The RCT That Will Never Happen

Here’s the Randomized Control Trial that I really want to see.

Take a lot of Type 2 Diabetics with BMIs in the obese range. Split them into two groups who are pair matched. Start one of the groups on Low Carb / High Fat diet and leave the control group on their customary Standard American Diet (SAD). Treat all of them with the standard of care as it is at the time. Track them for 40 years and look at the outcomes. Don’t just track some of the benchmarks like LDL cholesterol. Track all of their results including all-cause mortality. 

It won’t happen for too many reasons. And it doesn’t take a belief in conspiracy theories to figure out why. Perhaps the biggest reason is nobody makes money with Low Carb/High Fat and a study with sufficient statistical power would be very expensive.

In the meanwhile, we are all n=1. And none of us have 40 years. And no point in looking for the RCT above since it’s never going to happen. It would have had to start before anyone knew the right questions to ask.

Mice on an Ad Lib Keto Diet

Here is a nice paper from 2009 on mice fed an ad libitum ketogenic diet (Kennedy AR, Pissios P, Otu H, Roberson R, Xue B, Asakura K, Furukawa N, Marino FE, Liu FF, Kahn BB, Libermann TA, Maratos-Flier E. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1724-39. Epub 2007 Feb 13).

The study looked at:

C57BL/6 mice animals were fed one of four diets:

1) KD;

2) a commonly used obesogenic high-fat, high-sucrose diet (HF);

3) 66% caloric restriction (CR); and

4) control chow (C).

Calories were the same but weight was lower on the ketogenic diet.

Mice on KD ate the same calories as mice on C and HF, but weight dropped and stabilized at 85% initial weight, similar to CR.

In fact, they moved mice from the High Fat High Carb diet to the Ketogenic diet and had the following:

Animals made obese on HF and transitioned to KD lost all excess body weight, improved glucose tolerance, and increased energy expenditure. 

Even more along my own area of interest:

KD fed mice had a unique metabolic and physiological profile, exhibiting increased energy expenditure and very low respiratory quotient

The macronutrient composition of the diets was interesting:


Note this was not a high protein KD. I.e., The dietary advantage wasn’t protein. The percentage of calories from protein was the lowest on the KD – by far. This is a much higher level of fat than most people will tolerate and the protein level is pretty low.

Most telling was the body composition changes (Table 5).


The Chow fed mice were a bit over 10% heavier but at a lower % of Body Fat (13.5%) vs the Ketogenic fed mice. This can be attributed to the much lower protein consumption of the KD.

A contrasting study (Protein Leverage Hypothesis Counterpoint) showed an inflection point around 70% for fat where additional fat did not result in additional weight. In my opinion (study needed) – substituting protein for some of the fat should not be an issue.

The study concluded:

the effects that diet composition can have on metabolism and found that diets high in fat and low in carbohydrate do in fact lead to weight loss by increasing energy expenditure. 

Remarkably, animals eating ketogenic diet lost a small amount of weight and achieved the same weight and body composition as animals that were calorie restricted to 66% of usual daily intake.

In a related paper (Bielohuby M1, Menhofer D, Kirchner H, Stoehr BJ, Müller TD, Stock P, Hempel M, Stemmer K, Pfluger PT, Kienzle E, Christ B, Tschöp MH, Bidlingmaier M. Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein. Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E65-76) noted the same issue with KD :

One problem with ketogenic LC-HF diets is that it is difficult to attribute observed effects (e.g., loss of body weight) to either the presence of ketone bodies or to the normally very low protein content of these diets.

The ideal ketogenic diet for research purposes would be a LC-HF diet that is ketogenic but ensures the sufficient supply of protein at the same time. However, until now, it is not clear whether the absence of dietary carbohydrates per se or the absence of carbohydrates in combination with a specific abundance of the two other macronutrients, fat and protein, is required to induce ketosis.

Alcohol and Weight Loss

I get asked a lot about alcohol and weight loss. Here’s a study which took a look at what happens to fat oxidation when alcohol is consumed (Siler SQ, Neese RA, Hellerstein MK. De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am J Clin Nutr. 1999 Nov;70(5):928-36).


We used stable-isotope mass spectrometric methods with indirect calorimetry to establish the metabolic basis of changes in whole-body lipid balances in healthy men after consumption of 24 g alcohol.


Eight healthy subjects were studied and DNL (by mass-isotopomer distribution analysis), lipolysis (by dilution of [1,2,3,4-(13)C(4)]palmitate and [(2)H(5)]glycerol), conversion of alcohol to plasma acetate (by incorporation from [1-(13)C(1)]ethanol), and plasma acetate flux (by dilution of [1-(13)C(1)]acetate) were measured.


The fractional contribution from DNL to VLDL-triacylglycerol palmitate rose after alcohol consumption from 2 +/- 1% to 30 +/- 8%; nevertheless, the absolute rate of DNL (0.8 g/6 h) represented <5% of the ingested alcohol dose; 77 +/- 13% of the alcohol cleared from plasma was converted directly to acetate entering plasma. Acetate flux increased 2.5-fold after alcohol consumption. Adipose release of nonesterified fatty acids into plasma decreased by 53% and whole-body lipid oxidation decreased by 73%.


We conclude that the consumption of 24 g alcohol activates the hepatic DNL pathway modestly, but acetate produced in the liver and released into plasma inhibits lipolysis, alters tissue fuel selection, and represents the major quantitative fate of ingested ethanol.

It’s not so much that the alcohol itself gets turned to fat, it’s that alcohol inhibit lipolysis (fat burning).

Glycogen Shifts

Working on a theory of glycogen and caloric surplus/matching/deficit. My theory is that glycogen stores are somewhat related to carbohydrate consumption (how full the tank gets) but also to caloric status. My theory is that eating at a surplus of calories even on low carb will fill the glycogen stores higher than the “normal” keto level.

This explains to me the wide fluctuations in weight that I and others see when we gain or lose 5-7 lbs in a few days. In fact, I think it’s pretty easy to gain in a day or two and might take some days to lose again what was gained in that day or two. The reason is that glycogen stores can get filled quickly but unless you are at a caloric deficit they won’t get drawn down.

Explains the “LBM gains” people have when they increase their caloric intake. Normal body water amount vary greatly along with the glycogen.

See (Keto Flush – How Body Water and Glycogen Affect Ketogenic Weight Loss).

The Right Goal

Weight loss alone should never be your goal. Fat loss should be your goal. This can be demonstrated from the numbers. If you have 25% body fat then the weight you want to lose should come out of that 25% of body fat and not from the 75% of lean body mass. If you lose weight and most of the weight comes from your lean body mass you have not done yourself any favors.

Maximum Fat Loss

The fastest way to lose fat is to greatly reduce your carbohydrates and fat intake. Protein should never be reduced. For most people protein should be increased.

Macros for Fat Loss

There is a pretty simple set of macros for maximum body fat loss.

  • Protein at 1 gram per lb of goal weight. 
  • Carbs at less than 30 grams net. 
  • Fat at less than half the grams of protein. 

Macros Calculator

I made a calculator for maximum fat loss. The calculator estimates your current body fat and asks you to say what percentage body fat you want to reach.


The recommended daily protein minimums are pretty low. I suggest much more. If you have normal kidney function that is no problem.

You need enough protein in your diet to replace the protein your body will eat up during the diet. You also need some for gluconeogenesis. Since you will be eating at a caloric deficit any extra protein won’t be a problem – it won’t turn into chocolate cake.

Protein has essential nutrients. Eating 3 grams of Leucine (found in about 30g of protein) is a good goal to hit with every protein meal. That’s around 5 ozs of skinless chicken breast.


Eat the carbs as green leafy veggies. Broccoli is a great choice for micronutrients. You don’t like the taste? Get over it. It’s good for you. And you will eventually grow to like the taste.


If you want to lose fat faster, eat less fat. If you are losing too quickly, eat more fat. The fat you eat doesn’t come off your body. The fat you don’t eat in your diet comes off your body. Any fat you eat is stored on your body very efficiently. Fat has few essential nutrients.

Even a low fat diet is still relatively high fat. The fat is just coming off your body. You can’t stay on a low fat diet forever. You have to increase your fat over time as you reach your goals.

It’s a good idea to take a couple of fish oil capsules every day to get more of the good fats.

Studies on this Diet

This is also known as a variant on the Protein Sparing Modified Fast. It is well studied and effective. The PSMF is often done at very low (20g) of fat.

Calories-In and Calories-Out

Does Calories-In and Calories-Out work on Keto? In the last 162 days I have averaged 2391 calories a day. My weight is the same at the end of these 162 days. My total energy expenditure (TDEE) is calculated at 2232 calories a day. This is only 159 calories a day from my TDEE or 7% off the calculated amount and that’s less than half the assumed measurement error in the food (typically assumed to be 15%).

So, yes, I conclude that Calories-In and Calories-Out do fairly closely match. At least in my particular case and macros.

So Why Keto?

Where Keto comes in is that I have maintained a 120 lb loss for the past 5+ months without hunger. My hormones are in balance. My insulin level is kept low. I don’t have the blood sugar roller coaster ride.

Here’s a good podcast covering this subject (Sigma Nutrition Radio #85: What Drives Fat Gain? – Thoughts on CICO, Insulin & Obesity).

Low Carb vs Reduced Calorie

An interesting study that took a look at an ad libitum Low Carb diet compared to a Low Calorie diet (Foster, Gary D. A Randomized Trial of a Low-Carbohydrate Diet for Obesity. New England Journal of Medicine, 2003, VI 348, pp 2082-2090). The groups were:

We conducted a one-year, multicenter, randomized, controlled trial to evaluate the effect of the low-carbohydrate, high-protein, high-fat Atkins diet on weight loss and risk factors for coronary heart disease in obese persons. The subjects were randomly assigned to follow either a low-carbohydrate, high-protein, high-fat Atkins diet or a high-carbohydrate, low-fat, energy-deficit conventional diet.

The Low Calorie group was pretty restrictive:

1200 to 1500 kcal per day for women and 1500 to 1800 kcal per day for men, with approximately 60 percent of calories from carbohydrate, 25 percent from fat, and 15 percent from protein

You’d think that with the Low Carb group able to eat what they want that the calorie restricted group would beat them hands down. The results were:

Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months (mean [±SD], –6.8±5.0 vs. –2.7±3.7 percent of body weight; P=0.001) and 6 months (–7.0±6.5 vs. –3.2±5.6 percent of body weight, P=0.02), but the difference at 12 months was not significant (–4.4±6.7 vs. –2.5±6.3 percent of body weight, P=0.26). After three months, no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations. The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study. Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load.

Satiety Index

There’s a study that was done of food satiety (Holt SH, Miller JC, Petocz P, Farmakalidis E. A satiety index of common foods. Eur J Clin Nutr. 1995 Sep;49(9):675-90) (PDF).

Isoenergetic 1000 kJ (240 kcal) servings of 38 foods separated into six food categories (fruits, bakery products, snack foods, carbohydrate-rich foods, protein-rich foods, breakfast cereals) were fed to groups of 11-13 subjects. Satiety ratings were obtained every 15 min over 120 min after which subjects were free to eat ad libitum from a standard range of foods and drinks.

A satiety index (SI) score was calculated by dividing the area under the satiety response curve (AUC) for the test food by the group mean satiety AUC for white bread and multiplying by 100.

Thus, white bread had an SI score of 100% and the SI scores of the other foods were expressed as a percentage of white bread.

The results were:

There were significant differences in satiety both within and between the six food categories. The highest SI score was produced by boiled potatoes (323 +/- 51%) which was seven-fold higher than the lowest SI score of the croissant (47 +/- 17%).

Most foods (76%) had an SI score greater than or equal to white bread.

The amount of energy eaten immediately after 120 min correlated negatively with the mean satiety AUC responses (r = -0.37, P < 0.05, n = 43) thereby supporting the subjective satiety ratings. SI scores correlated positively with the serving weight of the foods (r = 0.66, P < 0.001, n = 38) and negatively with palatability ratings (r = -0.64, P < 0.001, n = 38).

Protein, fibre, and water contents of the test foods correlated positively with SI scores (r = 0.37, P < 0.05, n = 38; r = 0.46, P < 0.01; and r = 0.64, P < 0.001; respectively) whereas fat content was negatively associated (r = -0.43, P < 0.01).

This goes a long way to explain the Kitavan diet which is largely sweet potatoes. Can you imagine eating sweet potatoes every day as a main staple? Even though they are high carbohydrates it would be tough to over eat them.

Added: Gary Taubes takes on the palatable foods cause obesity theory (CATCHING UP ON LOST TIME – THE ANCESTRAL HEALTH SYMPOSIUM, FOOD REWARD, PALATABILITY, INSULIN SIGNALING AND CARBOHYDRATES… PART II(E, AS IN “END” AND “ENOUGH ALREADY”). Gary has some good points about the usefulness of this idea.

Carbs and Weight Gain

I looked earlier (Glycogen Stores – Why does it matter?) at this study (K J Acheson Y Schutz T Bessard K Anantharaman J P Flatt E Jéquier. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. The American Journal of Clinical Nutrition, Volume 48, Issue 2, 1 August 1988, Pages 240–247). The purpose of the study was to look at body glycogen stores. As part of the study they compared several diets. These diets were performed as a glycogen depletion/repletion strategy. The study shows the relatively short term weight loss on each diet (Low Carb High Fat, [overfed] High Carb Low Fat, and Protein Sparing Modified Fast diets).

Mean body weight decreased by 0.8 ± 1.4 kg during the 3 d on the restricted, high-fat, low-carbohydrate diet. After the 7 d of overfeeding the high-carbohydrate, low-fat diet (day 10), body weight had increased by 4.6 ± 1 .3 kg (ie, 5.6, 4.9, and 3.2 kg). During the 2 d on the restricted high-protein, low-energy diet (600 kcal/ d) 4.4 ± 0.9 kg were lost.

PSMF for the win!