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Efficacy and Safety of Low-Carbohydrate Diets

Efficacy and Safety of Low-Carbohydrate Diets ContextLow-carbohydrate diets have been popularized without detailed evidence of their efficacy or safety. The literature has no clear consensus as to what amount of carbohydrates per day constitutes a low-carbohydrate diet.ObjectiveTo evaluate changes in weight, serum lipids, fasting serum glucose, and fasting serum insulin levels, and blood pressure among adults using low-carbohydrate diets in the outpatient setting.Data SourcesWe performed MEDLINE and bibliographic searches for English-language studies published between January 1, 1966, and February 15, 2003, with key words such as low carbohydrate, ketogenic, and diet.Study SelectionWe included articles describing adult, outpatient recipients of low-carbohydrate diets of 4 days or more in duration and 500 kcal/d or more, and which reported both carbohydrate content and total calories consumed. Literature searches identified 2609 potentially relevant articles of low-carbohydrate diets. We included 107 articles describing 94 dietary interventions reporting data for 3268 participants; 663 participants received diets of 60 g/d or less of carbohydrates—of whom only 71 received 20 g/d or less of carbohydrates. Study variables (eg, number of participants, design of dietary evaluation), participant variables (eg, age, sex, baseline weight, fasting serum glucose level), diet variables (eg, carbohydrate content, caloric content, duration) were abstracted from each study.Data ExtractionTwo authors independently reviewed articles meeting inclusion criteria and abstracted data onto pretested abstraction forms.Data SynthesisThe included studies were highly heterogeneous with respect to design, carbohydrate content (range, 0-901 g/d), total caloric content (range, 525-4629 kcal/d), diet duration (range, 4-365 days), and participant characteristics (eg, baseline weight range, 57-217 kg). No study evaluated diets of 60 g/d or less of carbohydrates in participants with a mean age older than 53.1 years. Only 5 studies (nonrandomized and no comparison groups) evaluated these diets for more than 90 days. Among obese patients, weight loss was associated with longer diet duration (P= .002), restriction of calorie intake (P= .03), but not with reduced carbohydrate content (P= .90). Low-carbohydrate diets had no significant adverse effect on serum lipid, fasting serum glucose, and fasting serum insulin levels, or blood pressure.ConclusionsThere is insufficient evidence to make recommendations for or against the use of low-carbohydrate diets, particularly among participants older than age 50 years, for use longer than 90 days, or for diets of 20 g/d or less of carbohydrates. Among the published studies, participant weight loss while using low-carbohydrate diets was principally associated with decreased caloric intake and increased diet duration but not with reduced carbohydrate content.Between 1960 and 2000 the prevalence of obesity among adults aged 20 years to 74 years in the United States increased from 13.4% to 30.9%.An estimated 325 000 deaths and between 4.3% and 5.7% of direct health care costs (approximately $39-$52 billion) are attributed to obesity annually.Results from the 1998 Behavioral Risk Factor Surveillance Survey indicate that roughly one third of US adults were trying to lose weight at that time, and another third were trying to maintain weight.Recently, low-carbohydrate diets have resurged in popularity as a means of rapid weight loss, yet their long-term efficacy and safety remain poorly understood.The first low-carbohydrate diet to have enjoyed popular success was that described by William Banting in the 1860s.Banting claimed that he was never hungry and at the age of 66, in a period of a year, lost 46 of his initial 202 pounds. He wrote, "The great charms and comfort of the system are that its effects are palpable within a week of trial and creates a natural stimulus to persevere for a few weeks more."While it is difficult to estimate the number of people who have followed low-carbohydrate diets, the number and popularity of articles and books from the lay press advocating their use attest to a high level of interest in and demand for these diets by the US public. The most popular text, written by cardiologist and long-time proponent of low-carbohydrate diets Robert Atkins, has been on the New York Timesbestsellers' list continuously for more than 5 years.Over the past 5 years, 3 books on low-carbohydrate diets collectively sold millions of copies in the United States.Advocates of low-carbohydrate diets claim that diets higher in protein and lower in carbohydrates promote the metabolism of adipose tissue in the absence of available dietary carbohydrate and result in rapid weight loss without significant long-term adverse effects.However, numerous professional organizations, including the American Dietetic Association and the American Heart Association, have cautioned against the use of low-carbohydrate diets.There are concerns that low-carbohydrate diets lead to abnormal metabolic functioning that may have serious medical consequences, particularly for participants with cardiovascular disease, type 2 diabetes mellitus, dyslipidemia, or hypertension. Specifically, it has been cautioned that low-carbohydrate diets cause accumulation of ketones and may result in abnormal metabolism of insulin and impaired liver and kidney function; in salt and water depletion that may cause postural hypotension, fatigue, constipation, and nephrolithiasis; in excessive consumption of animal proteins and fats that may promote hyperlipidemia; and in higher dietary protein loads that may impair renal function.The medical literature pertaining to the efficacy and the metabolic effects of low-carbohydrate diets is composed of numerous heterogeneous studies of relatively few participants. The studies vary in terms of dietary interventions provided (eg, percentage of calories from carbohydrate, fat, and protein), type of participants enrolled (eg, participants with diabetes or with hyperlipidemia), and outcomes evaluated (eg, weight loss or change in glycemic control). The purpose of this study was to synthesize the literature on low-carbohydrate diets to evaluate changes in weight, serum lipid, fasting serum glucose, and fasting serum insulin levels, and blood pressure among adults using low-carbohydrate diets in the outpatient setting.METHODSData SourcesTwo authors and a professional librarian independently developed search strategies to identify studies that met the eligibility criteria. We performed searches on MEDLINE for English-language studies published between January 1, 1966, and February 15, 2003, that were indexed with key words including diet, low carbohydrate, high fat, high protein, and ketogenic(Table 1). We also reviewed the bibliographies of retrieved articles and conference proceedings to obtain additional citations.Table 1.Results of Literature SearchDescriptionNo. of ArticlesMEDLINE key word searchesSearch 1, diet*192 654Search 2, low carbohydrate*567Search 3, high fat*5782Search 4, high protein*3473Search 5, ketogenic706Search 6, isocaloric2808Search 7, hypocaloric706Search 8, protein sparing2014Search 9, carbohydrate restricted6362Combine searches: 1 AND (2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9) LIMIT by (participant types: adults and humans) then discard duplicates2609Exclusion criteriaArticles included only pediatric participants (no adults)21Diet duration <4 d95Did not report sufficient data to be able to calculate grams per day of carbohydrates per diet72Did not report sufficient data to be able to calculate calories per day per diet97Participants hospitalized or confined to a research center146Diets that provided <500 kcal/d26Review article36Article not in English17Included only pregnant participants5Did not report data for any of the outcomes of interest1994Total articles excluded from those found in the MEDLINE search†2509Articles included from manual searches of bibliographies7Total articles included in the analyses107Combine duplicated reports on the same study participants13Total studies of dietary interventions included94*All terms beginning with this root would be included in the search (eg, searching with the root dietincludes terms such as diets, dieting, and dietary).†Several articles met more than 1 of the exclusion criteria.Study Selection CriteriaEnglish-language studies were considered eligible for this analysis if they evaluated any of the following interventions: low-carbohydrate, ketogenic, higher-protein, or higher-fat diets for adults who were not pregnant. Additionally, the included studies had to report sufficient data to calculate both carbohydrate content (grams per day) and total calories consumed (kilocalories per day). Because we were interested in diets that could be followed by outpatient adults, studies that evaluated diets with the following characteristics were excluded: less than 500 kcal/d, duration of diet less than 4 days, or requirement for participants to be hospitalized or confined to a research or diet center. Articles were excluded if they did not report data for at least 1 of the clinical outcomes of interest.Abstraction MethodsOne author reviewed the 2609 titles and abstracts identified by the combined MEDLINE search for potentially relevant studies. Two authors independently abstracted study design and participant data onto pretested abstraction forms from each of these publications and reviewed bibliographies for additional potentially relevant studies. Abstraction discrepancies were resolved by repeated review and discussion. If 2 or more studies presented the same data from a single participant population, these data were included only once in the analyses. If a study presented data on 2 types of diets and if 1 of the diets did not meet our inclusion criteria (eg, studies that compared a fast with a lower-carbohydrate diet), then data were abstracted only for those participants receiving the diet that met the inclusion criteria.Data AbstractedThree types of variables were abstracted from each study: dietary intervention, participants studied, and clinical outcomes. The variables for dietary intervention abstracted were carbohydrate, fat, and protein content (grams/day), daily caloric content (kilocalories per day), and the duration of dietary intervention (days). The participant variables abstracted were type of participants enrolled (eg, athletes, healthy volunteers, or participants with obesity, hyperlipidemia, diabetes, or hypertension), age, sex, and race/ethnicity. The outcome variables abstracted were measures of body mass (weight in kilograms, body mass index [BMI] calculated as weight in kilograms divided by the square of height in meters, and percentage of body fat), measures of lipid levels (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and serum triglycerides), measures of glycemic control (fasting serum glucose and insulin levels), and a measure of hypertensive control (systolic blood pressure).Statistical AnalysesFor each study, a weighted mean was calculated for each of the participant and diet characteristics (weighted by the number of participants who completed the study). We calculated an effect size for each outcome variable for each study (ie, standardized mean difference) from the mean change in the variable from the start of the diet to the end of the diet and the variance about this change.If the study did not report these data, a pooled variance was calculated.If an individual study did not report a measure of variance for the start or the end values of each outcome variable, then a weighted mean variance was calculated, and this weighted mean variance was used to calculate the pooled variance.If a study did not report any measure of variance for an outcome, the overall mean pooled variance was used for that study.Typically, a meta-analysis is the quantitative synthesis of independent studies, each of which was designed to compare the effects of a standard treatment with an experimental treatment. Because the studies are independent, so are the effect sizes. In the case of our analysis, the participant, diet, and outcome variables for each participant studied are correlated; therefore, the corresponding estimated effect sizes for these measures are correlated.Multivariate analysis of variance (weighted by the number of participants who finished each diet) was used to calculate the summary effect of the dietary and participant characteristic variables on the outcome variables.For example, using this method, the effect of carbohydrate content controlled for diet duration and calorie content on weight loss could be determined.Bivariate analyses were performed to estimate the differences in weight loss, serum lipid, fasting serum glucose, and fasting serum insulin levels, and blood pressure between participants who were grouped into 2 general categories of lower vs higher-carbohydrate diets. The bivariate analyses required setting a threshold to classify lower vs higher-carbohydrate diets. Because the literature has no clear consensus as to what amount of carbohydrates per day constitutes a low-carbohydrate diet, the differences between lowest-, lower-, and higher-carbohydrate diets by carbohydrate thresholds of 20 g/d or less, 60 g/d or less, and more than 60 g/d, respectively, were evaluated. Unless otherwise specified, these thresholds will be used to define these categories of low-carbohydrate diets. These thresholds correspond to recommendations found in the popular literature of low-carbohydrate diets.For the bivariate analyses, effect sizes were combined using a fixed effects model, which produces a narrower 95% confidence interval (CI), thereby increasing the likelihood of finding a difference between lower- and higher-carbohydrate diets. Then tests of homogeneity on summary effect sizes using the Q statistic were calculated. We attempted to minimize multiple comparisons. Because 4 outcome groups of interest (changes in body mass, serum lipid levels, glycemic indicators, and blood pressure) were included, a Bonferroni adjustment was used and the null hypothesis was rejected only if the level of significance was less than .0125 (.05/4 = .0125). Analyses were performed using SAS version 6.12 (SAS Institute, Cary, NC), SPSS version 9.0 (SPSS Inc, Chicago, Ill) and Microsoft Excel 2000 (Microsoft Corp, Redmond, Wash).RESULTSIdentified StudiesOur MEDLINE search identified 2609 titles of potentially relevant articles. We obtained 7 additional references from manual searches of the bibliographies of retrieved articles (Table 1). A total of 107 articles met the inclusion criteria. After combining multiple reports on the same study participants, we included 94 dietary interventions (Table 1and Table 2).Table 2.Characteristics of Low-Carbohydrate Studies by Study Design*SourceTotal No. of Participants†Age, Mean (Range), ySex, % MaleDuration of Diet, dNo. of Arms in Study†Dietary Composition, RangeCarbohydrates, gProteins, gFats, gTotal Calories, kcalRandomized Controlled TrialsVessby et al16249 (30-65)53902236-24780-8188-892140-2150Hockaday et al9352 (22-65)563652150-2037543-671500Shah et al8936 (25-45)01802225-24263-6649-631684-1740Lean et al8251 (18-68)01802110-18662-8927-471197-1198Baron et al‡63401590150NANA1200Kratz et al5826 (18-43)0-100286272-30479-92100-1102318-2574Saltzman et al434543-50422229-23479-8267-691827-1872Schlundt et al4944131402179-21061-6428-301265-1426Foster et al‡4741084230-10070-9013-20660-800Skov et aland Haulrik et al4640 (18-56)231802248-38679-13170-832139-2605Heilbronn et al45NA (56-58)46-57562212-21878-8027-291436-1442Helge4127100493184-566127-14979-2453370-3561Scott et al3638 (29-49)0562104-15251-5322-461003-1005Brussaard et al35NA (19-30)6694.52315-37593-9857-852460-2470Wolever and Mehling3456 (30-65)18-231123223-23275-8247-741695-1879Brown et al3226 (16-62)94842359-631114-12450-1963378-3670Luscombe et al26NA (62-64)33-55562167-21964-11246-491583-1585Fagerberg et al2350 (44-56)10028281-20469-7026-721370-1400Kogon et al2340 (23-55)028229-1166923-62950Racette et al2339 (21-47)084476-18232-7469-741147-1231Hammer et al§1433011211145016800Mathieson et aland Walberg et al12NA (23-36)028244-94333-25530Foster et aland Wadden et al‡9410336114660411194Coyle et al725100142718-901113-1179-1054358-4444Randomized Crossover TrialsParker et al546135562167-21163-11145-491543-1587Miller et al43544356128995632100Peterson and Jovanovic-Peterson2536 (21-50)0421150NANA1500Muller et al2531020-223243-33077-8545-892069-2115vanStratum et al22530142174-2879053-1021970-1987Luscombe et al215767282202-272106-11077-42.41910-1924Rosen et al2029 (20-38)51420-5077-10533-55800-917Jenkins et al2056 (35-71)75302323-415111-18978-802764-2835Weinsier et al‡1859 (43-69)611122190-26469-7456-901847-1849Simpson et al145483422209-3759863-1372458-2462Straznicky et al1426100142250-301106-10960-1362187-2636Pomerleau et al125867212299-30252-12556-802103-2175Lousley et al1164 (51-75)NA422115-20267-7023-601240Wolfe and Piche1028 (20-57)20282258-30464-11684-852155-2178Wolfe and Giovannetti1050 (24-67)40282263-34452-10852-531909-2011Whitehead et al849 (31-57)257380-13338-9036-591004Carey et al72410062183-787183-18582-3464584-4629Holmback et al732 (26-43)10062299-48511266-1492988Spaulding et al6NA (25-43)NA1440-2000-550-71800-1066Bialkowska et al101NA042275-11355-7143-731066-1237Fleming10043 (23-67)47365436-31551-10015-971350-2100Golay et al68452284270-13285-8634-571142-1179Luntz and Reuter6154 (27-87)341802100NANA1000Mezzano et al4222100902207-2698659-871952Alford et al3539 (31-56)070375-22545-9013-601200Heilbronn et al355823843198-28065-7317-571541-1613Donnelly et al35NA090379501525Thompson et al‡2729100142183-668116-12677-2963856-3871Volek et aland Sharman et al2036.710042246-28380-17656-1571950-2335Ireland et al18303814287-12496-25028-1111617-1887Gumbiner et aland Low et al17534742239-31284-8721-1271635-1785Vaswani1731084210-70NANA800Young et al823 (21-28)10063330-104115103-135.51800Simonyi et al728-470-1006-10715-25NANA1537-2010Greenhaff et al6281004320-486100-17436-2072622-2673Greenhaff et al5311004222-61775-17929-2422988-3011Sequential Study DesignHulley et al41NA (24-59)1001802160-27797-102114-1172100-2523Pieke et al1939.2 (28-58)10014-282242-312101-10571-1022313-2390Bonanome et al1955 (40-61)53603182-24257-6142-721518-1616Serog et aland Apfelbaum et al18NA (18-22)NANA270-52510531-2332800Hallak et al16NA (18-30)100142160-32759-6417-1041696-1834O'Dea et al1061 (50-69)10014491-29295-24619-1291586-2115Cattran et al834 (24-57)6321392-24270-8440-1171638-1760Ekstedt et al7NA (21-37)10084323-542109-16254-2202300-3800Fery et al‡6NA (22-46)NA41251011692026Pre-Post StudiesNobels et al11337NA1801388429750Rabast et al1043733106140601001340Kirby et al59NA (18-70)20126130NANA1000Bettens et al57412160140NANA1200Calle-Pascual et al544315140111373541260Comi et al4652 (40-60)5730121163401400Harvey et al425238180118045401260Westman et al414424168123115981447Spiller et al2656 (29-81)NA631241103902194Mogul et al‡2647, 5403652159122381500Krotkiewski et al2540028165557544Larosa et al24NA (20-58)5856161071081461Engelhart et al19NA (34-71)15841193112451625De Lorenzo et al1932060121478431554Serog et aland Apfelbaum et al14NA (18-22)10141367016560Marsoobian et al13NA (18-28)014130NANA600Cangiano et al1043042124585872066Volek et al1026100561391471512110Buffenstein et al9NA (20-36)02811024115743Cordera et al83710060116598501500Evans et al8NA (21-40)04218675941490Benoit et aland Grande et al729 (22-45)1001011035911000Staudacher et al‡724100611971713514628Kwan et al621 (20-23)071491031642066Elliot et al223 (22-23)5024171802252773Abbreviation: NA, not available.*Study and design: Randomized controlled trials were those in which participants were randomized to receive 1 of 2 or more diets; randomized crossover trials were those in which participants were randomized to receive one diet first and then to receive a second diet. Sequential study designs were those in which all participants received 2 or more diets in the same order; pre-post studies were those in which a single group received a single diet.†Total number of participants completing the diets. Number of arms equals number of diets evaluated.‡Only data for participants receiving dietary interventions meeting the exclusion critria were included.Study CharacteristicsThe designs of the included studies were highly heterogeneous (Table 2). Several studies included a washout phase at the beginning of the study interval, during which participants typically received a standard or maintenance diet that was intended to simulate their usual diet in calories and macronutrient composition. For those studies including a washout phase, we considered the participants' weight at the end of the washout phase as their baseline weight.Forty-three studies used randomized research designs: 24 studies were randomized controlled trialsin which participants were randomized to receive 1 of 2 or more diets and 19 studies were randomized crossover trialsin which participants were randomized to receive one diet first and then to receive a second diet. Of those studies that did not use randomized research designs, 17 studiescompared participants receiving a lower-carbohydrate diet with a comparison group receiving an alternative diet. In some studies, participants were allowed to decide which diet they would prefer to maximize adherence to the prescribed diet. Nine studieshad a sequential design in which all participants received 2 or more diets in the same order. Twenty-five studieswere pre-post evaluations in which a single group received a single diet. For those participants in studies with randomized crossover and sequential diet designs, we did not use the data from the second diet interval in our analyses because participants did not typically return to their baseline weight between diets.Diet CharacteristicsThe included studies reported on 38 lower-carbohydrate diets,(≤ 60 g/d of carbohydrates); 13 of these 38 were lowest-carbohydrate diets (≤20g/d of carbohydrates). Lower-carbohydrate diets had lower caloric contents (mean, 1446 kcal/d) than higher-carbohydrate (>60 g/d of carbohydrates) diets (mean, 1913 kcal/d, P= .002). Studies of lower-carbohydrate diets tended to have a shorter duration than studies of higher-carbohydrate diets (mean, 50 days and mean, 73 days, respectively; P= .10) (Table 3). Studies of the lowest-carbohydrate diets had shorter duration (mean [range], 19 [4-84] days) than the lower- and higher-carbohydrate diets (P= .02). Only 5 studies evaluated lower-carbohydrate diets for more than 90 days, and these studies were nonrandomized and noncontrolled designs (Table 2).Table 3.Diet CharacteristicsCarbohydrates in Diet, g/dPValueLower, ≤60Higher, >60No. of DietsMean (SD)Median (Range)No. of DietsMean (SD)Median (Range)Carbohydrate content, g/d3829 (15)30 (0-60)157236 (141)211 (65-901)<.001Protein content, g/d2696 (45)95 (33-180)15089 (36)83 (0-250).30Fat content, g/d26104 (65)99 (16-242)15069 (58)57 (0-351).01Caloric content, kcal/d381446 (653)1454 (530-2988)1571913 (880)1740 (525-4629).002Diet duration, d3750 (70)24 (4-365)15273 (83)42 (4-365).10All of the studies in our systematic review included participants in the outpatient setting. The studies used a variety of methods to verify that the participants adhered to the prescribed diet. These methods included food diaries, measured ketonuria or serum β-hydroxybutyrate levels, comparison of the expected sodium intake with observed urinary sodium levels, and multiple or no verification methods.Because most weight loss programs include both diet and exercise, we were interested in comparing lower-carbohydrate diets with and without exercise. However, the included studies varied significantly with respect to the amount of description of the exercise component. For example, many studies simply stated that exercise was encouraged but did not present information about the type, frequency, or duration of exercise by participants. Therefore, given the lack of sufficiently detailed data, we excluded exercise information from our analyses.Participant CharacteristicsThe included studies present data on 3268 participants who completed the diets: 663 participants received lower-carbohydrate diets, of whom only 71 received lowest-carbohydrate diets (Table 4). No significant difference was found in the age or sex of recipients of lower vs higher-carbohydrate diets. The mean (SD) age of recipients of lower-carbohydrate diets was 37.6 (8.5) years and no study of lower-carbohydrate diets had a mean age older than 53.1 years. The participants' weight before diet, BMI, percentage of body fat, serum lipid, fasting serum glucose, and fasting serum insulin levels, and systolic blood pressure did not differ significantly between the lower- and higher-carbohydrate groups (Table 4). The definitions of what constituted a healthy volunteer, obese participant, or participant with diabetes varied among studies. The classifications of racial/ethnic groups also varied among studies that reported data on race/ethnicity; thus, these classifications were not included in our analyses.Table 4.Participant Characteristics Before and After DietCarbohydrates in Diet, g/dPValueLower, ≤60Higher, >60No. of DietsNo. of ParticipantsMean (SD)*Median (Range)No. of DietsNo. of ParticipantsMean (SD)*Median (Range)Age, y3869237.6 (8.5)35 (20-53.1)147260544.3 (12.6)39.6 (20-64.2).90Sex, % male3456130 (43)29 (0-100)131248342.0 (40.0)46 (0-100).60Weight, kgBefore diet2356891.7 (15.8)87 (57.2-115.6)118224786.2 (19.7)81.4 (61-217).90After diet1843579.3 (10.1)77.5 (55.5-94.5)113184482.8 (18.9)77.6 (60.1-210).30BMI, kg/m2Before diet314536.3 (5.2)36.3 (36.0-37.5)3692530.6 (4.1)29.2 (21.8-39.7).05After diet111329.7 (4.1)29.7 (29.7-29.7)2873928.0 (3.5)26.3 (21.7-35.0).50Percentage of body fat, %Before diet57638.1 (6.2)31.4 (20.5-44)3365537.2 (4.5)39.0 (12.8-47.3).70After diet56633.9 (5.0)22.3 (16.9-41)2753633.2 (4.9)33.2 (12.2-39.8).60Cholesterol, mg/dLTotalBefore diet13227191.1 (21.2)186 (148.2-214)791519246.4 (42.5)201 (124-267.8).03After diet12205188.3 (29.4)186 (119.6-348)751322201.8 (36.1)197 (136.6-252.5).60LDLBefore diet7181118.6 (20.7)119.9 (103.6-136)43934137.4 (30.9)129 (86.5-212.7).20After diet7168123.1 (20.7)116.6 (96.7-151)42852130.2 (20.2)127.9 (47-189.5).60HDLBefore diet1019751.3 (12.7)49.1 (27.1-87)48108048.7 (13.4)47.3 (30.9-72.8).60After diet917553.3 (8.1)53.0 (37.1-87)4898448.4 (9.9)46.4 (27.1-77.3).20Triglycerides, mg/dLBefore diet13227136.5 (60.8)115 (68.7-283.4)741674138.3 (53.4)129.6 (47.8-377.1).50After diet1321498.1 (38.7)93.0 (57.9-130.2)701245126.2 (46.8)123 (50-247.1).01Fasting serum glucose, mg/dLBefore diet11252101.3 (11.1)95.0 (73.8-226.8)601040130.5 (37.1)97.2 (72.5-225).90After diet1124991.4 (19.3)87.0 (68-144)59871112.4 (24.6)99 (67.5-205.2).10Fasting serum insulin, µIU/mLBefore diet65510.2 (4.7)10.2 (3.4-16.4)4483910.3 (8.5)10.3 (1.0-36.0).90After diet6556.6 (2.6)6.3 (2.2-10.2)467789.4 (4.3)7.9 (0.98-38.0).50Systolic blood pressure, mm HgBefore diet3132138.9 (16.2)126.0 (112-141.9)23507134.6 (16.7)133 (111-148).50After diet3132125.1 (12.6)119.0 (107.7-126.8)20403127.4 (12.3)129.6 (105-136).20Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein.SI conversion factors: To convert mg/dL to mmol/L for total cholesterol, LDL, and HDL, multiply by 0.0259. To convert mg/dL to mmol/L for triglycerides, multiply by 0.0113. To convert mg/dL to mmol/L for fasting serum glucose, multiply by 0.0555. To convert µIU/mL to pmol/L for fasting serum insulin, multiply by 6.945.*Means are weighted by the number of participants (eg, mean BMI before diet is weighted by the number of participants starting the diet and the mean BMI after diet is weighted by the number of participants completing the diet). Because the studies used to calculate the data before and after diet often differ, the change in outcomes should not be interpreted as the difference between the means before and after the diet (data reflecting the summary mean changes in outcomes are presented in Table 5).Effect of Diet and Participant Characteristics on Efficacy and Safety VariablesResults of the bivariate analyses compare the differences in each of the outcome variables between recipients of lower vs higher-carbohydrate diets (Table 5). The interpretation of these analyses is complicated by the significant heterogeneity of the included studies. For example, because the included diets were not isocaloric, the lower-carbohydrate diets vary significantly with respect to the percentage of calorie intake from carbohydrates. We have attempted to compare diets with similar caloric contents, durations, and study designs to account for this heterogeneity.Table 5.Summary Mean Change in Outcomes*Carbohydrates in Diet, g/dLower, ≤60Higher, >60No. of Diets†No. of ParticipantsSummary Mean Change‡ (SD)95% CINo. of DietsNo. of ParticipantsSummary Mean Change‡ (SD)95% CIWeight change, kgAll studies, all participants34668−16.9 (0.2)§−16.6, −17.31302092−1.9 (0.2)§−1.6, −2.2RCT and R-Cross only7132−3.6 (1.2)−1.2, −6.0751122−2.1 (0.3)−1.6, −2.7Caloric content of the diet, kcal/d<150018614−17.5 (0.2)§−17.1, −17.845870−3.1 (0.4)§−2.4, −3.8≥15001653−5.7 (0.2)§−5.4, −6.0841222−1.5 (0.2)§−1.2, −1.9Diet duration, d<151472−13.6 (0.1)§−13.5, −13.825198−1.5 (0.2)§−1.1, −1.816-609142−5.3 (0.6)§−4.2, −6.452827−3.5 (0.4)§−2.9, −4.3>6010447−2.4 (2.1)+1.8, −6.545968−1.1 (0.6)−.01, −2.3Participant age, y<4022426−17.7 (0.2)§−17.4, −18.159642−1.4 (0.2)§−1.0, −1.8≥4012242−5.0 (0.6)§−3.8, −6.2621231−2.9 (0.3)§−2.4, −3.5Baseline weight, kg<70322−19.6 (0.2)§−19.2, −20.019230−3.2 (0.6)§−1.9, −4.470-10013365−0.8 (1.6)+2.4, −4.0771357−2.4 (0.4)−1.3, −0.4>1007138−6.6 (0.7)§−5.2, −8.018301−8.1 (0.8)§−6.5, −9.7BMI, kg/m2All studies, all participants1113−1.4 (4.6)+7.6, −10.327739−0.4 (0.4)+0.3, −1.1Body fat, %All studies, all participants566−1.0 (5.6)+4.0, −6.027536−1.0 (0.6)+0.1, −2.1Cholesterol, mg/dLTotalAll studies, all participants13214−1.2 (7.3)+13.2, −15.5871633−8.1 (1.4)−5.5, −10.8RCT and R-Cross only377−1.9 (9.7)§+17.1, −20.843903−1.4 (3.3)+5.0, −7.9LDLAll studies, all participants7168−0.3 (9.7)+19.3, −18.742852−0.7 (3.1)+5.3, −6.8RCT and R-Cross only163+0.4 (30.7)+60.5, −59.722563−1.0 (3.7)+6.3, −8.3HDLAll studies, all participants9175−0.2 (2.1)+4.0, −4.346964−0.8 (0.6)+0.4, −2.0RCT and R-Cross only377−0.8 (4.2)+7.5, −9.122553−0.9 (0.7)+0.4, −2.3Triglycerides, mg/dLAll studies, all participants13214+4.1 (4.5)+13.0, −4.6781531−0.6 (3.3)+7.1, −6.0RCT and R-Cross only377+0.3 (19.0)+37.6, −37.043903−1.3 (4.4)+9.9, −7.4Fasting serum glucose, mg/dLAll studies, all participants11249−1.3 (2.8)+4.3, −6.859871−0.4 (1.2)+1.9, −2.7RCT and R-Cross only269−0.3 (27.4)+53.4, −54.017455−0.3 (1.3)+2.4, −3.0Fasting serum insulin, pmol/LAll studies, all participants545−0.8 (9.9)+18.5, −20.144764−0.4 (1.6)+2.9, −3.7RCT and R-Cross only0. . .. . .. . .26467−0.01 (2.3)+4.4, −4.5Systolic blood pressure, mm HgAll studies, all participants41730.7 (5.2)+10.8, −9.5254810.6 (2.5)+5.6, −4.3Abbreviations: BMI, body mass index; CI, confidence limits; ellipses, insufficient data to calculate outcome; HDL, high-density lipoprotein; LDL, low-density lipoprotein; RCT, randomized controlled trial; R-Cross, randomized crossover trial.*See Table 4 for the conversion of conventional units to SI units.†The reason that the number of diets and number of participants for whom we were able to calculate a difference in each of the outcomes is greater than the number of diets and number of participants for whom we presented in the data before and after diet (Table 4) is that some studies reported only the change in the outcome but not before or after diet data.‡Summary mean change in each outcome variable was calculated from a standardized mean difference. A negative change in any of the outcome variables denotes a reduction in that variable after the diet interval. For example, the absolute summary mean change in weight loss calculated from all studies of lower-carbohydrate diets was 16.9 kg.§The Q statistic for that summary mean change calculation was significant (ie, studies were not homogeneous).Change in Weight, BMI, and Percentage of Body Fat.At the end of both lower- and higher-carbohydrate diets, participants' weight, BMI, and percentage of body fat decreased (Table 5). In general, for both lower- and higher-carbohydrate diets, we found the greatest weight loss occurred among those participants receiving diets with the lowest caloric content and for those participants with the highest baseline weights (Table 5). The 72 young participants of the 14 dietsof very short duration (<15 days) receiving lower-calorie diets (mean [SD] age, 26.8 [8.5] years; mean [SD], 23 [13] g/d of carbohydrates; mean [SD], 1597 [715] kcal/d for participants with a mean [SD] weight before diet of 78.4 [5.2] kg) demonstrated significant mean [SD] weight loss (13.6 [0.1] kg); however, no data were available about whether they maintained this weight loss beyond the study period.Of the 34 of 38 lower-carbohydrate diets for which weight change after diet was calculated, these lower-carbohydrate diets were found to produce greater weight loss than higher-carbohydrate diets (absolute summary mean [SD] change, 16.9 [0.2] kg; 95% CI, 16.6-17.3 kg vs 1.9 [0.2] kg; 95% CI, 1.6-2.2 kg) (Table 5). Because the 95% CIs for the lower- and higher-carbohydrate diets do not overlap, it suggests that a difference may exist in weight change between the 2 types of diets. However, the highly heterogeneous nature of the 34 diets is reflected in the significant Q statistic associated with the summary mean changes in weight calculated when all studies were included in the analysis. Given this heterogeneity, little can be concluded about the summary mean change in weight loss when all studies are combined. When only the randomized controlled trials and the randomized crossover trials in the analysis are included, the result of the Q statistic suggests that the studies are homogeneous. From this selected group of relatively similar randomized studies of 7 lower-carbohydrate dietsand 75 higher-carbohydrate diets we found that the absolute summary mean [SD] change decrease in weight for lower-carbohydrate diets was 3.6 (1.2) kg (95% CI, 1.2-6.0 kg) and for higher-carbohydrate diets was 2.1 (0.3) kg (95% CI, 1.6-2.7 kg). This overlap in 95% CIs suggests no difference in weight loss between the lower- and higher-carbohydrate diets.To evaluate the weight loss demonstrated in the studies with the lowest-carbohydrate content, we calculated the summary mean [SD] change in weight loss found in the 13 dietsof these diets with 71 participants. In this group of studies, we found a summary mean (SD) change in weight of −1.2 (−2.3) kg (95% CI, −5.7 kg to 3.3 kg). The result of the Q statistic suggests homogeneity; however, we note that these studies vary with respect to study design, including studies that are not randomized and that do not include a comparison group. Thus, based on the data, it can be concluded that lowest-carbohydrate diets did not result in significantly greater weight loss than lower-carbohydrate diets.When we consider the 22 diets with the greatest mean weight loss (ie, mean weight loss of ≥10 kg), we found that they varied widely with respect to carbohydrate content (mean [range], 97 [10-271] g/d of carbohydrate) (data not shown). However, these diets restricted caloric intake (mean [range], 1077 [525-1800] kcal/d), were longer in duration (mean [range], 142 [42-365] days), and included participants who were significantly overweight at the start of the diets (mean [range], 101 [84-183] kg) (data not shown). These results suggest that these 3 variables may be more important predictors of weight loss than carbohydrate content.Change in Serum Lipid Levels.For all studies and participants of lower-carbohydrate diets, no change was found in any of the serum lipid levels (ie, the 95% CIs for the summary mean [SD] change in total, LDL, and HDL cholesterol, and triglycerides levels all included 0) (Table 5). However, heterogeneity and paucity of studies complicate the interpretation of the outcomes of serum lipid levels. In contrast, among the more homogeneous group of studies of higher-carbohydrate diets, we found a significant decline in total cholesterol levels (summary mean [SD] change, −8.1 [1.4] mg/dL; 95% CI, −5.5 to −10.8 or −0.21 [0.04] mmol/L; 95% CI, −0.14 to −0.28 mmol/L) but not in the other serum lipid levels (95% CIs include 0).From the 3 studiesof lowest-carbohydrate diets that reported data for total cholesterol levels for 36 participants, we found no change in serum lipid levels (summary mean [SD] change for total cholesterol, +0.1 [28.0] mg/dL; 95% CI, −54.8 to +55.1 mg/dL or 0.0026 [0.73] mmol/L; 95% CI, −1.4 to 1.4 mmol/L) (data not shown). None of the studies specifically evaluated the effect of lower-carbohydrate diets on serum lipid levels among participants with hyperlipidemia, and only 1 studyreported outcomes for serum lipid levels for participants with diabetes.Change in Fasting Serum Glucose and Insulin Levels.No change was observed in either fasting serum glucose or insulin levels among recipients of either lower- or higher-carbohydrate diets—even among those participants with the greatest weight loss or those participants receiving the lowest-carbohydrate diets (Table 5). Only 1 small study(9 participants) specifically evaluated the effect of lower-carbohydrate diets on fasting serum glucose or insulin levels among obese participants with diabetes (both 95% CIs include 0) (data not shown).Change in Systolic Blood Pressure.We found no change in systolic blood pressure after diet in participants receiving either lower- or higher-carbohydrate diets. Four studiesof 173 recipients of lower-carbohydrate diets demonstrated a summary mean (SD) change in decrease in blood pressure of 0.7 (5.2) mm Hg (95% CI, +10.8 to −9.5 mm Hg) (Table 5).Outcome Variables for Low-Carbohydrate DietsTo determine the effect of diet and participant characteristics on the outcomes of interest, a weighted analysis of variance was performed (Table 6). The weighted analysis of variance was used because the outcome variables are correlated; the diets vary with respect to total caloric content, duration, and carbohydrate content; and to avoid the use of a threshold to define what constitutes a lower-carbohydrate diet. Because only a few studies evaluated all of the dietary, participant, and outcome variables of interest, we were limited in our ability to include all studies or all variables in this analysis. The results of the analysis of variance using all diet data from all studies reporting weight loss, baseline weight, age, sex, and diet variables demonstrate that weight loss was significantly associated with longer diet duration (P= .008) and baseline weight (P<.001). For obese participants, restriction of calorie intake also was associated with weight loss, albeit not statistically significant after applying the Bonferroni adjustment (P= .03) (Table 6). Reduced carbohydrate content was not significantly associated with weight loss.Table 6.Results of Weighted Analysis of Variance to Determine the Effects of Diets and Participants on Outcome Variables for Lower-Carbohydrate Diets*OutcomeNo. of Diets†R2‡PValues§Baseline Weight, kg% MaleMean Age, yCarbohydrates, g/dCaloric Content, kcal/dDiet Duration, dWeight Loss, kg&par;Reduction of Fasting Glucose, mg/dL¶Weight loss, kgAll diets, all participants350.69<.001.04.02.90.50.008. . .. . .RCT and R-Cross studies only150.94<.001.90.30.10.50.06. . .. . .Healthy volunteers120.57. . .. . .. . ..40.90.08. . .. . .Obese participants330.33. . .. . .. . ..90.03.002. . .. . .Diabetic participants120.60. . .. . .. . ..40.02.30. . .. . .Reduction in total cholesterol, mg/dLAll diets, all participants250.31. . ..20.30.20.50.30.90. . .RCT and R-Cross studies only90.88. . ..80.80.20.30.70.40. . .Healthy volunteers90.59. . .. . .. . ..10.30.80.80. . .Obese participants120.21. . .. . .. . ..70.90.90.50. . .Diabetic participants290.12. . .. . .. . ..90.09.90. . .. . .Reduction in LDL cholesterol, mg/dLAll diets, all participants101.00.005.02.004.10.002.002.005. . .RCT and R-Cross studies only130.83.01.10.06.20.50.07. . .. . .Healthy volunteers110.21. . .. . .. . ..20.50.80. . .. . .Obese participants80.97.30.20.90.30.20.90. . .. . .Diabetic participants150.55.07.30.30.90.10.60. . .. . .Increase in HDL cholesterol, mg/dLAll diets, all participants90.94. . ..90.50.60.70.20.30. . .RCT and R-Cross studies only190.19. . ..20.70.60.70.60. . .. . .Healthy volunteers120.26. . .. . .. . ..90.20.70. . .. . .Obese participants130.73. . .. . .. . ..20.01.003. . .. . .Diabetic participants200.02. . .. . .. . ..60.90.90. . .. . .Reduction in triglycerides, mg/dLAll diets, all participants80.99. . .. . .. . ..04.05.20.09.40RCT and R-Cross studies only90.41. . .. . .. . ..90.80.30.60. . .Healthy volunteers220.19. . .. . .. . ..10.70.90. . .. . .Obese participants120.51. . .. . .. . ..10.20.70.30. . .Diabetic participants200.11. . .. . .. . ..50.90.40. . ..30Reduction in fasting serum glucose, mg/dLAll diets, all participants100.79. . .. . .. . ..90.10.01.06. . .RCT and R-Cross studies only310.56. . .. . .. . ..30.10<.001. . .. . .Healthy volunteers170.36. . .. . .. . ..10.20.20. . .. . .Obese participants200.09. . .. . .. . ..50.80.30. . .. . .Diabetic participants270.61. . .. . .. . ..90.003.001. . .. . .Change in fasting serum insulin, µIU/LAll diets, all participants490.24. . .. . .. . ..10.90.002. . .. . .RCT and R-Cross studies only280.46. . .. . .. . ..10.40<.001. . .. . .Healthy volunteers120.55. . .. . .. . ..03.20.70. . .. . .Obese participants160.35. . .. . .. . ..80.20.20. . .. . .Diabetic participants180.51. . .. . .. . ..10.50.003. . .. . .Change in systolic blood pressure, mm HgAll diets, all participants100.56. . .. . .. . ..30.20.20.40. . .RCT and R-Cross studies only90.53. . .. . .. . ..80.90.20.50. . .Healthy volunteers. . .. . .. . .. . .. . .. . .. . .. . .. . .. . .Obese participants160.21. . .. . .. . ..90.50.40. . .. . .Diabetic participants80.34. . .. . .. . ..80.80.50. . .. . .Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; RCT, randomized controlled trial; R-Cross, randomized crossover trial. Ellipses indicate insufficient data to calculate.*See Table 4 for the conversion of conventional units to SI units.†Number of diets refers to the number of dietary interventions that could be included in each analysis. To be included in the analysis of variance, a study had to report data for each of the predictor and outcome variables of interest. For example, studies of 10 dietary interventions provided data on change in fasting serum glucose levels and included information about the carbohydrate content of the diet, the caloric content of the diet duration, and participants' weight loss. However, the RCTs and R-Cross studies did not provide sufficient data about weight loss as a predictor of reduction in fasting serum glucose levels.‡Using the weighted analysis of variance (weighted by the number of participants who finished each diet), the R2was calculated to estimate the amount of variance in the outcome variables accounted for by the predictor variables.§Pvalue associated with the effect of these predictor variables on the outcome variables&par;Weight loss was included as a predictor variable for the weighted analyses of variance for change in serum lipid, fasting serum glucose, and fasting serum insulin levels, and systolic blood pressure as allowed by the availability of data.¶Reduction of fasting serum glucose levels was included as a predictor variable for the weighted analyses of variance for change in serum triglyceride levels as allowed by the availability of data.For all diets and all participants, reductions in LDL cholesterol levels were associated with high baseline weight (P= .005), weight loss (P= .005), younger age (P= .004), restriction of calorie intake (P= .002), and longer diet duration (P= .002)(Table 6). Overall dietary and participant characteristics were not significantly associated with changes in total cholesterol, HDL cholesterol, or triglyceride levels. Reductions in fasting serum glucose and insulin levels were consistently associated with longer diet duration (P= .01 and P= .002, respectively). Restriction of carbohydrate intake was not significantly associated with changes in serum lipid levels, change in fasting serum glucose levels, or systolic blood pressure.COMMENTOur quantitative synthesis of the 107 studies of 94 diets from the English-language literature on the efficacy and safety of low-carbohydrate diets suggests that there is insufficient evidence to make recommendations for or against the use of these diets. Despite the large number of Americans who have apparently adopted this approach to weight loss and/or weight maintenance, we know little of its effects or consequences. In particular, these diets have not been adequately evaluated for use longer than 90 days, for individuals aged 53 years or older, or for use by participants with hyperlipidemia, hypertension, or diabetes. The lowest-carbohydrate diets (eg, ≤20 g/d of carbohydrates, the recommended threshold for some of the most popular diets) have been studied in only 71 participants for whom no data on serum lipid, fasting serum glucose, and fasting serum insulin levels or blood pressure was reported.We found insufficient evidence to conclude that lower-carbohydrate content is independently associated with greater weight loss compared with higher-carbohydrate content. We did find, however, that diets that restricted calorie intake and were longer in duration were associated with weight loss. Given the limited evidence in this review, when lower-carbohydrate diets result in weight loss, it also is likely due to the restriction of calorie intake and longer duration rather than carbohydrate intake. Lower-carbohydrate diets were not associated with adverse effects on serum lipid levels, fasting serum glucose levels, or blood pressure. However, because few studies reported on these outcomes, this systematic review lacked statistical power to detect small changes in these measures.The heterogeneity of all the studies included in this review precludes drawing conclusions from the synthesis of the total group of studies. The statistically significant weight loss demonstrated when we compared all studies of lower- and higher-carbohydrate diets using the threshold of 60 g/d of carbohydrates was not confirmed by any other analyses (eg, evaluating the recipients of diets containing ≤20 g/d of carbohydrates or the participants with the greatest weight loss). We attribute this finding to the inclusion of studies of lower-carbohydrate diets with relatively short durations for obese participants in whom significant weight loss was achieved while using diets of 60 g/d or less of carbohydrates, primarily through restriction of calorie intake. It may be that these obese participants were better able to tolerate the restriction of calorie intake while using lower-carbohydrate diets than while using higher-carbohydrate diets. This observation suggests the need for additional studies of isocaloric diets with different carbohydrate contents in which participants are specifically assessed for symptoms of hunger and on the tolerability of the diet.Our analyses were limited by a small number of studies that evaluated more than 1 of the outcomes of interest or that provided sufficiently detailed information about their participants or dietary intervention. Specifically, our systematic review highlights 5 significant gaps in the published literature of low-carbohydrate diets. First, the lack of adequate long-term follow-up data significantly limits our understanding of the efficacy and safety of low-carbohydrate diets. In particular, the long-term effects of low-carbohydrate diets on serum lipid, fasting serum glucose, and fasting serum insulin levels and blood pressure may differ between hypocaloric diets intended for weight loss and isocaloric diets intended for weight maintenance. Second, we were not able to evaluate the effects of these diets on different racial/ethnic groups. The absence of data regarding the efficacy and safety of lower-carbohydrate diets by race/ethnicity critically limits our ability to make participant-specific recommendations about these diets. Third, because exercise can have a significant effect on weight loss, we had hoped to include a measure of energy expenditure as a covariate in our analyses. We were unable to report data on exercise because many studies either did not report any information about participants' exercise patterns or simply stated that participants were encouraged to maintain baseline levels of exercise. Fourth, some of the included diets provided counseling or other supportive measures to encourage participants to adhere to the dietary intervention. The heterogeneity of the information reported about how adherence was measured limited our ability to include them in our analyses. Finally, many of the included studies reported only the number of participants who completed the dietary intervention. Among those studies that reported both the total number enrolled and the total number who completed the intervention, very few performed an intention-to-treat analysis. This limitation of both the lower- and higher-carbohydrate diets has the potential to bias the results in the direction of overstating the effects of the dietary intervention.Our search strategies may have introduced biases into our results. First, we only included English-language studies. We found 17 foreign-language articles that we could not exclude on the basis of the English title or abstract. Extrapolating from our finding that 94 evaluated dietary interventions of 60 g/d or less of carbohydrates, it is likely that about a third of these would have evaluated lower-carbohydrate diets. However, we believe that the data from these estimated 5 or 6 foreign-language articles that may have met our inclusion criteria would not have changed the result of our analyses, as to do so all of these studies would need to have included significantly larger number of participants than the included studies, found very different results than those described, or evaluated diets for more than 90 days. Given the important cultural and ethnic differences in dietary habits, including foreign-language studies may have increased the heterogeneity of the participants evaluated. Second, our search was limited to MEDLINE and the bibliographies of retrieved publications. Although the major nutrition science publications are included in the MEDLINE database, we may have missed some relevant articles. Given the multiple clinical outcomes evaluated, we did not perform a formal analysis of publication bias.The results of our systematic review suggest that if participants without diabetes tolerate a lower-carbohydrate diet better than a higher-carbohydrate alternative, this diet may be an effective means of achieving short-term weight loss without significant adverse effects on serum lipid levels, glycemic control, or blood pressure. However, there is insufficient evidence to recommend or condemn the use of these diets among participants with diabetes or for long-term use. Because of the complex relationships between serum lipid levels, plasma insulin levels, cortisol and glucogon levels during dieting,and because of the claim by some proponents of low-carbohydrate diets that these diets work best when producing ketosis,future evaluations of lower-carbohydrate diets should enroll participants with and without diabetes and with and without abnormal lipid levels to more fully describe the effects of lower-carbohydrate (sometimes called "ketogenic") diets on lipid and glycemic indices and ketogenesis.Despite the abundance of lay literature on the topic of low-carbohydrate diets, to date our study is the first published synthesis of the evidence from the English-language literature. Our results demonstrated the marked discordance between the knowledge needed to guide dietary choices and the information that is available in the medical literature. 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n-3 fatty acids.J Am Coll Nutr.2000;19:383-391.JSVolekALGomezDMLoveNGAveryMJSharmanWJKraemerEffects of a high-fat diet on postabsorptive and postprandial testosterone responses to a fat-rich meal.Metabolism.2001;50:1351-1355.RBuffensteinAKarklinHSDriverBeneficial physiological and performance responses to a month of restricted energy intake in healthy overweight women.Physiol Behav.2000;68:439-444.RCorderaSBertoliniGAndraghettiGPistocchiMde AlessiRGherziInsulin receptor binding on red cells of hypertriglyceridemic patients: effect of a low fat, low carbohydrate diet.Diabetes Metab.1985;11:137-140.EEvansALStockJYudkinThe absence of undesirable changes during consumption of the low carbohydrate diet.Nutr Metab.1974;17:360-367.FLBenoitRLMartinRHWattenChanges in body composition during weight reduction in obesity: balance studies comparing effects of fasting and a ketogenic diet.Ann Intern Med.1965;63:604-612.Not AvailableWeight reduction: fasting versus a ketogenic diet.Nutr Rev.1966;24(5):133-134.FGrandeFasting versus a ketogenic diet.Nutr Rev.1967;25(6):189-191.HMStaudacherALCareyNKCummingsJAHawleyLMBurkeShort-term high-fat diet alters substrate utilization during exercise but not glucose tolerance in highly trained athletes.Int J Sport Nutr Exerc Metab.2001;11:273-286.RMKwanSThomasMAMirEffects of a low carbohydrate isoenergetic diet on sleep behavior and pulmonary functions in healthy female adult humans.J Nutr.1986;116(12):2393-2402.BElliotHPRoeserAWarrellILintonPOwensTGaffneyEffect of a high energy, low carbohydrate diet on serum levels of lipids and lipoproteins.Med J Aust.1981;1(5):237-240.Corresponding Author and Reprints:Dena M. Bravata, MD, MS, Center for Primary Care and Outcomes Research, 117 Encina Commons, Stanford, CA 94305-6019 (e-mail: bravata@healthpolicy.stanford.edu).Author Contributions:Study concept and design:Dena Bravata, Huang, Olkin, Gardner, Dawn Bravata.Acquisition of data:Dena Bravata, Sanders, Huang, Dawn Bravata.Analysis and interpretation of data:Dena Bravata, Huang, Krumholz, Olkin, Gardner, Dawn Bravata.Drafting of the manuscript:Dena Bravata, Dawn Bravata.Critical revision of the manuscript for important intellectual content:Dena Bravata, Sanders, Krumholz, Olkin, Gardner, Dawn Bravata.Statistical expertise:Dena Bravata, Olkin, Dawn Bravata.Obtained funding:Dena Bravata, Huang, Krumholz, Dawn Bravata.Administrative, technical, or material support:Dena Bravata, Sanders, Huang, Dawn Bravata.Study supervision:Dena Bravata, Krumholz, Gardner, Dawn Bravata.Funding/Support:During this project Dr Dawn Bravata was initially supported by the Robert Wood Johnson Clinical Scholars program at Yale University and is currently supported by a Veterans Administration HSR&D Service Research Career Development Award. Dr Huang's efforts were supported by a Seed Project grant from the American Medical Association. Dr Olkin is supported by National Science Foundation grant No. DMS 96-26-265.Previous Presention:Portions of this work were presented at the 23rd Annual Meeting of the Society for Medical Decision Making, San Diego, Calif, October 22, 2001; and the Society of General Internal Medicine Meeting, Atlanta, Ga, May 5, 2003.Disclaimer:None of the authors has financial or other conflicts of interest pertaining to the use of low-carbohydrate diets or diet products. This project received no funding from any manufacturer or purveyor of dietary goods or services.Acknowledgment:We thank Emilee Wilhem for her editorial support, Chris Stave for his assistance with literature searches, Ada Foley for her help with article retrieval, and Edward Miech, EdD, for his logistical support throughout the project. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

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American Medical Association
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Copyright 2003 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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Abstract

ContextLow-carbohydrate diets have been popularized without detailed evidence of their efficacy or safety. The literature has no clear consensus as to what amount of carbohydrates per day constitutes a low-carbohydrate diet.ObjectiveTo evaluate changes in weight, serum lipids, fasting serum glucose, and fasting serum insulin levels, and blood pressure among adults using low-carbohydrate diets in the outpatient setting.Data SourcesWe performed MEDLINE and bibliographic searches for English-language studies published between January 1, 1966, and February 15, 2003, with key words such as low carbohydrate, ketogenic, and diet.Study SelectionWe included articles describing adult, outpatient recipients of low-carbohydrate diets of 4 days or more in duration and 500 kcal/d or more, and which reported both carbohydrate content and total calories consumed. Literature searches identified 2609 potentially relevant articles of low-carbohydrate diets. We included 107 articles describing 94 dietary interventions reporting data for 3268 participants; 663 participants received diets of 60 g/d or less of carbohydrates—of whom only 71 received 20 g/d or less of carbohydrates. Study variables (eg, number of participants, design of dietary evaluation), participant variables (eg, age, sex, baseline weight, fasting serum glucose level), diet variables (eg, carbohydrate content, caloric content, duration) were abstracted from each study.Data ExtractionTwo authors independently reviewed articles meeting inclusion criteria and abstracted data onto pretested abstraction forms.Data SynthesisThe included studies were highly heterogeneous with respect to design, carbohydrate content (range, 0-901 g/d), total caloric content (range, 525-4629 kcal/d), diet duration (range, 4-365 days), and participant characteristics (eg, baseline weight range, 57-217 kg). No study evaluated diets of 60 g/d or less of carbohydrates in participants with a mean age older than 53.1 years. Only 5 studies (nonrandomized and no comparison groups) evaluated these diets for more than 90 days. Among obese patients, weight loss was associated with longer diet duration (P= .002), restriction of calorie intake (P= .03), but not with reduced carbohydrate content (P= .90). Low-carbohydrate diets had no significant adverse effect on serum lipid, fasting serum glucose, and fasting serum insulin levels, or blood pressure.ConclusionsThere is insufficient evidence to make recommendations for or against the use of low-carbohydrate diets, particularly among participants older than age 50 years, for use longer than 90 days, or for diets of 20 g/d or less of carbohydrates. Among the published studies, participant weight loss while using low-carbohydrate diets was principally associated with decreased caloric intake and increased diet duration but not with reduced carbohydrate content.Between 1960 and 2000 the prevalence of obesity among adults aged 20 years to 74 years in the United States increased from 13.4% to 30.9%.An estimated 325 000 deaths and between 4.3% and 5.7% of direct health care costs (approximately $39-$52 billion) are attributed to obesity annually.Results from the 1998 Behavioral Risk Factor Surveillance Survey indicate that roughly one third of US adults were trying to lose weight at that time, and another third were trying to maintain weight.Recently, low-carbohydrate diets have resurged in popularity as a means of rapid weight loss, yet their long-term efficacy and safety remain poorly understood.The first low-carbohydrate diet to have enjoyed popular success was that described by William Banting in the 1860s.Banting claimed that he was never hungry and at the age of 66, in a period of a year, lost 46 of his initial 202 pounds. He wrote, "The great charms and comfort of the system are that its effects are palpable within a week of trial and creates a natural stimulus to persevere for a few weeks more."While it is difficult to estimate the number of people who have followed low-carbohydrate diets, the number and popularity of articles and books from the lay press advocating their use attest to a high level of interest in and demand for these diets by the US public. The most popular text, written by cardiologist and long-time proponent of low-carbohydrate diets Robert Atkins, has been on the New York Timesbestsellers' list continuously for more than 5 years.Over the past 5 years, 3 books on low-carbohydrate diets collectively sold millions of copies in the United States.Advocates of low-carbohydrate diets claim that diets higher in protein and lower in carbohydrates promote the metabolism of adipose tissue in the absence of available dietary carbohydrate and result in rapid weight loss without significant long-term adverse effects.However, numerous professional organizations, including the American Dietetic Association and the American Heart Association, have cautioned against the use of low-carbohydrate diets.There are concerns that low-carbohydrate diets lead to abnormal metabolic functioning that may have serious medical consequences, particularly for participants with cardiovascular disease, type 2 diabetes mellitus, dyslipidemia, or hypertension. Specifically, it has been cautioned that low-carbohydrate diets cause accumulation of ketones and may result in abnormal metabolism of insulin and impaired liver and kidney function; in salt and water depletion that may cause postural hypotension, fatigue, constipation, and nephrolithiasis; in excessive consumption of animal proteins and fats that may promote hyperlipidemia; and in higher dietary protein loads that may impair renal function.The medical literature pertaining to the efficacy and the metabolic effects of low-carbohydrate diets is composed of numerous heterogeneous studies of relatively few participants. The studies vary in terms of dietary interventions provided (eg, percentage of calories from carbohydrate, fat, and protein), type of participants enrolled (eg, participants with diabetes or with hyperlipidemia), and outcomes evaluated (eg, weight loss or change in glycemic control). The purpose of this study was to synthesize the literature on low-carbohydrate diets to evaluate changes in weight, serum lipid, fasting serum glucose, and fasting serum insulin levels, and blood pressure among adults using low-carbohydrate diets in the outpatient setting.METHODSData SourcesTwo authors and a professional librarian independently developed search strategies to identify studies that met the eligibility criteria. We performed searches on MEDLINE for English-language studies published between January 1, 1966, and February 15, 2003, that were indexed with key words including diet, low carbohydrate, high fat, high protein, and ketogenic(Table 1). We also reviewed the bibliographies of retrieved articles and conference proceedings to obtain additional citations.Table 1.Results of Literature SearchDescriptionNo. of ArticlesMEDLINE key word searchesSearch 1, diet*192 654Search 2, low carbohydrate*567Search 3, high fat*5782Search 4, high protein*3473Search 5, ketogenic706Search 6, isocaloric2808Search 7, hypocaloric706Search 8, protein sparing2014Search 9, carbohydrate restricted6362Combine searches: 1 AND (2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9) LIMIT by (participant types: adults and humans) then discard duplicates2609Exclusion criteriaArticles included only pediatric participants (no adults)21Diet duration <4 d95Did not report sufficient data to be able to calculate grams per day of carbohydrates per diet72Did not report sufficient data to be able to calculate calories per day per diet97Participants hospitalized or confined to a research center146Diets that provided <500 kcal/d26Review article36Article not in English17Included only pregnant participants5Did not report data for any of the outcomes of interest1994Total articles excluded from those found in the MEDLINE search†2509Articles included from manual searches of bibliographies7Total articles included in the analyses107Combine duplicated reports on the same study participants13Total studies of dietary interventions included94*All terms beginning with this root would be included in the search (eg, searching with the root dietincludes terms such as diets, dieting, and dietary).†Several articles met more than 1 of the exclusion criteria.Study Selection CriteriaEnglish-language studies were considered eligible for this analysis if they evaluated any of the following interventions: low-carbohydrate, ketogenic, higher-protein, or higher-fat diets for adults who were not pregnant. Additionally, the included studies had to report sufficient data to calculate both carbohydrate content (grams per day) and total calories consumed (kilocalories per day). Because we were interested in diets that could be followed by outpatient adults, studies that evaluated diets with the following characteristics were excluded: less than 500 kcal/d, duration of diet less than 4 days, or requirement for participants to be hospitalized or confined to a research or diet center. Articles were excluded if they did not report data for at least 1 of the clinical outcomes of interest.Abstraction MethodsOne author reviewed the 2609 titles and abstracts identified by the combined MEDLINE search for potentially relevant studies. Two authors independently abstracted study design and participant data onto pretested abstraction forms from each of these publications and reviewed bibliographies for additional potentially relevant studies. Abstraction discrepancies were resolved by repeated review and discussion. If 2 or more studies presented the same data from a single participant population, these data were included only once in the analyses. If a study presented data on 2 types of diets and if 1 of the diets did not meet our inclusion criteria (eg, studies that compared a fast with a lower-carbohydrate diet), then data were abstracted only for those participants receiving the diet that met the inclusion criteria.Data AbstractedThree types of variables were abstracted from each study: dietary intervention, participants studied, and clinical outcomes. The variables for dietary intervention abstracted were carbohydrate, fat, and protein content (grams/day), daily caloric content (kilocalories per day), and the duration of dietary intervention (days). The participant variables abstracted were type of participants enrolled (eg, athletes, healthy volunteers, or participants with obesity, hyperlipidemia, diabetes, or hypertension), age, sex, and race/ethnicity. The outcome variables abstracted were measures of body mass (weight in kilograms, body mass index [BMI] calculated as weight in kilograms divided by the square of height in meters, and percentage of body fat), measures of lipid levels (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and serum triglycerides), measures of glycemic control (fasting serum glucose and insulin levels), and a measure of hypertensive control (systolic blood pressure).Statistical AnalysesFor each study, a weighted mean was calculated for each of the participant and diet characteristics (weighted by the number of participants who completed the study). We calculated an effect size for each outcome variable for each study (ie, standardized mean difference) from the mean change in the variable from the start of the diet to the end of the diet and the variance about this change.If the study did not report these data, a pooled variance was calculated.If an individual study did not report a measure of variance for the start or the end values of each outcome variable, then a weighted mean variance was calculated, and this weighted mean variance was used to calculate the pooled variance.If a study did not report any measure of variance for an outcome, the overall mean pooled variance was used for that study.Typically, a meta-analysis is the quantitative synthesis of independent studies, each of which was designed to compare the effects of a standard treatment with an experimental treatment. Because the studies are independent, so are the effect sizes. In the case of our analysis, the participant, diet, and outcome variables for each participant studied are correlated; therefore, the corresponding estimated effect sizes for these measures are correlated.Multivariate analysis of variance (weighted by the number of participants who finished each diet) was used to calculate the summary effect of the dietary and participant characteristic variables on the outcome variables.For example, using this method, the effect of carbohydrate content controlled for diet duration and calorie content on weight loss could be determined.Bivariate analyses were performed to estimate the differences in weight loss, serum lipid, fasting serum glucose, and fasting serum insulin levels, and blood pressure between participants who were grouped into 2 general categories of lower vs higher-carbohydrate diets. The bivariate analyses required setting a threshold to classify lower vs higher-carbohydrate diets. Because the literature has no clear consensus as to what amount of carbohydrates per day constitutes a low-carbohydrate diet, the differences between lowest-, lower-, and higher-carbohydrate diets by carbohydrate thresholds of 20 g/d or less, 60 g/d or less, and more than 60 g/d, respectively, were evaluated. Unless otherwise specified, these thresholds will be used to define these categories of low-carbohydrate diets. These thresholds correspond to recommendations found in the popular literature of low-carbohydrate diets.For the bivariate analyses, effect sizes were combined using a fixed effects model, which produces a narrower 95% confidence interval (CI), thereby increasing the likelihood of finding a difference between lower- and higher-carbohydrate diets. Then tests of homogeneity on summary effect sizes using the Q statistic were calculated. We attempted to minimize multiple comparisons. Because 4 outcome groups of interest (changes in body mass, serum lipid levels, glycemic indicators, and blood pressure) were included, a Bonferroni adjustment was used and the null hypothesis was rejected only if the level of significance was less than .0125 (.05/4 = .0125). Analyses were performed using SAS version 6.12 (SAS Institute, Cary, NC), SPSS version 9.0 (SPSS Inc, Chicago, Ill) and Microsoft Excel 2000 (Microsoft Corp, Redmond, Wash).RESULTSIdentified StudiesOur MEDLINE search identified 2609 titles of potentially relevant articles. We obtained 7 additional references from manual searches of the bibliographies of retrieved articles (Table 1). A total of 107 articles met the inclusion criteria. After combining multiple reports on the same study participants, we included 94 dietary interventions (Table 1and Table 2).Table 2.Characteristics of Low-Carbohydrate Studies by Study Design*SourceTotal No. of Participants†Age, Mean (Range), ySex, % MaleDuration of Diet, dNo. of Arms in Study†Dietary Composition, RangeCarbohydrates, gProteins, gFats, gTotal Calories, kcalRandomized Controlled TrialsVessby et al16249 (30-65)53902236-24780-8188-892140-2150Hockaday et al9352 (22-65)563652150-2037543-671500Shah et al8936 (25-45)01802225-24263-6649-631684-1740Lean et al8251 (18-68)01802110-18662-8927-471197-1198Baron et al‡63401590150NANA1200Kratz et al5826 (18-43)0-100286272-30479-92100-1102318-2574Saltzman et al434543-50422229-23479-8267-691827-1872Schlundt et al4944131402179-21061-6428-301265-1426Foster et al‡4741084230-10070-9013-20660-800Skov et aland Haulrik et al4640 (18-56)231802248-38679-13170-832139-2605Heilbronn et al45NA (56-58)46-57562212-21878-8027-291436-1442Helge4127100493184-566127-14979-2453370-3561Scott et al3638 (29-49)0562104-15251-5322-461003-1005Brussaard et al35NA (19-30)6694.52315-37593-9857-852460-2470Wolever and Mehling3456 (30-65)18-231123223-23275-8247-741695-1879Brown et al3226 (16-62)94842359-631114-12450-1963378-3670Luscombe et al26NA (62-64)33-55562167-21964-11246-491583-1585Fagerberg et al2350 (44-56)10028281-20469-7026-721370-1400Kogon et al2340 (23-55)028229-1166923-62950Racette et al2339 (21-47)084476-18232-7469-741147-1231Hammer et al§1433011211145016800Mathieson et aland Walberg et al12NA (23-36)028244-94333-25530Foster et aland Wadden et al‡9410336114660411194Coyle et al725100142718-901113-1179-1054358-4444Randomized Crossover TrialsParker et al546135562167-21163-11145-491543-1587Miller et al43544356128995632100Peterson and Jovanovic-Peterson2536 (21-50)0421150NANA1500Muller et al2531020-223243-33077-8545-892069-2115vanStratum et al22530142174-2879053-1021970-1987Luscombe et al215767282202-272106-11077-42.41910-1924Rosen et al2029 (20-38)51420-5077-10533-55800-917Jenkins et al2056 (35-71)75302323-415111-18978-802764-2835Weinsier et al‡1859 (43-69)611122190-26469-7456-901847-1849Simpson et al145483422209-3759863-1372458-2462Straznicky et al1426100142250-301106-10960-1362187-2636Pomerleau et al125867212299-30252-12556-802103-2175Lousley et al1164 (51-75)NA422115-20267-7023-601240Wolfe and Piche1028 (20-57)20282258-30464-11684-852155-2178Wolfe and Giovannetti1050 (24-67)40282263-34452-10852-531909-2011Whitehead et al849 (31-57)257380-13338-9036-591004Carey et al72410062183-787183-18582-3464584-4629Holmback et al732 (26-43)10062299-48511266-1492988Spaulding et al6NA (25-43)NA1440-2000-550-71800-1066Bialkowska et al101NA042275-11355-7143-731066-1237Fleming10043 (23-67)47365436-31551-10015-971350-2100Golay et al68452284270-13285-8634-571142-1179Luntz and Reuter6154 (27-87)341802100NANA1000Mezzano et al4222100902207-2698659-871952Alford et al3539 (31-56)070375-22545-9013-601200Heilbronn et al355823843198-28065-7317-571541-1613Donnelly et al35NA090379501525Thompson et al‡2729100142183-668116-12677-2963856-3871Volek et aland Sharman et al2036.710042246-28380-17656-1571950-2335Ireland et al18303814287-12496-25028-1111617-1887Gumbiner et aland Low et al17534742239-31284-8721-1271635-1785Vaswani1731084210-70NANA800Young et al823 (21-28)10063330-104115103-135.51800Simonyi et al728-470-1006-10715-25NANA1537-2010Greenhaff et al6281004320-486100-17436-2072622-2673Greenhaff et al5311004222-61775-17929-2422988-3011Sequential Study DesignHulley et al41NA (24-59)1001802160-27797-102114-1172100-2523Pieke et al1939.2 (28-58)10014-282242-312101-10571-1022313-2390Bonanome et al1955 (40-61)53603182-24257-6142-721518-1616Serog et aland Apfelbaum et al18NA (18-22)NANA270-52510531-2332800Hallak et al16NA (18-30)100142160-32759-6417-1041696-1834O'Dea et al1061 (50-69)10014491-29295-24619-1291586-2115Cattran et al834 (24-57)6321392-24270-8440-1171638-1760Ekstedt et al7NA (21-37)10084323-542109-16254-2202300-3800Fery et al‡6NA (22-46)NA41251011692026Pre-Post StudiesNobels et al11337NA1801388429750Rabast et al1043733106140601001340Kirby et al59NA (18-70)20126130NANA1000Bettens et al57412160140NANA1200Calle-Pascual et al544315140111373541260Comi et al4652 (40-60)5730121163401400Harvey et al425238180118045401260Westman et al414424168123115981447Spiller et al2656 (29-81)NA631241103902194Mogul et al‡2647, 5403652159122381500Krotkiewski et al2540028165557544Larosa et al24NA (20-58)5856161071081461Engelhart et al19NA (34-71)15841193112451625De Lorenzo et al1932060121478431554Serog et aland Apfelbaum et al14NA (18-22)10141367016560Marsoobian et al13NA (18-28)014130NANA600Cangiano et al1043042124585872066Volek et al1026100561391471512110Buffenstein et al9NA (20-36)02811024115743Cordera et al83710060116598501500Evans et al8NA (21-40)04218675941490Benoit et aland Grande et al729 (22-45)1001011035911000Staudacher et al‡724100611971713514628Kwan et al621 (20-23)071491031642066Elliot et al223 (22-23)5024171802252773Abbreviation: NA, not available.*Study and design: Randomized controlled trials were those in which participants were randomized to receive 1 of 2 or more diets; randomized crossover trials were those in which participants were randomized to receive one diet first and then to receive a second diet. Sequential study designs were those in which all participants received 2 or more diets in the same order; pre-post studies were those in which a single group received a single diet.†Total number of participants completing the diets. Number of arms equals number of diets evaluated.‡Only data for participants receiving dietary interventions meeting the exclusion critria were included.Study CharacteristicsThe designs of the included studies were highly heterogeneous (Table 2). Several studies included a washout phase at the beginning of the study interval, during which participants typically received a standard or maintenance diet that was intended to simulate their usual diet in calories and macronutrient composition. For those studies including a washout phase, we considered the participants' weight at the end of the washout phase as their baseline weight.Forty-three studies used randomized research designs: 24 studies were randomized controlled trialsin which participants were randomized to receive 1 of 2 or more diets and 19 studies were randomized crossover trialsin which participants were randomized to receive one diet first and then to receive a second diet. Of those studies that did not use randomized research designs, 17 studiescompared participants receiving a lower-carbohydrate diet with a comparison group receiving an alternative diet. In some studies, participants were allowed to decide which diet they would prefer to maximize adherence to the prescribed diet. Nine studieshad a sequential design in which all participants received 2 or more diets in the same order. Twenty-five studieswere pre-post evaluations in which a single group received a single diet. For those participants in studies with randomized crossover and sequential diet designs, we did not use the data from the second diet interval in our analyses because participants did not typically return to their baseline weight between diets.Diet CharacteristicsThe included studies reported on 38 lower-carbohydrate diets,(≤ 60 g/d of carbohydrates); 13 of these 38 were lowest-carbohydrate diets (≤20g/d of carbohydrates). Lower-carbohydrate diets had lower caloric contents (mean, 1446 kcal/d) than higher-carbohydrate (>60 g/d of carbohydrates) diets (mean, 1913 kcal/d, P= .002). Studies of lower-carbohydrate diets tended to have a shorter duration than studies of higher-carbohydrate diets (mean, 50 days and mean, 73 days, respectively; P= .10) (Table 3). Studies of the lowest-carbohydrate diets had shorter duration (mean [range], 19 [4-84] days) than the lower- and higher-carbohydrate diets (P= .02). Only 5 studies evaluated lower-carbohydrate diets for more than 90 days, and these studies were nonrandomized and noncontrolled designs (Table 2).Table 3.Diet CharacteristicsCarbohydrates in Diet, g/dPValueLower, ≤60Higher, >60No. of DietsMean (SD)Median (Range)No. of DietsMean (SD)Median (Range)Carbohydrate content, g/d3829 (15)30 (0-60)157236 (141)211 (65-901)<.001Protein content, g/d2696 (45)95 (33-180)15089 (36)83 (0-250).30Fat content, g/d26104 (65)99 (16-242)15069 (58)57 (0-351).01Caloric content, kcal/d381446 (653)1454 (530-2988)1571913 (880)1740 (525-4629).002Diet duration, d3750 (70)24 (4-365)15273 (83)42 (4-365).10All of the studies in our systematic review included participants in the outpatient setting. The studies used a variety of methods to verify that the participants adhered to the prescribed diet. These methods included food diaries, measured ketonuria or serum β-hydroxybutyrate levels, comparison of the expected sodium intake with observed urinary sodium levels, and multiple or no verification methods.Because most weight loss programs include both diet and exercise, we were interested in comparing lower-carbohydrate diets with and without exercise. However, the included studies varied significantly with respect to the amount of description of the exercise component. For example, many studies simply stated that exercise was encouraged but did not present information about the type, frequency, or duration of exercise by participants. Therefore, given the lack of sufficiently detailed data, we excluded exercise information from our analyses.Participant CharacteristicsThe included studies present data on 3268 participants who completed the diets: 663 participants received lower-carbohydrate diets, of whom only 71 received lowest-carbohydrate diets (Table 4). No significant difference was found in the age or sex of recipients of lower vs higher-carbohydrate diets. The mean (SD) age of recipients of lower-carbohydrate diets was 37.6 (8.5) years and no study of lower-carbohydrate diets had a mean age older than 53.1 years. The participants' weight before diet, BMI, percentage of body fat, serum lipid, fasting serum glucose, and fasting serum insulin levels, and systolic blood pressure did not differ significantly between the lower- and higher-carbohydrate groups (Table 4). The definitions of what constituted a healthy volunteer, obese participant, or participant with diabetes varied among studies. The classifications of racial/ethnic groups also varied among studies that reported data on race/ethnicity; thus, these classifications were not included in our analyses.Table 4.Participant Characteristics Before and After DietCarbohydrates in Diet, g/dPValueLower, ≤60Higher, >60No. of DietsNo. of ParticipantsMean (SD)*Median (Range)No. of DietsNo. of ParticipantsMean (SD)*Median (Range)Age, y3869237.6 (8.5)35 (20-53.1)147260544.3 (12.6)39.6 (20-64.2).90Sex, % male3456130 (43)29 (0-100)131248342.0 (40.0)46 (0-100).60Weight, kgBefore diet2356891.7 (15.8)87 (57.2-115.6)118224786.2 (19.7)81.4 (61-217).90After diet1843579.3 (10.1)77.5 (55.5-94.5)113184482.8 (18.9)77.6 (60.1-210).30BMI, kg/m2Before diet314536.3 (5.2)36.3 (36.0-37.5)3692530.6 (4.1)29.2 (21.8-39.7).05After diet111329.7 (4.1)29.7 (29.7-29.7)2873928.0 (3.5)26.3 (21.7-35.0).50Percentage of body fat, %Before diet57638.1 (6.2)31.4 (20.5-44)3365537.2 (4.5)39.0 (12.8-47.3).70After diet56633.9 (5.0)22.3 (16.9-41)2753633.2 (4.9)33.2 (12.2-39.8).60Cholesterol, mg/dLTotalBefore diet13227191.1 (21.2)186 (148.2-214)791519246.4 (42.5)201 (124-267.8).03After diet12205188.3 (29.4)186 (119.6-348)751322201.8 (36.1)197 (136.6-252.5).60LDLBefore diet7181118.6 (20.7)119.9 (103.6-136)43934137.4 (30.9)129 (86.5-212.7).20After diet7168123.1 (20.7)116.6 (96.7-151)42852130.2 (20.2)127.9 (47-189.5).60HDLBefore diet1019751.3 (12.7)49.1 (27.1-87)48108048.7 (13.4)47.3 (30.9-72.8).60After diet917553.3 (8.1)53.0 (37.1-87)4898448.4 (9.9)46.4 (27.1-77.3).20Triglycerides, mg/dLBefore diet13227136.5 (60.8)115 (68.7-283.4)741674138.3 (53.4)129.6 (47.8-377.1).50After diet1321498.1 (38.7)93.0 (57.9-130.2)701245126.2 (46.8)123 (50-247.1).01Fasting serum glucose, mg/dLBefore diet11252101.3 (11.1)95.0 (73.8-226.8)601040130.5 (37.1)97.2 (72.5-225).90After diet1124991.4 (19.3)87.0 (68-144)59871112.4 (24.6)99 (67.5-205.2).10Fasting serum insulin, µIU/mLBefore diet65510.2 (4.7)10.2 (3.4-16.4)4483910.3 (8.5)10.3 (1.0-36.0).90After diet6556.6 (2.6)6.3 (2.2-10.2)467789.4 (4.3)7.9 (0.98-38.0).50Systolic blood pressure, mm HgBefore diet3132138.9 (16.2)126.0 (112-141.9)23507134.6 (16.7)133 (111-148).50After diet3132125.1 (12.6)119.0 (107.7-126.8)20403127.4 (12.3)129.6 (105-136).20Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein.SI conversion factors: To convert mg/dL to mmol/L for total cholesterol, LDL, and HDL, multiply by 0.0259. To convert mg/dL to mmol/L for triglycerides, multiply by 0.0113. To convert mg/dL to mmol/L for fasting serum glucose, multiply by 0.0555. To convert µIU/mL to pmol/L for fasting serum insulin, multiply by 6.945.*Means are weighted by the number of participants (eg, mean BMI before diet is weighted by the number of participants starting the diet and the mean BMI after diet is weighted by the number of participants completing the diet). Because the studies used to calculate the data before and after diet often differ, the change in outcomes should not be interpreted as the difference between the means before and after the diet (data reflecting the summary mean changes in outcomes are presented in Table 5).Effect of Diet and Participant Characteristics on Efficacy and Safety VariablesResults of the bivariate analyses compare the differences in each of the outcome variables between recipients of lower vs higher-carbohydrate diets (Table 5). The interpretation of these analyses is complicated by the significant heterogeneity of the included studies. For example, because the included diets were not isocaloric, the lower-carbohydrate diets vary significantly with respect to the percentage of calorie intake from carbohydrates. We have attempted to compare diets with similar caloric contents, durations, and study designs to account for this heterogeneity.Table 5.Summary Mean Change in Outcomes*Carbohydrates in Diet, g/dLower, ≤60Higher, >60No. of Diets†No. of ParticipantsSummary Mean Change‡ (SD)95% CINo. of DietsNo. of ParticipantsSummary Mean Change‡ (SD)95% CIWeight change, kgAll studies, all participants34668−16.9 (0.2)§−16.6, −17.31302092−1.9 (0.2)§−1.6, −2.2RCT and R-Cross only7132−3.6 (1.2)−1.2, −6.0751122−2.1 (0.3)−1.6, −2.7Caloric content of the diet, kcal/d<150018614−17.5 (0.2)§−17.1, −17.845870−3.1 (0.4)§−2.4, −3.8≥15001653−5.7 (0.2)§−5.4, −6.0841222−1.5 (0.2)§−1.2, −1.9Diet duration, d<151472−13.6 (0.1)§−13.5, −13.825198−1.5 (0.2)§−1.1, −1.816-609142−5.3 (0.6)§−4.2, −6.452827−3.5 (0.4)§−2.9, −4.3>6010447−2.4 (2.1)+1.8, −6.545968−1.1 (0.6)−.01, −2.3Participant age, y<4022426−17.7 (0.2)§−17.4, −18.159642−1.4 (0.2)§−1.0, −1.8≥4012242−5.0 (0.6)§−3.8, −6.2621231−2.9 (0.3)§−2.4, −3.5Baseline weight, kg<70322−19.6 (0.2)§−19.2, −20.019230−3.2 (0.6)§−1.9, −4.470-10013365−0.8 (1.6)+2.4, −4.0771357−2.4 (0.4)−1.3, −0.4>1007138−6.6 (0.7)§−5.2, −8.018301−8.1 (0.8)§−6.5, −9.7BMI, kg/m2All studies, all participants1113−1.4 (4.6)+7.6, −10.327739−0.4 (0.4)+0.3, −1.1Body fat, %All studies, all participants566−1.0 (5.6)+4.0, −6.027536−1.0 (0.6)+0.1, −2.1Cholesterol, mg/dLTotalAll studies, all participants13214−1.2 (7.3)+13.2, −15.5871633−8.1 (1.4)−5.5, −10.8RCT and R-Cross only377−1.9 (9.7)§+17.1, −20.843903−1.4 (3.3)+5.0, −7.9LDLAll studies, all participants7168−0.3 (9.7)+19.3, −18.742852−0.7 (3.1)+5.3, −6.8RCT and R-Cross only163+0.4 (30.7)+60.5, −59.722563−1.0 (3.7)+6.3, −8.3HDLAll studies, all participants9175−0.2 (2.1)+4.0, −4.346964−0.8 (0.6)+0.4, −2.0RCT and R-Cross only377−0.8 (4.2)+7.5, −9.122553−0.9 (0.7)+0.4, −2.3Triglycerides, mg/dLAll studies, all participants13214+4.1 (4.5)+13.0, −4.6781531−0.6 (3.3)+7.1, −6.0RCT and R-Cross only377+0.3 (19.0)+37.6, −37.043903−1.3 (4.4)+9.9, −7.4Fasting serum glucose, mg/dLAll studies, all participants11249−1.3 (2.8)+4.3, −6.859871−0.4 (1.2)+1.9, −2.7RCT and R-Cross only269−0.3 (27.4)+53.4, −54.017455−0.3 (1.3)+2.4, −3.0Fasting serum insulin, pmol/LAll studies, all participants545−0.8 (9.9)+18.5, −20.144764−0.4 (1.6)+2.9, −3.7RCT and R-Cross only0. . .. . .. . .26467−0.01 (2.3)+4.4, −4.5Systolic blood pressure, mm HgAll studies, all participants41730.7 (5.2)+10.8, −9.5254810.6 (2.5)+5.6, −4.3Abbreviations: BMI, body mass index; CI, confidence limits; ellipses, insufficient data to calculate outcome; HDL, high-density lipoprotein; LDL, low-density lipoprotein; RCT, randomized controlled trial; R-Cross, randomized crossover trial.*See Table 4 for the conversion of conventional units to SI units.†The reason that the number of diets and number of participants for whom we were able to calculate a difference in each of the outcomes is greater than the number of diets and number of participants for whom we presented in the data before and after diet (Table 4) is that some studies reported only the change in the outcome but not before or after diet data.‡Summary mean change in each outcome variable was calculated from a standardized mean difference. A negative change in any of the outcome variables denotes a reduction in that variable after the diet interval. For example, the absolute summary mean change in weight loss calculated from all studies of lower-carbohydrate diets was 16.9 kg.§The Q statistic for that summary mean change calculation was significant (ie, studies were not homogeneous).Change in Weight, BMI, and Percentage of Body Fat.At the end of both lower- and higher-carbohydrate diets, participants' weight, BMI, and percentage of body fat decreased (Table 5). In general, for both lower- and higher-carbohydrate diets, we found the greatest weight loss occurred among those participants receiving diets with the lowest caloric content and for those participants with the highest baseline weights (Table 5). The 72 young participants of the 14 dietsof very short duration (<15 days) receiving lower-calorie diets (mean [SD] age, 26.8 [8.5] years; mean [SD], 23 [13] g/d of carbohydrates; mean [SD], 1597 [715] kcal/d for participants with a mean [SD] weight before diet of 78.4 [5.2] kg) demonstrated significant mean [SD] weight loss (13.6 [0.1] kg); however, no data were available about whether they maintained this weight loss beyond the study period.Of the 34 of 38 lower-carbohydrate diets for which weight change after diet was calculated, these lower-carbohydrate diets were found to produce greater weight loss than higher-carbohydrate diets (absolute summary mean [SD] change, 16.9 [0.2] kg; 95% CI, 16.6-17.3 kg vs 1.9 [0.2] kg; 95% CI, 1.6-2.2 kg) (Table 5). Because the 95% CIs for the lower- and higher-carbohydrate diets do not overlap, it suggests that a difference may exist in weight change between the 2 types of diets. However, the highly heterogeneous nature of the 34 diets is reflected in the significant Q statistic associated with the summary mean changes in weight calculated when all studies were included in the analysis. Given this heterogeneity, little can be concluded about the summary mean change in weight loss when all studies are combined. When only the randomized controlled trials and the randomized crossover trials in the analysis are included, the result of the Q statistic suggests that the studies are homogeneous. From this selected group of relatively similar randomized studies of 7 lower-carbohydrate dietsand 75 higher-carbohydrate diets we found that the absolute summary mean [SD] change decrease in weight for lower-carbohydrate diets was 3.6 (1.2) kg (95% CI, 1.2-6.0 kg) and for higher-carbohydrate diets was 2.1 (0.3) kg (95% CI, 1.6-2.7 kg). This overlap in 95% CIs suggests no difference in weight loss between the lower- and higher-carbohydrate diets.To evaluate the weight loss demonstrated in the studies with the lowest-carbohydrate content, we calculated the summary mean [SD] change in weight loss found in the 13 dietsof these diets with 71 participants. In this group of studies, we found a summary mean (SD) change in weight of −1.2 (−2.3) kg (95% CI, −5.7 kg to 3.3 kg). The result of the Q statistic suggests homogeneity; however, we note that these studies vary with respect to study design, including studies that are not randomized and that do not include a comparison group. Thus, based on the data, it can be concluded that lowest-carbohydrate diets did not result in significantly greater weight loss than lower-carbohydrate diets.When we consider the 22 diets with the greatest mean weight loss (ie, mean weight loss of ≥10 kg), we found that they varied widely with respect to carbohydrate content (mean [range], 97 [10-271] g/d of carbohydrate) (data not shown). However, these diets restricted caloric intake (mean [range], 1077 [525-1800] kcal/d), were longer in duration (mean [range], 142 [42-365] days), and included participants who were significantly overweight at the start of the diets (mean [range], 101 [84-183] kg) (data not shown). These results suggest that these 3 variables may be more important predictors of weight loss than carbohydrate content.Change in Serum Lipid Levels.For all studies and participants of lower-carbohydrate diets, no change was found in any of the serum lipid levels (ie, the 95% CIs for the summary mean [SD] change in total, LDL, and HDL cholesterol, and triglycerides levels all included 0) (Table 5). However, heterogeneity and paucity of studies complicate the interpretation of the outcomes of serum lipid levels. In contrast, among the more homogeneous group of studies of higher-carbohydrate diets, we found a significant decline in total cholesterol levels (summary mean [SD] change, −8.1 [1.4] mg/dL; 95% CI, −5.5 to −10.8 or −0.21 [0.04] mmol/L; 95% CI, −0.14 to −0.28 mmol/L) but not in the other serum lipid levels (95% CIs include 0).From the 3 studiesof lowest-carbohydrate diets that reported data for total cholesterol levels for 36 participants, we found no change in serum lipid levels (summary mean [SD] change for total cholesterol, +0.1 [28.0] mg/dL; 95% CI, −54.8 to +55.1 mg/dL or 0.0026 [0.73] mmol/L; 95% CI, −1.4 to 1.4 mmol/L) (data not shown). None of the studies specifically evaluated the effect of lower-carbohydrate diets on serum lipid levels among participants with hyperlipidemia, and only 1 studyreported outcomes for serum lipid levels for participants with diabetes.Change in Fasting Serum Glucose and Insulin Levels.No change was observed in either fasting serum glucose or insulin levels among recipients of either lower- or higher-carbohydrate diets—even among those participants with the greatest weight loss or those participants receiving the lowest-carbohydrate diets (Table 5). Only 1 small study(9 participants) specifically evaluated the effect of lower-carbohydrate diets on fasting serum glucose or insulin levels among obese participants with diabetes (both 95% CIs include 0) (data not shown).Change in Systolic Blood Pressure.We found no change in systolic blood pressure after diet in participants receiving either lower- or higher-carbohydrate diets. Four studiesof 173 recipients of lower-carbohydrate diets demonstrated a summary mean (SD) change in decrease in blood pressure of 0.7 (5.2) mm Hg (95% CI, +10.8 to −9.5 mm Hg) (Table 5).Outcome Variables for Low-Carbohydrate DietsTo determine the effect of diet and participant characteristics on the outcomes of interest, a weighted analysis of variance was performed (Table 6). The weighted analysis of variance was used because the outcome variables are correlated; the diets vary with respect to total caloric content, duration, and carbohydrate content; and to avoid the use of a threshold to define what constitutes a lower-carbohydrate diet. Because only a few studies evaluated all of the dietary, participant, and outcome variables of interest, we were limited in our ability to include all studies or all variables in this analysis. The results of the analysis of variance using all diet data from all studies reporting weight loss, baseline weight, age, sex, and diet variables demonstrate that weight loss was significantly associated with longer diet duration (P= .008) and baseline weight (P<.001). For obese participants, restriction of calorie intake also was associated with weight loss, albeit not statistically significant after applying the Bonferroni adjustment (P= .03) (Table 6). Reduced carbohydrate content was not significantly associated with weight loss.Table 6.Results of Weighted Analysis of Variance to Determine the Effects of Diets and Participants on Outcome Variables for Lower-Carbohydrate Diets*OutcomeNo. of Diets†R2‡PValues§Baseline Weight, kg% MaleMean Age, yCarbohydrates, g/dCaloric Content, kcal/dDiet Duration, dWeight Loss, kg&par;Reduction of Fasting Glucose, mg/dL¶Weight loss, kgAll diets, all participants350.69<.001.04.02.90.50.008. . .. . .RCT and R-Cross studies only150.94<.001.90.30.10.50.06. . .. . .Healthy volunteers120.57. . .. . .. . ..40.90.08. . .. . .Obese participants330.33. . .. . .. . ..90.03.002. . .. . .Diabetic participants120.60. . .. . .. . ..40.02.30. . .. . .Reduction in total cholesterol, mg/dLAll diets, all participants250.31. . ..20.30.20.50.30.90. . .RCT and R-Cross studies only90.88. . ..80.80.20.30.70.40. . .Healthy volunteers90.59. . .. . .. . ..10.30.80.80. . .Obese participants120.21. . .. . .. . ..70.90.90.50. . .Diabetic participants290.12. . .. . .. . ..90.09.90. . .. . .Reduction in LDL cholesterol, mg/dLAll diets, all participants101.00.005.02.004.10.002.002.005. . .RCT and R-Cross studies only130.83.01.10.06.20.50.07. . .. . .Healthy volunteers110.21. . .. . .. . ..20.50.80. . .. . .Obese participants80.97.30.20.90.30.20.90. . .. . .Diabetic participants150.55.07.30.30.90.10.60. . .. . .Increase in HDL cholesterol, mg/dLAll diets, all participants90.94. . ..90.50.60.70.20.30. . .RCT and R-Cross studies only190.19. . ..20.70.60.70.60. . .. . .Healthy volunteers120.26. . .. . .. . ..90.20.70. . .. . .Obese participants130.73. . .. . .. . ..20.01.003. . .. . .Diabetic participants200.02. . .. . .. . ..60.90.90. . .. . .Reduction in triglycerides, mg/dLAll diets, all participants80.99. . .. . .. . ..04.05.20.09.40RCT and R-Cross studies only90.41. . .. . .. . ..90.80.30.60. . .Healthy volunteers220.19. . .. . .. . ..10.70.90. . .. . .Obese participants120.51. . .. . .. . ..10.20.70.30. . .Diabetic participants200.11. . .. . .. . ..50.90.40. . ..30Reduction in fasting serum glucose, mg/dLAll diets, all participants100.79. . .. . .. . ..90.10.01.06. . .RCT and R-Cross studies only310.56. . .. . .. . ..30.10<.001. . .. . .Healthy volunteers170.36. . .. . .. . ..10.20.20. . .. . .Obese participants200.09. . .. . .. . ..50.80.30. . .. . .Diabetic participants270.61. . .. . .. . ..90.003.001. . .. . .Change in fasting serum insulin, µIU/LAll diets, all participants490.24. . .. . .. . ..10.90.002. . .. . .RCT and R-Cross studies only280.46. . .. . .. . ..10.40<.001. . .. . .Healthy volunteers120.55. . .. . .. . ..03.20.70. . .. . .Obese participants160.35. . .. . .. . ..80.20.20. . .. . .Diabetic participants180.51. . .. . .. . ..10.50.003. . .. . .Change in systolic blood pressure, mm HgAll diets, all participants100.56. . .. . .. . ..30.20.20.40. . .RCT and R-Cross studies only90.53. . .. . .. . ..80.90.20.50. . .Healthy volunteers. . .. . .. . .. . .. . .. . .. . .. . .. . .. . .Obese participants160.21. . .. . .. . ..90.50.40. . .. . .Diabetic participants80.34. . .. . .. . ..80.80.50. . .. . .Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; RCT, randomized controlled trial; R-Cross, randomized crossover trial. Ellipses indicate insufficient data to calculate.*See Table 4 for the conversion of conventional units to SI units.†Number of diets refers to the number of dietary interventions that could be included in each analysis. To be included in the analysis of variance, a study had to report data for each of the predictor and outcome variables of interest. For example, studies of 10 dietary interventions provided data on change in fasting serum glucose levels and included information about the carbohydrate content of the diet, the caloric content of the diet duration, and participants' weight loss. However, the RCTs and R-Cross studies did not provide sufficient data about weight loss as a predictor of reduction in fasting serum glucose levels.‡Using the weighted analysis of variance (weighted by the number of participants who finished each diet), the R2was calculated to estimate the amount of variance in the outcome variables accounted for by the predictor variables.§Pvalue associated with the effect of these predictor variables on the outcome variables&par;Weight loss was included as a predictor variable for the weighted analyses of variance for change in serum lipid, fasting serum glucose, and fasting serum insulin levels, and systolic blood pressure as allowed by the availability of data.¶Reduction of fasting serum glucose levels was included as a predictor variable for the weighted analyses of variance for change in serum triglyceride levels as allowed by the availability of data.For all diets and all participants, reductions in LDL cholesterol levels were associated with high baseline weight (P= .005), weight loss (P= .005), younger age (P= .004), restriction of calorie intake (P= .002), and longer diet duration (P= .002)(Table 6). Overall dietary and participant characteristics were not significantly associated with changes in total cholesterol, HDL cholesterol, or triglyceride levels. Reductions in fasting serum glucose and insulin levels were consistently associated with longer diet duration (P= .01 and P= .002, respectively). Restriction of carbohydrate intake was not significantly associated with changes in serum lipid levels, change in fasting serum glucose levels, or systolic blood pressure.COMMENTOur quantitative synthesis of the 107 studies of 94 diets from the English-language literature on the efficacy and safety of low-carbohydrate diets suggests that there is insufficient evidence to make recommendations for or against the use of these diets. Despite the large number of Americans who have apparently adopted this approach to weight loss and/or weight maintenance, we know little of its effects or consequences. In particular, these diets have not been adequately evaluated for use longer than 90 days, for individuals aged 53 years or older, or for use by participants with hyperlipidemia, hypertension, or diabetes. The lowest-carbohydrate diets (eg, ≤20 g/d of carbohydrates, the recommended threshold for some of the most popular diets) have been studied in only 71 participants for whom no data on serum lipid, fasting serum glucose, and fasting serum insulin levels or blood pressure was reported.We found insufficient evidence to conclude that lower-carbohydrate content is independently associated with greater weight loss compared with higher-carbohydrate content. We did find, however, that diets that restricted calorie intake and were longer in duration were associated with weight loss. Given the limited evidence in this review, when lower-carbohydrate diets result in weight loss, it also is likely due to the restriction of calorie intake and longer duration rather than carbohydrate intake. Lower-carbohydrate diets were not associated with adverse effects on serum lipid levels, fasting serum glucose levels, or blood pressure. However, because few studies reported on these outcomes, this systematic review lacked statistical power to detect small changes in these measures.The heterogeneity of all the studies included in this review precludes drawing conclusions from the synthesis of the total group of studies. The statistically significant weight loss demonstrated when we compared all studies of lower- and higher-carbohydrate diets using the threshold of 60 g/d of carbohydrates was not confirmed by any other analyses (eg, evaluating the recipients of diets containing ≤20 g/d of carbohydrates or the participants with the greatest weight loss). We attribute this finding to the inclusion of studies of lower-carbohydrate diets with relatively short durations for obese participants in whom significant weight loss was achieved while using diets of 60 g/d or less of carbohydrates, primarily through restriction of calorie intake. It may be that these obese participants were better able to tolerate the restriction of calorie intake while using lower-carbohydrate diets than while using higher-carbohydrate diets. This observation suggests the need for additional studies of isocaloric diets with different carbohydrate contents in which participants are specifically assessed for symptoms of hunger and on the tolerability of the diet.Our analyses were limited by a small number of studies that evaluated more than 1 of the outcomes of interest or that provided sufficiently detailed information about their participants or dietary intervention. Specifically, our systematic review highlights 5 significant gaps in the published literature of low-carbohydrate diets. First, the lack of adequate long-term follow-up data significantly limits our understanding of the efficacy and safety of low-carbohydrate diets. In particular, the long-term effects of low-carbohydrate diets on serum lipid, fasting serum glucose, and fasting serum insulin levels and blood pressure may differ between hypocaloric diets intended for weight loss and isocaloric diets intended for weight maintenance. Second, we were not able to evaluate the effects of these diets on different racial/ethnic groups. The absence of data regarding the efficacy and safety of lower-carbohydrate diets by race/ethnicity critically limits our ability to make participant-specific recommendations about these diets. Third, because exercise can have a significant effect on weight loss, we had hoped to include a measure of energy expenditure as a covariate in our analyses. We were unable to report data on exercise because many studies either did not report any information about participants' exercise patterns or simply stated that participants were encouraged to maintain baseline levels of exercise. Fourth, some of the included diets provided counseling or other supportive measures to encourage participants to adhere to the dietary intervention. The heterogeneity of the information reported about how adherence was measured limited our ability to include them in our analyses. Finally, many of the included studies reported only the number of participants who completed the dietary intervention. Among those studies that reported both the total number enrolled and the total number who completed the intervention, very few performed an intention-to-treat analysis. This limitation of both the lower- and higher-carbohydrate diets has the potential to bias the results in the direction of overstating the effects of the dietary intervention.Our search strategies may have introduced biases into our results. First, we only included English-language studies. We found 17 foreign-language articles that we could not exclude on the basis of the English title or abstract. Extrapolating from our finding that 94 evaluated dietary interventions of 60 g/d or less of carbohydrates, it is likely that about a third of these would have evaluated lower-carbohydrate diets. However, we believe that the data from these estimated 5 or 6 foreign-language articles that may have met our inclusion criteria would not have changed the result of our analyses, as to do so all of these studies would need to have included significantly larger number of participants than the included studies, found very different results than those described, or evaluated diets for more than 90 days. Given the important cultural and ethnic differences in dietary habits, including foreign-language studies may have increased the heterogeneity of the participants evaluated. Second, our search was limited to MEDLINE and the bibliographies of retrieved publications. Although the major nutrition science publications are included in the MEDLINE database, we may have missed some relevant articles. Given the multiple clinical outcomes evaluated, we did not perform a formal analysis of publication bias.The results of our systematic review suggest that if participants without diabetes tolerate a lower-carbohydrate diet better than a higher-carbohydrate alternative, this diet may be an effective means of achieving short-term weight loss without significant adverse effects on serum lipid levels, glycemic control, or blood pressure. However, there is insufficient evidence to recommend or condemn the use of these diets among participants with diabetes or for long-term use. Because of the complex relationships between serum lipid levels, plasma insulin levels, cortisol and glucogon levels during dieting,and because of the claim by some proponents of low-carbohydrate diets that these diets work best when producing ketosis,future evaluations of lower-carbohydrate diets should enroll participants with and without diabetes and with and without abnormal lipid levels to more fully describe the effects of lower-carbohydrate (sometimes called "ketogenic") diets on lipid and glycemic indices and ketogenesis.Despite the abundance of lay literature on the topic of low-carbohydrate diets, to date our study is the first published synthesis of the evidence from the English-language literature. Our results demonstrated the marked discordance between the knowledge needed to guide dietary choices and the information that is available in the medical literature. 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Bravata, MD, MS, Center for Primary Care and Outcomes Research, 117 Encina Commons, Stanford, CA 94305-6019 (e-mail: bravata@healthpolicy.stanford.edu).Author Contributions:Study concept and design:Dena Bravata, Huang, Olkin, Gardner, Dawn Bravata.Acquisition of data:Dena Bravata, Sanders, Huang, Dawn Bravata.Analysis and interpretation of data:Dena Bravata, Huang, Krumholz, Olkin, Gardner, Dawn Bravata.Drafting of the manuscript:Dena Bravata, Dawn Bravata.Critical revision of the manuscript for important intellectual content:Dena Bravata, Sanders, Krumholz, Olkin, Gardner, Dawn Bravata.Statistical expertise:Dena Bravata, Olkin, Dawn Bravata.Obtained funding:Dena Bravata, Huang, Krumholz, Dawn Bravata.Administrative, technical, or material support:Dena Bravata, Sanders, Huang, Dawn Bravata.Study supervision:Dena Bravata, Krumholz, Gardner, Dawn Bravata.Funding/Support:During this project Dr Dawn Bravata was initially supported by the Robert Wood Johnson Clinical Scholars program at Yale University and is currently supported by a Veterans Administration HSR&D Service Research Career Development Award. Dr Huang's efforts were supported by a Seed Project grant from the American Medical Association. Dr Olkin is supported by National Science Foundation grant No. DMS 96-26-265.Previous Presention:Portions of this work were presented at the 23rd Annual Meeting of the Society for Medical Decision Making, San Diego, Calif, October 22, 2001; and the Society of General Internal Medicine Meeting, Atlanta, Ga, May 5, 2003.Disclaimer:None of the authors has financial or other conflicts of interest pertaining to the use of low-carbohydrate diets or diet products. This project received no funding from any manufacturer or purveyor of dietary goods or services.Acknowledgment:We thank Emilee Wilhem for her editorial support, Chris Stave for his assistance with literature searches, Ada Foley for her help with article retrieval, and Edward Miech, EdD, for his logistical support throughout the project.

Journal

JAMAAmerican Medical Association

Published: Apr 9, 2003

References