Author Manuscript Author Manuscript HHS Public Access Author manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Published in final edited form as: Lancet Diabetes Endocrinol. 2015 December ; 3(12): 968–979. doi:10.1016/S2213-8587(15)00367-8. Effect of Low-Fat vs. Other Diet Interventions on Long-Term Weight Change in Adults: A Systematic Review and MetaAnalysis Deirdre K. Tobias, ScD1,2, Mu Chen, ScD2, JoAnn E. Manson, MD1,3,*, David S. Ludwig, MD4,2,*, Walter Willett, MD2,3,5,*, and Frank B. Hu, MD2,3,5,* 1Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, 900 Commonwealth Avenue Boston, MA 02215 2Department of Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, MA 02115 3Department of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue Boston, MA 02115 4New Balance Foundation Obesity Prevention Center, Boston Children’s Hospital, One Autumn Street, Fifth Floor Boston, MA 02215 5Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue Boston, MA 02115 Abstract Background—The effectiveness of low-fat diets for long-term weight loss has been debated for decades, with dozens of randomized trials (RCTs) and recent reviews giving mixed results. Methods—We conducted a random effects meta-analysis of RCTs to estimate the long-term effect of low-fat vs. higher fat dietary interventions on weight loss. Our search included RCTs conducted in adult populations reporting weight change outcomes at ≥1 year, comparing low-fat with higher fat interventions, published through July 2014. The primary outcome measure was mean difference in weight change between interventions. This manuscript version is made available under the CC BY-NC-ND 4.0 license. Corresponding author: Deirdre K. Tobias; dtobias@partners.org, Phone: 617-525-9857, Brigham and Women’s Hospital and Harvard Medical School, Division of Preventive Medicine, 900 Commonwealth Avenue Boston, MA 02215. *Full professor Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of interest statement Drs. Tobias, Chen, Manson, and Willett have no disclosures. Author contributions Dr. Tobias developed the study protocol, conducted the literature search, data extraction, analysis, and interpretation, and draft manuscript. Dr. Chen conducted the literature search, and data extraction. Drs. Manson, Ludwig, Willett, and Hu contributed to study protocol and key data interpretation and manuscript review. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Tobias et al. Page 2 Findings—Fifty-three studies met inclusion criteria representing 68,128 participants. In the setting of weight loss trials, low-carbohydrate interventions led to significantly greater weight loss than low-fat interventions (n comparisons=18; weighted mean difference [WMD]=1.15 kg, 95% CI=0.52 to 1.79; I2=10%). Low-fat did not lead to differences in weight change compared with other moderate fat weight loss interventions (n=19; WMD=0.36, 95% CI=-0.66 to 1.37; I2=82%), and were superior only when compared with “usual diet” (n=8; WMD=-5.41, 95% CI=-7.29 to −3.54; I2=68%). Similarly, non-weight loss trials and weight maintenance trials, for which there were no low-carbohydrate comparisons, had similar effects for low-fat vs moderate fat interventions, and were superior compared with “usual diet”. Weight loss trials achieving a greater difference in fat intake at follow-up significantly favored the higher fat dietary interventions, as indicated by difference of ≥5% of calories from fat (n=18; WMD=1.04, 95% CI=0.06 to 2.03; I2=78%) or by difference in change serum triglycerides of ≥5 mg/dL (n=17; WMD=1.38, 95% CI=0.50 to 2.25; I2=62%). Interpretation—These findings suggest that the long-term effect of low-fat diets on body weight depends on the intensity of intervention in the comparison group. When compared to dietary interventions of similar intensity, evidence from RCTs does not support low-fat diets over other dietary interventions. Introduction Identifying effective strategies for long-term weight control will be critical to reduce the alarming prevalence of overweight and obesity worldwide. The macronutrient composition of the diet, or the proportions of calories contributed by fat, carbohydrate, and protein, has received significant attention in past decades for its potential relevance in weight loss and weight maintenance. Numerous short- and long-term randomized trials across a variety of general and clinical populations have attempted to identify the optimal ratio of macronutrients for weight loss. Lowering the proportion of daily calories consumed from total fat has been targeted for many reasons, one of which is that a single gram of fat contains more than twice the calories of a gram of carbohydrates or protein (9 kcal/gram vs. 4 kcal/gram). Thus, reducing total fat intake may theoretically lead to an appreciable impact on total calories consumed. However, randomized trials have failed to consistently demonstrate that reducing the percent of energy from total fat leads to long-term weight loss compared to other dietary interventions. This systematic review and meta-analysis aimed to summarize the large body of evidence from randomized control trials (RCTs) lasting ≥1 year in which weight changes on low-fat diets vs. other dietary intervention groups were compared. Trials were included regardless of whether weight loss was intended or not, for example in studies evaluating lipids or cancer endpoints. We considered stratification by characteristics of the interventions that may affect differences in weight loss, including whether the intervention arms received similar attention and intervention intensity, or the composition of the comparison diet. We hypothesized that low-fat diets would not be associated with greater weight loss when differences in these intervention characteristics were taken into account, and that differences in weight loss favoring higher fat interventions would be larger when adherence was greater. Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Tobias et al. Page 3 Methods Search strategy and inclusion criteria Predefined search strategy, study eligibility criteria, and statistical methodological approaches, were detailed in our unpublished research protocol. Full details of our literature search (Page 2) and PRISMA checklist (Pages 7–10) are outlined in the Appendix. Briefly, we used the MEDLINE, EMBASE, CENTRAL, and Cochrane Database of Systematic Reviews to identify eligible trials. We included trials lasting ≥1 year comparing weight change on a low-fat diet (as defined by authors) with any higher fat dietary intervention, including “usual diet” among non-pregnant adults. Trials of shorter duration were excluded because weight-loss trials frequently observe an initial maximal weight loss around 6 months with subsequent weight regain. The outcome of interest was long-term (≥1 year) change in body weight (reported as mean change from baseline, mean change difference, or mean body weight at end of follow-up). Efforts were made to contact authors to obtain variance measures, if not reported, but were ultimately excluded if unavailable. We excluded trials if one intervention group included a non-dietary weight loss component (e.g., exercise regimen, pharmaceutical intervention) while the other did not. We did not make exclusions based on concomitant dietary components (e.g., increase fruits and vegetables). Nonrandomized trials were excluded as well as dietary supplements or meal replacement drink interventions as these were beyond the scope of our investigation. If trial results were published more than once, the paper with the most complete follow-up was included in the main analysis. Screening of abstracts for relevance was conducted by two reviewers (DT, MC) and eligible full texts were reviewed with an inclusion/exclusion criteria sheet independently and in duplicate by two reviewers (DT, MC). Data extraction Variables captured from the final accepted studies included study level information (authors, country, center), study population characteristics, intervention details, including weight loss intention (yes, no, maintain) and the relative intensity of each intervention, as described by study authors (i.e., systematically greater attention, time spent with study clinicians, dieticians, program materials, etc for one intervention group over the other), and outcomes by treatment arm. We also recorded dietary adherence, including change in serum triglyceride levels and the percent calories from fat during follow-up. We analyzed the intention-to-treat estimates, when reported. We evaluated the trials’ potential for bias using the Cochrane risk of bias assessment tool.(1) Data were extracted independently by two investigators (DT, MC), and discrepancies resolved with a third reviewer (FH), if necessary. Data analysis We calculated the mean difference in body weight change from baseline by subtracting the mean change of the comparison diet group from the mean change in the low-fat diet group. If the mean change was not reported we compared the groups’ final mean body weights, Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Tobias et al. Page 4 under the assumption that randomization resulted in similar average baseline body weights between treatment arms. We estimated the pooled weighted mean difference and 95% confidence interval (CI) with a DerSimonian and Laird random effects model. P<0.05 was considered statistically significant. We assessed heterogeneity from the Mantel-Haenszel model and I2 values (the percent of variance in the pooled estimate due to between-study differences), with I2>50% indicating moderate heterogeneity.(2) Analyses established a priori were conducted to evaluate potential heterogeneity by the whether the trial was designed with the intention of weight loss, the composition of the comparison diet (low-carbohydrate, other moderate fat/”healthful” diet, or usual diet), the interventions’ relative intensity, , whether either, neither, or both of the interventions included caloric restriction, and the baseline health status of the participants. Additionally, we stratified by change in triglyceride levels and in attained self-reported percent calories from fat, with an increase in triglycerides reflecting a relative decrease in fat intake.(3) Finally, we conducted sensitivity analyses to assess the robustness of findings. We evaluated the impact of removing the largest study or studies, based on their percent weight in the pooled estimates and restricted to trials conducting intention-to-treat analyses and with ≥100 participants. Primary analyses were repeated using an inverse variance weighted fixed effect model. The Begg (4) and Egger (5, 6) tests were conducted to test for the potential of publication bias by plotting the inverse of the variance against the treatment effect. Analyses were performed using STATA® version 13.1. Role of the funding source The funding sources did not participate in the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review, or approval of the manuscript. DT had full access to all of the data and the final responsibility to submit for publication. RESULTS Our search yielded 3,517 citations (Figure 1), of which 53 RCTs were eligible for inclusion in our analysis (Table 1). The majority of trials were conducted in North America (n=37) and were 1 year in duration (n=27). Twenty trials specifically enrolled participants with prevalent chronic diseases, including breast cancer,(7–10) hypercholesterolemia,(11–13) and type 2 diabetes.(14–22) In addition to 35 weight loss trials, there were 13 trials with no intended intervention on weight, (7–10, 12, 13, 22–28) and 5 weight maintenance trials designed to maintain baseline body weight. (11, 29–32) The low-fat dietary interventions ranged from very low-fat ≤10% of calories from fat, to more moderate goals of ≤30% of calories from fat. Comparator diets of higher fat intake were diverse, ranging from a single baseline interaction with instructions to maintain “usual diet”, to a variety of other dietary interventions, including low-carbohydrate and other moderate-to-high-fat diets. The intensity of the interventions varied from pamphlets or instructions given at baseline only, to multicomponent programs integrating counseling Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Tobias et al. Page 5 sessions, regular meetings with dieticians, food diaries, cooking lessons, etc., to feeding studies, in which participants were given a significant portion of their food. Caloric restriction was a component of many weight loss interventions, but not all. For example, despite being a weight loss intervention, a low-carbohydrate Atkins-style diet is often ad libitum (i.e., eat until satiated). Our primary meta-analysis included 68,128 adults from eligible randomized clinical trials, reporting a mean weight loss of 2.71 kg (SD=2.8) after a median of 1 year of follow-up, and 3.75 kg (SD=2.7) among weight loss trials. Figure 2 presents the overall results according to weight loss trial design (yes, no, or maintain) and composition of comparator intervention (low-carbohydrate, other higher fat intervention, or usual diet). No difference between lowfat and higher fat dietary interventions was observed when all weight loss trials were combined, although there was significant between-study heterogeneity. Low-carbohydrate weight loss interventions led to an average 1.15 kg greater long-term weight loss than lowfat weight loss interventions, with minimal between-study heterogeneity. No difference, however, was observed between low-fat and other higher fat dietary interventions. Compared with groups only following their usual diet, low-fat weight loss interventions led to 5.41 kg greater weight loss. Non-weight loss trials and weight maintenance trials also found a significant but smaller magnitude of weight loss in low-fat interventions when compared with usual diet, and no difference between low-fat and other higher fat dietary interventions. No long-term non-weight loss or weight maintenance trials compared low-fat with low-carbohydrate dietary interventions. Table 2 presents analyses stratified by additional trial characteristics, limited to trials of similar intensity to minimize bias from one group receiving more attention and higher intervention intensity. Only 4 of the 17 comparisons among trials without a weight loss goal (13, 22, 24) and 1 of the 6 comparisons among weight maintenance trials (31) remained, limiting our ability to stratify further; thus, Table 2 includes weight loss trials only, which trended towards greater weight loss for higher fat interventions. Stratifying by caloric restriction indicated no significant difference in weight loss between low-fat and higher fat dietary weight loss interventions when interventions were concordant for caloric restriction. Calorie-restricted low-fat diets, however, fared significantly worse compared with noncalorie restricted higher fat interventions. Results were similar for weight loss trials among participants with or without a specific chronic disease at baseline (e.g., breast cancer). When groups differed by >5% calories from fat at follow-up, higher fat led to significantly greater weight loss than low-fat weight loss interventions. Similarly, weight loss trials with a ≥5 mg/dL greater change in triglycerides for low-fat vs. higher fat interventions, led to significantly greater weight loss for the higher fat groups. Excluding the Women’s Health Initiative trial (96.90% of weight) from weight maintenance trials, did not impact findings (n=5; WMD=-0.77 kg, 95% CI=-1.50 to −0.04, p=0.039; I2=0.0%, p-heterogeneity=0.95). Results were similar when restricted studies conducting to intention-to-treat analyses (Appendix pages 3–4) and when excluding smaller trials of <100 total participants, although few non-weight loss or weight maintenance trials remained eligible according to these criteria. The fixed effect meta-analysis (Appendix pages 5–6), Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Tobias et al. Page 6 which gives less weight to smaller trials with greater variance, estimated 0.44 kg greater weight loss for the comparator vs. low-fat interventions among the weight loss trials. Fixed effect analyses stratified by comparator group also indicated greater weight loss for “other higher fat interventions” vs. low-fat in trials with and without a weight loss goal, which showed no difference in the random effects analysis. Results from the Cochrane risk of bias assessment tool (Appendix pages 10–12) were variable and evaluation was limited for many studies by a lack of reporting. Incomplete outcome data was a high potential source of bias for 39 trials due to dropout and lost-tofollow-up rates exceeding 5%. Differential intervention intensity was deemed a source of bias for 20 trials. Both the Begg and Egger’s tests for small-study effects did not indicate publication bias (p=0.83 and p=0.85, respectively). Visual inspection of the funnel plot demonstrated an approximately symmetrical distribution of the inverse variances, which is consistent with these findings (Appendix page 13). Discussion Results from this comprehensive meta-analysis of RCTs with at least 1 year of follow-up indicate low-fat dietary interventions do not lead to greater weight loss when compared with higher fat dietary interventions of similar intensity, regardless of the weight loss intention of the trial. In fact, in the setting of weight loss trials, higher fat, low-carbohydrate dietary interventions led to a modest but significant greater long-term weight loss than low-fat interventions. Other higher fat dietary interventions led to similar weight loss as the low-fat groups, whether the trial had a weight loss goal or not. Low-fat interventions were favored only in comparison with interventions of lesser intensity, particularly those in which controls were only asked to maintain their usual diet. Furthermore, trials achieving greater differences in dietary fat intake and serum triglyceride concentrations resulted in greater weight loss under the higher fat interventions. Although these are not perfect measures of dietary fat intake, given the potential for measurement error in self-reported diet and confounding by weight loss for triglycerides as a marker of fat intake, results were consistent between these two methods. This systematic literature review and meta-analysis highlights several important points. First, of the 53 eligible RCTs, 19 included higher fat comparator groups which maintained their usual intake, while the low-fat groups underwent interventions with more frequent and/or more intense interaction with research staff. Such comparisons do not provide evidence to support the effect of the low-fat diets themselves, since the effect of lowering total fat intake cannot be distinguished from the other components of the intervention. Stratifying by this type of comparator group (Figure 2), it is clear that lowering fat intake was not an independent contributor to weight loss. Second, despite concerted efforts among motivated clinical trial participants and staff, the average weight loss in all groups after a median 1 year of follow-up was a modest 2.7 kg, and 3.8 kg when calculated among weight loss trials only. Our findings contrast with the findings of a previous systematic review and meta-analysis, which concluded that reduction in total fat intake leads to clinically meaningful weight loss, Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Tobias et al. Page 7 reporting 1.57 kg (95% CI=1.97 to 1.16) greater weight loss for low-fat vs. other diet interventions.(33) The main differences in their study selection criteria from ours were their inclusion of trials with <1 year of follow-up and their deliberate exclusion of trials with any weight loss intention. Trials of short duration (e.g. 6 months) are unlikely to demonstrate effects representative of long-term effects of diet on weight. Additionally, evaluating low-fat diets for weight loss exclusively among trials without a weight loss goal excluded a substantial proportion of the available literature, giving a pooled estimate that was overweighted by trials comparing low-fat with “usual diet”, as well as trials conducted among populations at high risk for specific non-body weight related endpoints of interest (e.g., cholesterol-lowering, breast cancer prevention, etc). In our current meta-analysis among trials without a weight loss goal and at least 1 year duration, we found that after removing comparisons between low-fat and “usual diet”, low-fat interventions did not lead to greater weight loss that higher fat interventions (n=7; WMD=0.26 kg, 95% CI=-0.39 to 0.91). In fact, of the 33 trials included in their overall analysis, only 8 comparisons were conducted among trials giving similar attention to the low-fat and comparator treatment arms, and only 1 of these lasted at least 1 year. Furthermore, only 3 were among healthy participants. Therefore, generalizability of their findings to overall populations intending to lose weight is highly questionable, and their estimated effects of reducing fat intake are likely to be seriously confounded by differences in comparator group intensity, which was demonstrated to be a major source of heterogeneity in our analysis. Johnston, et al, conducted a network meta-analysis among trials comparing named popular diet programs.(34) Pooling both direct (i.e., head-to-head comparison of two interventions within a single RCT) and indirect comparison (i.e., non-randomized comparisons of two intervention effects derived from separate trials) produced estimates similar to ours, indicating significant weight loss at 12 months for low-fat interventions compared with “usual diet”, and no significant benefit when compared with other dietary interventions of similar intensity. Limitations of indirect comparisons, however, include the inability to control for between-study and between-participant differences that may confound the pooled estimates. Another recent meta-analysis evaluated 13 trials of low-fat vs. very lowcarbohydrate diet interventions with at least 12 months of follow-up.(35) Their pooled estimate indicated a 0.91 kg (95% CI=1.65 to 0.17) greater weight loss for very lowcarbohydrate compared with low-fat diet interventions, consistent with our pooled estimate of 1.15 kg for low-carbohydrate vs. low-fat weight loss interventions. A limitation of this meta-analysis is the substantial heterogeneity within several strata, indicating inconsistent effects across studies. Heterogeneity to some degree would be expected given the various intervention designs, baseline characteristics of the participants, and comparator diets. Stratified analyses reduced heterogeneity in many cases. Additionally, our manuscript did not have a pre-published protocol, and our search was limited to English language publications, did not include other potential databases, or a search of grey literature, which may have missed trials. Finally, the majority of RCTs of ≥1 year duration were not feeding trials, since large-scale long-term trials of this nature can be costly; therefore, our analysis addresses the effectiveness of dietary interventions, and not necessarily the diets themselves. Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Tobias et al. Page 8 The strength of evidence of the literature included in this systematic review is variable with a high concern for attrition bias from significant drop-out and loss-to-follow-up rates in the majority of trials. Retaining participants for long-term lifestyle interventions can be difficult and bias is a concern when attrition is related to intervention assignment. Other bias measures were difficult to assess as a whole, without details of methods for randomization and allocation concealment, and whether staff members measuring outcomes were blinded. Findings from our systematic literature review and meta-analysis of RCTs fail to support the efficacy of low-fat diet interventions over higher fat diet interventions of similar intensity for significant long-term clinically meaningful weight control. Previous trials comparing low-fat diet interventions with “usual diet” or minimal intensity control groups have mislead perceptions of the efficacy of reductions in fat intake as a strategy for long-term weight loss. In fact, comparisons of similar intervention intensity conclude that dietary interventions lower in total fat intake lead to significantly less weight loss compared with higher fat, lowcarbohydrate diets. Health and nutrition guidelines should cease recommending low-fat diets for weight loss given the clear lack of long-term efficacy over other similar intensity dietary interventions. Additional research is needed to identify optimal intervention strategies for long-term weight loss and weight maintenance, including the need to look beyond variations in macronutrient composition. Supplementary Material Refer to Web version on PubMed Central for supplementary material. Acknowledgements This study was supported by grants from the National Institutes of Health (DK082730, HL34594, HL60712, CA176726, DK58845, DK46200, DK103720, and CA155626). Dr. Tobias was supported by a fellowship from the American Diabetes Association (7-12-MN-34). The funding sources did not participate in the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review, or approval of the manuscript. Dr. Ludwig received royalties for books on nutrition and obesity. Dr. Hu has received research support from California Walnut Commission and Metagenics. References 1. Higgins, JPTAD.; JAC, Sterne, editors. 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Br J Nutr. 2007; 97(2):399–404. [PubMed: 17298711] Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Tobias et al. Page 12 62. Turner-McGrievy GM, Barnard ND, Scialli AR. A two-year randomized weight loss trial comparing a vegan diet to a more moderate low-fat diet. Obesity (Silver Spring). 2007; 15(9): 2276–2281. [PubMed: 17890496] 63. Viegener BJ, Perri MG, Nezu AM, Renjilian DA, McKelvey WF, Schein RL. Effects of an intermittent, low-fat, low-calorie diet in the behavioral treatment of obesity. Behavior Therapy. 1990; 21(4):499–509. 64. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med. 1991; 325(7):461–466. [PubMed: 1852180] Author Manuscript Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Tobias et al. Page 13 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Figure 1. PRISMA Flow Diagram Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Tobias et al. Page 14 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Figure 2. Random effects pooled weighted mean difference (kg) for low-fat vs. comparator dietary interventions from 53 randomized trials reporting at least 1 year of follow-up, by weight loss intention and comparator intervention. Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Table 1 Randomized trials of low-fat versus other dietary interventions of at least 1 year duration among adults, included in the meta-analysis. Tobias et al. Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Trial Name A to Z (36) Anderson 1992 (11) Barnard 2009 (14) Bazzano 2014 (37) Bertz 2012 (38) Boyd 1990 (29) Breast Cancer Prevention Program (23) Brehm 2009 (15) BRIDGES (7) Brinkworth 2009 (39, 40) CALERIE Phase I (41) Canadian Diet and Breast Cancer Prevention Study (30) Dansinger 2005 (42) N randomized; Population 311; Overweight, premenopausal women 117; Moderate hypercholesterolemia 99; Type 2 diabetes 148; Obese 68; Breastfeeding mothers 295; Women at high breast cancer risk 194; Women at high breast cancer risk 124; Overweight/obese with type 2 diabetes 172; Women with recent breast cancer 118; At risk for metabolic syndrome 34; Overweight 4690; Women at high breast cancer risk 160; At risk for cardiovascular disease Country US US Weight loss goal Yes Maintain Low-fat diet(s) intervention [1] LEARN (reduced calorie); [2] Ornish (<10% fat; reduced calorie) American Heart Association Phase II (25% fat) US US Sweden Yes Vegan (10% fat) National Cholesterol Education Program (<30% Yes fat) Nordic Nutrition Guidelines Yes (<30% fat; reduced calorie) Canada Maintain 15% fat US No 15% fat High carbohydrate (25% fat; US Yes reduced calorie) Nutrition Education Program US No (20% fat) Australia US Canada Yes Yes Maintain 30% fat (reduced calorie) High glycemic index, food provided (20% fat; reduced calorie) 15% fat US Yes Ornish (<10% fat) Comparator diet(s) intervention [1] Atkins low-carbohydrate; [2] Zone (30% fat; reduced calorie) Usual diet American Diabetes Association Diet 2003 (30% fat; reduced calorie) Low carbohydrate Usual diet Canadian Food Guide (No fat intake advice) Usual diet High mono-unsaturated fat (40% fat; reduced calorie) Usual diet Atkins low-carbohydrate (61% fat; reduced calorie) Low glycemic index, food provided (30% fat; reduced calorie) Canadian Food Guide (No fat intake advice) [1] Atkins low-carbohydrate; [2] Zone (30% fat); [3] Weight Watchers (reduced Followup duration (years) 1 1 1.4 1 1 1 1 1 1 1 1 10 1 Page 15 Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Trial Name Davis 2009 (16) DEER (12) The Dietary Alternatives Study (13) DIRECT (17) Ebbeling 2007 (43) Elhayany 2010 (18) Esposito 2009 (19) Foster 2003 (44) Foster 2010 (45) Guldbrand 2012 (20) Harvey-Berino 1999 (46) Iqbal 2010 (21) Keogh 2007 (47) Klemsdal 2010 (48) N randomized; Population Country 105; Type 2 diabetes US 377; Hypercholesterolemia US 508; Men with hypercholesterolemia 322; Type 2 diabetes, cardiovascular disease, or obese 73; Obese young adults US Israel US 259; Type 2 diabetes Israel 215; Type 2 diabetes Italy 63; Obese US 307; Obese US 61; Type 2 diabetes 80; Overweight/obese 144; Type 2 diabetes, obese 44; Overweight/obese 202; Metabolic syndrome Sweden US US Australia Norway Author Manuscript Weight loss goal Yes No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Author Manuscript Low-fat diet(s) intervention Diabetes Prevention Program diet (25% fat) National Cholesterol Education Program (<30% fat) Comparator diet(s) intervention calorie) Atkins low-carbohydrate Usual diet [1] 26% fat; [2] 22% fat; [3] 18% fat American Heart Association (30% fat; reduced calorie) 20% fat [1] American Diabetes Association 2003 (30% fat; reduced calorie); [2] Low-fat Mediterranean (30% fat; reduced calorie) American Heart Association 2000 (<30% fat; reduced calorie) 30% fat [1] Mediterranean diet (35% fat; reduced calorie); [2] Atkins low-carbohydrate Low glycemic-index carbohydrates (35% fat) Low carbohydrate Mediterranean diet (45% fat; reduced calorie) Mediterranean diet (>30% fat; reduced calorie) 25% fat (reduced calorie) Atkins low-carbohydrate 30% fat (reduced calorie) <30% fat (reduced calorie) Atkins low-carbohydrate Low-carbohydrate (50% fat; reduced calorie) 20% fat Low-calorie <30% fat (reduced calorie) 20% fat (reduced calorie) 30% fat (reduced calorie) Low-carbohydrate Low-carbohydrate (27% fat; reduced calorie) Low glycemic load (35–40% fat; reduced calorie) Followup duration (years) 1 1 1 2 1.5 1 4 1 2 2 1.5 2 1 1 Author Manuscript Page 16 Tobias et al. Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Trial Name Kristal 2005 (49) Lapointe 2010 (50) N randomized; Population 93; Overweight/obese with esophageal metaplasia 68; Overweight/obese postmenopausal women Country Weight loss goal Low-fat diet(s) intervention US Yes 20% fat (reduced calorie) Canada Yes Reduce fat intake Lim 2010 (51) 113; High cardiovascular disease risk McAuley 2006 (52) McManus 2001 (53) Nutrition and Exercise in Women Study (54) Nutrition and Breast Health Study (31) Pilkington 1960 (24) Polyp Prevention Trial (25) 96; Women overweight/obese with insulin resistance 101; Overweight 439; Postmenopausal overweight/obese women 122; Premenopausal women at risk of breast cancer 58; Men with ischemic heart disease 2079; Recent colorectal adenoma Pounds Lost Trial (55) 811; Overweight/obese Food provided (10% fat; Australia Yes reduced calorie) New Zealand Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes Yes (<30% fat) US Yes 20% fat (reduced calorie) US Yes <30% fat (reduced calorie) (1) 15% fat; (2) High fruits US Maintain and vegetables (15% fat) UK No 20 g fat/day US No 20% fat [1] 20% fat (reduced calorie); [2] high protein US Yes (20% fat; reduced calorie) PREDIMED (26) PREMIER (56) 7447; High cardiovascular disease risk 810; Prehypertension Spain US No Reduce fat intake Yes DASH (<25% fat; reduced Author Manuscript Comparator diet(s) intervention Followup duration (years) Usual diet 3 Increase fruits and vegetables [1] Low-carbohydrate, food provided (60% fat; reduced calorie); [2] High unsaturated fat, food provided (30% fat; reduced calorie); [3] Usual diet 1.5 1.25 [1] low carbohydrate Atkins diet; [2] Zone diet (30% fat) 35% fat (reduced calorie) 1 1.5 Usual diet (1) Usual diet; (2) High fruits and vegetables 1 1 Increase unsaturated fats 1.5 Usual diet [1] 40% fat (reduced calorie); [2] high protein (40% fat; reduced calorie) Mediterranean Diet + [1] increase extra-virgin olive oil intake, [2] mixed nuts intake 30% fat (reduced calorie) 3.1 2 4.8 1.5 Author Manuscript Page 17 Tobias et al. Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Trial Name N randomized; Population Shah 1996 (57) SMART Study (58) Stern 2004 (59, 60) Swinburn 2001 (28) Tapsell 2004 (22) Tehran Lipid and Glucose Study (61) TurnerMcGrievy 2007 (62) Viegener 1990 (63) Women’s Health Initiative Dietary Modification Trial (32) Women’s Health Trial Vanguard Study (27) Women’s Healthy Eating and Living (WHEL) (9) Women’s Intervention Nutrition Study (WINS) (8) 122; Obese women 200; Overweight/obese 132; Morbidly obese 176; Glucose intolerance 63; Type 2 diabetes 100; Overweight/obese 64; Overweight/obese postmenopausal women 85; Overweight/obese women 48835; Postmenopausal women 303; Women at high breast cancer risk 3088; Women with previous breast cancer 2437; Women with breast cancer Author Manuscript Country US Germany US New Zealand Weight loss goal Yes Yes Yes No Low-fat diet(s) intervention calorie) 20 g fat/day German Nutrition Society (30% fat; reduced calorie) NHLBI (30% fat; reduced calorie) Reduce fat Australia No 27% fat Comparator diet(s) intervention Followup duration (years) 30% fat (reduced calorie) Low-carbohydrate (35% fat; reduced calorie) Low-carbohydrate Usual diet 37% fat 1 1 1 5 1 Iran Yes 20% fat (reduced calorie) 30% fat (reduced calorie) US Yes Vegan (10% fat) National Cholesterol Education Program (<30% fat) 1.2 2 US Yes 15–25% fat (reduced calorie) 30% fat (reduced calorie) 1 US Maintain 20% fat US No 20% fat US No 15–20% fat US No 15% fat Usual diet 7.5 Usual diet 2 USDA guidelines (<30% fat) 7.3 General counseling on nutritional adequacy 5 Author Manuscript Author Manuscript Page 18 Tobias et al. Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Author Manuscript Trial Name Women’s Intervention Nutrition Study (WINS) Feasibility (10) N randomized; Population 290; Women with postmenopausal breast cancer 294; Wood 1991 (64) Overweight/obese Country Weight loss goal Low-fat diet(s) intervention Comparator diet(s) intervention US No 20% fat General counseling on nutritional adequacy National Cholesterol Education Program (<30% US Yes fat; reduced calorie) Usual diet Author Manuscript Followup duration (years) 1.5 1 Author Manuscript Page 19 Tobias et al. Tobias et al. Page 20 Author Manuscript Author Manuscript Table 2 Random effects pooled weighted mean difference (kg) for low-fat vs. comparator dietary interventions from 36 randomized weight loss trials reporting at least 1 year of follow-up, stratified by trial characteristics. Weight Loss Goal     Similar Intervention Intensity         Comparator Diet         Low-Carbohydrate         Other Higher Fat Intervention         Usual Diet         Caloric Restriction         Both Interventions         Neither Intervention         Low-Fat Only         Comparator Only         Chronic Disease Population         No         Yes         Difference in Fat Intake at Follow-up (% Calories)         <5% Difference in Fat Intake         ≥5% Difference in Fat Intake         Difference in Triglycerides at Follow-up (mg/dL Change)         <5 mg/dL Change Difference         ≥5 mg/dL Greater Change in Low-Fat Group No Weight Loss Goal     Similar Intervention Intensity         Comparator Diet         Low-Carbohydrate         Other Higher Fat Intervention         Usual Diet         Caloric Restriction         Both Interventions         Neither Intervention         Low-Fat Only         Comparator Only         Chronic Disease Population         No         Yes         Difference in Fat Intake at Follow-up (% Calories)         <5% Difference in Fat Intake         ≥5% Difference in Fat Intake pN Comparisons WMD (95% CI) value I2 (p-value for heterogeneity) 33 0.62 (−0.08, 1.32) 0.084 71.6% (p<0.0001) 18 1.15 (0.52, 1.79) <0.001 10.4% ( p=0.33) 19 0.36 (−0.66, 1.37) 0.49 82.0% (p<0.0001) 0 -- -- 18 0.74 (−0.19, 1.68) 0.12 78.4% (p <0.0001) 8 0.33 (−1.18, 1.83) 0.67 65.1% (p=0.005) 6 1.49 (0.53, 2.45) 0.002 7.7% (p=0.37) 5 −0.62 (−1.95, 0.72) 0.37 15.5% (p=0.32) 25 0.77 (−0.15, 1.69) 0.10 76.1% (p <0.0001) 8 0.37 (−0.33, 1.07) 0.30 10.3% (p=0.35) 8 0.14 (−0.80, 1.09) 0.77 30.1% ( p=0.19) 18 1.04 (0.06, 2.03) 0.038 77.7% (p<0.0001) 8 −0.21 (−0.86, 0.43) 0.52 0.0% (p =0.92) 17 1.38 (0.50, 2.25) 0.002 62.3% (p<0.0001) 4 −1.71 (−4.52, 1.10) 0.23 59.3% (p=0.061) 0 -- -- -- 4 −1.71 (−4.52, 1.10) 0.23 59.3% (p=0.061) 0 -- -- 0 -- -- 2 −1.47 (−5.85, 2.91) 0.51 76.3% (p=0.04) 0 -- -- 0 -- -- 0 -- -- 4 −1.71 (−4.52, 1.10) 0.23 59.3% (p=0.061) 1 NA NA NA 2 −2.18 (−6.19, 1.83) 0.29 45.0% (p=0.18) Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01. Author Manuscript Tobias et al. Page 21         Difference in Triglycerides at Follow-up (mg/dL Change)         <5 mg/dL Change Difference         ≥5 mg/dL Greater Change in Low-Fat Group pN Comparisons WMD (95% CI) value I2 (p-value for heterogeneity) 1 NA NA NA 1 NA NA NA WMD=DerSimonian and Laird random effects weighted mean difference, in kg; Negative value favors low-fat dietary intervention; Positive value favors higher fat comparator intervention Author Manuscript Author Manuscript Author Manuscript Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2016 December 01.