VLC diet should remove hold caused only over a kilogram of weight loss-- but it didn't-- the VLC diet grouping genuinely gained a pocket-sized amount of weight (0.5 kg).  This internal inconsistency inward the information may propose that ane or to a greater extent than of their measures is incorrect, either torso weight (unlikely), release energy intake (likely, equally explained below), and/or release energy expenditure (possible, equally explained below).

Ludwig responded that torso weight is an unreliable mensurate of release energy residual over brusk periods of time-- inward other words, in that place could remove hold been differential changes inward torso composition betwixt groups that masked a torso weight loss effect.  I arrive at concord that pocket-sized changes inward torso weight over brusk periods of fourth dimension aren't a really enterprise mensurate of release energy balance, but what Ludwig is proposing hither is basically that the VLC grouping was gaining H2O weight and/or thin volume to offset fatty loss that was simultaneously occurring.  This hypothesized water/lean mas gain would remove hold to offset to a greater extent than than 1.5 kg of weight alter (just over 1 kg predicted from TEE, + 0.5 kg weight gain on VLC diet).  Since nosotros know that VLC diets tend to reduce H2O weight, as well as are unlikely to pack on 1.5+ kg of thin volume inward a calendar month (particularly inward the confront of a diet that does non run into release energy needs), Ludwig's explanation is difficult to believe.

This brings us to what is in all probability the existent argue for the lack of alter inward weight.

Incomplete diet adherence

When I starting fourth dimension wrote well-nigh this study, I don't shout out upward I fully appreciated the likelihood that the volunteers would "cheat" as well as eat exterior food.  Ludwig's squad provided them amongst all study foods, but since it wasn't a metabolic ward study, volunteers had the mightiness to eat additional nutrient at home.  I'll add together that these people had a potent incentive to eat more, because they were maintaining a 10-15% reduced torso weight throughout the study.  This agency they were hungry as well as highly motivated to eat additional nutrient at home.

And they in all probability did.  This may explicate the fact that the volunteers gained a flake of weight on all diets, despite the fact that their supposed release energy intake was hundreds of kilocalories lower than their release energy expenditure!  Ludwig acknowledges this inward his comment, maxim "it is probable that roughly non-study foods were consumed".  He downplays it, but we're talking well-nigh 200-500+ kcal/day here, which is non insignificant.

I sympathise that this sort of study is challenging to do, as well as the blueprint is sure as shooting a lot to a greater extent than rigorous than the type of diet study where yous only transportation people abode amongst diet advice as well as allow them seat upward their ain food.  This type of study blueprint industrial plant good inward a lot of contexts, but perchance it isn't the best suited for situations where your volunteers are weight-reduced as well as remove hold a potent incentive to eat additional food.

Statistical weaknesses

The study declared REE equally the primary outcome, as well as it institute that the VLC diet had a significantly higher REE than the LF diet.  The deviation was only 67 kcal/day, but this finding is robust because it was declared inward advance equally the primary outcome.  I shout out upward nosotros tin last fairly confident that, nether the weather condition tested, the VLC diet led to an increment inward REE vs. the LF diet.  However, the increment is pocket-sized plenty that it has fiddling clinical or practical significance.

But the large splash made past times this study wasn't the 67 kcal/day increment inward REE-- it was the 300 kcal/day increment inward TEE!  Although this finding got all the press, it rests on much less enterprise ground, equally pointed out past times Hall.  The argue is that it's ane of many secondary outcomes (66 possible statistical tests performed on 22 measured variables, to last exact), as well as when yous remove hold as well as then many possible outcomes, yous destination upward amongst a high likelihood of a fake positive finding unless yous role specific statistical tools to right the problem.  This is called the multiple comparisons problem as well as it's really mutual inward science.  In fact, it's ane of the leading causes of unreliable findings inward the scientific literature.

As I said, the multiple comparisons work tin last avoided past times using the right statistical tools (essentially, raising the bar for statistical significance inward proportion to the issue of statistical tests yous perform), but inward Ludwig's study, these tools were non sufficiently applied to laissez passer on us confidence inward the secondary outcomes.  And that's non genuinely equally bad equally it sounds, but it does involve an additional layer of interpretation.  Basically, if yous don't adequately right for multiple comparisons, your finding is "exploratory"-- pregnant it's non a statistically robust finding, but it is suggestive as well as tin last used to guide farther research.  Researchers arrive at this all the time, as well as inward my thought it's acceptable equally long equally it's clearly labeled equally exploratory.  But it also agency that yous can't (or shouldn't) proclaim to Earth that a diet increases TEE past times hundreds of kilocalories per day, because that final result is non statistically robust.

So to summarize, we're left amongst a pocket-sized REE lawsuit that is statistically robust, as well as a large TEE lawsuit that is statistically questionable.  And equally nosotros volition see, the REE lawsuit is probable explained past times the higher poly peptide content of the VLC diet.

The confounding lawsuit of protein

The VLC diet was 30% poly peptide past times calories, spell the other 2 diets were 20% protein.  Since high-protein diets are known to increment release energy expenditure, this may supply a plausible explanation for the observed increment inward REE on the VLC diet.

In Ludwig's reply to Hall's critique, Ludwig states that the higher poly peptide content of the VLC diet can't explicate the higher REE: "A poly peptide deviation of this magnitude can’t explicate differences inward REE inward the fasting state, long subsequently the thermic effects of nutrient remove hold dissipated".  But inward fact, other RCTs demonstrate that it can explicate the increment inward REE.

In 2013, the enquiry grouping of Margriet Westerterp-Plantenga at Maastricht University-- ane of the leading researchers inward this area-- published a study that examined the effects of high-protein vs. normal-protein diets on REE subsequently weight loss (13).  It's worth noting that poly peptide was increased at the expense of fat, non carbohydrate.

Following a weight loss of well-nigh vii kg inward both groups, the normal-protein grouping experienced a reduction of REE, but the high-protein grouping didn't.  The between-group deviation inward REE during weight maintenance?  81 kcal/day.  This is very similar to the 67 kcal/day that Ludwig reported, except that it was produced past times increasing poly peptide alone, non a combination of high poly peptide as well as really depression saccharide equally inward Ludwig's study.  In my view, high poly peptide intake in all probability explains the elevated REE inward the VLC diet group.


The 2012 study past times David Ludwig's grouping reported that inward subjects maintaining weight loss, a high-protein, very-low-carbohydrate diet increased resting release energy expenditure past times a pocket-sized amount (67 kcal/day), as well as total release energy expenditure past times a large amount ( 300 kcal/day), relative to a normal-protein, low-fat diet.  Superficially, this seems to back upward the thought of a substantial "metabolic advantage" for very-low-carbohydrate diets.  However, in that place are reasons to last skeptical of roughly of the findings, which Kevin Hall seat out inward a comment on NIH Commons.  Here's a summary of my electrical flow views:

  • There was in all probability important dietary non-compliance, amongst volunteers eating extra nutrient at abode inward add-on to what they were supplied past times the lab.  This in all probability explains at to the lowest degree business office of why they didn't lose weight, despite the fact that they should remove hold lost weight according to the reported release energy intake as well as expenditure figures.
  • The finding that resting release energy expenditure was elevated on the VLC diet is statistically robust.  However, the increment is pocket-sized plenty that it has fiddling clinical or practical significance.
  • The increment inward resting release energy expenditure tin last explained past times the higher poly peptide content of the VLC diet, as well as it in all probability had fiddling to arrive at amongst the fact that the VLC diet was depression inward carbohydrate.
  • The finding that total release energy expenditure was elevated past times 300 kcal/day on the VLC diet is non statistically robust, as well as it's also difficult to reconcile amongst the results of other studies.  
For me, here's the bottom line.  Aspects of the study nonetheless stand upward equally reliable, but the findings arrive at non back upward the decision that reducing saccharide intake yields a metabolic advantage.  My best interpretation is that the study is consistent amongst other findings suggesting that high-protein diets yield a pocket-sized metabolic advantage, but that calorie intake is nonetheless the fundamental determinant of fatty volume changes.



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