Dan Schwarzfuchs

Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet

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

Dietary Intervention to Reverse Carotid Atherosclerosis

Background— It is currently unknown whether dietary weight loss interventions can induce regression of carotid atherosclerosis. Methods and Results— In a 2-year Dietary Intervention Randomized Controlled Trial–Carotid (DIRECT-Carotid) study, participants were randomized to low-fat, Mediterranean, or low-carbohydrate diets and were followed for changes in carotid artery intima-media thickness, measured with standard B-mode ultrasound, and carotid vessel wall volume (VWV), measured with carotid 3D ultrasound. Of 140 complete images of participants (aged 51 years; body mass index, 30 kg/m2; 88% men), higher baseline carotid VWV was associated with increased intima-media thickness, age, male sex, baseline weight, blood pressure, and insulin levels (P<0.05 for all). After 2 years of dietary intervention, we observed a significant 5% regression in mean carotid VWV (−58.1 mm3; 95% confidence interval, −81.0 to −35.1 mm3; P<0.001), with no differences in the low-fat, Mediterranean, or low-carbohydrate groups (−60.69 mm3, −37.69 mm3, −84.33 mm3, respectively; P=0.28). Mean change in intima-media thickness was −1.1% (P=0.18). A reduction in the ratio of apolipoprotein B100 to apolipoprotein A1 was observed in the low-carbohydrate compared with the low-fat group (P=0.001). Participants who exhibited carotid VWV regression (mean decrease, −128.0 mm3; 95% confidence interval, −148.1 to −107.9 mm3) compared with participants who exhibited progression (mean increase, +89.6 mm3; 95% confidence interval, +66.6 to +112.6 mm3) had achieved greater weight loss (−5.3 versus −3.2 kg; P=0.03), greater decreases in systolic blood pressure (−6.8 versus −1.1 mm Hg; P=0.009) and total homocysteine (−0.06 versus +1.44 &mgr;mol/L; P=0.04), and a higher increase of apolipoprotein A1 (+0.05 versus −0.00 g/L; P=0.06). In multivariate regression models, only the decrease in systolic blood pressure remained a significant independent modifiable predictor of subsequent greater regression in both carotid VWV (β=0.23; P=0.01) and intima-media thickness (β=0.28; P=0.008) levels. Conclusions— Two-year weight loss diets can induce a significant regression of measurable carotid VWV. The effect is similar in low-fat, Mediterranean, or low-carbohydrate strategies and appears to be mediated mainly by the weight loss–induced decline in blood pressure. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique Identifier: NCT00160108.

Adherence and Success in Long-Term Weight Loss Diets: The Dietary Intervention Randomized Controlled Trial (DIRECT)

Background: Data are limited as to whether participants in diet trials truly adhere to their assigned diet and the factors that affect their adherence. Methods: We evaluated success and adherence in a two-year dietary intervention randomized controlled trial (DIRECT) in which 322 moderately obese participants (mean age 52 yrs, mean body-mass-index (BMI) 31 kg/m2, 86% men) were randomized to one of three groups: low-fat, Mediterranean, or low-carbohydrate diets. Results: Overall compliance at month-24 was 85%, with 90% in low-fat, 85% in Mediterranean, and 78% in low-carbohydrate diet (p = .042 between groups). Attrition was higher in women (29% vs. 14% men, p = .001) and current smokers (25% vs. 14% among maintainers, p = 0.04). In a multivariate model, independent predictors of dropping-out were: higher baseline BMI (OR = 1.11; CI: 1.03–1.21) and less weight loss at month-6 (OR = 1.20; CI: 1.1–1.3). In a multivariate model, greater weight loss achieved at month-6 was the main predictor associated with success in weight loss (> 5%) over 2 years (OR = 1.5; CI: 1.35–1.67). Self-reported complete adherence score to diet was greater on low-carbohydrate diet (p < .05 compared to low-fat) until month-6, but dropped overall from 81% at month-1 to 57% at month-24. Holidays were a trigger to a significant decrease in adherence followed by a partial rebound. Changes in diet composition from month-1 to month-12 were more pronounced in the multi-stage low-carbohydrate diet-group (p < .05). Generally, the most irresistible restricted food items were cookies (45% of dieters) and fruits (30%). Among the physically active (n = 107), 44% reported a tendency to eat less after exercising compared to 10% who tended to eat more. Conclusion: Initial 6-month reduction in weight is the main predictor of both long-term retention and success in weight loss. Special attention is needed for women, current smokers, and during holidays. Physical activity is associated with subsequent reduction in energy intake.

Two Patterns of Adipokine and Other Biomarker Dynamics in a Long-Term Weight Loss Intervention

OBJECTIVE Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain. RESEARCH DESIGN AND METHODS We analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss. RESULTS We identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol-binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0–6) going in the opposite direction to that in the weight maintenance/regain phase (months 7–24) (P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL cholesterol [HDL-C], high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement (P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B. CONCLUSIONS hsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns.

Abdominal Superficial Subcutaneous Fat: A putative distinct protective fat subdepot in type 2 diabetes

OBJECTIVE Unlike visceral adipose tissue (VAT), the association between subcutaneous adipose tissue (SAT) and obesity-related morbidity is controversial. In patients with type 2 diabetes, we assessed whether this variability can be explained by a putative favorable, distinct association between abdominal superficial SAT (SSAT) (absolute amount or its proportion) and cardiometabolic parameters. RESEARCH DESIGN AND METHODS We performed abdominal magnetic resonance imaging (MRI) in 73 patients with diabetes (mean age 58 years, 83% were men) and cross-sectionally analyzed fat distribution at S1-L5, L5-L4, and L3-L2 levels. Patients completed food frequency questionnaires, and subgroups had 24-h ambulatory blood pressure monitoring and 24-h ambulatory electrocardiography. RESULTS Women had higher %SSAT (37 vs. 23% in men; P < 0.001) despite a similar mean waist circumference. Fasting plasma glucose (P = 0.046) and HbA1c (P = 0.006) were both lower with increased tertile of absolute SSAT. In regression models adjusted for age, waist circumference, and classes of medical treatments used in this patient population, increased %SSAT was significantly associated with decreased HbA1c (β = −0.317; P = 0.013), decreased daytime ambulatory blood pressure (β = −0.426; P = 0.008), and increased HDL cholesterol (β = 0.257; P = 0.042). In contrast, increased percent of deep SAT (DSAT) was associated with increased HbA1c (β = 0.266; P = 0.040) and poorer heart rate variability parameters (P = 0.030). Although total fat and energy intake were not correlated with fat tissue distribution, increased intake of trans fat tended to be associated with total SAT (r = 0.228; P = 0.05) and DSAT (r = 0.20; P = 0.093), but not with SSAT. CONCLUSIONS Abdominal SAT is composed of two subdepots that associate differently with cardiometabolic parameters. Higher absolute and relative distribution of fat in abdominal SSAT may signify beneficial cardiometabolic effects in patients with type 2 diabetes.

Dairy calcium intake, serum vitamin D, and successful weight loss

BACKGROUND The role of dairy calcium intake and serum vitamin D concentrations in weight loss is controversial. OBJECTIVE The objective was to assess the association of dairy calcium intake and serum vitamin D with weight loss. DESIGN We analyzed data from participants in the 2-y Dietary Intervention Randomized Controlled Trial (DIRECT) [n = 322; mean body mass index (BMI; in kg/m²): 31; mean age: 52 y]. A representative sample (n = 126) was followed for 6 mo for serum vitamin D changes. RESULTS Baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations decreased significantly across the tertiles of baseline BMI (25.6 ± 8.0, 24.1 ± 8.9, and 22.9 ± 6.8 ng/mL, respectively; P for trend = 0.02). Baseline concentrations of vitamin D and dairy calcium intake were not associated with subsequent weight loss. However, in repeated-measures models adjusted for age, sex, baseline BMI, total fat intake, and diet group assignment, higher 6-mo tertile levels of dairy calcium intake (median for tertiles: 156.5, 358.0, and 582.9 mg/d, respectively) and serum 25(OH)D (14.5, 21.2, and 30.2 ng/mL, respectively) were associated with increased weight loss across the 2-y intervention (-3.3, -3.5, and -5.3 kg, respectively, for dairy calcium; P = 0.043; -3.1, -3.8, and -5.6 kg, respectively, for vitamin D; P = 0.013). In a multivariate logistic regression adjusted simultaneously for age, sex, baseline BMI, total fat intake, diet group, vitamin D concentration, and dairy calcium, an increase of 1 SD in dairy calcium intake increased the likelihood of weight loss of >4.5 kg in the preceding 6 mo [odds ratio (OR): 1.45; P = 0.046]. A similar increase was seen for serum 25(OH)D at the 6-mo point (OR: 1.7; P = 0.009). CONCLUSION Our study suggests that both higher dairy calcium intake and increased serum vitamin D are related to greater diet-induced weight loss. This trial was registered at clinicaltrials.gov as NCT00160108.

Renal Function Following Three Distinct Weight Loss Dietary Strategies During 2 Years of a Randomized Controlled Trial

OBJECTIVE This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes. RESEARCH DESIGN AND METHODS In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m2; mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m2; mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine <176 μmol/L (eGFR ≥30 mL/min/1.73 m2) were randomized to low-fat, Mediterranean, or low-carbohydrate diets. The 2-year compliance was 85%, and the proportion of protein intake significantly increased to 22% of energy only in the low-carbohydrate diet (P < 0.05 vs. low-fat and Mediterranean). We examined changes in urinary microalbumin and eGFR, estimated by Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formulas. RESULTS Significant (P < 0.05 within groups) improvements in eGFR were achieved in low-carbohydrate (+5.3% [95% CI 2.1–8.5]), Mediterranean (+5.2% [3.0–7.4]), and low-fat diets (+4.0% [0.9–7.1]) with similar magnitude (P > 0.05) across diet groups. The increased eGFR was at least as prominent in participants with (+6.7%) or without (+4.5%) type 2 diabetes or those with lower baseline renal function of eGFR <60 mL/min/1.73 m2 (+7.1%) versus eGFR ≥60 mL/min/1.73 m2 (+3.7%). In a multivariable model adjusted for age, sex, diet group, type 2 diabetes, use of ACE inhibitors, 2-year weight loss, and change in protein intake (confounders and univariate predictors), only a decrease in fasting insulin (β = −0.211; P = 0.004) and systolic blood pressure (β = −0.25; P < 0.001) were independently associated with increased eGFR. The urine microalbumin-to-creatinine ratio improved similarly across the diets, particularly among participants with baseline sex-adjusted microalbuminuria, with a mean change of −24.8 (P < 0.05). CONCLUSIONS A low-carbohydrate diet is as safe as Mediterranean or low-fat diets in preserving/improving renal function among moderately obese participants with or without type 2 diabetes, with baseline serum creatinine <176 μmol/L. Potential improvement is likely to be mediated by weight loss–induced improvements in insulin sensitivity and blood pressure.

Four-Year Follow-up after Two-Year Dietary Interventions

This follow-up study, conducted 4 years after a 2-year trial that involved healthy dietary changes, showed that the interventions had long-lasting, favorable effects, particularly in those receiving the Mediterranean or low-carbohydrate diet, despite partial weight regain.

Dietary strategies for patients with type 2 diabetes in the era of multi-approaches; review and results from the Dietary Intervention Randomized Controlled Trial (DIRECT)

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

Phenotypic and genetic variation in leptin as determinants of weight regain

Aims:Over 75% of obese subjects fail to maintain their weight following weight loss interventions. We aimed to identify phenotypic and genetic markers associated with weight maintenance/regain following a dietary intervention.Subjects and methods:In the 2-year Dietary Intervention Randomized Controlled Trial, we assessed potential predictors for weight changes during the ‘weight loss phase’ (0–6 months) and the ‘weight maintenance/regain phase’ (7–24 months). Genetic variation between study participants was studied using single-nucleotide polymorphisms in the leptin gene (LEP).Results:Mean weight reduction was −5.5% after 6 months, with a mean weight regain of 1.2% of baseline weight during the subsequent 7–24 months. In a multivariate regression model, higher baseline high-molecular-weight adiponectin was the only biomarker predictor of greater success in 0- to 6-month weight loss (β=−0.222, P-value=0.044). In a multivariate regression model adjusted for 6-month changes in weight and various biomarkers, 6-month plasma leptin reduction exhibited the strongest positive association with 6-month weight loss (β=0.505, P-value<0.001). Conversely, 6-month plasma leptin reduction independently predicted weight regain during the following 18 months (β=−0.131, P-value<0.013). Weight regain was higher among participants who had a greater (top tertiles) 6-month decrease in both weight and leptin (+3.4% (95% confidence interval 2.1–4.8)) as compared with those in the lowest combined tertiles (+0.2% (95% confidence interval −1.1 to 1.4)); P-value<0.001. Weight regain was further significantly and independently associated with genetic variations in LEP (P=0.006 for both rs4731426 and rs2071045). Adding genetic data to the phenotypic multivariate model increased its predictive value for weight regain by 34%.Conclusion:Although greater reduction in leptin concentrations during the initial phase of a dietary intervention is associated with greater weight loss in the short term, plasma leptin reduction, combined with the degree of initial weight loss and with genetic variations in the LEP gene, constitutes a significant predictor of subsequent long-term weight regain.