You are on page 1of 23

List of Atkins Supporting Research (w/Abstracts) as of December 7, 2011 1.

Accurso, Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal. Nutrition & Metabolism, 2008. 10.1186/1743-7075-5-9 Current nutritional approaches to metabolic syndrome and type 2 diabetes generally rely on reductions in dietary fat. The success of such approaches has been limited and therapy more generally relies on pharmacology. The argument is made that a re-evaluation of the role of carbohydrate restriction, the historical and intuitive approach to the problem, may provide an alternative and possibly superior dietary strategy. The rationale is that carbohydrate restriction improves glycemic control and reduces insulin fluctuations which are primary targets. Experiments are summarized showing that carbohydrate-restricted diets are at least as effective for weight loss as lowfat diets and that substitution of fat for carbohydrate is generally beneficial for risk of cardiovascular disease. These beneficial effects of carbohydrate restriction do not require weight loss. Finally, the point is reiterated that carbohydrate restriction improves all of the features of metabolic syndrome. 2. Arvio, Modified Atkins diet brought back the joy of life to a developmentally severely disabled youth. Duodecim, 2010. 126(5): p. 557-560

Ketogenic diet is worth considering for persons with refractory epilepsy who cannot be helped with conventional means, for instance patients receiving gavage feeding are an ideal target group but patients eating normally have to adapt themselves to an unbalanced and fat-rich diet. We describe a developmentally severely disabled man, whose epilepsy settled, autistic features were alleviated, behavioral problems disappeared and whose weight and blood lipid and glucose values have remained normal for one year during a modified Atkins diet. 3. Aude, The National Cholesterol Education Program Diet vs a Diet Lower in Carbohydrates and Higher in Protein and Monounsaturated Fat. Arch Intern Med, 2004. 164: p. 2141-2146

Background: In the United States, obesity is a major clinical and public health problem causing diabetes, dyslipidemia, and hypertension, as well as increasing cardiovascular and total mortality. Dietary restrictions of calories and saturated fat are beneficial. However, it remains unclear whether replacement of saturated fat with carbohydrates (as in the US National Cholesterol Education Program [NCEP] diet) or protein and monounsaturated fat (as in our isocaloric modified lowcarbohydrate [MLC] diet, which is lower in total carbohydrates but higher in protein, monounsaturated fat, and complex carbohydrates) is optimal. Methods: We randomized 60 participants (29 women and 31 men) to the NCEP or the MLC diet and evaluated them every 2 weeks for 12 weeks. They were aged 28 to 71 years (mean age, 44 years in the NCEP and 46 years in the MLC group). A total of 36% of participants from the NCEP group and 35% from the MLC group had a body mass index (calculated as weight in kilograms divided by the square of height in meters) greater than 27. The primary end point was weight loss, and secondary end points were blood lipid levels and waist-to-hip ratio. Results: Weight loss was significantly greater in the MLC (13.6 lb) than in the NCEP group (7.5 lb), a difference of 6.1 lb (P=.02). There were no significant differences between the groups for total, low density, and highdensity lipoprotein cholesterol, triglycerides, or the proportion of small, dense low-density lipoprotein particles. There were significantly favorable changes in all lipid levels within the MLC but not within the NCEP group. Waist-to-hip ratio was not significantly reduced between the groups (P=.27), but it significantly decreased within the MLC group (P=.009). Conclusions: Compared with the NCEP diet, the MLC diet, which is lower in total carbohydrates but higher in complex carbohydrates, protein, and monounsaturated fat, caused significantly greater weight loss over 12 weeks. There were no significant differences between the groups in blood lipid levels, but favorable changes were observed within the MLC diet group. Arch Intern Med. 4. Austin, A Very Low-carbohydrate Diet Improves Symptoms and Quality of Life in Diarrhea-Predominant Irritable Bowel Syndrome. Clin Gastroenterol Hepatol, 2009. 7(6): p. 706-708

Background & AimsPatients with diarrhea-predominant IBS (IBS-D) anecdotally report symptom improvement after initiating a very lowcarbohydrate diet (VLCD). This is the first study to prospectively evaluate a VLCD in IBS-D. MethodsParticipants with moderate to severe IBS-D were provided a 2-week standard diet, then 4 weeks of a VLCD (20 grams of carbohydrates/day). A responder was defined as having adequate relief (AR) of gastrointestinal symptoms for 2 or more weeks during the VLCD. Changes in abdominal pain, stool habits, and quality of life (QOL) were also measured. ResultsOf the 17 participants enrolled, 13 completed the study and all met the responder definition, with 10 (77%) reporting AR for all 4 VLCD weeks. Stool frequency decreased (2.6 0.8/ day to 1.4 0.6/day; p<0.001). Stool consistency improved from diarrheal to normal form (Bristol Stool Score: 5.3 0.7 to 3.8 1.2; p<0.001). Pain scores and QOL measures significantly improved. Outcomes were independent of weight loss. ConclusionA VLCD provides adequate relief, and improves abdominal pain, stool habits, and quality of life in IBS-D. 5. Bailes, Effect of Low-Carbohydrate, Unlimited Calorie Diet on the Treatment of Childhood Obesity: A Prospective Controlled Study. Metabolic Syndrome and Related Disorders, 2003. 1(3): p. 221-225

Background: Childhood obesity has been recognized as the new epidemic in developed countries. Caloric restriction with physical activity is the main therapeutic treatment available for these children. We compared two different dietary protocols to assess treatment efficacy. Methods: Obese children from the Pediatric Endocrinology clinic were prospectively recruited for the study. Children and their parents were allowed to choose one of two dietary protocols: (1) carbohydrate restricted diet (<30 g/day), with unlimited calories, protein, and fat

(High protein, Low CHO Diet), and (2) calorie restricted diet (Low Cal Diet). Anthropometric data were measured at baseline and at the 2 month follow up appointment. Results: Thirty-seven children completed the study of whom 27 chose High Protein, Low CHO Diet and 10 chose Low Cal diet. No differences in gender ratio, age, or BMI were observed at baseline. At 2 months, children in the High Protein, Low CHO Diet lost an average of 5.21 3.44 kg (p < 0.001) and decreased their BMI by 2.42 1.3 points (p < 0.001), compared to the children in the Low Cal Diet who gained an average of 2.36 2.54 kg and 1.00 point on the BMI value (p < 0.001). Conclusions: A high protein, low carbohydrate, unlimited calorie diet was superior to a restricted calorie protocol for weight loss in obese school age children; moreover, compliance was better. 6. Ben-Avraham, Dietary strategies for patients with type 2 diabetes in the era of multi-approaches; review and results from the Dietary Intervention Randomized Controlled Trial (DIRECT). Diabetes Research and Clinical Practice, 2009. 86(Supplement 1): p. S41-S48

Dietary intervention is recognized as a key component in prevention and management of type 2 diabetes (T2DM) and the debate persists: which dietary strategy is most effective. In the Dietary Intervention Randomized Controlled Trial (DIRECT) 322 moderately obese participants were randomized for 2 years to one of three diet groups: low-fat, Mediterranean and low-carbohydrate. Differential effects were observed in the sub-group of patients with T2DM at 24 months: participants randomized to the Mediterranean diet, which had the highest intake of previous termdietarynext term fibers and unsaturated to saturated fat ratio, achieved greater significant improvements in fasting plasma glucose and insulin levels. Patients who were randomized to the low-carbohydrate diet, which had the minimal intake of carbohydrates, achieved a significant reduction of hemoglobin A1C. Although improvements were observed in all groups, the low-fat diet was likely to be less beneficial in terms of glycemic control and lipid metabolism. Interpretation of results from different studies on previous termdietary strategiesnext term may be complex since there is often no consistency in diet compositions, calorie restriction, intensity of intervention, previous termdietarynext term assessment or extent of adherence in the trial. Nevertheless, it seems that low fat restricted calorie diets are effective for weight loss and are associated with some metabolic benefits; however, some recent trials have shown that low carbohydrate diets are as efficient in inducing weight loss and in some metabolic measures such as serum triglycerides and HDL-cholesterol may be even superior to low fat diets. When addressing the issue of diet quality rather than quantity applying the glycemic index may have some added benefits. Furthermore special features of the Mediterranean diet have apparent additional favorable effects for patients with T2DM. 7. Boden, Effect of a Low-Carbohydrate Diet on Appetite, Blood Glucose Levels, and Insulin Resistance in Obese Patients with Type 2 Diabetes. Annals of Internal Medicine, 2005. 142: p. 403-411

Background: It is not known how a low-carbohydrate, highprotein, high-fat diet causes weight loss or how it affects blood glucose levels in patients with type 2 diabetes. Objective: To determine effects of a strict low-carbohydrate diet on body weight, body water, energy intake and expenditure, glycemic control, insulin sensitivity, and lipid levels in obese patients with type 2 diabetes. Design: Inpatient comparison of 2 diets. Setting: General clinical research center of a university hospital. Patients: 10 obese patients with type 2 diabetes. Intervention: Usual diets for 7 days followed by a low-carbohydrate diet for 14 days. Measurements: Body weight, water, and composition; energy intake and expenditure; diet satisfaction; hemoglobin A1c; insulin sensitivity; 24-hour urinary ketone excretion; and plasma profiles of glucose, insulin, leptin, and ghrelin. Results: On the low-carbohydrate diet, mean energy intake decreased from 3111 kcal/d to 2164 kcal/d. The mean energy deficit of 1027 kcal/d (median, 737 kcal/d) completely accounted for the weight loss of 1.65 kg in 14 days (median, 1.34 kg in 14 days). Mean 24-hour plasma profiles of glucose levels normalized, mean hemoglobin A1c decreased from 7.3% to 6.8%, and insulin sensitivity improved by approximately 75%. Mean plasma triglyceride and cholesterol levels decreased (change, _35% and _10%, respectively). Limitations: The study was limited by the short duration, small number of participants, and lack of a strict control group. Conclusion: In a small group of obese patients with type 2 diabetes, a low-carbohydrate diet followed for 2 weeks resulted in spontaneous reduction in energy intake to a level appropriate to their height; weight loss that was completely accounted for by reduced caloric intake; much improved 24-hour blood glucose profiles, insulin sensitivity, and hemoglobin A1c; and decreased plasma triglyceride and cholesterol levels. The long-term effects of this diet, however, remain uncertain. 8. Brehm, A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab, 2003. 88(4): p. 1617-23

Untested alternative weight loss diets, such as very low carbohydrate diets, have unsubstantiated efficacy and the potential to adversely affect cardiovascular risk factors. Therefore, we designed a randomized, controlled trial to determine the effects of a very low carbohydrate diet on body composition and cardiovascular risk factors. Subjects were randomized to 6 months of either an ad libitum very low carbohydrate diet or a calorie-restricted diet with 30% of the calories as fat. Anthropometric and metabolic measures were assessed at baseline, 3 months, and 6 months. Fifty-three healthy, obese female volunteers (mean body mass index, 33.6 +/- 0.3 kg/m(2)) were randomized; 42 (79%) completed the trial. Women on both diets reduced calorie consumption by comparable amounts at 3 and 6 months. The very low carbohydrate diet group lost more weight (8.5 +/- 1.0 vs. 3.9 +/- 1.0 kg; P < 0.001) and more body fat (4.8 +/- 0.67 vs. 2.0 +/- 0.75 kg; P < 0.01) than the low fat diet group. Mean levels of blood pressure, lipids, fasting glucose, and insulin were within normal ranges in both groups at baseline. Although all of these parameters improved over the course of the study, there were no

differences observed between the two diet groups at 3 or 6 months. beta- Hydroxybutyrate increased significantly in the very low carbohydrate group at 3 months (P = 0.001). Based on these data, a very low carbohydrate diet is more effective than a low fat diet for short-term weight loss and, over 6 months, is not associated with deleterious effects on important cardiovascular risk factors in healthy women. 9. Brehm, The role of energy expenditure in the differential weight loss in obese women on low-fat and low-carbohydrate diets. J Clin Endocrinol Metab, 2005. 90(3): p. 1475-82

We have recently reported that obese women randomized to a low-carbohydrate diet lost more than twice as much weight as those following a low-fat diet over 6 months. The difference in weight loss was not explained by differences in energy intake because women on the two diets reported similar daily energy consumption. We hypothesized that chronic ingestion of a low-carbohydrate diet increases energy expenditure relative to a low-fat diet and that this accounts for the differential weight loss. To study this question, 50 healthy, moderately obese (body mass index, 33.2 +/- 0.28 kg/m(2)) women were randomized to 4 months of an ad libitum low-carbohydrate diet or an energy-restricted, low-fat diet. Resting energy expenditure (REE) was measured by indirect calorimetry at baseline, 2 months, and 4 months. Physical activity was estimated by pedometers. The thermic effect of food (TEF) in response to low-fat and low-carbohydrate breakfasts was assessed over 5 h in a subset of subjects. Forty women completed the trial. The low-carbohydrate group lost more weight (9.79 +/- 0.71 vs. 6.14 +/- 0.91 kg; P < 0.05) and more body fat (6.20 +/- 0.67 vs. 3.23 +/- 0.67 kg; P < 0.05) than the low-fat group. There were no differences in energy intake between the diet groups as reported on 3-d food records at the conclusion of the study (1422 +/- 73 vs. 1530 +/- 102 kcal; 5954 +/- 306 vs. 6406 +/- 427 kJ). Mean REE in the two groups was comparable at baseline, decreased with weight loss, and did not differ at 2 or 4 months. The low-fat meal caused a greater 5-h increase in TEF than did the low-carbohydrate meal (53 +/- 9 vs. 31 +/- 5 kcal; 222 +/- 38 vs. 130 +/- 21 kJ; P = 0.017). Estimates of physical activity were stable in the dieters during the study and did not differ between groups. These results confirm that short-term weight loss is greater in obese women on a low-carbohydrate diet than in those on a low-fat diet even when reported food intake is similar. The differential weight loss is not explained by differences in REE, TEF, or physical activity and likely reflects underreporting of food consumption by the low-fat dieters. 10. Carrette, A pilot trial with modified Atkins diet in adult patients with refractory epilepsy. Clinical Neurology and Neurosurgery, 2008. 110(8): p. 797-803

Objectives At Ghent University Hospital, the feasibility and efficacy of the modified Atkins diet was evaluated in adult patients with refractory epilepsy. The Atkins diet restricts carbohydrate intake and was originally designed for weight loss. Patients and methods During a 6-month trial period, a carbohydrate restriction of 20 g/day was in place. During a 36 h hospital admission, patients were instructed about the diet. Patients underwent clinical neurological testing, EEG, ECG, blood and urine analyses and mood evaluation before and during the trial. Seizure frequency and side effects were recorded in seizure diaries and followed up at monthly clinic visits. Results Eight patients were included in the study. Three out of eight patients followed the diet for 6 months. One out of three patients showed a >50% seizure reduction, 1/3 > 30%, and 1/3 < 30%. Side effects such as constipation and diarrhoea were mild and occurred mainly during the initial week of the diet. Patients reported improved concentration and well being. This was confirmed by improved scores on the Beck Depression Inventory Scale. Conclusion This pilot study shows that the modified Atkins diet is feasible in an adult population, and that seizure frequency reduction is possible. The results need to be confirmed in larger prospective, controlled studies with comparison groups. 11. Coleman, Urinary ketones reflect serum ketone concentration but do not relate to weight loss in overweight premenopausal women following a low-carbohydrate/high-protein diet. J Am Diet Assoc, 2005. 105(4): p. 608-11

Abstract This study examined the effect of a low-carbohydrate/high-protein diet on serum and urine ketone body concentrations. Thirteen overweight premenopausal women aged 32 to 45 years consumed </=20 g carbohydrate/day with liberal intakes of protein and fat for 2 weeks; thereafter, carbohydrate intake increased 5 g/week for 10 weeks. Women were weighed and provided fasting urine and blood samples to detect urinary ketones and quantify serum ketone concentrations, respectively, at baseline and weeks 1 to 4, 6, and 12. Women lost 8.3%+/-2.8% of initial body weight by week 12. Serum beta-hydroxybutyrate production was highest at week 1 and declined weekly, with all values higher than baseline ( P <.05). Each week, serum beta-hydroxybutyrate was correlated with presence of urinary ketones ( P <.05), but no relationship was found between weekly weight change and serum ketone production. Carbohydrate restriction was an effective method of achieving short-term weight loss compared with standard advice, but this was at the expense of an increase in relative saturated fat intake.

12.

Daly, Short-term effects of severe dietary carbohydrate-restriction advice in Type 2 diabetes--a randomized controlled trial. Diabet Med, 2006. 231(1): p. 15-20

OBJECTIVE: This study sought to examine the effects of a 3-month programme of dietary advice to restrict carbohydrate intake compared with reduced-portion, low-fat advice in obese subjects with poorly controlled Type 2 diabetes. RESEARCH DESIGN AND METHODS: One hundred and two patients with Type 2 diabetes were recruited across three centres and randomly allocated to receive group education

and individual dietary advice. Weight, glycaemic control, lipids and blood pressure were assessed at baseline and 3 months. Dietary quality was assessed at the end of study. RESULTS: Weight loss was greater in the low-carbohydrate (LC) group (-3.55 +/- 0.63, mean +/sem) vs. -0.92 +/- 0.40 kg, P = 0.001) and cholesterol : high-density lipoprotein (HDL) ratio improved (-0.48 +/- 0.11 vs. -0.10 +/- 0.10, P = 0.01). However, relative saturated fat intake was greater (13.9 +/- 0.71 vs. 11.0 +/- 0.47% of dietary intake, P < 0.001), although absolute intakes were moderate. CONCLUSIONS: Carbohydrate restriction was an effective method of achieving short-term weight loss compared with standard advice, but this was at the expense of an increase in relative saturated fat intake. 13. Dansinger, Comparison of the Atkins, Ornish, Weight Watchers, and Zone Diets for Weight Loss and Heart Disease Risk Reduction. Journal of the American Medical Association, 2005. 293(1): p. 43-53

Context The scarcity of data addressing the health effects of popular diets is an important public health concern, especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention. Objective To assess adherence rates and the effectiveness of 4 popular diets (Atkins, Zone, Weight Watchers, and Ornish) for weight loss and cardiac risk factor reduction. Design, Setting, and Participants A single-center randomized trial at an academic medical center in Boston, Mass, of overweight or obese (body mass index: mean, 35; range, 27-42) adults aged 22 to 72 years with known hypertension, dyslipidemia, or fasting hyperglycemia. Participants were enrolled starting July 18, 2000, and randomized to 4 popular diet groups until January 24, 2002. Intervention A total of 160 participants were randomly assigned to either Atkins (carbohydrate restriction, n=40), Zone (macronutrient balance, n=40), Weight Watchers (calorie restriction, n=40), or Ornish (fat restriction, n=40) diet groups. After 2 months of maximum effort, participants selected their own levels of dietary adherence. Main Outcome Measures One-year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report. Results Assuming no change from baseline for participantswhodiscontinued the study, mean (SD) weight loss at 1 year was 2.1 (4.8) kg for Atkins (21 [53%] of 40 participants completed, P=.009), 3.2 (6.0) kg for Zone (26 [65%] of 40 completed, P=.002), 3.0 (4.9) kg for Weight Watchers (26 [65%] of 40 completed, P_.001), and 3.3 (7.3) kg for Ornish (20 [50%] of 40 completed, P=.007). Greater effects were observed in study completers. Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein (HDL) cholesterol ratio by approximately 10% (all P_.05), with no significant effects on blood pressure or glucose at 1 year. Amount of weight loss was associated with selfreported dietary adherence level (r=0.60; P_.001) but not with diet type (r=0.07; P=.40). For each diet, decreasing levels of total/HDL cholesterol, C-reactive protein, and insulin were significantly associated with weight loss (mean r=0.36, 0.37, and 0.39, respectively) with no significant difference between diets (P=.48, P=.57, P=.31, respectively). Conclusions Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year. Overall dietary adherence rates were low, although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group. 14. Dashti, Ketogenic diet modifies the risk factors of heart disease in obese patients. Nutrition, 2003. 19(10): p. 901-2

It is generally believed that high-fat diets may lead to the development of obesity and several other diseases such as coronary heart disease, diabetes, and cancer. This view is based on studies carried out in animals that were given a high-fat diet rich in polyunsaturated fatty acids. However, various recent epidemiologic studies have not explained a specific causal relation between dietary fat and obesity or obesity-associated diseases.1 Further, contrary to the common notion, a high intake of carbohydrates was found to increase the levels of triacylglycerols, total cholesterol, and low-density lipoprotein (LDL) cholesterol and decrease the level of high-density lipoprotein (HDL) cholesterol. Elevated levels of triacylglycerols and low levels of HDL were associated with hyperinsulinemia. Also, an elevated triacylglycerol level, particularly a high ratio of triacylglycerols to HDL, is an important predictor of heart attack.2 Recent studies have quite evidently shown that the ketogenic diet is a natural therapy for obesity and obesity-associated diseases. However, there are very few studies that have addressed the longterm influence of a ketogenic diet in modifying various obesity-associated diseases. Hence, the purpose of this study was to investigate the long-term effect of a ketogenic diet on the activation and modification of heart disease risk factors in obese patients. 15. Dashti, Long Term Effects of a Ketogenic Diet in Obese Patients. Clinical Cardiology, 2004. 9(3): p. 200-205

BACKGROUND: Although various studies have examined the short-term effects of a ketogenic diet in reducing weight in obese patients, its longterm effects on various physical and biochemical parameters are not known. OBJECTIVE: To determine the effects of a 24-week ketogenic diet (consisting of 30 g carbohydrate, 1 g/kg body weight protein, 20% saturated fat, and 80% polyunsaturated and monounsaturated fat) in obese patients. PATIENTS AND METHODS: In the present study, 83 obese patients (39 men and 44 women) with a body mass index greater than 35 kg/m2, and high glucose and cholesterol levels were selected. The body weight, body mass index, total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, fasting blood sugar, urea and creatinine levels were determined before and after the administration of the ketogenic diet. Changes in these parameters were monitored after eight, 16 and 24 weeks of treatment. RESULTS: The weight and body mass index of the patients decreased significantly (P<0.0001). The level of total cholesterol decreased from week 1 to week 24. HDL cholesterol levels significantly increased, whereas LDL cholesterol levels significantly decreased after treatment. The level of triglycerides decreased significantly following 24 weeks of treatment. The level of blood glucose significantly decreased. The changes in the level of urea and creatinine were not statistically significant. CONCLUSIONS: The present study shows the beneficial effects of a long-term ketogenic diet. It significantly reduced the body weight and body mass index of the patients. Furthermore, it decreased the level of triglycerides, LDL cholesterol and blood glucose, and increased the level of HDL cholesterol. Administering a ketogenic diet for a relatively longer period of time did not produce any significant side effects in the

patients. Therefore, the present study confirms that it is safe to use a ketogenic diet for a longer period of time than previously demonstrated. 16. Davis, Comparative Study of the Effects of a 1-Year Dietary Intervention of a Low-Carbohydrate Diet Versus a Low-Fat Diet on Weight and Glycemic Control in Type 2 Diabetes. Diabetes Care, 2009. 32(7): p. 1147-1152

OBJECTIVE To compare the effects of a 1-year intervention with a low-carbohydrate and a low-fat diet on weight loss and glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This study is a randomized clinical trial of 105 overweight adults with type 2 diabetes. Primary outcomes were weight and A1C. Secondary outcomes included blood pressure and lipids. Outcome measures were obtained at 3, 6, and 12 months. RESULTS The greatest reduction in weight and A1C occurred within the first 3 months. Weight loss occurred faster in the low-carbohydrate group than in the low-fat group (P_0.005), but at 1 year a similar 3.4% weight reduction was seen in both dietary groups. There was no significant change in A1C in either group at 1 year. There was no change in blood pressure, but a greater increase in HDL was observed in the low-carbohydrate group (P _ 0.002). CONCLUSIONS Among patients with type 2 diabetes, after 1 year a low-carbohydrate diet had effects on weight and A1C similar to those seen with a low-fat diet. There was no significant effect on blood pressure, but the low-carbohydrate diet produced a greater increase in HDL cholesterol. Diabetes Care 32:11471152, 2009 17. Forsythe, Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation. Lipids, 2008. 43(1):65-77 Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome. We tested whether these components of metabolic syndrome, like dyslipidemia and glycemia, are responsive to carbohydrate restriction. Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate (VLCKD) (1504 kcal:%CHO:fat:protein = 12:59:28) or low in fat (LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for 12 weeks. In comparison to the LFD, the VLCKD resulted in an increased proportion of serum total n-6 PUFA, mainly attributed to a marked increase in arachidonate (20:4n-6), while its biosynthetic metabolic intermediates were decreased. The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply. Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD. Both diets significantly decreased the concentration of several serum inflammatory markers, but there was an overall greater anti-inflammatory effect associated with the VLCKD, as evidenced by greater decreases in TNF-alpha, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1. Increased 20:4n-6 and the ratios of 20:4n6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory, but unexpectedly were consistently inversely associated with responses in inflammatory proteins. In summary, a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet. 18. Forsythe, Limited Effect of Dietary Saturated Fat on Plasma Saturated Fat in the Context of a Low Carbohydrate Diet. Lipids, 2010. 45(10): p. 947-962

We recently showed that a hypocaloric carbohydrate restricted diet (CRD) had two striking effects: (1) a reduction in plasma saturated fatty acids (SFA) despite higher intake than a low fat diet, and (2) a decrease in inflammation despite a significant increase in arachidonic acid (ARA). Here we extend these findings in 8 weight stable men who were fed two 6-week CRD (12%en carbohydrate) varying in quality of fat. One CRD emphasized SFA (CRD-SFA, 86 g/d SFA) and the other, unsaturated fat (CRD-UFA, 47 g SFA/d). All foods were provided to subjects. Both CRD decreased serum triacylglycerol (TAG) and insulin, and increased LDL-C particle size. The CRD-UFA significantly decreased plasma TAG SFA (27.48 2.89 mol%) compared to baseline (31.06 4.26 mol%). Plasma TAG SFA, however, remained unchanged in the CRD-SFA (33.14 3.49 mol%) despite a doubling in SFA intake. Both CRD significantly reduced plasma palmitoleic acid (16:1n-7) indicating decreased de novo lipogenesis. CRD-SFA significantly increased plasma phospholipid ARA content, while CRD-UFA significantly increased EPA and DHA. Urine 8-iso PGF2a, a free radical-catalyzed product of ARA, was significantly lower than baseline following CRD-UFA (-32%). There was a significant inverse correlation between changes in urine 8-iso PGF2a and PL ARA on both CRD (r = -0.82 CRD-SFA; r = -0.62 CRD-UFA). These findings are consistent with the concept that dietary saturated fat is efficiently metabolized in the presence of low carbohydrate, and that a CRD results in better preservation of plasma ARA. 19. Foster, A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med, 2003. 348(21): p. 2082-90

BACKGROUND: Despite the popularity of the low-carbohydrate, high-protein, high-fat (Atkins) diet, no randomized, controlled trials have evaluated its efficacy. METHODS: We conducted a one-year, multicenter, controlled trial involving 63 obese men and women who were randomly assigned to either a low-carbohydrate, high-protein, high-fat diet or a low-calorie, high-carbohydrate, low-fat (conventional) diet. Professional contact was minimal to replicate the approach used by most dieters. RESULTS: 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. CONCLUSIONS: The low-carbohydrate diet produced a greater weight loss (absolute difference, approximately 4 percent) than did the conventional diet for the first six months, but the differences were not significant at one year. The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease. Adherence was poor and attrition was high in both groups. Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate, high-protein, high-fat diets. 20. Foster, Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet: A Randomized Trial. Annals of Internal Medicine, 2010. 153(3): p. 147-157

Background: Previous studies comparing low-carbohydrate and low-fat diets have not included a comprehensive behavioral treatment, resulting in suboptimal weight loss. Objective: To evaluate the effects of 2-year treatment with a low-carbohydrate or low-fat diet, each of which was combined with a comprehensive lifestyle modification program. Design: Randomized parallel-group trial. (ClinicalTrials.gov registration number: NCT00143936) Setting: 3 academic medical centers. Patients.307 participants with a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m2 (SD, 3.5 kg/m2). Intervention: A low-carbohydrate diet, which consisted of limited carbohydrate intake (20 g/d for 3 months) in the form of low.glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants in the low-carbohydrate diet group increased their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. A low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d; 30% calories from fat). Both diets were combined with comprehensive behavioral treatment. Measurements: Weight at 2 years was the primary outcome. Secondary measures included weight at 3, 6, and 12 months and serum lipid concentrations, blood pressure, urinary ketones, symptoms, bone mineral density, and body composition throughout the study. Results: Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There ere no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in lowdensity lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years. Limitation: tensive behavioral treatment was provided, patients with dyslipidemia and diabetes were excluded, and attrition at 2 years was high. Conclusion: Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years. 21. Gann, A low-carbohydrate diet in overweight patients undergoing stable statin therapy raises high-density lipoprotein and lowers triglycerides substantially. Clin Cardiol, 2004. 27(10): p. 563-4

BACKGROUND: A low-carbohydrate diet remains controversial, especially in patients with arteriosclerotic heart disease. HYPOTHESIS: This study was undertaken to evaluate the effect of a low-carbohydrate diet on the lipid levels in obese patients with known arteriosclerotic heart disease on chronic statin therapy. METHODS: Thirty-eight overweight patients with angiographically documented arteriosclerotic heart disease were followed in a private cardiology practice setting. All patients were undergoing stable statin therapy. Patients received a 15min consultation and a 4-page pamphlet explaining a low-carbohydrate diet; no other diet instruction was given. Patients were followed weekly for 2 weeks, then monthly for 3 months, then every third month. A fasting finger stick lipid panel (cholesterol, high-density and low-density lipoprotein [HDL/ LDL], triglycerides, and glucose) was obtained with each visit and patients were weighed in street clothes. RESULTS: The 38 patients were followed for a average of 11.8 months (range 6-22 months). Average body mass index declined from 33.5 kg/m2 before to 27.9 kg/m2 at the end of the study. Weight loss averaged 31 lbs (range 16-107 lbs). Triglyceride levels were lowered by 29.5%, HDL raised by 17.6%, and cholesterol decreased by 8.4%. The cholesterol/ HDL ratio changed from 5.31 to 3.78 and LDL cholesterol decreased by 5%. CONCLUSION: The addition of a low-carbohydrate diet for overweight patients with known coronary artery disease undergoing stable statin therapy causes significant weight loss and a favorable change in the lipid panel. 22. Gannon, Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes. Diabetes, 2004. 53(9): p. 2375-82

There has been interest in the effect of various types and amounts of dietary carbohydrates and proteins on blood glucose. On the basis of our previous data, we designed a high-protein/low-carbohydrate, weight-maintaining, nonketogenic diet. Its effect on glucose control in people with untreated type 2 diabetes was determined. We refer to this as a low-biologically-available-glucose (LoBAG) diet. Eight men were studied using a randomized 5-week crossover design with a 5-week washout period. The carbohydrate:protein:fat ratio of the control diet was 55:15:30. The test diet ratio was 20:30:50. Plasma and urinary beta-hydroxybutyrate were similar on both diets. The mean 24-h integrated serum glucose at the end of the control and LoBAG diets was 198 and 126 mg/dl, respectively. The percentage of glycohemoglobin was 9.8 +/- 0.5 and 7.6 +/- 0.3, respectively. It was still decreasing at the end of the LoBAG diet. Thus, the final calculated glycohemoglobin was estimated to be approximately 6.3-5.4%. Serum insulin was decreased, and plasma glucagon was increased. Serum cholesterol was unchanged. Thus, a LoBAG diet ingested for 5 weeks dramatically reduced the circulating glucose concentration in people with untreated type 2 diabetes. Potentially, this could be a patient-empowering way to ameliorate hyperglycemia without pharmacological intervention. The long-term effects of such a diet remain to be determined.

Gardner, Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA, 2007. 297(9):969-77 CONTEXT: Popular diets, particularly those low in carbohydrates, have challenged current recommendations advising a low-fat, high-carbohydrate diet for weight loss. Potential benefits and risks have not been tested adequately. OBJECTIVE: To compare 4 weight-loss diets representing a spectrum of low to high carbohydrate intake for effects on weight loss and related metabolic variables. DESIGN, SETTING, AND PARTICIPANTS: Twelve-month randomized trial conducted in the United States from February 2003 to October 2005 among 311 free-living, overweight/obese (body mass index, 27-40) nondiabetic, premenopausal women. INTERVENTION: Participants were randomly assigned to follow the Atkins (n = 77), Zone (n = 79), LEARN (n = 79), or Ornish (n = 76) diets and received weekly instruction for 2 months, then an additional 10-month follow-up. MAIN OUTCOME MEASURES: Weight loss at 12 months was the primary outcome. Secondary outcomes included lipid profile (low-density lipoprotein, high-density lipoprotein, and non-high-density lipoprotein cholesterol, and triglyceride levels), percentage of body fat, waist-hip ratio, fasting insulin and glucose levels, and blood pressure. Outcomes were assessed at months 0, 2, 6, and 12. The Tukey studentized range test was used to adjust for multiple testing. RESULTS: Weight loss was greater for women in the Atkins diet group compared with the other diet groups at 12 months, and mean 12-month weight loss was significantly different between the Atkins and Zone diets (P<.05). Mean 12-month weight loss was as follows: Atkins, -4.7 kg (95% confidence interval [CI], -6.3 to -3.1 kg), Zone, -1.6 kg (95% CI, -2.8 to -0.4 kg), LEARN, -2.6 kg (-3.8 to -1.3 kg), and Ornish, -2.2 kg (-3.6 to 0.8 kg). Weight loss was not statistically different among the Zone, LEARN, and Ornish groups. At 12 months, secondary outcomes for the Atkins group were comparable with or more favorable than the other diet groups. CONCLUSIONS: In this study, premenopausal overweight and obese women assigned to follow the Atkins diet, which had the lowest carbohydrate intake, lost more weight at 12 months than women assigned to follow the Zone diet, and had experienced comparable or more favorable metabolic effects than those assigned to the Zone, Ornish, or LEARN diets [corrected] While questions remain about long-term effects and mechanisms, a lowcarbohydrate, high-protein, high-fat diet may be considered a feasible alternative recommendation for weight loss. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00079573. PMID: 17341711 [PubMed - indexed for MEDLINE]Free Article 24. Goldstein, Influence of a modified Atkins diet on weight loss and glucose metabolism in obese type 2 diabetic patients. Israel Medical Association Journal, 2004. 6: p. 314

23.

Objectives: To compare a very low carbohydrate diet (similar to the Atkins diet) with the standard diet for diabetics, as prescribed by the American Diabetes Association (ADA), and assess its effect on weight loss and glucose metabolism in obese type 2 diabetic patients. The study was conducted under clinically controlled conditions. Methods: In stage 1, 56 obese type 2 diabetics, aged 3575, 30 <body mass index (BMI) <40 and glycosylated hemoglobin (HbA1c) >7, who were being treated via diet or oral medication, were placed on the DASH diet (the Dietary Approach to Stop Hypertension) for 1 month. In stage 2, 52 patients (26 per group) were then randomly assigned either to a modified Atkins diet or to a standard ADA calorierestricted diet. They were to adhere to their respective diets for 3 months and were monitored weekly. The diets were as follows: Very Low Carbohydrate Diet (ATK): 6 weeks with up to 25 g of carbohydrates daily. Afterwards an increase of up to 40 g of carbohydrates daily is permitted. No restrictions are put on calorie consumption. (The patients are also advised that fats consumed should be monounsaturated and that protein should come from poultry and fish rather than from red meat.) Standard ADA diet: Calorie-restricted diet up to 1,500 calories daily for males and 1,200 calories daily for females. The diet should consist of 45% carbohydrates, 35% fats and 20% protein. Results: Four patients dropped out of the study during stage 1. Out of the remaining 52, two groups of 26 were formed. The overall statistical data of the two groups at the outset of stage 2 were very similar. Twenty-two patients in each group remained on their respective diets for the next 3 months until the end of stage 2. Weight loss: the average weight loss in all patients during stage 1 was 2.3 kg. During stage 2, the ATK group lost, on average, an additional 2.3 kg per person, whereas the ADA group lost only an additional 1.7 kg per person. HbA1c: There was a significant decrease in the HbA1c level in both groups, but with no significant difference between the groups. In the Atkins group the level dropped by 1.3%, and in the ADA group by 0.9%. In both diet groups the amount of hypoglycemic medication was reduced for many of the patients (ATK 17/26; ADA 11/26; P = 0.16). Lipids, blood pressure and kidney function: After 3 months there was a statistically significant reduction of triglycerides in the ATK group. In both groups blood pressure was reduced with no significant advantage to either of the diets. In neither of the groups were there changes in microalbumin, creatinine, or uric acid. In the ATK however, there was an increase in blood urea (P = 0.002). Conclusions: Intensive nutritional monitoring brings about reductions of weight and blood pressure, and stabilization of sugar levels in obese type 2 diabetics. In this randomized controlled clinical trial we found no statistical difference in weight loss and HbA1c between the ATK and ADA diets, although the results slightly favored the Atkins diet. Furthermore, there was no evidence of deleterious effects on cardiovascular risk factors or renal function due to the high fat high protein diet after 3 months of follow-up. Based on our results, some patients who are unable to adhere to the ADA diet might find the ATK diet useful for a short period. It is premature to draw conclusions as to the long-term safety of the Atkins diet. 25. 26. Greene. Effects of low-fat vs ultra-low-carbohydrate weight-loss diets: a 12-week pilot feeding study. in Nutrition Week 2004. 2004. Las Vegas, NV. Gutierrez, Utility of a short-term 25% carbohydrate diet on improving glycemic control in type 2 diabetes mellitus. J Am Coll Nutr, 1998. 17(6): p. 595-600

OBJECTIVE: To determine if introduction of a low carbohydrate diet might be a useful option for type 2 diabetic patients who do not achieve glucose target levels despite conventional treatment. METHODS: Subjects with type 2 diabetes, either treated with diet alone (n=9) or second generation sulfonylurea agents (n= 19), which were discontinued, were placed on a diet based on ideal body weight and comprised of 25% carbohydrate. After a mean of 8 weeks, they were then switched to a caloricly equivalent diet, but composed of 55%

carbohydrate. RESULTS: Compared to baseline diet, after 8 weeks of a 25% diet, subjects showed significantly improved glycemia as evidenced by fasting blood glucose values (p<0.005) and hemoglobin A1c levels (p<0.05). Those previously treated with oral hypoglycemic agents showed, in addition, a significant decrease in weight and diastolic blood pressure despite the discontinuation of the oral agent. When then placed on a 55% carbohydrate diet, the hemoglobin A1c rose significantly over the ensuing next 12 weeks (p<0.05). CONCLUSION: A low carbohydrate, caloricly-restricted diet has beneficial short-term effects in subjects with type 2 who have failed either diet or sulfonylurea therapy and may obviate the necessity for insulin. Our study also affirms the need for reassessing the role of diet whenever type 2 diabetic patients manifests hyperglycemia, despite conventional oral treatment or diet management. 27. Hays, Results of use of metformin and replacement of starch with saturated fat in diets of patients with type 2 diabetes. Endocr Pract, 2002. 8(3): p. 177-83

OBJECTIVE: To improve glycemic control by substituting saturated fat for starch, to identify any adverse effect on lipids masked by the extensive use of metformin and lipid-lowering drugs, and to attempt to separate dietary effects from effects of multiple drugs. METHODS: We undertook a retrospective review of medical records of patients who completed 1 year of follow-up after dietary prescription. The study subjects included 151 patients in the diet group (whose dietary instructions included high saturated fat but starch avoidance) and 132 historical control subjects (who were allowed unlimited monounsaturated fat but had restriction of starch in their diets). RESULTS: Hemoglobin A1c (HbA1c) levels improved in both study groups (-1.4 +/- 0.2% [P<0.001]; 95% confidence interval [CI], -1.9 to -0.9). Use of metformin was associated with a decrease in HbA1c (-0.12 +/- 0.003%/mo [P<0.001]; 95% CI, -0.17 to -0.07). The diet group had an additional decrease of -0.7 +/- 0.2% (P<0.001; 95% CI, -1.1 to -0.3). Weight increase was associated with the use of insulin (+0.3 +/- 0.07 kg/mo [P<0.001]; 95% CI, 0.2 to 0.5), sulfonylurea (+0.18 +/- 0.06 kg/mo [P<0.01]; 95% CI, 0.05 to 0.30), and troglitazone (+0.7 +/- 0.2 kg/mo [P<0.005]; 95% CI, 0.3 to 1.2). Although not statistically significant, metformin therapy showed a trend for weight loss (-0.14 +/0.08 kg/mo; P = 0.07). An additional weight loss was noted in the diet group (-2.65 +/- 0.62 kg [P<0.001]; 95% CI, -3.87 to -1.44). Hydroxymethylglutaryl-coenzyme A reductase inhibitor use was associated with reduced total cholesterol level (-1.7 +/- 0.6 mg/dL per month [P<0.005]; 95% CI, -2.9 to -0.5). The diet group had an additional decrease of -13.0 +/- 4.5 mg/dL (P<0.001; 95% CI, -21.9 to -4.1). No significant effect of the diet on triglyceride, low-density lipoprotein, or high-density lipoprotein levels was detected. CONCLUSION: Addition of saturated fat and removal of starch from a high-monounsaturated fat and starch-restricted diet improved glycemic control and were associated with weight loss without detectable adverse effects on serum lipids. 28. Hays, Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease. Mayo Clin Proc, 2003. 78(11): p. 1331-6

OBJECTIVE: To determine whether a diet of high saturated fat and avoidance of starch (HSF-SA) results in weight loss without adverse effects on serum lipids in obese nondiabetic patients. PATIENTS AND METHODS: Twenty-three patients with atherosclerotic cardiovascular disease participated in a prospective 6-week trial at the Christiana Care Medical Center in Newark, Del, between August 2000 and September 2001. All patients were obese (mean +/- SD body mass index [BMI], 39.0+/-7.3 kg/m2) and had been treated with statins before entry in the trial. Fifteen obese patients with polycystic ovary syndrome (BMI, 36.1+/-9.7 kg/m2) and 8 obese patients with reactive hypoglycemia (BMI, 46.8+/-10 kg/m2) were monitored during an HSF-SA diet for 24 and 52 weeks, respectively, between 1997 and 2000. RESULTS: In patients with atherosclerotic cardiovascular disease, mean +/- SD total body weight (TBW) decreased 5.2%+/-2.5% (P<.001) as did body fat percentage (P=.02). Nuclear magnetic resonance spectroscopic analysis of lipids showed decreases in total triglycerides (P<.001), very low-density lipoprotein (VLDL) triglycerides (P<.001), VLDL size (P<.001), large VLDL concentration (P<.001), and medium VLDL concentration (P<.001). High-density lipoprotein (HDL) and LDL concentrations were unchanged, but HDL size (P=.01) and LDL size (P=.02) increased. Patients with polycystic ovary syndrome lost 14.3%+/-20.3% of TBW (P=.008) and patients with reactive hypoglycemia lost 19.9%+/-8.7% of TBW (P<.001) at 24 and 52 weeks, respectively, without adverse effects on serum lipids. CONCLUSION: An HSF-SA diet results in weight loss after 6 weeks without adverse effects on serum lipid levels verified by nuclear magnetic resonance, and further weight loss with a lipid-neutral effect may persist for up to 52 weeks. 29. Hickey, Clinical Use of a Carbohydrate-Restricted Diet to Treat the Dyslipidemia of the Metabolic Syndrome. Metabolic Syndrome and Related Disorders, 2003. 1(3): p. 227-232

Background: The metabolic syndrome is characterized by an atherogenic dyslipidemia identifiable using lipoprotein subclass analysis. This study assesses the effect of a carbohydrate-restricted diet on the dyslipidemia of the metabolic syndrome in a clinical setting. Methods: This is a retrospective chart review of patients attending a preventive medicine clinic using lipoprotein subclass analysis (by NMR spectroscopy) to identify the atherogenic dyslipidemia. If present, patients were counseled to begin a carbohydrate-restricted diet (< 20 g/day). Patients already on statin therapy were included only if the medication dose was not changed. The outcomes were changes in body weight, fasting serum lipid profiles and serum lipoprotein subclasses. Results: Of 122 patients identified, 80 patients had complete pre- and post-treatment data. The mean (SD) age was 66 9 years, baseline weight was 85 12 kg, BMI was 28.1 3.6, 73% were male, 99% were Caucasian. Sixty-five percent were taking statin medication. Carbohydraterestriction led to a 13% reduction in total cholesterol, 16% reduction in LDL cholesterol, 38% reduction in triglycerides, and a 13% increase in HDL cholesterol (all p values < 0.001). Carbohydrate-restriction also led to a reduction in LDL particle concentration of 28%, a reduction in small LDL of 82%, a reduction of large VLDL of 62%, and an increase in large HDL of 30% (all p values < 0.001). Conclusions: A carbohydrate-restricted diet recommendation led to improvements in lipid profiles and lipoprotein subclass traits of the metabolic syndrome in a clinical outpatient setting, and should be considered as a treatment for the metabolic syndrome. 30. Husain, Diet therapy for narcolepsy. Neurology, 2004. 62(12): p. 2300-2

The effects of a low-carbohydrate, ketogenic diet (LCKD) on sleepiness and other narcolepsy symptoms were studied. Nine patients with narcolepsy were asked to adhere to the Atkins' diet plan, and their symptoms were assessed using the Narcolepsy Symptom Status Questionnaire (NSSQ). The NSSQ-Total score decreased by 18% from 161.9 to 133.5 (p = 0.0019) over 8 weeks. Patients with narcolepsy experienced modest improvements in daytime sleepiness on an LCKD. 31. Ito, Modified Atkins diet therapy for a case with glucose transporter type 1 deficiency syndrome. Brain and Development, 2008. 30(3): p. 226-228

Glucose transporter type 1 deficiency syndrome (GLUT-1 DS), giving rise to impaired glucose transport across the bloodbrain barrier, is characterized by infantile seizures, complex motor disorders, global developmental delay, acquired microcephaly, and hypoglycorrhachia. GLUT-1 DS can be treated effectively with a ketogenic diet because it can provide an alternative fuel for brain metabolism; however, the excessive restriction of food intake involved frequently makes it difficult for patients to initiate or continue the diet. Recently, the modified Atkins diet, which is much less restrictive in terms of the total calorie and protein intake than the classical ketogenic diet, has been shown to be effective and well tolerated in children with intractable epilepsy. We successfully introduced the modified Atkins diet to a 7-year-old boy with GLUT-1 DS, whose caregivers refused ketogenic diet treatment because of strong concerns over restricting the diet. The modified Atkins diet should be considered for patients with GLUT-1 DS as an alternative to the traditional ketogenic diet. 32. Kang, Use of a Modified Atkins Diet in Intractable Childhood Epilepsy. Epilepsia, 2007. 48(1): p. 182-186

Purpose: To evaluate the efficacy, safety and tolerability of a modified Atkins diet in intractable childhood epilepsy. Methods: Fourteen children with epilepsy were treated prospectively with a modified Atkins diet. Outcome measures included seizure frequency, adverse reactions and tolerability to the diet; blood -hydroxybutyrate and urine ketones were also measured. Results: Six months after diet initiation, seven (50%) remained on the diet, five (36%) had >50% seizure reduction, and three (21%) were seizure free. The dietwas well tolerated by 12 (86%) patients. Most complications were transient and were successfully managed by careful follow-up and conservative strategies. Aconsistently strong ketosis (-hydroxybutyrate of>3 mmol/L) seemed to be important for maintaining the efficacy of the diet therapy. Conclusions: The modified Atkins diet was well tolerated and sometimes a modified Atkins diet can be substituted for the conventional ketogenic diet. Serious complications were rare, but long-term complications remain to be determined. 33. Kima, Various indications for a modified Atkins diet in intractable childhood epilepsy. Brain and Development, 2011 Purpose: We reviewed retrospectively our experiences with children with intractable epilepsy who were indicated for a modified Atkins diet (MAD). Methods: Twenty children (8 female, 12 male) who were aged 217 years with intractable epilepsy and tried the MAD between September 2008 and December 2010 were enrolled. Outcome measures included seizure frequency, adverse reactions and tolerability of the diet. Results: Finally 9 patients maintained the MAD with favorable seizure outcomes (a reduction of seizure frequency by over 50%) or successfully completed the diet therapy. Two patients who required a long-term trial of the diet therapy respectively due to Leighs syndrome and uncategorized mitochondrial cytopathy derived from cytochrome c oxidase defect, respectively, successfully maintained the diet treatment without any significant complications. In 7 patients, the ketogenic diet (KD) was not only effective but also too restrictive or caused serious unwanted events. Five of them maintained the seizure outcome previously achieved by the KD with the MAD. Ten patients began the MAD because they were reluctant to start the KD. Unfortunately, only 2 patients maintained the MAD with favorable seizure outcomes. One patient who chose the MAD to bridge the KD and complete discontinuation of the treatment successfully completed the diet therapy. Conclusion: A long-term treatment with the MAD was well tolerated. Moreover, the MAD can successfully substitute the classic KD in patients who showed improvement in seizure outcomes by the KD but could not tolerate it. 34. Kossoff, Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology, 2003. 61(12): p. 1789-91

The ketogenic diet is effective for treating seizures in children with epilepsy. The Atkins diet can also induce a ketotic state, but has fewer protein and caloric restrictions, and has been used safely by millions of people worldwide for weight reduction. Six patients, aged 7 to 52 years, were started on the Atkins diet for the treatment of intractable focal and multifocal epilepsy. Five patients maintained moderate to large ketosis for periods of 6 weeks to 24 months; three patients had seizure reduction and were able to reduce antiepileptic medications. This provides preliminary evidence that the Atkins diet may have a role as therapy for patients with medically resistant epilepsy. 35. Kossoff, When do seizures usually improve with the ketogenic diet? Epilepsia, 2008. 49(2): p. 329-33

Purpose: Parents often expect immediate seizure improvement after starting the ketogenic diet (KD) for their children. The purpose of this study was to determine the typical time to seizure reduction as well as the time after which it was unlikely to be helpful in those children started on the KD. Methods: Records of all children started on the KD at Johns Hopkins Hospital, Baltimore (n=83) andChildrensMemorialHospital, Chicago (n = 35) from November 2003 to December 2006 were examined to determine the first day in which seizures were reportedly improved. Results: Of the 118 children started on the KD, 99 (84%) had documented seizure reduction. The overall median time to first improvement was 5days (range: 165 days). Seventy-five percent of children improved within 14 days. In those children who were fasted at KD onset, the

time to improvement was quicker (median 5 vs. 14 days, p < 0.01) with a higher percentage improving within 5 days (60% vs. 31%, p = 0.01). No difference was identified between fasting and nonfasting in regards to long-term outcomes, however. Discussion: The KD works quickly when effective, typically within the first 12 weeks. Starting the KD after a fasting periodmay lead to a more rapid, but equivalent long-term seizure reduction, confirming prior reports. If the KD has not led to seizure reduction after 2 months, it can probably be discontinued. 36. Kossoff, Ketogenic diets: evidence for short- and long-term efficacy. Neurotherapeutics, 2009. 6(2): p. 406-14

The use of dietary treatments for epilepsy (ketogenic, modified Atkins, and low glycemic index diets) has been in continuous use since 1921. These treatments have been well studied in the short term, with approximately half of children having at least a 50% reduction in seizures after 6 months. Approximately one third will attain >90% reduction in their seizures. Animal studies confirm these findings, with broad evidence demonstrating acute anticonvulsant effects of the diet. Furthermore, the diet appears to maintain its efficacy in humans when provided continuously for several years. Interestingly, benefits may be seen long term even when the diet is discontinued after only a few months of use, suggesting neuroprotective effects. This potential antiepileptogenic activity has been recently demonstrated in some animal studies as well. This review discusses the animal and human evidence for both short- and long-term benefits of dietary therapies. 37. Kossoff, Use of the modified Atkins diet for adolescents with chronic daily headache. Cephalalgia, 2010. 30(8): p. 1014-1016

Chronic daily headache is a difficult problem to treat for many adolescents, with a natural tendency for parents to look into alternative treatments such as acupuncture, herbal remedies, biofeedback and relaxation techniques ( 1). Data on food trigger avoidance are controversial and not universally recommended even as an adjunctive treatment ( 2 4). Obesity may be a factor in frequent migraines ( 5) and therefore weight loss through exercise and diets may be theoretically beneficial ( 6). The modified Atkins diet (MAD) is a high-fat, very low carbohydrate diet used in the treatment of children and adults with intractable epilepsy ( 7). This diet creates a ketotic state similar to the traditional ketogenic diet, but is started as an out-patient without a fast, or calorie, fluid or protein restriction ( 7). Weight loss can occur as well. Similar to anticonvulsant drugs, there has been recent interest in the potential benefits of ketogenic diets for the treatment of neurological conditions other than epilepsy, including Alzheimer disease, amyotrophic lateral sclerosis, brain tumours and autism ( 8). In 2006, a single case report was published regarding a 43-year-old woman with daily migraines who completely responded to a ketosisinducing diet containing several high-protein and low-carbohydrate shakes per day ( 9). 38. Kossoff, Will seizure control improve by switching from the modified Atkins diet to the traditional ketogenic diet? Epilepsia, 2010. 51(12): p. 2496-2499

It has been reported that children can maintain seizure control when the ketogenic diet (KD) is transitioned to the less-restrictive modified Atkins diet (MAD). What is unknown, however, is the likelihood of additional seizure control from a switch from the MAD to the KD. Retrospective information was obtained from 27 patients who made this dietary change from four different institutions. Ten (37%) patients had .10% additional seizure reduction with the KD over the MAD, of which five became seizure-free. The five children who did not improve on the MAD failed to improve when transitioned to the KD. A higher incidence of improvement with the KD occurred for those with myoclonic.astatic epilepsy (70% vs. 12% for all other etiologies, p = 0.004), including all who became seizure-free. These results suggest that the KD probably represents a ghigher dose h of dietary therapy than the MAD, which may parcularly benefit those with myoclonic.astatic epilepsy. 39. Kossoff, A pilot study of the modified Atkins diet for SturgeWeber syndrome. Epilepsy Research, 2010. 92(2): p. 240-243

The modified Atkins diet (MAD) is a dietary treatment for epilepsy which does not restrict fluids or calories. This theoretically makes the MAD safer than the ketogenic diet for children with SturgeWeber syndrome (SWS). Five children aged 418 years with SWS and at least monthly intractable seizures were started prospectively on the MAD for 6 months. All children had urinary ketosis and seizure improvement, including 3 with >50% seizure reduction. 40. Kossoff, Prospective Study of the Modified Atkins Diet in Combination With a Ketogenic Liquid Supplement During the Initial Month. Journal of Child Neurology, 2011. 26(2): p. 147-151

The modified Atkins diet is a high-fat, low-carbohydrate treatment for intractable childhood epilepsy. As data suggest that a stricter diet onset can be more effective, we added a ketogenic supplement to the modified Atkins diet during its initial month. Thirty children with intractable epilepsy were prospectively started on the modified Atkins diet in combination with a daily 400-calorie KetoCal shake. At 1 month, 24 (80%) children had >50% seizure reduction, of which 11 (37%) had >90% seizure reduction. There was no significant loss of efficacy during the second month after KetoCal was discontinued. The use of this ketogenic supplement increased daily fat intake and thus the ketogenic ratio (1.8:1 versus 1.0:1 in the modified Atkins diet alone, P = .0002), but did not change urinary or serum ketosis. The addition of a ketogenic supplement to the modified Atkins diet during its initial month appears to be beneficial. 41. Kossoff, E.H., More fat and fewer seizures: dietary therapies for epilepsy. Lancet Neurol, 2004. 3(7): p. 415-420

The ketogenic diet is a high-fat, adequate protein, low carbohydrate diet that has been used for the treatment of intractable childhood epilepsy since the 1920s. The diet mimics the biochemical changes associated with starvation, which create ketosis. Although less commonly used in later decades because of the increased availability of anticonvulsants, the ketogenic diet has re-emerged as a therapeutic option. Only

10

a decade ago the ketogenic diet was seen as a last resort; however, it has become more commonly used in academic centres throughout the world even early in the course of epilepsy. The Atkins diet is a recently used, less restrictive, therapy that also creates ketosis and can lower the number of seizures. Dietary therapies may become even more valuable in the therapy of epilepsy when the mechanisms underlying their success are understood. 42. Krebs, Efficacy and Safety of a High Protein, Low Carbohydrate Diet for Weight Loss in Severely Obese Adolescents. J Pediatr, 2010 OBJECTIVE: To evaluate the efficacy and safety of a carbohydrate restricted versus a low fat diet on weight loss, metabolic markers, body composition, and cardiac function tests in severely obese adolescents. STUDY DESIGN: Subjects were randomly assigned to 1 of 2 diets: a high protein, low carbohydrate (20 g/d) diet (high protein, low carbohydrate, HPLC) or low fat (30% of calories) regimen for 13 weeks; close monitoring was maintained to evaluate safety. After the intervention, no clinical contact was made until follow-up measurements were obtained at 24 and 36 weeks from baseline. The primary outcome was change in body mass index Z-score for age and sex (BMI-Z) at 13, 24, and 36 weeks. RESULTS: Forty-six subjects (24 HPLC, 22 in low fat) initiated and 33 subjects completed the intervention; follow-up data were available on approximately half of the subjects. Significant reduction in (BMI-Z) was achieved in both groups during intervention and was significantly greater for the HPLC group (P = .03). Both groups maintained significant BMI-Z reduction at follow-up; changes were not significantly different between groups. Loss of lean body mass was not spared in the HPLC group. No serious adverse effects were observed related to metabolic profiles, cardiac function, or subjective complaints. CONCLUSIONS: The HPLC diet is a safe and effective option for medically supervised weight loss in severely obese adolescents. Copyright 2010 Mosby, Inc. All rights reserved. PMID: 20304413 [PubMed - as supplied by publisher] 43. Kumada, Modified Atkins Diet for the Treatment of Nonconvulsive Status Epilepticus in Children. Journal of Child Neurology, 2010. 25(4): p. 485-489

The authors describe the use of a modified Atkins diet for the treatment of 2 children with nonconvulsive status epilepticus. Patient 1 was a 4-yearand-11-month-old girl diagnosed with frontal lobe epilepsy. Since the age of 3 years and 10 months, she had daily nonconvulsive status epilepticus resistant to antiepileptic agents. Patient 2 was a 5-year-and-5-month-old girl with subcortical band heterotopia. She had nonconvulsive status epilepticus daily since the age of 5 years. They were treated with the modified Atkins diet, in which carbohydrate intake was restricted to 10 g/d without restriction on protein, caloric, or fluid intake. The nonconvulsive status epilepticus disappeared 5 and 10 days after the initiation of the diet treatment, respectively. They have been on the diet treatment and free from nonconvulsive status epilepticus for 19 and 4 months, respectively. The modified Atkins diet appears to be very effective for the treatment of nonconvulsive status epilepticus. Kumada, Efficacy and tolerability of modified Atkins diet in Japanese children with medication-resistant epilepsy. Brain and Development, 2011 Ten Japanese patients aged 1.517 years with medication-resistant epilepsy were placed on the modified Atkins diet (MAD) for 3 weeks during admission to our hospital. Dietary carbohydrate was restricted to 10 g per day. We studied the efficacy of the diet regarding the seizure frequency and tolerability of the diet at the end of the 3 weeks on the diet. Those who decided to continue the MAD at the time of discharge were followed up in the out-patient clinic to observe the effect of the diet on the seizure frequency. Three of the 10 patients could not continue the diet during the 3-week admission; one had rotavirus enterocolitis and the other 2 disliked the diet. Among the remaining 7 patients who could continue the diet for 3 weeks, 3 achieved the seizure reduction; 2 became seizure-free and 1 showed about 75% reduction in the seizure frequency within 10 days on the diet. All of these 3 patients continued the diet after the 3-week admission. The other 4 patients did not show a reduction of the seizure frequency by the end of the 3 weeks on the diet. Two of them discontinued the diet on discharge. The remaining 2 still continued the diet at home and one became seizure-free 3 months after the start of the diet. In total, 4 of 10 patients achieved >75% reduction in the seizure frequency, although relapse occurred in 2 of the patients, at 5 months and 2 years after seizure reduction, respectively. The MAD was effective and well-tolerated in children with medication-resistant epilepsy in Japan. 45. Martin, Change in food cravings, food preferences, and appetite during a low-carbohydrate and low-fat diet. Obesity, 2011. 19(10): p. 1963-1970 44.

The study objective was to evaluate the effect of prescribing a low-carbohydrate diet (LCD) and a low-fat diet (LFD) on food cravings, food preferences, and appetite. Obese adults were randomly assigned to a LCD (n=134) or a LFD (n=136) for two years. Cravings for specific types of foods (sweets, high-fats, fast-food fats, carbohydrates/starches); preferences for high-sugar, highcarbohydrate, and lowcarbohydrate/high-protein foods; and appetite were measured during the trial and evaluated during this secondary analysis of trial data. Differences between the LCD and LFD on change in outcome variables were examined with mixed linear models. Compared to the LFD, the LCD had significantly larger decreases in cravings for carbohydrates/starches and preferences for high-carbohydrate and high-sugar foods. The LCD group reported being less bothered by hunger compared to the LFD group. Compared to the LCD group, the LFD group had significantly larger decreases in cravings for high-fat foods and preference for low-carbohydrate/high-protein foods. Men had larger decreases in appetite ratings compared to women. Prescription of diets that promoted restriction of specific types of foods resulted in decreased cravings and preferences for the foods that were targeted for restriction. The results also indicate that the LCD group was less bothered by hunger compared to the LFD group and that men had larger reductions in appetite compared to women. 46. Mavropoulos, The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutrition and Metabolism, 2005. 2(35) Background

11

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age and is associated with obesity, hyperinsulinemia, and insulin resistance. Because low carbohydrate diets have been shown to reduce insulin resistance, this pilot study investigated the six-month metabolic and endocrine effects of a low-carbohydrate, ketogenic diet (LCKD) on overweight and obese women with PCOS. Results Eleven women with a body mass index >27 kg/m2 and a clinical diagnosis of PCOS were recruited from the community. They were instructed to limit their carbohydrate intake to 20 grams or less per day for 24 weeks. Participants returned every two weeks to an outpatient research clinic for measurements and reinforcement of dietary instruction. In the 5 women who completed the study, there were significant reductions from baseline to 24 weeks in body weight (-12%), percent free testosterone (-22%), LH/FSH ratio (-36%), and fasting insulin (54%). There were non-significant decreases in insulin, glucose, testosterone, HgbA1c, triglyceride, and perceived body hair. Two women became pregnant despite previous infertility problems. Conclusion In this pilot study, a LCKD led to significant improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity and PCOS over a 24 week period. 47. McAuley, Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin-resistant obese women. Diabetologia, 2005. 48(1): p. 8-16

AIMS/HYPOTHESIS: A diet low in saturated fatty acids and rich in wholegrains, vegetables and fruit is recommended in order to reduce the risk of obesity, cardiovascular disease and type 2 diabetes mellitus. However there is widespread interest in high-fat ("Atkins Diet") and highprotein ("Zone Diet") alternatives to the conventional high-carbohydrate, high-fibre approach. We report on a randomised trial that compared these two alternative approaches with a conventional diet in overweight insulin-resistant women. METHODS: Ninety-six normoglycaemic, insulin-resistant women (BMI >27 kg/m(2)) were randomised to one of three dietary interventions: a highcarbohydrate, high-fibre (HC) diet, the high-fat (HF) Atkins Diet, or the high-protein (HP) Zone Diet. The experimental approach was designed to mimic what might be achieved in clinical practice: the recommendations involved advice concerning food choices and were not prescriptive in terms of total energy. There were supervised weight loss and weight maintenance phases (8 weeks each), but there was no contact between the research team and the participants during the final 8 weeks of the study. Outcome was assessed in terms of body composition and indicators of cardiovascular and diabetes risk. RESULTS: Body weight, waist circumference, triglycerides and insulin levels decreased with all three diets but, apart from insulin, the reductions were significantly greater in the HF and HP groups than in the HC group. These observations suggest that the popular diets reduced insulin resistance to a greater extent than the standard dietary advice did. When compared with the HC diet, the HF and HP diets were shown to produce significantly (p<0.01) greater reductions in several parameters, including weight loss (HF -2.8 kg, HF -2.7 kg), waist circumference (HF -3.5 cm, HF -2.7 cm) and triglycerides (HF -0.30 mmol/l, HF -0.22 mmol/l). LDL cholesterol decreased in individuals on the HC and HP diets, but tended to fluctuate in those on the HF diet to the extent that overall levels were significantly lower in the HP group than in the HF group (-0.28 mmol/l, 95% CI 0.04-0.52, p=0.02). Of those on the HF diet, 25% showed a >10% increase in LDL cholesterol, whereas this occurred in only 13% of subjects on the HC diet and 3% of those on the HP diet. CONCLUSIONS/INTERPRETATION: In routine practice a reduced-carbohydrate, higher protein diet may be the most appropriate overall approach to reducing the risk of cardiovascular disease and type 2 diabetes. To achieve similar benefits on a HC diet, it may be necessary to increase fibre-rich wholegrains, legumes, vegetables and fruits, and to reduce saturated fatty acids to a greater extent than appears to be achieved by implementing current guidelines. The HF approach appears successful for weight loss in the short term, but lipid levels should be monitored. The potential deleterious effects of the diet in the long term remain a concern. 48. McClellan, Clinical Calorimetry. XLV: Prolonged Meat Diets with a Study Kidney Function & Ketosis. The Journal of Biological Chemistry, 1930 McClellan, Clinical calorimetry. XLV: Prolonged Meat Diets with a Study of the Metabolism of Nitrogen, Calcium and Phosphorous. The Journal of Biological Chemistry, 1930 Meckling, Comparison of a low-fat diet to a low-carbohydrate diet on weight loss, body composition, and risk factors for diabetes and cardiovascular disease in free-living, overweight men and women. J Clin Endocrinol Metab, 2004. 89(6): p. 2717-23

49.

50.

Overweight and obese men and women (24-61 yr of age) were recruited into a randomized trial to compare the effects of a low-fat (LF) vs. a lowcarbohydrate (LC) diet on weight loss. Thirty-one subjects completed all 10 wk of the diet intervention (retention, 78%). Subjects on the LF diet consumed an average of 17.8% of energy from fat, compared with their habitual intake of 36.4%, and had a resulting energy restriction of 2540 kJ/d. Subjects on the LC diet consumed an average of 15.4% carbohydrate, compared with habitual intakes of about 50% carbohydrate, and had a resulting energy restriction of 3195 kJ/d. Both groups of subjects had significant weight loss over the 10 wk of diet intervention and nearly identical improvements in body weight and fat mass. LF subjects lost an average of 6.8 kg and had a decrease in body mass index of 2.2 kg/m(2), compared with a loss of 7.0 kg and decrease in body mass index of 2.1 kg/m(2) in the LC subjects. The LF group better preserved lean body mass when compared with the LC group; however, only the LC group had a significant decrease in circulating insulin concentrations. Group results indicated that the diets were equally effective in reducing systolic blood

12

pressure by about 10 mm Hg and diastolic pressure by 5 mm Hg and decreasing plasminogen activator inhibitor-1 bioactivity. Blood betahydroxybutyrate concentrations were increased in the LC only, at the 2- and 4-wk time points. These data suggest that energy restriction achieved by a very LC diet is equally effective as a LF diet strategy for weight loss and decreasing body fat in overweight and obese adults. 51. Miranda, Danish study of a Modified Atkins diet for medically intractable epilepsy in children: Can we achieve the same results as with the classical ketogenic diet. Seizure, 2011. 20(2): p. 151-155

Modified Atkins diet (MAD) is a less restrictive variety of the classical ketogenic diet (KD), used for treating patients with medically resistant epilepsy. There are only few reports comparing the two types of diets in terms of seizure reduction and tolerability. We compared the effect of a MAD evaluated prospectively on 33 consecutive children with medically resistant epilepsy, with a group of 50 patients, previously treated with KD. Patients who had >50% seizure reduction were considered responders. After 3 months on the MAD, 17 patients (52%) were responders, including 14 (42%) who had >90% seizure reduction. After 6 months, 13 patients (39%) were responders. Seventeen patients (52%) remained on the MAD at least 12 months with excellent overall tolerance and compliance, including 9 patients (27%) who were responders, 4 of them (12%) having >90% seizure reduction. Although there was a trend for higher incidence of responders in the KD group, this failed to reach the level of significance: after 6 months 39% on MAD and 60% on KD were responders. However, this trend was not observed when the two groups were adjusted for difference in age (patients in the MAD group were older than the KD group). In conclusion, our experience suggests that the MAD is similarly effective as the KD in reducing seizure frequency in children with medically resistant epilepsy. 52. Morgan, Comparison of the effects of four commercially available weight-loss programmes on lipid-based cardiovascular risk factors. Public Health Nutrition, 2008. 12(6): p. 799-807

Objective: To investigate the relative efficacy of four popular weight-loss programmes on plasma lipids and lipoproteins as measures of CVD risk. Design: A multi-centred, randomised, controlled trial of four diets Dr Atkins New Diet Revolution, The Slim-Fast Plan, Weight Watchers Pure Points programme and Rosemary Conleys Eat yourself Slim Diet and Fitness Plan against a control diet, in parallel for 6 months. Setting and subjects: The trial was conducted at five universities across the UK (Surrey, Nottingham, Ulster (Coleraine), Bristol and Edinburgh (Queen Margaret University College)) and involved the participation of 300 overweight and obese males and females aged 21 60 years in a community setting. Results: Significant weight loss was achieved by all dieting groups (59 kg at 6 months) but no significant difference was observed between diets at 6 months. The Weight Watchers and Rosemary Conley (low-fat) diets were followed by significant reductions in plasma LDL cholesterol (both 212?2% after 6 months, P,0?01), whereas the Atkins (low-carbohydrate) and Weight Watchers diets were followed by marked reductions in plasma TAG (38?2% and 22?6% at 6 months respectively, P,0?01). These latter two diets were associated with an increase in LDL particle size, a change that has been linked to reduced CVD risk. Conclusions: Overall, these results demonstrate the favourable effects of weight loss on lipid-mediated CVD risk factors that can be achieved through commercially available weight-loss programmes. No detrimental effects on lipid-based CVD risk factors were observed in participants consuming a low-carbohydrate diet. 53. 54. Nickols-Richardson. Premenopausal women following a low-carbohydrate/high-protein diet experience greater weight loss and less hunger compared to a high-carbohydrate/low-fat diet. in Experiemental Biology 2004. 2004. Washington, D.C. Nielsen, Low-carbohydrate diet in type 2 diabetes: stable improvement of bodyweight and glycemic control during 44 months follow-up. Nutrition and Metabolism, 2008. 5(14): p. 1-6

Background: Low-carbohydrate diets, due to their potent antihyperglycemic effect, are an intuitively attractive approach to the management of obese patients with type 2 diabetes. We previously reported that a 20% carbohydrate diet was significantly superior to a 5560% carbohydrate diet with regard to bodyweight and glycemic control in 2 groups of obese diabetes patients observed closely over 6 months (intervention group, n = 16; controls, n = 15) and we reported maintenance of these gains after 22 months. The present study documents the degree to which these changes were preserved in the low-carbohydrate group after 44 months observation time, without close follow-up. In addition, we assessed the performance of the two thirds of control patients from the high-carbohydrate diet group that had changed to a low-carbohydrate diet after the initial 6 month observation period. We report cardiovascular outcome for the lowcarbohydrate group as well as the control patients who did not change to a lowcarbohydrate diet. Method: Retrospective follow-up of previously studied subjects on a low carbohydrate diet. Results: The mean bodyweight at the start of the initial study was 100.6 14.7 kg. At six months it was 89.2 14.3 kg. From 6 to 22 months, mean bodyweight had increased by 2.7 4.2 kg to an average of 92.0 14.0 kg. At 44 months average weight has increased from baseline g to 93.1 14.5 kg. Of the sixteen patients, five have retained or reduced bodyweight since the 22 month point and all but one have lower weight at 44 months than at start. The initial mean HbA1c was 8.0 1.5%. After 6, 12 and 22 months, HbA1c was 6.1 1.0%, 7.0 1.3% and 6.9 1.1% respectively. After 44 months mean HbA1c is 6.8 1.3%. Of the 23 patients who have used a low-carbohydrate diet and for whom we have long-term data, two have suffered a cardiovascular event while four of the six controls who never changed diet have suffered several cardiovascular events. Conclusion: Advice to obese patients with type 2 diabetes to follow a 20% carbohydrate diet with some caloric restriction has lasting effects on bodyweight and glycemic control. 55. OBrien, Diet-Induced Weight Loss Is Associated with Decreases in Plasma Serum Amyloid A and C-Reactive Protein Independent of Dietary Macronutrient Composition in Obese Subjects. The Journal of Clinical Endocrinology & Metabolism, 2005. 90(4): p. 2244-2249

13

Elevated levels of serum amyloid A (SAA) and C-reactive protein (CRP) have been associated with increased cardiovascular risk. Although levels of CRP decrease with weight loss, it is not known whether SAA decreases with weight loss or whether dietary macronutrient composition affects levels of either SAA or CRP. SAA and CRP levels were measured retrospectively on baseline and 3-month plasma samples from 41obese (mean body mass index 33.63 _ 1.86 kg/m2) women completing a randomized trial comparing a low-fat diet (n _ 19)and a very low-carbohydrate diet (n _ 22). For the 41 participants, there were significant decreases from baseline to 3 months in both LogSAA (P _ 0.049) and LogCRP (P _ 0.035). The very low-carbohydrate dieters had a significantly greater decrease in LogSAA (P _ 0.04), but their weight loss also was significantly greater (_7.6 _ 3.2 vs. _4.3 _ 3.5 kg, P < 0.01). In this study, the decreases in inflammatory markers correlated significantly with weight loss (r _ 0.44, P _ 0.004 vs. LogSAA and r _ 0.35, P _ 0.03 vs. LogCRP). Also, change in LogSAA correlated with change in insulin resistance (r _ 0.35, P _0.03). Thus, in otherwise healthy, obese women, weight loss was associated with significant decreases in both SAA and CRP. These effects were proportional to the amount of weight lost but independent of dietary macronutrient composition. (J Clin Endocrinol Metab 90: 22442249, 2005) 56. Phinney, The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation. Metabolism, 1983. 32(8): p. 757-68

To study the metabolic effects of ketosis without weight loss, nine lean men were fed a eucaloric balanced diet (EBD) for one week providing 35-50 kcal/kg/d, 1.75 g of protein per kilogram per day and the remaining kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD)--isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented with minerals and vitamins. Weight and whole-body potassium estimated by potassium-40 counting (40K) did not vary significantly during the five-week study. Nitrogen balance (N-Bal) was regained after one week of the EKD. The fasting blood glucose remained lower during the EKD than during the control diet (4.4 mmol/L at EBD, 4.1 mmol/L at EKD4, P less than 0.01). The fasting whole-body glucose oxidation rate determined by a 13C-glucose primed constant infusion technique fell from 0.71 mg/kg/min during the control diet to 0.50 mg/kg/min (P less than 0.01) during the fourth week of the EKD. The mean serum cholesterol level rose (from 159 to 208 mg/dL) during the EKD, while triglycerides fell from 107 to 79 mg/dL. No disturbance of hepatic or renal function was noted at EKD-4. These findings indicate that the ketotic state induced by the EKD was well tolerated in lean subjects; nitrogen balance was regained after brief adaptation, serum lipids were not pathologically elevated, and blood glucose oxidation at rest was measurably reduced while the subjects remained euglycemic. 57. Porta, Comparison of seizure reduction and serum fatty acid levels after receiving the ketogenic and modified Atkins diet. Seizure, 2009. 18(1): p. 359-364

The ketogenic diet (KD) and the modified Atkins diet are effective therapies for intractable epilepsy. We compared retrospectively the KD and modified Atkins diet in 27 children and also assessed serum long chain fatty acid profiles. After 3 months, using an intent-to-treat analysis, the KD was more successful, with >50% seizure reduction in 11/17 (65%) vs. 2/10 (20%) with the modified Atkins diet, p = 0.03. After 6 months, however, the difference was no longer significant: 7/17 (41%) vs. 2/10 (20%) (p = 0.24). We observed a preventive effect of both diets on the occurrence of status epilepticus. After 1 and 3 months of either diet, responders experienced a significant decrease in serum arachidonic acid concentration compared to non-responders. The KD and modified Atkins diet led to seizure reduction in this small pilot series, with slightly better results after 3 months with the KD, but not after 6 months. The decrease of serum arachidonic acid levels might be involved in the anticonvulsive effects of KD or modified Atkins diet. 58. Samaha, A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med, 2003. 348(21): p. 2074-81

BACKGROUND: The effects of a carbohydrate-restricted diet on weight loss and risk factors for atherosclerosis have been incompletely assessed. METHODS: We randomly assigned 132 severely obese subjects (including 77 blacks and 23 women) with a mean body-mass index of 43 and a high prevalence of diabetes (39 percent) or the metabolic syndrome (43 percent) to a carbohydrate-restricted (low-carbohydrate) diet or a calorie- and fat-restricted (low-fat) diet. RESULTS: Seventy-nine subjects completed the six-month study. An analysis including all subjects, with the last observation carried forward for those who dropped out, showed that subjects on the low-carbohydrate diet lost more weight than those on the low-fat diet (mean [+/-SD], -5.8+/-8.6 kg vs. -1.9+/-4.2 kg; P=0.002) and had greater decreases in triglyceride levels (mean, -20+/-43 percent vs. -4+/-31 percent; P=0.001), irrespective of the use or nonuse of hypoglycemic or lipidlowering medications. Insulin sensitivity, measured only in subjects without diabetes, also improved more among subjects on the lowcarbohydrate diet (6+/-9 percent vs. -3+/-8 percent, P=0.01). The amount of weight lost (P<0.001) and assignment to the lowcarbohydrate diet (P=0.01) were independent predictors of improvement in triglyceride levels and insulin sensitivity. CONCLUSIONS: Severely obese subjects with a high prevalence of diabetes or the metabolic syndrome lost more weight during six months on a carbohydrate-restricted diet than on a calorie- and fat-restricted diet, with a relative improvement in insulin sensitivity and triglyceride levels, even after adjustment for the amount of weight lost. This finding should be interpreted with caution, given the small magnitude of overall and between-group differences in weight loss in these markedly obese subjects and the short duration of the study. Future studies evaluating long-term cardiovascular outcomes are needed before a carbohydrate-restricted diet can be endorsed. 59. 60. Segal-Isaacson. One Year Data From A Prospective Cohort of Low Carbohydrate Dieters. in 2004 North American Society for the Study of Obesity Conference. 2004. Las Vegas, Nevada. Seshadri, A randomized study comparing the effects of a low-carbohydrate diet and a conventional diet on lipoprotein subfractions and Creactive protein levels in patients with severe obesity. Am J Med, 2004. 117(6): p. 398-405

14

PURPOSE: To compare the effects of a low-carbohydrate diet and a conventional (fat- and calorie-restricted) diet on lipoprotein subfractions and inflammation in severely obese subjects. METHODS: We compared changes in lipoprotein subfractions and C-reactive protein levels in 78 severely obese subjects, including 86% with either diabetes or metabolic syndrome, who were randomly assigned to either a lowcarbohydrate or conventional diet for 6 months. RESULTS: Subjects on a low-carbohydrate diet experienced a greater decrease in large very low-density lipoprotein (VLDL) levels (difference = -0.26 mg/dL, P = 0.03) but more frequently developed detectable chylomicrons (44% vs. 22%, P = 0.04). Both diet groups experienced similar decreases in the number of low-density lipoprotein (LDL) particles (difference = -30 nmol/L, P = 0.74) and increases in large high-density lipoprotein (HDL) concentrations (difference = 0.70 mg/dL, P = 0.63). Overall, C-reactive protein levels decreased modestly in both diet groups. However, patients with a high-risk baseline level (>3 mg/dL, n = 48) experienced a greater decrease in C-reactive protein levels on a low-carbohydrate diet (adjusted difference = -2.0 mg/dL, P = 0.005), independent of weight loss. CONCLUSION: In this 6-month study involving severely obese subjects, we found an overall favorable effect of a low-carbohydrate diet on lipoprotein subfractions, and on inflammation in high-risk subjects. Both diets had similar effects on LDL and HDL subfractions. 61. Shai, Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet. The New England Journal of Medicine, 2008. 359(3): p. 229241

Background Trials comparing the effectiveness and safety of weight-loss diets are frequently limited by short follow-up times and high dropout rates. Methods In this 2-year trial, we randomly assigned 322 moderately obese subjects (mean age, 52 years; mean body-mass index [the weight in kilograms divided by the square of the height in meters], 31; male sex, 86%) to one of three diets: low-fat, restricted-calorie; Mediterranean, restricted-calorie; or low-carbohydrate, nonrestricted-calorie. Results The rate of adherence to a study diet was 95.4% at 1 year and 84.6% at 2 years. The Mediterranean-diet group consumed the largest amounts of dietary fiber and had the highest ratio of monounsaturated to saturated fat (P<0.05 for all comparisons among treatment groups). The low-carbohydrate group consumed the smallest amount of carbohydrates and the largest amounts of fat, protein, and cholesterol and had the highest percentage of participants with detectable urinary ketones (P<0.05 for all comparisons among treatment groups). The mean weight loss was 2.9 kg for the low-fat group, 4.4 kg for the Mediterranean-diet group, and 4.7 kg for the low-carbohydrate group (P<0.001 for the interaction between diet group and time); among the 272 participants who completed the intervention, the mean weight losses were 3.3 kg, 4.6 kg, and 5.5 kg, respectively. The relative reduction in the ratio of total cholesterol to high-density lipoprotein cholesterol was 20% in the low-carbohydrate group and 12% in the low-fat group (P = 0.01). Among the 36 subjects with diabetes, changes in fasting plasma glucose and insulin levels were more favorable among those assigned to the Mediterranean diet than among those assigned to the low-fat diet (P<0.001 for the interaction among diabetes and Mediterranean diet and time with respect to fasting glucose levels). Conclusions Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets. The more favorable effects on lipids (with the low-carbohydrate diet) and on glycemic control (with the Mediterranean diet) suggest that personal preferences and metabolic considerations might inform individualized tailoring of dietary interventions. (ClinicalTrials.gov number, NCT00160108.) 62. Shai, Dietary Intervention to Reverse Carotid Atherosclerosis. CIRCULATION AHA, 2010. 121(10): p. 1200-8

Dietary intervention to reverse carotid atherosclerosis. Shai I, Spence JD, Schwarzfuchs D, Henkin Y, Parraga G, Rudich A, Fenster A, Mallett C, Liel-Cohen N, Tirosh A, Bolotin A, Thiery J, Fiedler GM, Blher M, Stumvoll M, Stampfer MJ; DIRECT Group. Department of Epidemiology and Health Systems Evaluation, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. irish@bgu.ac.il Abstract BACKGROUND: It is currently unknown whether dietary weight loss interventions can induce regression of carotid atherosclerosis. METHODS AND RESULTS: In a 2-year Dietary Intervention Randomized Controlled Trial-Carotid (DIRECT-Carotid) study, participants were randomized to low-fat, Mediterranean, or low-carbohydrate diets and were followed for changes in carotid artery intima-media thickness, measured with standard B-mode ultrasound, and carotid vessel wall volume (VWV), measured with carotid 3D ultrasound. Of 140 complete images of participants (aged 51 years; body mass index, 30 kg/m(2); 88% men), higher baseline carotid VWV was associated with increased intima-media thickness, age, male sex, baseline weight, blood pressure, and insulin levels (P<0.05 for all). After 2 years of dietary intervention, we observed a significant 5% regression in mean carotid VWV (-58.1 mm(3;) 95% confidence interval, -81.0 to -35.1 mm(3); P<0.001), with no differences in the low-fat, Mediterranean, or low-carbohydrate groups (-60.69 mm(3), -37.69 mm(3), -84.33 mm(3), respectively; P=0.28). Mean change in intima-media thickness was -1.1% (P=0.18). A reduction in the ratio of apolipoprotein B(100) to apolipoprotein A1 was observed in the low-carbohydrate compared with the low-fat group (P=0.001). Participants who exhibited carotid VWV regression (mean decrease, -128.0 mm(3); 95% confidence interval, -148.1 to -107.9 mm(3)) compared with participants who exhibited progression (mean increase, +89.6 mm(3); 95% confidence interval, +66.6 to +112.6 mm(3)) had achieved greater weight loss (5.3 versus -3.2 kg; P=0.03), greater decreases in systolic blood pressure (-6.8 versus -1.1 mm Hg; P=0.009) and total homocysteine (-0.06 versus +1.44 mumol/L; P=0.04), and a higher increase of apolipoprotein A1 (+0.05 versus -0.00 g/L; P=0.06). In multivariate regression models, only the decrease in systolic blood pressure remained a significant independent modifiable predictor of subsequent greater regression in both carotid VWV (beta=0.23; P=0.01) and intima-media thickness (beta=0.28; P=0.008) levels. CONCLUSIONS: Two-year weight loss diets can induce a significant regression of measurable carotid VWV. The effect is similar in low-fat, Mediterranean, or lowcarbohydrate strategies and appears to be mediated mainly by the weight loss-induced decline in blood pressure. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00160108.

15

PMID: 20194883 [PubMed - indexed for MEDLINE] 63. Sharma, Use of the modified Atkins diet in infantile spasms refractory to first-line treatment. Seizure, 2011 This prospective, open label, uncontrolled study was performed to evaluate the efficacy and tolerability of the modified Atkins diet in children with refractory infantile spasms. Fifteen consecutive children aged six months to three years having daily infantile spasms in clusters with electroencephalographic evidence of hypsarrhythmia despite treatment with hormonal treatment (oral corticosteroids/adrenocorticotrophic hormone) and/or vigabatrin, and at least one additional anti-epileptic drug were enrolled. Children with known or suspected inborn errors of metabolism or systemic illnesses were excluded. Carbohydrate intake was restricted to ten grams/day. Among these 12 boys and three girls (median age-24 months), 13 had symptomatic etiology. After three months of diet, six children were spasm free. The time to spasm freedom after diet initiation ranged from two days to two months. The most frequent adverse effect observed was constipation. The modified Atkins diet was found to be effective and well tolerated in children with refractory infantile spasms (ClinicalTrials.gov identifier: NCT01006811). 64. Sharman, A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. J Nutr, 2002. 132(7): p. 1879-85

Very low-carbohydrate (ketogenic) diets are popular yet little is known regarding the effects on serum biomarkers for cardiovascular disease (CVD). This study examined the effects of a 6-wk ketogenic diet on fasting and postprandial serum biomarkers in 20 normal-weight, normolipidemic men. Twelve men switched from their habitual diet (17% protein, 47% carbohydrate and 32% fat) to a ketogenic diet (30% protein, 8% carbohydrate and 61% fat) and eight control subjects consumed their habitual diet for 6 wk. Fasting blood lipids, insulin, LDL particle size, oxidized LDL and postprandial triacylglycerol (TAG) and insulin responses to a fat-rich meal were determined before and after treatment. There were significant decreases in fasting serum TAG (-33%), postprandial lipemia after a fat-rich meal (-29%), and fasting serum insulin concentrations (-34%) after men consumed the ketogenic diet. Fasting serum total and LDL cholesterol and oxidized LDL were unaffected and HDL cholesterol tended to increase with the ketogenic diet (+11.5%; P = 0.066). In subjects with a predominance of small LDL particles pattern B, there were significant increases in mean and peak LDL particle diameter and the percentage of LDL-1 after the ketogenic diet. There were no significant changes in blood lipids in the control group. To our knowledge this is the first study to document the effects of a ketogenic diet on fasting and postprandial CVD biomarkers independent of weight loss. The results suggest that a short-term ketogenic diet does not have a deleterious effect on CVD risk profile and may improve the lipid disorders characteristic of atherogenic dyslipidemia. 65. Sharman, Very low-carbohydrate and low-fat diets affect fasting lipids and postprandial lipemia differently in overweight men. J Nutr, 2004. 134(4): p. 880-5

Hypoenergetic very low-carbohydrate and low-fat diets are both commonly used for short-term weight loss; however, few studies have directly compared their effect on blood lipids, with no studies to our knowledge comparing postprandial lipemia, an important independently identified cardiovascular risk factor. The primary purpose of this study was to compare the effects of a very low-carbohydrate and a lowfat diet on fasting blood lipids and postprandial lipemia in overweight men. In a balanced, randomized, crossover design, overweight men (n = 15; body fat >25%; BMI, 34 kg/m(2)) consumed 2 experimental diets for 2 consecutive 6-wk periods. One was a very lowcarbohydrate (<10% energy as carbohydrate) diet and the other a low-fat (<30% energy as fat) diet. Blood was drawn from fasting subjects on separate days and an oral fat tolerance test was performed at baseline, after the very low-carbohydrate diet period, and after the low-fat diet period. Both diets had the same effect on serum total cholesterol, serum insulin, and homeostasis model analysis-insulin resistance (HOMA-IR). Neither diet affected serum HDL cholesterol (HDL-C) or oxidized LDL (oxLDL) concentrations. Serum LDL cholesterol (LDL-C) was reduced (P < 0.05) only by the low-fat diet (-18%). Fasting serum triacylglycerol (TAG), the TAG/HDL-C ratio, and glucose were significantly reduced only by the very low-carbohydrate diet (-44, -42, and -6%, respectively). Postprandial lipemia was significantly reduced when the men consumed both diets compared with baseline, but the reduction was significantly greater after intake of the very low-carbohydrate diet. Mean and peak LDL particle size increased only after the very low-carbohydrate diet. The short-term hypoenergetic low-fat diet was more effective at lowering serum LDL-C, but the very low-carbohydrate diet was more effective at improving characteristics of the metabolic syndrome as shown by a decrease in fasting serum TAG, the TAG/HDL-C ratio, postprandial lipemia, serum glucose, an increase in LDL particle size, and also greater weight loss (P < 0.05). Sharman, Weight loss leads to reductions in inflammatory biomarkers after a very low-carbohydrate and low-fat diet in overweight men. Clinical Science (London), 2004 In recent years, it has become apparent that low-grade vascular inflammation plays a key role in all stages of the pathogenesis of atherosclerosis. Weight loss has been shown to improve blood inflammatory markers; however, it is unknown if weight loss diets varying in macronutrient composition differentially affect inflammatory responses. The primary purpose of this study was to compare a very lowcarbohydrate and a low-fat weight loss diet on inflammatory biomarkers in overweight men. In a randomized cross-over design, fifteen overweight men (body fat >25%, body mass index 34 kg/m 2) consumed two experimental weight loss diets for 2 consecutive 6 wk periods: a very low-carbohydrate (<10% energy carbohydrate) and a low-fat (<30% energy fat) diet. Both the low-fat and the very lowcarbohydrate diet resulted in significant decreases in absolute concentrations of hsTNF-alpha, hsIL-6, hs-CRP and sICAM-1. There was no significant change in absolute sP-selectin concentrations after either diet. Normalized inflammatory values represented as the delta change per one kilogram reduction in body mass showed a significant difference between the two diets only for sP-selectin (P<0.05). In summary, energy-restricted low-fat and very low-carbohydrate diets both significantly decreased several biomarkers of inflammation. 66.

16

These data suggest that in the short-term weight loss is primarily the driving force underlying the reductions in most of the inflammatory biomarkers. 67. Siegel, A 6-Month, Office-Based, Low-Carbohydrate Diet Intervention in Obese Teens. Clinical Pediatrics, 2009. 48(7): p. 745-749

Background. Previous studies have shown the success of a low-carbohydrate diet (LCD) in adults. In one study, the LCD has also been shown as safe and effective in teens, the study period was only 12 weeks. Furthermore, there is no information on whether the LCD is a practical intervention in a pediatric office setting. Objective. The object of this study was to demonstrate the effectiveness of a LCD in obese children in a primary care pediatric setting. Design/Methods . The study was done in 11 community pediatric practices. Children ages 12 to 18 years with a body mass index (BMI) greater than 95th percentile were put on a LCD of less than 50 grams of carbohydrate daily. Results . A total of 38 of the 63 teens finished the 6-month study and 32 (84%) lost weight (range from a gain of 5.5 kg to a loss of 23.9 kg). There was also a significant decrease in mean BMI (34.9 to 32.5). Conclusions. The LCD appears to an effective and practical officebased intervention in obese teenagers. 68. Siri-Tarino, Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. American Journal of Clinical Nutrition, 2010. 91(3): p. 535-546

Background: A reduction in dietary saturated fat has generally been thought to improve cardiovascular health. Objective: The objective of this meta-analysis was to summarize the evidence related to the association of dietary saturated fat with risk of coronary heart disease (CHD), stroke, and cardiovascular disease (CVD; CHD inclusive of stroke) in prospective epidemiologic studies. Design: Twenty-one studies identified by searching MEDLINE and EMBASE databases and secondary referencing qualified for inclusion in this study. A random-effects model was used to derive composite relative risk estimates for CHD, stroke, and CVD. Results: During 523 y of follow-up of 347,747 subjects, 11,006 developed CHD or stroke. Intake of saturated fat was not associated with an increased risk of CHD, stroke, or CVD. The pooled relative risk estimates that compared extreme quantiles of saturated fat intake were 1.07 (95% CI: 0.96, 1.19; P = 0.22) for CHD, 0.81 (95% CI: 0.62, 1.05; P = 0.11) for stroke, and 1.00 (95% CI: 0.89, 1.11; P = 0.95) for CVD. Consideration of age, sex, and study quality did not change the results. Conclusions: A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD. More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat. 69. Siri-Tarino, Saturated fat, carbohydrate, and cardiovascular disease. American Journal of Clinical Nutrition, 2010. 91(3): p. 502-509

A focus of dietary recommendations for cardiovascular disease (CVD) prevention and treatment has been a reduction in saturated fat intake, primarily as a means of lowering LDL-cholesterol concentrations. However, the evidence that supports a reduction in saturated fat intake must be evaluated in the context of replacement by other macronutrients. Clinical trials that replaced saturated fat with polyunsaturated fat have generally shown a reduction in CVD events, although several studies showed no effects. An independent association of saturated fat intake with CVD risk has not been consistently shown in prospective epidemiologic studies, although some have provided evidence of an increased risk in young individuals and in women. Replacement of saturated fat by polyunsaturated or monounsaturated fat lowers both LDL and HDL cholesterol. However, replacement with a higher carbohydrate intake, particularly refined carbohydrate, can exacerbate the atherogenic dyslipidemia associated with insulin resistance and obesity that includes increased triglycerides, small LDL particles, and reduced HDL cholesterol. In summary, although substitution of dietary polyunsaturated fat for saturated fat has been shown to lower CVD risk, there are few epidemiologic or clinical trial data to support a benefit of replacing saturated fat with carbohydrate. Furthermore, particularly given the differential effects of dietary saturated fats and carbohydrates on concentrations of larger and smaller LDL particles, respectively, dietary efforts to improve the increasing burden of CVD risk associated with atherogenic dyslipidemia should primarily emphasize the limitation of refined carbohydrate intakes and a reduction in excess adiposity. 70. Smith, Efficacy and tolerability of the Modified Atkins Diet in adults with pharmacoresistant epilepsy: A prospective observational study. Epilepsia, 2011. 52(4): p. 775-780

Purpose: Evidence from the pediatric population exists for the efficacy of ketogenic diets in reducing seizure frequency in patients with intractable epilepsy. Recent evidence suggests that a Modified Atkins Diet may be a beneficial form of cotherapy for adult patients with pharmacoresistant epilepsy. Methods: A prospective, open-label study was performed of adults >18 years of age with pharmacoresistant epilepsy. Carbohydrates were restricted to 20 g/day. Fluids and calories from protein and fat were allowed ad libitum. Key Findings: Eighteen patients, ages 1855 years, were initially enrolled. Using an intent-to-treat analysis, 12% had a >50% seizure reduction after 3 months; 28% after 6 months, and 21% after 12 months. Response at 3 months predicted response at 12 months in 79% of patients. The mean decrease in weight was 10.9 kg and the mean decrease in body mass index (BMI) was 3.8, p = 0.01. Fourteen of 18 patients (78%) completed 12 months of this diet. Patients experienced a decrease in triglycerides from (mean) 1.22 to 0.9 mM (p = 0.02). Significance: The Modified Atkins Diet demonstrates modest efficacy as cotherapy for some adults with pharmacoresistant epilepsy and may be also helpful for weight loss. Financial and logistical barriers were significant factors for those who declined enrollment and for those who discontinued the study.

17

71.

Sondike, Effects of a low-carbohydrate diet on weight loss and cardiovascular risk factor in overweight adolescents. J Pediatr, 2003. 142(3): p. 253-8

OBJECTIVES: To compare the effects of a low-carbohydrate (LC) diet with those of a low-fat (LF) diet on weight loss and serum lipids in overweight adolescents. DESIGN: A randomized, controlled 12-week trial. SETTING: Atherosclerosis prevention referral center. METHODS: Random, nonblinded assignment of participants referred for weight management. The study group (LC) (n = 16) was instructed to consume <20 g of carbohydrate per day for 2 weeks, then <40 g/day for 10 weeks, and to eat LC foods according to hunger. The control group (LF) (n = 14) was instructed to consume <30% of energy from fat. Diet composition and weight were monitored and recorded every 2 weeks. Serum lipid profiles were obtained at the start of the study and after 12 weeks. RESULTS: The LC group lost more weight (mean, 9.9 +/9.3 kg vs 4.1 +/- 4.9 kg, P <.05) and had improvement in non-HDL cholesterol levels (P <.05). There was improvement in LDL cholesterol levels (P <.05) in the LF group but not in the LC group. There were no adverse effects on the lipid profiles of participants in either group. CONCLUSIONS: The LC diet appears to be an effective method for short-term weight loss in overweight adolescents and does not harm the lipid profile. 72. 73. Stadler. Impact of 42-day atkins diet and energy-matched low-fat diet on weight and anthropometric indices. in 12th Annual FASEB Meeting on Experimental Biology: Translating the Genome. 2003. San Diego, CA. Stern, The Effects of Low-Carbohydrate versus Conventional Weight Loss Diets in Severely Obese Adults: One-Year Follow-up of a Randomized Trial. Ann Intern Med, 2004. 140(10): p. 778-785

BACKGROUND: A previous paper reported the 6-month comparison of weight loss and metabolic changes in obese adults randomly assigned to either a low-carbohydrate diet or a conventional weight loss diet. OBJECTIVE: To review the 1-year outcomes between these diets. DESIGN: Randomized trial. SETTING: Philadelphia Veterans Affairs Medical Center. PARTICIPANTS: 132 obese adults with a body mass index of 35 kg/m(2) or greater; 83% had diabetes or the metabolic syndrome. INTERVENTION: Participants received counseling to either restrict carbohydrate intake to <30 g per day (low-carbohydrate diet) or to restrict caloric intake by 500 calories per day with <30% of calories from fat (conventional diet). MEASUREMENTS: Changes in weight, lipid levels, glycemic control, and insulin sensitivity. RESULTS: By 1 year, mean (+/-SD) weight change for persons on the low-carbohydrate diet was -5.1 +/- 8.7 kg compared with -3.1 +/- 8.4 kg for persons on the conventional diet. Differences between groups were not significant (-1.9 kg [95% CI, -4.9 to 1.0 kg]; P = 0.20). For persons on the low-carbohydrate diet, triglyceride levels decreased more (P = 0.044) and high-density lipoprotein cholesterol levels decreased less (P = 0.025). As seen in the small group of persons with diabetes (n = 54) and after adjustment for covariates, hemoglobin A(1c) levels improved more for persons on the low-carbohydrate diet. These more favorable metabolic responses to a low-carbohydrate diet remained significant after adjustment for weight loss differences. Changes in other lipids or insulin sensitivity did not differ between groups. Limitations: These findings are limited by a high dropout rate (34%) and by suboptimal dietary adherence of the enrolled persons. CONCLUSION: Participants on a low-carbohydrate diet had more favorable overall outcomes at 1 year than did those on a conventional diet. Weight loss was similar between groups, but effects on atherogenic dyslipidemia and glycemic control were still more favorable with a low-carbohydrate diet after adjustment for differences in weight loss. 74. Tonekaboni, Efficacy of the Atkins Diet as Therapy for Intractable Epilepsy in Children. Archives of Iranian Medicine, 2010. 13(6): p. 492497

Background and Aims: The ketogenic diet is an effective medical therapy for intractable childhood epilepsy. However, it has drawbacks in that it restricts calories, fluids and protein. The Atkins diet may also induce ketosis without those restrictions. Our objective was to evaluate the effcacy of a modifed Atkins diet in children with intractable childhood epilepsy. Methods: This clinical trial was conducted in 51 epileptic children aged 1 16 years with refractory seizures from Feb. 2004 to Oct. 2006. Outcome measures included seizure frequency and adverse reactions. Twenty-seven patients left the study for various reasons, leaving 24 who continued the Atkins diet for a minimum of three months. Carbohydrates were initially limited to 10 g/day and fats constituted 60% of the total energy requirement. All participants received vitamin and calcium supplementation. Results: Following three months of treatment with the Atkins diet, 16 patients (67%) had >50% decrease in seizure frequency, and 6 (25%) had >90% improvement, of whom 5 were seizure-free. Mean seizure frequency after the _rst, second and third months of treatment were signi_cantly lower than at baseline (P values <0.001, 0.001 and 0.002, respectively). Conclusion: The Atkins diet can be considered as a safe and effective alternative therapy for intractable childhood epilepsy. Atkins diet was well tolerated in our patients with rare complications and it appears to demonstrate preliminary efficacy in childhood refractory epilepsy. 75. Vernon, Clinical Experience of a Carbohydrate-Restricted Diet: Effect on Diabetes Mellitus. Metabolic Syndrome and Related Disorders, 2003. 1(3): p. 233-237

OUR OBJECTIVE was to assess the effect of a carbohydrate-restricted dietary approach on diabetes mellitus. The rationale for using a carbohydraterestricted diet for diabetes mellitus derives from the known effect of dietary carbohydrate on insulin secretion.1 For type 1 diabetes, less dietary carbohydrate will lead to a lower requirement for insulin to control postprandial blood glucoses. For type 2 diabetes, less dietary carbohydrate will lead to lower insulin levels and less insulin resistanceif insulin resistance is an adaptive response to high insulin levels. Less insulin resistance will then lead to improved glycemic control. 76. Vernon, Clinical Experience of a Carbohydrate-Restricted Diet for the Metabolic Syndrome. Metabolic Syndrome and Related Disorders, 2004. 2: p. 180-186

18

77.

Volek, Fasting lipoprotein and postprandial triacylglycerol responses to a low-carbohydrate diet supplemented with n-3 fatty acids. J Am Coll Nutr, 2000. 19(3): p. 383-91

BACKGROUND: The effects of a prolonged low-carbohydrate diet rich in n-3 fatty acids on blood lipid profiles have not been addressed in the scientific literature. OBJECTIVE: This study examined the effects of an eight-week ketogenic diet rich in n-3 fatty acids on fasting serum lipoproteins and postprandial triacylglycerol (TG) responses. DESIGN: Ten men consumed a low-carbohydrate diet rich in monounsaturated fat (MUFA) and supplemented with n-3 fatty acids for eight weeks. Fasting blood samples were collected before and after one week of habitual diet and on two consecutive days after 2, 4, 6 and 8 weeks of the intervention diet. Postprandial TG responses to a fat-rich test meal were measured prior to and after the intervention diet. RESULTS: Compared to the habitual diet, subjects consumed significantly (p < or = 0.05) greater quantities of protein, fat, MUFA and n-3 fatty acids and significantly less total energy, carbohydrate and dietary fiber. Body weight significantly declined over the experimental period (4.2+/-2.7 kg). Compared to baseline, fasting total cholesterol, LDL cholesterol and HDL cholesterol were not significantly different after the intervention diet (+1.5%, +9.7% and +10.0%, respectively). Fasting TG were significantly reduced after the intervention diet (-55%). There was a significant reduction in peak postprandial TG (-42%) and TG area under the curve (-48%) after the intervention diet. CONCLUSIONS: A hypocaloric low-carbohydrate diet rich in MUFA and supplemented with n-3 fatty acids significantly reduced postabsorptive and postprandial TG in men that were not hypertriglyceridemic as a group before the diet. This may be viewed as a clinically significant positive adaptation in terms of cardiovascular risk status. However, transient increases in total cholesterol and LDL cholesterol were also evident and should be examined further in regard to which particular subfractions are elevated. 78. Volek, Body composition and hormonal responses to a carbohydrate-restricted diet. Metabolism, 2002. 51(7): p. 864-70

The few studies that have examined body composition after a carbohydrate-restricted diet have reported enhanced fat loss and preservation of lean body mass in obese individuals. The role of hormones in mediating this response is unclear. We examined the effects of a 6-week carbohydrate-restricted diet on total and regional body composition and the relationships with fasting hormone concentrations. Twelve healthy normal-weight men switched from their habitual diet (48% carbohydrate) to a carbohydrate-restricted diet (8% carbohydrate) for 6 weeks and 8 men served as controls, consuming their normal diet. Subjects were encouraged to consume adequate dietary energy to maintain body mass during the intervention. Total and regional body composition and fasting blood samples were assessed at weeks 0, 3, and 6 of the experimental period. Fat mass was significantly (P <or=.05) decreased (-3.4 kg) and lean body mass significantly increased (+1.1 kg) at week 6. There was a significant decrease in serum insulin (-34%), and an increase in total thyroxine (T(4)) (+11%) and the free T(4) index (+13%). Approximately 70% of the variability in fat loss on the carbohydrate-restricted diet was accounted for by the decrease in serum insulin concentrations. There were no significant changes in glucagon, total or free testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-I (IGF-I), cortisol, or triiodothyronine (T(3)) uptake, nor were there significant changes in body composition or hormones in the control group. Thus, we conclude that a carbohydrate-restricted diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men, which may be partially mediated by the reduction in circulating insulin concentrations. 79. Volek, Very-low-carbohydrate weight-loss diets revisited. Cleve Clin J Med, 2002. 69(11): p. 849-862

Overview of research that has been conducted on LCD. Much scientific and anecdotal data demonstrate favorable metabolic responses to verylow-carbohydrate diets. We believe that very-low-carbohydrate diets merit further study for weight loss, and that criticisms of these diets lack scientific evidence. 80. Volek, An isoenergetic very low carbohydrate diet improves serum HDL cholesterol and triacylglycerol concentrations, the total cholesterol to HDL cholesterol ratio and postprandial pipemic responses compared with a low fat diet in normal weight, normolipidemic women. J Nutr, 2003. 133(9): p. 2756-61

Very low carbohydrate diets are popular, yet little is known about their effects on blood lipids and other cardiovascular disease risk factors. We reported previously that a very low carbohydrate diet favorably affected fasting and postprandial triacylglycerols, LDL subclasses and HDL cholesterol (HDL-C) in men but the effects in women are unclear. We compared the effects of a very low carbohydrate and a low fat diet on fasting lipids, postprandial lipemia and markers of inflammation in women. We conducted a balanced, randomized, two-period, crossover study in 10 healthy normolipidemic women who consumed both a low fat (<30% fat) and a very low carbohydrate (<10% carbohydrate) diet for 4 wk each. Two blood draws were performed on separate days at 0, 2 and 4 wk and an oral fat tolerance test was performed at baseline and after each diet period. Compared with the low fat diet, the very low carbohydrate diet increased (P <or= 0.05) fasting serum total cholesterol (16%), LDL cholesterol (LDL-C) (15%) and HDL-C (33%) and decreased serum triacylglycerols (-30%), the total cholesterol to HDL ratio (-13%) and the area under the 8-h postprandial triacylglycerol curve (-31%). There were no significant changes in LDL size or markers of inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) after the very low carbohydrate diet. In normal weight, normolipidemic women, a short-term very low carbohydrate diet modestly increased LDL-C, yet there were favorable effects on cardiovascular disease risk status by virtue of a relatively larger increase in HDL-C and a decrease in fasting and postprandial triaclyglycerols.

19

81.

Volek, Comparison of a Very Low-Carbohydrate and Low-Fat Diet on Fasting Lipids, LDL Subclasses, Insulin Resistance, and Postprandial Lipemic Responses in Overweight Women. J Am Coll Nutr, 2004. 23(2): p. 177-84

OBJECTIVE: Very low-carbohydrate diets are widely used for weight loss yet few controlled studies have determined how these diets impact cardiovascular risk factors compared to more traditional low-fat weight loss diets. The primary purpose of this study was to compare a very low-carbohydrate and a low-fat diet on fasting blood lipids, LDL subclasses, postprandial lipemia, and insulin resistance in overweight and obese women. METHODS: Thirteen normolipidemic, moderately overweight (body fat >30%) women were prescribed two hypocaloric (-500 kcal/day) diets for 4 week periods, a very low-carbohydrate (<10% carbohydrate) and a low-fat (<30% fat) diet. The diets were consumed in a balanced and randomized fashion. Two fasting blood draws were performed on separate days and an oral fat tolerance test was performed at baseline, after the very low-carbohydrate diet, and after the low-fat diet. RESULTS: Compared to corresponding values after the very low-carbohydrate diet, fasting total cholesterol, LDL-C, and HDL-C were significantly (p </= 0.05) lower, whereas fasting glucose, insulin, and insulin resistance (calculated using the homeostatic model assessment) were significantly higher after the low-fat diet. Both diets significantly decreased postprandial lipemia and resulted in similar nonsignificant changes in the total cholesterol/HDL-C ratio, fasting triacylglycerols, oxidized LDL, and LDL subclass distribution. CONCLUSIONS: Compared to a low-fat weight loss diet, a short-term very low-carbohydrate diet did not lower LDL-C but did prevent the decline in HDL-C and resulted in improved insulin sensitivity in overweight and obese, but otherwise healthy women. Small decreases in body mass improved postprandial lipemia, and therefore cardiovascular risk, independent of diet composition. 82. Volek, Comparison of energy-restricted very low-carbohydrate and low-fat diets on weight loss and body composition in overweight men and women. Nutr Metab (Lond), 2004. 1(1): p. 13

OBJECTIVE: To compare the effects of isocaloric, energy-restricted very low-carbohydrate ketogenic (VLCK) and low-fat (LF) diets on weight loss, body composition, trunk fat mass, and resting energy expenditure (REE) in overweight/obese men and women. DESIGN: Randomized, balanced, two diet period clinical intervention study. Subjects were prescribed two energy-restricted (-500 kcal/day) diets: a VLCK diet with a goal to decrease carbohydrate levels below 10% of energy and induce ketosis and a LF diet with a goal similar to national recommendations (%carbohydrate:fat:protein = ~60:25:15%). Subjects: 15 healthy, overweight/obese men (mean s.e.m.: age 33.2 2.9 y, body mass 109.1 4.6 kg, body mass index 34.1 1.1 kg/m2) and 13 premenopausal women (age 34.0 2.4 y, body mass 76.3 3.6 kg, body mass index 29.6 1.1 kg/m2). Measurements: Weight loss, body composition, trunk fat (by dual-energy X-ray absorptiometry), and resting energy expenditure (REE) were determined at baseline and after each diet intervention. Data were analyzed for between group differences considering the first diet phase only and within group differences considering the response to both diets within each person. RESULTS: Actual nutrient intakes from food records during the VLCK (%carbohydrate:fat:protein = ~9:63:28%) and the LF (~58:22:20%) were significantly different. Dietary energy was restricted, but was slightly higher during the VLCK (1855 kcal/day) compared to the LF (1562 kcal/day) diet for men. Both between and within group comparisons revealed a distinct advantage of a VLCK over a LF diet for weight loss, total fat loss, and trunk fat loss for men (despite significantly greater energy intake). The majority of women also responded more favorably to the VLCK diet, especially in terms of trunk fat loss. The greater reduction in trunk fat was not merely due to the greater total fat loss, because the ratio of trunk fat/total fat was also significantly reduced during the VLCK diet in men and women. Absolute REE (kcal/day) was decreased with both diets as expected, but REE expressed relative to body mass (kcal/kg), was better maintained on the VLCK diet for men only. Individual responses clearly show the majority of men and women experience greater weight and fat loss on a VLCK than a LF diet. CONCLUSION: This study shows a clear benefit of a VLCK over LF diet for short-term body weight and fat loss, especially in men. A preferential loss of fat in the trunk region with a VLCK diet is novel and potentially clinically significant but requires further validation. These data provide additional support for the concept of metabolic advantage with diets representing extremes in macronutrient distribution. 83. Volek, Effects of dietary carbohydrate restriction versus low-fat diet on flow-mediated dilation. Metabolism, 2009. 58(12):1769-77 We previously reported that a carbohydrate-restricted diet (CRD) ameliorated many of the traditional markers associated with metabolic syndrome and cardiovascular risk compared with a low-fat diet (LFD). There remains concern how CRD affects vascular function because acute meals high in fat have been shown to impair endothelial function. Here, we extend our work and address these concerns by measuring fasting and postprandial vascular function in 40 overweight men and women with moderate hypertriacylglycerolemia who were randomly assigned to consume hypocaloric diets (approximately 1500 kcal) restricted in carbohydrate (percentage of carbohydrate-fatprotein = 12:59:28) or LFD (56:24:20). Flow-mediated dilation of the brachial artery was assessed before and after ingestion of a high-fat meal (908 kcal, 84% fat) at baseline and after 12 weeks. Compared with the LFD, the CRD resulted in a greater decrease in postprandial triacylglycerol (-47% vs -15%, P = .007), insulin (-51% vs -6%, P = .009), and lymphocyte (-12% vs -1%, P = .050) responses. Postprandial fatty acids were significantly increased by the CRD compared with the LFD (P = .033). Serum interleukin-6 increased significantly over the postprandial period; and the response was augmented in the CRD (46%) compared with the LFD (-13%) group (P = .038). After 12 weeks, peak flow-mediated dilation at 3 hours increased from 5.1% to 6.5% in the CRD group and decreased from 7.9% to 5.2% in the LFD group (P = .004). These findings show that a 12-week low-carbohydrate diet improves postprandial vascular function more than a LFD in individuals with atherogenic dyslipidemia. 84. Volek, Carbohydrate Restriction has a More Favorable Impact on the Metabolic Syndrome than a Low Fat Diet. Lipids, 2009. 44(4): p. 297309

We recently proposed that the biological markers improved by carbohydrate restriction were precisely those that define the metabolic syndrome (MetS), and that the common thread was regulation of insulin as a control element. We specifically tested the idea with a 12-week study comparing two hypocaloric diets (~1,500 kcal): a carbohydrate-restricted diet (CRD) (%carbohydrate:fat:protein = 12:59:28) and a low-fat

20

diet (LFD) (56:24:20) in 40 subjects with atherogenic dyslipidemia. Both interventions led to improvements in several metabolic markers, but subjects following the CRD had consistently reduced glucose (-12%) and insulin (-50%) concentrations, insulin sensitivity (-55%), weight loss (-10%), decreased adiposity (-14%), and more favorable triacylglycerol (TAG) (-51%), HDL-C (13%) and total cholesterol/HDL-C ratio (-14%) responses. In addition to these markers for MetS, the CRD subjects showed more favorable responses to alternative indicators of cardiovascular risk: postprandial lipemia (-47%), the Apo B/Apo A-1 ratio (-16%), and LDL particle distribution. Despite a threefold higher intake of dietary saturated fat during the CRD, saturated fatty acids in TAG and cholesteryl ester were significantly decreased, as was palmitoleic acid (16:1n-7), an endogenous marker of lipogenesis, compared to subjects consuming the LFD. Serum retinol binding protein 4 has been linked to insulin-resistant states, and only the CRD decreased this marker (-20%). The findings provide support for unifying the disparate markers of MetS and for the proposed intimate connection with dietary carbohydrate. The results support the use of dietary carbohydrate restriction as an effective approach to improve features of MetS and cardiovascular risk. 85. Weber, Modified Atkins diet to children and adolescents with medical intractable epilepsy. Seizure, 2009. 18(5): p. 237-240

The aim of the present study was to evaluate the tolerability and efficacy of the modified Atkins diet given to children and adolescents with antiepileptic drug (AED) treatment resistant epilepsy. 15 children with medically intractable epilepsy were enrolled in the study. Inclusion criteria were at least one seizure a week and a trial of at least two AEDs without obtaining seizure freedom documented in a seizure calendar. At baseline subjects initiated a diet with carbohydrates restricted to make up 10 energy percent. If seizures were reduced by less than 50% after 714 days carbohydrates were further restricted to 10 g per day. No change in AED treatment was allowed. The diet was well tolerated. After 3months six out of the fifteen children (40%) had a seizure reduction of more than 50%, which was seen in different epileptic syndromes and different age groups. The responders reported an increase in quality of life and cognition. At 12 months follow-up 3 (20%) continued the diet with an unchanged marked seizure reduction. The present study confirms the high tolerability and effect of the modified Atkins diet on seizure control in AED treatment resistant epilepsy. Further larger prospective studies are however needed to confirm these results. 86. Westman, Effect of 6-month adherence to a very low carbohydrate diet program. Am J Med, 2002. 113(1): p. 30-6

To determine the effect of a 6-month very low carbohydrate diet program on body weight and other metabolic parameters.Fifty-one overweight or obese healthy volunteers who wanted to lose weight were placed on a very low carbohydrate diet (<25 g/d), with no limit on caloric intake. They also received nutritional supplementation and recommendations about exercise, and attended group meetings at a research clinic. The outcomes were body weight, body mass index, percentage of body fat (estimated by skinfold thickness), serum chemistry and lipid values, 24-hour urine measurements, and subjective adverse effects.Forty-one (80%) of the 51 subjects attended visits through 6 months. In these subjects, the mean (+/- SD) body weight decreased 10.3% +/- 5.9% (P <0.001) from baseline to 6 months (body weight reduction of 9.0 +/- 5.3 kg and body mass index reduction of 3.2 +/- 1.9 kg/m(2)). The mean percentage of body weight that was fat decreased 2.9% +/- 3.2% from baseline to 6 months (P <0.001). The mean serum bicarbonate level decreased 2 +/- 2.4 mmol/L (P <0.001) and blood urea nitrogen level increased 2 +/- 4 mg/dL (P <0.001). Serum total cholesterol level decreased 11 +/- 26 mg/dL (P = 0.006), low-density lipoprotein cholesterol level decreased 10 +/- 25 mg/dL (P = 0.01), triglyceride level decreased 56 +/- 45 mg/dL (P <0.001), high-density lipoprotein (HDL) cholesterol level increased 10 +/- 8 mg/dL (P <0.001), and the cholesterol/HDL cholesterol ratio decreased 0.9 +/- 0.6 units (P <0.001). There were no serious adverse effects, but the possibility of adverse effects in the 10 subjects who did not adhere to the program cannot be eliminated.A very low carbohydrate diet program led to sustained weight loss during a 6-month period. Further controlled research is warranted. 87. Westman, A Review of Low-carbohydrate Ketogenic Diets. Curr Atheroscler Rep, 2003. 5(6): p. 476-83

In response to the emerging epidemic of obesity in the United States, a renewal of interest in alternative diets has occurred, especially in diets that limit carbohydrate intake. Recent research has demonstrated that low-carbohydrate ketogenic diets can lead to weight loss and favorable changes in serum triglycerides and high-density lipoprotein cholesterol. This review summarizes the physiology and recent clinical studies regarding this type of diet. 88. Westman, A Pilot Study of a Low-Carbohydrate, Ketogenic Diet for Obesity-Related Polycystic Ovary Syndrome. Journal of General Internal Medicine, 2004. 19(1S): p. 111

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, and is frequently associated with central obesity, insulin resistance, and dyslipidemia. Because recent evidence demonstrates that a low carbohydrate ketogenic diet (LCKD) leads to weight loss and improvements in insulin sensitivity, we conducted this uncontrolled trial of the diet for PCOS. Westman, The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutrition & Metabolism, 2008. 5:36(Nutrition & Metabolism 2008, 5:36 doi:10.1186/1743-7075-5-36) Objective: Dietary carbohydrate is the major determinant of postprandial glucose levels, and several clinical studies have shown that lowcarbohydrate diets improve glycemic control. In this study, we tested the hypothesis that a diet lower in carbohydrate would lead to greater improvement in glycemic control over a 24-week period in patients with obesity and type 2 diabetes mellitus. Research design and methods: Eighty-four community volunteers with obesity and type 2 diabetes were randomized to either a low-carbohydrate, ketogenic diet (<20 g of carbohydrate 89.

21

daily; LCKD) or a low-glycemic, reduced-calorie diet (500 kcal/day deficit from weight maintenance diet; LGID). Both groups received group meetings, nutritional supplementation, and an exercise recommendation. The main outcome was glycemic control, measured by hemoglobin A1c. Results: Forty-nine (58.3%) participants completed the study. Both interventions led to improvements in hemoglobin A1c, fasting glucose, fasting insulin, and weight loss. The LCKD group had greater improvements in hemoglobin A1c (1.5% vs. -0.5%, p = 0.03), body weight (-11.1 kg vs. -6.9 kg, p = 0.008), and high density lipoprotein cholesterol (+5.6 mg/dL vs. 0 mg/dL, p < 0.001) compared to the LGID group. Diabetes medications were reduced or eliminated in 95.2% of LCKD vs. 62% of LGID participants (p < 0.01). Conclusion: Dietary modification led to improvements in glycemic control and medication reduction/elimination in motivated volunteers with type 2 diabetes. The diet lower in carbohydrate led to greater improvements in glycemic control, and more frequent medication reduction/elimination than the low glycemic index diet. Lifestyle modification using low carbohydrate interventions is effective for improving and reversing type 2 diabetes. 90. Yancy, Improvement of gastroesophageal reflux disease after initiation of a low-carbohydrate diet: five brief case reports. Altern Ther Health Med, 2001. 7(6): p. 120, 116-9

The 5 individuals described in these case reports experienced resolution of GERD symptoms after self-initiation of a low-carbohydrate diet. Their observations suggest that carbohydrate restriction may have contributed to their symptom relief. However, this conclusion is confounded by concurrent reduction of caffeine intake in 3 of the individuals and reduction of acidic and high-osmolal food intake in all of them. Observations from some of these individuals suggest that carbohydrates may be a precipitating factor for GERD symptoms and that other classic exacerbating foods such as coffee and fat may be less pertinent when a low-carbohydrate diet is followed. However, these conclusions are preliminary. These findings primarily suggest that prospective research should be performed on the effect of lowcarbohydrate diets on GERD symptoms. Trials that control for all of the confounders mentioned above and that contain objective endpoints are needed to further investigate these issues. 91. Yancy, A Pilot Trial of a Low-Carbohydrate, Ketogenic Diet in Patients with Type 2 Diabetes. Metabolic Syndrome and Related Disorders, 2003. 1(3): p. 239-243

THE ETIOLOGY OF HYPERINSULINISM, insulin resistance, and type 2 diabetes mellitus is probably multi-factorial and as yet undetermined. It is known, however, that these hallmarks of the metabolic syndrome are highly associated with obesity.1 It is also known that treatment of obesity in patients with these disorders can result in lower insulin levels plus improvements in insulin sensitivity, glycemia, hypertension, and dyslipidemia, which constitute the metabolic syndrome.25 Despite the multiple benefits, patients have extreme difficulty achieving and maintaining weight loss. American Diabetic Association (ADA) diet recommendations for type 2 diabetic patients include reduction of fat (especially saturated fats) and cholesterol intake combined with a relatively high carbohydrate intake.6 The aim of the diabetic diet is to reduce hyperlipidemia, a risk factor for heart disease.1 However, prospective studies of this diet are not convincing in regard to prevention of cardiac events,7 and this type of diet has been shown to increase triglycerides, postprandial blood glucose, and insulin levels as well as lower HDL cholesterol. 811 In contrast, two recent randomized trials examining a low-carbohydrate, ketogenic diet (LCKD) demonstrated improvements in the above parameters, and one gave indication that the LCKD may be more effective than a lowfat diet for glycemic control in the sub-group of diabetics in the study.12,13 The purpose of this pilot study was to evaluate the efficacy, safety, and metabolic effects of a low-carbohydrate, ketogenic diet (LCKD) in overweight type 2 diabetic patients over 16 weeks. 92. Yancy, A Low-Carbohydrate, Ketogenic Diet versus a Low-Fat Diet To Treat Obesity and Hyperlipidemia: A Randomized, Controlled Trial. Ann Intern Med, 2004. 140(10): p. 769-777

BACKGROUND: Low-carbohydrate diets remain popular despite a paucity of scientific evidence on their effectiveness. OBJECTIVE: To compare the effects of a low-carbohydrate, ketogenic diet program with those of a low-fat, low-cholesterol, reduced-calorie diet. DESIGN: Randomized, controlled trial. SETTING: Outpatient research clinic. PARTICIPANTS: 120 overweight, hyperlipidemic volunteers from the community. INTERVENTION: Low-carbohydrate diet (initially, <20 g of carbohydrate daily) plus nutritional supplementation, exercise recommendation, and group meetings, or low-fat diet (<30% energy from fat, <300 mg of cholesterol daily, and deficit of 500 to 1000 kcal/d) plus exercise recommendation and group meetings. MEASUREMENTS: Body weight, body composition, fasting serum lipid levels, and tolerability. RESULTS: A greater proportion of the low-carbohydrate diet group than the low-fat diet group completed the study (76% vs. 57%; P = 0.02). At 24 weeks, weight loss was greater in the low-carbohydrate diet group than in the low-fat diet group (mean change, 12.9% vs. -6.7%; P < 0.001). Patients in both groups lost substantially more fat mass (change, -9.4 kg with the low-carbohydrate diet vs. 4.8 kg with the low-fat diet) than fat-free mass (change, -3.3 kg vs. -2.4 kg, respectively). Compared with recipients of the low-fat diet, recipients of the low-carbohydrate diet had greater decreases in serum triglyceride levels (change, -0.84 mmol/L vs. -0.31 mmol/L [-74.2 mg/dL vs. -27.9 mg/dL]; P = 0.004) and greater increases in high-density lipoprotein cholesterol levels (0.14 mmol/L vs. -0.04 mmol/L [5.5 mg/dL vs. -1.6 mg/dL]; P < 0.001). Changes in low-density lipoprotein cholesterol level did not differ statistically (0.04 mmol/L [1.6 mg/dL] with the low-carbohydrate diet and -0.19 mmol/L [-7.4 mg/dL] with the low-fat diet; P = 0.2). Minor adverse effects were more frequent in the low-carbohydrate diet group. Limitations: We could not definitively distinguish effects of the low-carbohydrate diet and those of the nutritional supplements provided only to that group. In addition, participants were healthy and were followed for only 24 weeks. These factors limit the generalizability of the study results. CONCLUSIONS: Compared with a low-fat diet, a low-carbohydrate diet

22

program had better participant retention and greater weight loss. During active weight loss, serum triglyceride levels decreased more and high-density lipoprotein cholesterol level increased more with the low-carbohydrate diet than with the low-fat diet. 93. Yancy, A Low-Carbohydrate, Ketogenic Diet for Type 2 Diabetes Mellitus. Journal of General Internal Medicine, 2004. 19(1S): p. 110

94. Yancy, A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutrition and Metabolism, 2005. 2(34) Background: The low-carbohydrate, ketogenic diet (LCKD) may be effective for improving glycemia and reducing medications in patients with type 2 diabetes. Methods: From an outpatient clinic, we recruited 28 overweight participants with type 2 diabetes for a 16-week single-arm pilot diet intervention trial. We provided LCKD counseling, with an initial goal of <20 g carbohydrate/day, while reducing diabetes medication dosages at diet initiation. Participants returned every other week for measurements, counseling, and further medication adjustment. The primary outcome was hemoglobin A1c. Results: Twenty-one of the 28 participants who were enrolled completed the study. Twenty participants were men; 13 were White, 8 were African-American. The mean [ SD] age was 56.0 7.9 years and BMI was 42.2 5.8 kg/m2. Hemoglobin A1c decreased by 16% from 7.5 1.4% to 6.3 1.0% (p < 0.001) from baseline to week 16. Diabetes medications were discontinued in 7 participants, reduced in 10 participants, and unchanged in 4 participants. The mean body weight decreased by 6.6% from 131.4 18.3 kg to 122.7 18.9 kg (p < 0.001). In linear regression analyses, weight change at 16 weeks did not predict change in hemoglobin A1c. Fasting serum triglyceride decreased 42% from 2.69 2.87 mmol/L to 1.57 1.38 mmol/L (p = 0.001) while other serum lipid measurements did not change significantly. Conclusion: The LCKD improved glycemic control in patients with type 2 diabetes such that diabetes medications were discontinued or reduced in most participants. Because the LCKD can be very effective at lowering blood glucose, patients on diabetes medication who use this diet should be under close medical supervision or capable of adjusting their medication. 95. Yancy, Effects of two weight-loss diets on health-related quality of life. Qual Life Res, 2009. 18(3):281-9 PURPOSE: To compare the effects of two diets on health-related quality of life (HRQOL). METHODS: Overweight volunteers (n = 119) were randomized to follow a low-carbohydrate, ketogenic diet (LCKD) or a low-fat diet (LFD) for 24 weeks. HRQOL was measured every 4 weeks using the Short Form-36 and analyzed using linear mixed-effects models. RESULTS: The mean age was 45 years and mean baseline body mass index was 34 kg/m(2); 76% were women. At 24 weeks, five subscales (Physical Functioning, Role-Physical, General Health, Vitality, Social Functioning) and the Physical Component Summary score improved similarly in both diet groups. Bodily Pain improved in the LFD group only, whereas the Role-Emotional and Mental Health subscales and the Mental Component Summary (MCS) score improved in the LCKD group only. In comparison with the LFD group, the LCKD group had a statistically significant greater improvement in MCS score (3.1; 95%CI 0.2-6.0; effect size = 0.44) and a borderline significant greater improvement in the Mental Health subscale (5.0; 95%CI -0.3-10.4; effect size = 0.37). CONCLUSIONS: Mental aspects of HRQOL improved more in participants following an LCKD than an LFD, possibly resulting from the LCKD's composition, lack of explicit energy restriction, higher levels of satiety or metabolic effects. PMID: 19212822 [PubMed - indexed for MEDLINE] 96. Yancy, A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Arch Intern Med, 2010. 170(2):136-45 BACKGROUND: Two potent weight loss therapies, a low-carbohydrate, ketogenic diet (LCKD) and orlistat therapy combined with a low-fat diet (O + LFD), are available to the public but, to our knowledge, have never been compared. METHODS: Overweight or obese outpatients (n = 146) from the Department of Veterans Affairs primary care clinics in Durham, North Carolina, were randomized to either LCKD instruction (initially, <20 g of carbohydrate daily) or orlistat therapy, 120 mg orally 3 times daily, plus low-fat diet instruction (<30% energy from fat, 500-1000 kcal/d deficit) delivered at group meetings over 48 weeks. Main outcome measures were body weight, blood pressure, fasting serum lipid, and glycemic parameters. RESULTS: The mean age was 52 years and mean body mass index was 39.3 (calculated as weight in kilograms divided by height in meters squared); 72% were men, 55% were black, and 32% had type 2 diabetes mellitus. Of the study participants, 57 of the LCKD group (79%) and 65 of the O + LFD group (88%) completed measurements at 48 weeks. Weight loss was similar for the LCKD (expected mean change, -9.5%) and the O + LFD (-8.5%) (P = .60 for comparison) groups. The LCKD had a more beneficial impact than O + LFD on systolic (-5.9 vs 1.5 mm Hg) and diastolic (-4.5 vs 0.4 mm Hg) blood pressures (P < .001 for both comparisons). High-density lipoprotein cholesterol and triglyceride levels improved similarly within both groups. Low-density lipoprotein cholesterol levels improved within the O + LFD group only, whereas glucose, insulin, and hemoglobin A(1c) levels improved within the LCKD group only; comparisons between groups, however, were not statistically significant. CONCLUSION: In a sample of medical outpatients, an LCKD led to similar improvements as O + LFD for weight, serum lipid, and glycemic parameters and was more effective for lowering blood pressure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00108524.

23