Obesity has become a health emergency in Western countries 1 2 . As is well known, obesity and in particular abdominal obesity is one of the principle risk factors for cardiovascular disease and along with dyslipidemia, hypertension and diabetes contributes to the metabolic syndrome 3 . Even though weight loss is a desired goal for most overweight individuals, and its health benefits have been clearly determined 4 5 , there are still no definitive data on what dietary protocols are most effective in both the short and long term 6 or even what is the correct nutritional approach in general 7 .

The most commonly accepted dietary strategy is based on relatively high levels of carbohydrates and low fat content but according to some studies these low fat diets yield only modest weight loss and suffer from low long-term compliance 8 . In fact adherence of overweight/obese individuals to high carbohydrate/low fat nutrition is often a problem because the majority have been shown to have dietary preferences for foods with a rich fat content. Furthermore rather than consume complex carbohydrates there is a tendency to prefer highly processed food containing simple sugars 9 10 11 such that a low fat diet can actually encourage the consumption of sugars and refined carbohydrates that can worsen weight problems and also facilitate dyslipidemia especially in insulin resistance individuals 12 13 . As a consequence of the relative inefficacy of these types of diet there has been increased interest in recent years in very low carbohydrate ketogenic diets (VLCKD) 14 that, have undoubtedly been shown to be effective, at least in the short to medium term, as a tool to tackle obesity, hyperlipidemia and some cardiovascular risk factors 15 16 17 18 . The Mediterranean diet is often proposed as the healthy standard but many of the advantages associated with it can actually be linked to life style and the true original Mediterranean diet did not contemplate the current high levels of refined carbohydrates on which the typical Italian diet is based 19 20 . For this reason the standard ketogenic diet is not associated with high compliance in populations, like the Italian, that are used to carbohydrate based diets. The objective of the present study, which was devised as a case pilot trial, is to assess the safety, compliance and effects of a "Mediterranean style" ketogenic diet that utilizes very low carbohydrate ingredients formulated to simulate the aspect and taste of common carbohydrate rich foods (e.g. pasta) and which contain phytoextracts intended to add beneficial effects of important vegetable components. The aim of using herbal extracts during the diet period was to reduce some commonly reported light side effects of ketogenic diets. The parameters measured include blood biomarkers, body composition, weight loss and compliance in a cohort of council employees in Rome, Italy.

Of the 106 persons recruited 87 completed the study (83, 6% compliance). Of the 19 subjects that withdrew 4 were for family/personal reasons, 8 subjects were lost to follow up and only 7 withdrew due to inadequate compliance to the diet protocol. Adjusted for causes of withdrawal only 7 of 104 were not able to follow the KEMEPHY diet for an adjusted compliance of 93.4%

Blood analysis did not reveal significant modification in ALT, AST, GGT and bilirubin values, nor were there significant variations in creatinine, uric acid, nitrogen and electrolytes (NA, K, Cl, Ca, Mg). There were significant changes in lipid profiles with reductions in triglycerides, total cholesterol and LDL along with a rise in HDL levels which all reached significance - see Table 4 and 5.

Anthropometric and body composition measurements revealed an average weight loss of 6.72 kg or 7.8% (pre 86.15 ± 16.38 vs post 79.43 ± 15.31; p < 0.0001). Fat mass was reduced from 41.24 ± 6.74 to 34.99 ± 6.74, a fall of 15.1% (p < 0.0001). As in previous studies no significant differences were observed in total body water expressed as percent of body weight 22 27 . Waist circumference was reduced by an average of 9.46 cm from 106.56 ± 15.38 to 97.10 ± 12.69, a fall of 8.9% (p < 0.0001). There were also significant reductions in hip and thigh circumferences of 7.41 cm (from 115 ± 11.24 to 107.78 ± 10.39; p < 0.0001) and 3.32 cm respectively (from 58.65 ± 5.43 to 55.32 ± 4.90). Anthropometric and body composition results are showed in tables 6.

Many weight loss diet procedures continue to focus on the reduction of fat content and controlled protein intake, however our results appear to demonstrate that the KEMEPHY diet, which is a modification of the VLCKD, is effective not only for weight and fat loss but also leads to improvements in the values of various biomarkers which are associated with increased risk of metabolic and cardiovascular disease. The weight loss effect of VLCKD diets may be caused by several factors:

1. Satiety effect of proteins leading to appetite reduction 28 29 30 31 32 33 34 35 36 in which also ketone bodies may have a role 37 38 , although the mechanism is not clear 39 ;

2. Reduction in lipid synthesis and increased lipolysis mechanisms 40 41 42 43 44 ;

3. Reduction in at rest respiratory quotient and therefore an increase in fat metabolism for energy use 22 45 ;

4. Increased metabolic expenditure caused by gluconeogenesis and the thermic effect of proteins 46 47 48 49 50 51

The beneficial effects on cardiovascular risk factors involve the reduction of blood triglycerides 17 18 22 and also the reduction of total and LDL cholesterol along with a rise in HDL cholesterol 17 18 22 52 53 54 . Furthermore the VLCKD can cause modifications in LDL-C particles leading to increased size 53 which may reduce cardiovascular risk since smaller LDL particles have been shown to be more atherogenic 55 .

The cholesterol lowering effect of VLCKD is also mediated by the well known facilitating action of insulin on HMGCoA reductase and inhibition of the latter by cholesterol and fats 56 . Insulin then increases the production of endogenous cholesterol while exogenous cholesterol has the opposite effect 56 .

The KEMEPHY diet protocol used in this study maintains some advantages of the Mediterranean diet such as the use of olive oil 21 and some vegetables 19 (selected to avoid stimulating insulin production) but at the same time by inducing a physiological ketosis 57 promotes beneficial modifications in cardiovascular risk factors and body composition 22 . The use of the phyoextracts in this study may have contributed to the absence of commonly reported mild effects of ketosis (e.g. weakness, constipation, bad breath, headache). During the first three weeks of the KEMEPHY diet subjects avoided fructose completely and during the second three weeks only a moderate amount of fructose, exclusively from fruit, and therefore together with starch, was permitted. As a matter of fact fructose may stimulate fat biosynthesis via mechanisms which are not yet fully characterised 58 , also several studies have reported that excessive concentrations of fructose can induce some or all of the features of metabolic syndrome independently of energy intake. Clinical and epidemiologic data further suggest that excessive fructose intake can contribute to the causes of metabolic syndrome 59 .

Adjusted compliance in this study was 93.4% which is higher than reported compliances of standard VLCK diets (in the 20% to 58% range). 22 60 61 . It is tempting to speculate that the inclusion of "carbohydrate-like" formulated foods is one of the reasons for high compliance - however this, along with the potential benefits of the phytoextracts, requires further verification in a future study with a matched control group.

Some limitations to this study include the lack of a matched control group and the short trial period. There are though many studies that demonstrate that VLCK diets are more effective than low fat or standard Mediterranean diets, at least over the short term 21 , and the main aims of the present initial study were to assess safety aspects, acceptance & palatability and weight loss & biomarker changes. We are able to conclude that at least in the short term it was able to lead to positive changes including the reduction of fasting blood glucose, improvements in lipid profiles, significant and rapid weight and fat loss with the preservation of lean mass. We also note a high level of compliance, whether this was due to specific unique features of the present diet requires confirmation in a future matched control trial.

KEMEPHY: ketogenic Mediterranean with phytoextracts; VLCKD: very low carbohydrate ketogenic diet; high-density lipoprotein cholesterol; LDLc: low-density lipoprotein cholesterol; TG: Triglycerides; GLU: Glucose; BUN: Blood Urea Nitrogen; UA: Uric acid; ALT: Alanine aminotransferase; AST: Aspartate Aminotransferase; GGT Gamma-glutamyl transpeptidase; Cr: Creatinine.

This work was partially funded by Gianluca Mech SpA, Orgiano (VI), Italy. AP and LC research activity is funded by dept. of Human Anatomy and Physiology, University of Padova; KG research activity is funded by the Biomedical Engineering Laboratory, Institute of Communication and Computer Systems, National Technical University of Athens, Athens, Greece.

LC is scientific consultant for Gianluca Mech SpA, Orgiano (VI), Italy.

Investigators conducted the study in its entirety and maintained exclusive control of all data and analyses. The funding source had no involvement in any part of the recruitment of participants, study intervention, data collection, data analyses, interpretation of the data, or preparation or review of this manuscript.

AP was the main researcher and was responsible for study design, statistical analysis and interpretation of data and draft of manuscript. conceived the study, participated in its design, drafted the manuscript and performed the statistical analysis. LC was responsible for study design and acquisition of data. KG was was responsible for analysis and interpretation of data and helped to draft the manuscript. All authors read and approved the final manuscript.