NPB 132

Craig Warden

Tiffany Hu, Joanna Watterson, Theodore Mitchell, Vinay Nittur

11/22/14

Utilizing Evidence-based Evaluation System in Examining effects of Paleolithic Diets

Introduction: At its core, research is designed to investigate areas of concern and honestly
inform others. Yet several findings in literature suffer from publication bias and fundamental
inaccuracies. Investigators and academic journals alike often seek to publish positive results to
introduce profitable products or to secure personal funding (Pannucci and Wilkins 2010). Diet
research is especially vulnerable to several types of bias. While the US Food and Drug
Administration (FDA) may enforce heightened requirements for clinical studies, readers may
still be unknowingly following study results that are detrimental to their health. With the advent
of novel diets and fads, there is often a lack of long-term investigation and inadequate
information. Thus, one is in dire need of an evaluation system to determine the quality of
research.
In order to objectively analyze the effects of any diet on overall health, an informed
reader should utilize the GRADE system and Positive Predictive values (PPV) which allows
assessment of individual research articles and an evaluation of the integrity of study design and
the value of the results. This evidence based system can serve to create a trustworthy body of
knowledge with which to make healthy decisions and improve health education overall. In
addition to GRADE and PPV there are other questions to ask as one analyzes the validity of a
diet for oneself, loved one or patient/client: What is the reason for creation and promotion of the
diet to the general public or subpopulations thereof? What evidence supports a purported benefit
that it could have on the metabolism and or physiology of healthy vs. diseased person? How
likely are people to follow the diet, and is there is benefit to short or long term adherence?
(Though adherence is a weak endpoint in a study it is important in considering whether or not to
recommend a diet). Does it supply all dietary needs i.e. macronutrient and micronutrient
requirements or is there need for supplementation?
This paper will use the method laid out to analyze the Paleo Diet, including its history,
founder, and promoters. It will also review its use among the general public and those with
specific health conditions as reported in the literature. The quality of available evidence and
reliability upon it to make recommendations will be provided. Recommendations for future
research and areas of investigation will be provided as well.
History/Background of Diet;
The idea of a clean diet free of modern processing is appealing to lots of people. The
introduction of the Paleo Diet to the general public came via a self-published book titled The
Stone Age Diet, by Walter Voegtlin in 1975. In 1985 there was a paper published in in the New
England Journal of Medicine by medical anthropologists/doctors and researchers Boyd Eaton
and Melvin Konner on Paleolithic nutrition. The evolutionary discordance hypothesis was first

articulated in this article "Paleolithic Nutrition: A Consideration of Its Nature and Current
Implications". After that time and increasingly after the late 1990s many others have published
books and articles promoting the diet, including medical doctor/anthropologist/researcher Staffan
Lindeberg, Health and fitness entrepreneurs like Mark Sisson blogger and fitness author;
economist turned fitness expert Arthur De Vany developed theories about nutrition and exercise
during the Paleolithic period. The paleo diet was overshadowed by other popular diets such as
the Atkins and South Beach Diet until the publication of a popular book by Loren Cordain. It is
important to note that Cordain holds a bachelors degree in health science, a masters and doctoral
degree in exercise physiology, and has studied nutrition professionally for over twenty years he
is not a Registered Dietician or Clinical Nutritionist but a supporter and researcher in the field.
He has a web site that styles him as "Dr Loren Cordain, world's leading expert on paleolithic
diets and founder of The Paleo Movement". He owns of the trademark "The Paleo Diet", and the
paleolithic diet has grown greatly in popularity since the publication of Cordain's book, and was
Googles most searched-for weight loss method in 2013.
The Paleo diet as we now came to know it was developed from historical studies by
medical doctors, and physiologists who constructed the probable diet of pre-agricultural
humans. This analysis led to estimated macronutrient intakes and found that hunter-gatherers
relied on high amounts of animal and plant foods and very little on carbohydrates (Cordain,
Miller et al. 2000; Cordain 2002). Research has continued in regards to the biological and
clinical applications of the PD (Paleo diet) by teams of medical doctors and researchers in the
field of nutrition (Kowlaski , Bujiko 2012; Klonoff, 2009; Lindberg, Cordain, Eaton 2003)
reporting promising results for the use of the PD in prevention of and reduced risk of acquiring
cardiovascular disease, diabetes, hypertension, metabolic syndrome, cancer acne and myopia.
Some purported mechanisms are by decreasing insulin resistance, decreasing gut permeability,
decreasing serum triglyceride levels and increasing satiety and thus adherence to the protocol but
quality studies supporting these claims are few.
There have been human observational studies of indigenous people living and eating in a
manner similar to the Paleolithic period in regard to macronutrient and fatty acid intake and
general health vs. people following a traditionally western diet (Kupers R, Luxwolda M, DijickBrouwer, J. et al 2010; Klonoff, D. 2009). These studies have found that there is a difference in
amounts, ratios and types of macronutrients, micronutrients and fatty acids consumed that could
lead to progression of certain disease common in western societies like cardiovascular disease
and diabetes. All of these studies though self- reported as being inconclusive as to application the
general public and recommended further study using larger numbers of participants and
adherence to a diet and lifestyle of that similar to ones Paleolithic ancestors. Some preliminary
findings from related studies report the risk of deficient intake of vitamin D and calcium and an
increased risk of exposure to toxins from high levels of fish consumed. These are areas that need
to be addressed as our Paleolithic ancestor undoubtedly spent more time in the sun and had less
exposure to mercury and heavy metals than are now in our environments. True clinical trials are

few and thus meta-analysis and systematic reviews of randomized controlled trials are scarce.
The following articles are presented as a culmination of various search engines including
PubMed, EBSCOHOST, Google Scholar, Medline, and EScholarship.
In regards to obesity the most up to date article comes a research team in Sweden through
the Department of Public Health and Clinical Medicine at Umea University supported by a grant
from The Swedish Council for Working life and Social research and various other entities related
to public health is studying the effects of glucocorticoid metabolism in postmenopausal women
(Stomby, A., Simonyte, K., Melberg, C. et al 2014). recently published a paper that was prereleased for online publication this October in the International Journal of Obesity. The study
intended to find the relationship between diet induced weight loss and chronic tissue specific
effects of glucocorticoid metabolism in post-menopausal women. The effects of tissue specific
glucocorticoid metabolism, is altered in obesity and has been shown to increase cardiovascular
risk.
The aim of this study was to find if long term changes in diet (>6months) would lead to
normalization of tissue specific glucocorticoid metabolism in overweight and obese women. The
study was a randomized cohort trial in which 49 obese women were randomized to either a
Paleolithic or Nordic nutrition recommendations for period of 24 months. The Nordic diet is
similar to the Mediterranean diet but excludes the use of olive oil as it is not common to the area.
The diet emphasizes consumption of fish and fish oils in place of the oils commonly found in the
Mediterranean diet. The PD aimed to provide 30 % energy as protein 30& as carbs and 40% as
fat, whereas the Nordic diet was geared to have 55-60% as carbs, 30 % as fat and 15% as protein.
Thus these two diets could be considered high fat vs. high carb. A dietician was included to help
ensure compliance as well as food diaries and nitrogen excretion in 24 hour urine sample, were
taken at baseline, 6 and 24 months. In addition the women were had tests to measure insulin
sensitivity, excretion of urinary glucocorticoid metabolites, administered cortisone to plasma
cortisol and transcript levels of 11HSD1 (an enzyme shown to have an active role in
glucocorticoid metabolism in obesity) in subcutaneous adipose tissue were studied.
The results show that both diets led to significant and sustained weight loss. The PD
group showed greater weight loss after 6 months (p<0.001) but at 24 months both groups were
equal. Urinary excretion measurement of 5-reductase activity showed an increase after 24
months for both groups compared to baseline (p<0.001). Subcutaneous adipose tissue expression
of 11HSD1 gene decreased at 6 and 24 months in both diets (p=0.036). This was accompanied
by an increase in liver 11HSD1, and the conversion of oral cortisone to cortisol increased at 6
months (p=0.023) but was unchanged at 24 months. The PD had no significantly greater effect
than the Nordic diet past the 24 month period.
The greater weight loss at 6 months may be appealing to some but the application of
these results to the general population of obese people throughout the world and strength of the
recommendation would be low. With a possible PPV of <0.2 due to the small size of the cohort

and lack of control group the large effect size is negligible. The endpoints though relevant to
current ideas and theories about the genetic basis of obesity and effects of cortisol on energy
metabolism are interesting and lend to the notion of further testing in true determination of
causal link between enzyme levels and obesity rather than a strong correlation. The researchers
show no apparent bias and none is seen in the support or publishing of this research save a desire
to increase knowledge as to the efficacy of treatment of obesity. Future research from this group
could extend to a larger sample size with use of non-obese people as control for enzyme level
fluctuations. Better endpoint such as all cause mortality, decreased rate of CVD (cardiovascular
disease) or TIIDM (Type II diabetes mellitus) and the two diet types. This is the only study
found utilizing a randomized trial relating directly to obesity and the PD.
A team of researchers at UCSF has been studying the PD since 2008-2009. They have
since published two papers in the European journal of clinical nutrition. One in 2009 one in
2013 ( Frasseto LA., Shi, L., Schlotter et al 2013; Frasseto, LA., Scholtter, M., Mietus-Snyder,
M. et al 2009). An initial metabolically controlled cohort study of 9 outpatient non-obese
sedentary healthy volunteers. The intervention included consumption of normal diet for 3 days, a
diet with extra potassium and fiber for 7 days then a PD for 10 days. Arterial blood pressure,
urine Na & K excretion, plasma glucose and insulin, insulin sensitivity during an oral glucose
tolerance test, plasma lipid concentrations, brachial artery activity and weight loss were
endpoints in in application to healthy users in this trial.
The team reports significant reductions in BP associated with an improvement in arterial
blood distensibility which is the ability of the artery to be dilated or relaxed. (-3.1 + or 2.9,
p=0.01 and 0.19 = or 0.23, p= 0.05), significant changes in cholesterol, ldl and triglycerides, (0.8 + or 0.6, p= 0.007), -0.7 + or 0.5 p=0.003 and 0.3 + or 0.3 p=0.01 mmol/1
respectively). In all measured variable ether 8 or the total 9 displayed identical results in
directional responses when switched to the PD vs. their standard diet or the loaded diet. Meaning
there was a consistent improved status in circulatory, carbohydrate and lipid
metabolism/physiology. They conclude that even a short term intervention with the PD can yield
significant results. The low number of participants, lack of randomization and use of only health
non obese subjects negates in large effects reported and the study receives a low PPV <0.2 and
grade of a D. Their needs to be a larger sample size and use of a control group in addition to an
extended period of time for intervention to see if effects are truly due to intervention as they may
have been due to increase in potassium during the 7 day pre intervention phase.
In 2013 the team released another study this time with a focus on net acid excretion
(NAE) in patients with TIIDM on a PD. Net acid excretion is a measure of the acid excreted in
urine at a time. The only established pathology associated with NAE is and an increase in
respiratory acidosis and a decrease in respiratory alkalosis. Though there is causal linkage to OA
which is organic acid production and an increase in body weight. NAE has been linked with OA
and is thus serving as a measure of it in this case. The results show that with patients on the PD it
is hard to determine NAE with increase intake of fruit and vegetables due to the increase in

protein. While there is a reduction in comparison to the ADA diet for diabetes the full extent to
which it decreases the NAE is offset due to the increase in protein intatke which in and of itself
is liable to increase OA organic acid production, Due to the indirect endpoint being studied, the
low number of participants and short intervention time make this a weak study in support of diet
recommendation. The research group should get a larger sample size and use a control or two
such as non b=diabetic and uncontrolled diabetic. Though the ethics of using such a diet on an a
patient with uncontrolled diabetes, may prevent that trial from gaining IRB approval.
Other groups have studied the PD and its effects on TIIDM but they have all had small
sample sizes and with slightly longer (3 month) interventions but moderate endpoints like the
study of TIIDM and cardio-metabolic risk factors like C-reactive protein levels, blood pressure,
insulin sensitivity, HbA1c, and OGTT (oral glucose tolerance test) and others such as weak
endpoints such as subjective satiety; or strong results with non-human animals such as pigs.
(Jonson et al 2013; Jonson et al.2009, Jonson et al 2006). These studies too need have larger
sample sizes and controls.
Article
Title
Author
Journal
Study Type
# of Participants
Gender
Ethnicity
Endpoints
PPV
Grade
Risk of Bias
publication bias
# of citations
# of references
Authors Affiliations
Conflicts of intrests
Exclusion criteria
length of
intervention

1
Diet Induced Weight loss has chronic tissue specific.
Stomby, A et al
International journal of obesity
Randomized Cohort trial
49
F
european- Swede
Glucocorticoid metabolism, insulin sensitivity, enzyme activity, weight loss
>0.2
D
low
low
0 just published
38
Umea University, Sweden; University of Edinburgh, Scotland
none apparent a preference of the nordic diet maybe
history of diabetes, current glucocorticoid treatment, those already on strict diet
24 months

Work Cited
Cordain, L., et al. (2000). "Plant-animal subsistence ratios and macronutrient energy estimations
in worldwide hunter-gatherer diets." Am J Clin Nutr 71(3): 682-692.
Cordain, L (2002). The nutritional characteristics of a contemporary diet based upon Paleolithic
food groups. JANA (Journal of American Nutrition Association) 5(3) 15-24
Eaton, S.B., Konner, M (1985) Paleolithic nutrition: a consideration of its nature and
implications. New England Journal of Medicine 312(5) 283-289
Frassetto, LA., Shi, L., Schlotter, M., et al (2013) Established dietary estimates of net acid
excretion do not predict measured net acid excretion in type 2 diabetes on Paleolithic
hunter gatherer type diets. European Journal of Clinical Nutrtion 67 899-903
Frasseto LA, Schlotter, M., Mietus-Snyder, M., et al (2009) Metabolic and Physiologic
improvements form consuming a Paleolithic hunter gatherer type diet. European Journal
of Clinical Nutrition 63 947-955
Jonson, T., Granfeldt Y., Lindberg, S., Halberg, A.C. (2013) Subjective Satiety and other
experiences of a Paleolithic diet compared to diabetes diet in patients with type 2
diabetes Nutrition Journal 12(105) 1-7
Jonson, T., Granfeldt Y., Ahren, B., et al (2009) Beneficial effects of a Paleolithic diet on cardio
metabolic risk factors in type 2 diabetes: a randomized controlled cross over pilot study.
Cardiovascular Diabetology 8(35) 1-7
Jonson, T., Ahren, B., Pacini, G., et al (2006) A paloelithic diet confers higher insulin
sensitivity, lower C-reactive protein and lower blood pressure than a cereal based diet in
domestic pigs Nutrition & Metabolism 3(39) 1-10
Klonoff, D.C. (2009) The beneficial effects of a paleolithic diet on type 2 diabetes and other
risk factors for cardiovascular disease. Journal of Diabetes Science and Technology 3(6)
1229-1232
Kowlaski, L.M, Bujiko, J. (2012) Evaluation of biological and clinical potential of Paleolithic
diet. Roc Panstw Zakl Hig 63(1) 9-15
Kueipers, R.S., Luxwolda M.F., Dijck-Brouwer, J. et al (2010) Estimated macronutrient intake
and fatty acid intakes from an East African Paleolithic diet. British Journal of Nutrition
104 1666-1687
Miller, J.B., Mann, N., Cordain, L., (2009) Paleolithic nutrition what did our ancestors eat?
Genes to Galaxies 1(1) 28-42

Pannucci, C. J. and E. G. Wilkins (2010). "Identifying and avoiding bias in research." Plast
Reconstr Surg 126(2): 619-625.
Stomby, A., Simonyte, K., Melborne, C., et al (2014) Diet induced weight loss has chronic
tissue specific effects on glucocorticoid metabolism in overweight postmenopausal
women International Journal of Obesity accepted article preview 28, October 2014; doi:
10.1038/ijo.2014.188