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

Warning: this transportation service volition live on 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 yesteryear Ludwig, Gary Taubes, together with others to back upwards the carbohydrate-insulin hypothesis of obesity, although in that place is no testify that the upshot was mediated yesteryear insulin, together with also no testify that it was mediated yesteryear reduced saccharide rather than increased poly peptide (3).

Since I published that post, my confidence inwards the finding-- together with specially the mutual interpretation of it that reducing saccharide intake to a real depression score increases REE together with TEE-- has gradually been eroding.  This is partially because other studies remove hold to a greater extent than ofttimes than non reported that the carbohydrate:fat ratio of the diet has footling or no upshot 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 inwards PubMed Commons (11).  Ludwig together with colleagues remove hold since responded (12).  Here's my perspective on the exchange, organized yesteryear topic:

Inconsistency betwixt reported release energy expenditure together with 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 inwards 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 simply over a kilogram of weight loss-- but it didn't-- the VLC diet grouping truly gained a modest amount of weight (0.5 kg).  This internal inconsistency inwards the information may propose that 1 or to a greater extent than of their measures is incorrect, either trunk weight (unlikely), release energy intake (likely, equally explained below), and/or release energy expenditure (possible, equally explained below).

Ludwig responded that trunk weight is an unreliable stair out of release energy ease over brusk periods of time-- inwards other words, in that place could remove hold been differential changes inwards trunk composition betwixt groups that masked a trunk weight loss effect.  I attain concur that modest changes inwards trunk weight over brusk periods of fourth dimension aren't a real corporation stair out of release energy balance, but what Ludwig is proposing hither is basically that the VLC grouping was gaining H2O weight and/or thin majority 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, together with are unlikely to pack on 1.5+ kg of thin majority inwards a calendar month (particularly inwards the aspect upwards of a diet that does non come across release energy needs), Ludwig's explanation is difficult to believe.

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

Incomplete diet adherence

When I start wrote almost this study, I don't retrieve I fully appreciated the likelihood that the volunteers would "cheat" together with eat exterior food.  Ludwig's squad provided them amongst all study foods, but since it wasn't a metabolic ward study, volunteers had the might 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 trunk weight throughout the study.  This agency they were hungry together with highly motivated to eat additional nutrient at home.

And they in all likelihood 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 inwards his comment, maxim "it is probable that to a greater extent than or less non-study foods were consumed".  He downplays it, but we're talking almost 200-500+ kcal/day here, which is non insignificant.

I sympathise that this form of study is challenging to do, together with the pattern is for sure a lot to a greater extent than rigorous than the type of diet study where you lot simply transportation people habitation amongst diet advice together with permit them gear upwards their ain food.  This type of study pattern industrial plant good inwards a lot of contexts, but maybe it isn't the best suited for situations where your volunteers are weight-reduced together with remove hold a potent incentive to eat additional food.

Statistical weaknesses

The study declared REE equally the primary outcome, together with it institute that the VLC diet had a significantly higher REE than the LF diet.  The departure was only 67 kcal/day, but this finding is robust because it was declared inwards advance equally the primary outcome.  I retrieve nosotros tin live on fairly confident that, nether the weather tested, the VLC diet led to an increment inwards REE vs. the LF diet.  However, the increment is modest plenty that it has footling clinical or practical significance.

But the large splash made yesteryear this study wasn't the 67 kcal/day increment inwards REE-- it was the 300 kcal/day increment inwards TEE!  Although this finding got all the press, it rests on much less corporation ground, equally pointed out yesteryear Hall.  The argue is that it's 1 of many secondary outcomes (66 possible statistical tests performed on 22 measured variables, to live on exact), together with when you lot remove hold together with therefore many possible outcomes, you lot halt upwards amongst a high likelihood of a simulated positive finding unless you lot run specific statistical tools to right the problem.  This is called the multiple comparisons problem together with it's real mutual inwards science.  In fact, it's 1 of the leading causes of unreliable findings inwards the scientific literature.

As I said, the multiple comparisons work tin live on avoided yesteryear using the right statistical tools (essentially, raising the bar for statistical significance inwards proportion to the issue of statistical tests you lot perform), but inwards Ludwig's study, these tools were non sufficiently applied to hand us confidence inwards the secondary outcomes.  And that's non truly equally bad equally it sounds, but it does remove an additional layer of interpretation.  Basically, if you lot don't adequately right for multiple comparisons, your finding is "exploratory"-- important it's non a statistically robust finding, but it is suggestive together with tin live on used to guide farther research.  Researchers attain this all the time, together with inwards my sentiment it's acceptable equally long equally it's clearly labeled equally exploratory.  But it also agency that you lot can't (or shouldn't) proclaim to Earth that a diet increases TEE yesteryear hundreds of kilocalories per day, because that final result is non statistically robust.

So to summarize, we're left amongst a modest REE upshot that is statistically robust, together with a large TEE upshot that is statistically questionable.  And equally nosotros volition see, the REE upshot is probable explained yesteryear the higher poly peptide content of the VLC diet.

The confounding upshot of protein

The VLC diet was 30% poly peptide yesteryear calories, spell the other 2 diets were 20% protein.  Since high-protein diets are known to increment release energy expenditure, this may render a plausible explanation for the observed increment inwards 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 departure of this magnitude can’t explicate differences inwards REE inwards the fasting state, long later the thermic effects of nutrient remove hold dissipated".  But inwards fact, other RCTs demonstrate that it can explicate the increment inwards REE.

In 2013, the enquiry grouping of Margriet Westerterp-Plantenga at Maastricht University-- 1 of the leading researchers inwards this area-- published a study that examined the effects of high-protein vs. normal-protein diets on REE later weight loss (13).  It's worth noting that poly peptide was increased at the expense of fat, non carbohydrate.

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

Summary

The 2012 study yesteryear David Ludwig's grouping reported that inwards subjects maintaining weight loss, a high-protein, very-low-carbohydrate diet increased resting release energy expenditure yesteryear a modest amount (67 kcal/day), together with total release energy expenditure yesteryear a large amount ( 300 kcal/day), relative to a normal-protein, low-fat diet.  Superficially, this seems to back upwards the thought of a substantial "metabolic advantage" for very-low-carbohydrate diets.  However, in that place are reasons to live on skeptical of to a greater extent than or less of the findings, which Kevin Hall position out inwards a comment on NIH Commons.  Here's a summary of my electrical flow views:

• There was in all likelihood important dietary non-compliance, amongst volunteers eating extra nutrient at habitation inwards add-on to what they were supplied yesteryear the lab.  This in all likelihood 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 together with expenditure figures.
• The finding that resting release energy expenditure was elevated on the VLC diet is statistically robust.  However, the increment is modest plenty that it has footling clinical or practical significance.
• The increment inwards resting release energy expenditure tin live on explained yesteryear the higher poly peptide content of the VLC diet, together with it in all likelihood had footling to attain amongst the fact that the VLC diet was depression inwards carbohydrate.
• The finding that total release energy expenditure was elevated yesteryear 300 kcal/day on the VLC diet is non statistically robust, together with it's also difficult to reconcile amongst the results of other studies.  

For me, here's the bottom line.  Aspects of the study withal stand upwards equally reliable, but the findings attain non back upwards the determination 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 modest metabolic advantage, but that calorie intake is withal the fundamental determinant of fatty majority changes.