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Clinical Studies and Practice

Weight loss maintenance in overweight subjects on ad libitum diets with high or low protein content and glycemic index: the DIOGENES trial 12-month results



A high dietary protein (P) content and low glycemic index (LGI) have been suggested to be beneficial for weight management, but long-term studies are scarce.


The DIOGENES randomized clinical trial investigated the effect of P and GI on weight loss maintenance in overweight or obese adults in eight centers across Europe. This study reports the 1-year results in two of the centers that extended the intervention to 1 year.


After an 8-week low-calorie diet (LCD), 256 adults (body mass index >27 kg m2) were randomized to five ad libitum diets for 12 months: high P/LGI (HP/LGI), HP/high GI (HP/HGI), low P/LGI (LP/LGI), LP/HGI and a control diet. During the first 6 months, foods were provided for free through a shop system and during the whole 12-month period, subjects received guidance by a dietician. Primary outcome variable was the change in body weight over the 12-month intervention period.


During the LCD period, subjects lost 11.2 (10.8, 12.0) kg (mean (95% confidence interval (CI))). Average weight regain over the 12-month intervention period was 3.9 (95% CI 3.0–4.8) kg. Subjects on the HP diets regained less weight than subjects on the LP diets. The difference in weight regain after 1 year was 2.0 (0.4, 3.6) kg (P=0.017) (completers analysis, N=139) or 2.8 (1.4, 4.1) kg (P<0.001) (intention-to-treat analysis, N=256). No consistent effect of GI on weight regain was found. There were no clinically relevant differences in changes in cardiometabolic risk factors among diet groups.


A higher protein content of an ad libitum diet improves weight loss maintenance in overweight and obese adults over 12 months.


The primary prevention of weight gain in the whole population and the secondary prevention of weight regain in overweight and obese individuals who have lost weight are crucial to limit the adverse health consequences of overweight and obesity, but difficult to achieve.

Studies have shown that an increase in dietary protein content of an ad libitum diet results in more pronounced weight loss in overweight individuals1,2 and also contributes to better weight maintenance after weight loss,3, 4, 5 most likely because of the high satiating and thermogenic effect of proteins.6 Two recent meta-analyses support the beneficial effects of higher protein intake in weight management.7,8 Most of the studies included in these meta-analyses were of limited duration, that is, 6 months or shorter. Longer duration studies, so far, have found no evidence for better weight management with higher protein intake.9,10

Besides, the quantity and quality of dietary carbohydrates (for example, the glycemic index (GI)) may be important in weight management. So far, there is little evidence for a role of dietary GI in body weight management,11 although a meta-regression analysis suggested that a reduction in dietary GI under ad libitum or limited energy restriction conditions is associated with a modest body weight reduction.12 A more recent meta-analysis, however, concluded that there was no evidence for a beneficial effect of low GI (LGI)/glycemic load diets on body weight in obesity.13

To study the role of dietary protein content and GI in the prevention of weight regain after weight loss, the large-scale multicenter DIOGENES dietary intervention study was initiated. The 6-month weight maintenance outcome of the study has been reported previously.14 Given the paucity of data from more long-term studies, we report here the 12-month results of the study in two of the study centers involved in the DIOGENES trial, Maastricht and Copenhagen, on the primary outcome body weight and secondary outcomes body composition and cardiometabolic variables. In these two centers, the intervention was continued for another 6 months, thus total intervention duration was 12 months.

Materials and Methods


Volunteer families were recruited in Copenhagen and Maastricht. Families (two parent or single parent) were eligible for participation if family members were generally healthy and if (1) at least one parent was overweight (body mass index >27 kg m2) and aged <65 years; (2) at least one overweight child was between 8 and 15 years of age. The complete list of inclusion and exclusion criteria has been published previously.15

The study protocol and informed consent document were approved by the Medical Ethical Committees of Maastricht University and the University of Copenhagen. All subjects gave written informed consent before being enrolled into the study. The study was registered with, number NCT00390637.

Study design

Only the adult family members who were overweight or obese at baseline were included in the current data analysis. The full study protocol has been described previously in detail15 (Figure 1). In short, between screening and the first (pre-LCD (low-calorie diet)) test day, all adults enrolled into the study completed a 3-day weighed dietary record and collected 24-h urine (=baseline). On the test day, subjects came to the research centers in the morning after an overnight fast. Weight, height, waist and hip circumference, abdominal sagittal diameter, body composition and blood pressure were measured. Fasting blood samples were collected. Subsequently, a 2-h oral glucose tolerance test was performed.15

Figure 1

Study protocol.

After these baseline measurements, subjects initiated an 8-week weight loss phase on a LCD providing 3.4–3.7 MJ per day (800–880 kcal per day). If at least one of the parents of a two-parent family or the parent in a single-parent family had attained a weight loss of 8% of initial body weight after 8 weeks, the family was randomized into one of five diet groups, varying in protein content and GI, for the 12-month dietary intervention period. The second test day took place on the last day of the LCD period (post LCD) and was similar to the pre-LCD test day. However, no 3-day food record and no 24-h urine were collected at this time point.

After the post-LCD test day, families started the ad libitum diets. Laboratory shops were established to provide families with the majority of foods at no cost for 6 months. The shop system allowed us to more tightly control dietary intake of subjects,16,17 in this case on a family level. During the second 6 months of the intervention, families had to purchase foods again in their own shops. Subjects came to the research center at regular intervals to meet a dietitian. At all visits, body weight was monitored and dietary counseling was provided.15 At 4 weeks into the randomized phase, subjects completed a 3-day weighed dietary record and collected 24-h urine to check compliance to the diets. After 6 and 12 months, subjects returned to the research center for the third and fourth test day (post intervention, week 26 and 52), which were the same as the previous test days including the 3-day weighed food diary and 24-h urine collection.15

Low-calorie diet

The LCD we used was Modifast (Nutrition et Santé, Revel, France). Subjects were instructed to use four sachets per day (providing 3.4–3.7 MJ per day). Additional consumption of tomatoes (200 g per day), cucumber (125 g per day) and lettuce (50g per day) was allowed. In exceptional cases, particularly people with persistent hunger, five sachets per day could be taken.

Randomization procedure

Eligible families, in which at least one of the overweight/obese parents achieved the target weight loss (8% of body weight on pre-LCD test day), were cluster randomized to one of five diet groups using a simple block randomization procedure with stratification according to the center, the number of eligible parents in the family and the number of parents with body mass index >34 kg m2. The randomization was performed with a web-based program.15

For obvious reasons, neither subjects nor dietitians or investigators could be blinded to the diet assignment. However, the investigators who performed the statistical analysis of this paper had not been in contact with the study participants.

Diet groups and dietary instruction

Subjects were randomized into five diet groups: (1) low protein, LGI (LP/LGI); (2) LP, high GI (LP/HGI); (3) high protein, LGI (HP/LGI); (4) HP, HGI; and (5) a diet according to national healthy eating recommendations (healthy).18 All diets were low in fat (25–30% of energy from fat) and ad libitum, that is, no energy restriction was imposed. We aimed at a protein consumption of 10–15% of total energy intake in the LP groups and of 23–28% in the HP groups. With respect to GI, a distinction was made between HGI and LGI foods within each food group. The assignment of GI values to foods was performed as described by Aston et al.19 Subjects in the LGI groups were advised to mainly consume the LGI foods within a food group, those in the HGI groups the HGI foods. The aim was to attain a 15-unit difference in GI between the HGI and LGI groups. More detailed information on the diets and dietary counseling is provided in the paper by Moore et al.18

Laboratory shops

During the first 6 months, adherence to dietary compositions was optimized by providing >80% of all relevant foods for each of the different diet groups at no cost through a lab-based shop system as previously described to increase compliance.16,17


Clinical examinations, oral glucose tolerance test and blood analysis

Body weight, waist circumference, body composition and blood pressure were measured as described previously.15 In each center, the same equipment was used for all measurements. Subsequently, an oral glucose tolerance test was performed.15 The Matsuda index, a measure of insulin sensitivity in stimulated condition derived from the fasting glucose and insulin and the glucose and insulin responses during the oral glucose tolerance test, was calculated.15,20 From the fasting glucose and insulin concentrations, the homeostatic model assessment-insulin resistance (HOMA-IR) and the HOMA-beta (HOMA-%B),21 measures of (hepatic) insulin resistance and insulin secretion, respectively, were calculated.

In fasting blood samples, plasma adiponectin concentration and serum concentrations of glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, triglycerides and C-reactive protein were measured as described previously.15,22 Analysis of all samples was performed at the Department of Clinical Biochemistry, Gentofte University Hospital, Gentofte, Denmark.

Dietary records

We provided all families with weighing scales (Soehnle 1208 Actuell (Leifheit AG, Nassau an der Lahn, Germany) or (Salter Microtonic, Salter Housewares, Tonbridge, UK)). Dietitians instructed the subjects on how to complete the 3-day food record on 3 consecutive days, including 2 weekdays and 1 weekend day. Participants were instructed to weigh all their foods and left overs and provide brand names and details on cooking and processing where relevant. When weighing was not possible (for example, when eating out), we instructed subjects to record the food intake in household measures (cups, glasses, table spoons and so on). The food diaries were coded at each shop center using the national Danish and Dutch food composition tables and GI values were added to the tables using a procedure described in more detail elsewhere.19

24-h urine

The completeness of the 24-h urinary collection was checked by recovery rate of para amino benzoic acid (PABA) taken as tablets three times during the collection period. Urinary volume was recorded. Urinary nitrogen was determined by Dumas combustion methodology, using a VarioMax CN analyzer (Elementar, Hanau, Germany). Urinary C-peptide was determined by a chemiluminescent immunometric assay (Immulite 2500, Siemens Healthcare, Den Haag, The Netherlands). Urinary PABA was measured by spectrophotometry (Stasar, Gilford Instruments Laboratories, Oberlin, OH, USA).

Statistical analysis

Results are presented as mean±s.d., and estimates of effects as means and 95% confidence intervals. Differences between the five diet groups were analyzed by one-way analysis of variance.

The effects of protein content and GI on weight and risk factor changes were analyzed by a linear mixed model analysis with repeated measurements. In these analyses, the ‘healthy diet’ group was not included. For weight changes, the model considered all available weight recordings (15 different time points) during the intervention. The analysis was adjusted for body mass index at randomization, total weight loss during the LCD and age as covariates. Diet group, center (Maastricht or Copenhagen), family structure (single parent, couple: 1 parent randomized, couple: both parents randomized) and gender were included as factors. The completers analysis involved all subjects who completed the 12-month intervention period (N=139). The intention-to-treat analysis (ITT) involved all subjects who were randomized (N=256) and assumed that the weight changes in participants who dropped out of the study followed the same course as in the completers from the moment they dropped out. Furthermore, a sensitivity analysis was performed with the same sample as the ITT analysis. In this analysis, we assumed a 1-kg weight gain per month in participants who had dropped out of the study from the moment they dropped out. Additional analyses were performed on changes in other anthropometric measures, body composition and risk factors, which were measured at three time points (post LCD, 6 months (=week 26) and 12 months (=week 52). For these analyses we also used a mixed model with the same factors described above and with the post-LCD value of the tested variable as covariate. Self-reported dietary intake at 4, 26 and 52 weeks of the intervention was also analyzed by mixed model analysis.

If there was no statistically significant interaction between dietary GI and protein, only the main effects of protein content and GI were considered.

Significance was set at a P-value <0.05. Data were analyzed with SPSS for Macintosh version 16.0 (SPSS Inc., Chicago, IL, USA).


Out of 339 subjects (137 male, 202 female) attending the screening visit, 256 subjects (103 male, 153 female, age 42±6 years) were randomized for the 12-month dietary intervention after the initial 8-week weight loss phase (Supplementary Figure 1). Total weight loss during the LCD period for the randomized study population was 11.2±3.3 kg with no significant differences among diet groups. Other subject characteristics did not differ significantly among either groups (Supplementary Table 1). One hundred and seventeen subjects dropped out during the intervention period (46%), 51 during the first 6 months and 66 during the second 6 months. Characteristics of the completers are shown in the Supplementary Table 1b. Dropout rates were highest in the LP/HGI group (61%) and lowest in the HP/LGI group (26%). Post-LCD characteristics of these drop outs did not differ among groups (data not shown).

Dietary intake

Data on dietary intakes were obtained from 3-day dietary records. The habitual diet at screening had a carbohydrate content of 46±7%, fat content of 35±6% and protein content of 16±4% of energy intake. Total energy intake was 9.6±2.9 MJ. On the basis of average 24-h urinary nitrogen excretion (14.1 g per day), calculated from urines with a PABA recovery 85% (158 out of 240), habitual protein intake was 88 g per day. Habitual GI (GI) was 63±5 units and the glycemic load was 162±56 g per day. A description of the dietary intakes at different time points during the 12-month intervention period in the five groups is presented in Supplementary Table 2. Over the 12-month intervention, average protein intake, based on three 3-day dietary records and expressed as percent of total energy intake, was higher (P<0.001) and carbohydrate intake was lower (P<0.001) in the HP compared with the LP groups. Protein intake was higher in the HGI compared with the LGI groups (P=0.036) (Table 1). GI was lower in the LGI compared with the HGI groups (P<0.001). There were no statistically significant differences in fat and fiber intake between groups. Reported dietary intakes were similar after 6 and 12 months of intervention in all groups.

Table 1 Estimates of average self-reported total energy and macronutrient intake, glycemic index, glycemic load and fiber (based on the average of 3-day dietay records at week 4, 26 and 52), and urinary nitrogen and peptide excretion (at week 4, 14, 26 and 52) (mean and 95% confidence interval)

Average urinary nitrogen excretion in the four 24-h urine collections, a marker for protein intake, was higher in the HP groups compared with the LP group (P=0.002) (Table 1). In accordance, the change in plasma urea during the intervention differed between the HP groups and the LP groups (P=0.003) (Table 4). When only 24 h urines with a PABA recovery 85% were taken into account, urinary N excretion was 13.7 g per day in the LP group and 16.9 g per day in the HP group, translating into a dietary protein intake of 86 g per day in the LP group and 106 g per day in the HP group.

Table 4 Estimates of changes in metabolic and cardiovascular risk factors (mean and 95% confidence interval) from post LCD to the end of the 12-month randomized diet period

The reported difference in protein intake between the LP and HP groups (7 energy%) and the difference in GI between the LGI and HGI groups (5 units) were smaller than intended (10 energy% and 15 units, respectively).

Changes in body weight

Average weight regain was 3.9 (95% CI 3.0–4.8) kg in the completers. Weight regain in the five diet groups after the 12-month intervention is shown in Supplementary Figure 2. There was no significant interaction between protein content and GI of the diet (P=0.871), therefore the main effects of protein content and GI were analyzed. Weight regain was more pronounced in the LP compared with the HP groups in the completers (difference 2.0 (95% CI 0.4–3.6) kg, P=0.017). The ITT analysis and the sensitivity analysis were in agreement with a better weight loss maintenance on the HP compared with the LP diets (Table 2). HGI groups showed 2.1 (0.5–3.8) kg less weight regain than LGI groups (P=0.013). According to the ITT and sensitivity analyses, however, there was no significant effect of GI on weight regain (Table 2 and Figure 2).

Table 2 Estimates of weight regain (mean and 95% confidence interval) from post LCD to the end of the 12-month randomized diet period
Figure 2

Body weight change in the completers during the 12-month randomized dietary intervention in the HP and LP groups (a) and in the HGI and LGI groups (b) (mean±s.e.).

Changes in body composition

Over the 12-month intervention, the subjects in the HP groups showed more favorable changes in other anthropometric variables and body composition than those in the LP groups, whereas no differences were found between the HGI and LGI groups (Table 3). The HP groups increased less in fat mass (difference 1.6 (0–3.1) kg; P=0.043) and sagittal diameter (0.9 (0.2–1.5) cm; P=0.012) compared with the LP groups. In the LP group, 49% of the weight regain was fat-free mass, in the HP group this was 61% (P=0.378).

Table 3 Estimates of changes in body composition (mean and 95% confidence interval) from post LCD to the end of the 12-month randomized diet period

Changes in metabolic and cardiovascular risk factors

After 12 months, triglycerides, C-reactive protein, fasting insulin, 2-h glucose and insulin, HOMA-IR and HOMA-%B were significantly lower, whereas Matsuda index, adiponectin, HDL, LDL, total cholesterol and fructosamine were significantly higher than at baseline (pre-LCD). Blood pressure and fasting glucose did not differ (data not shown). Table 4 shows the changes in cardiovascular and metabolic risk factors over the 12-month intervention period (from post LCD to month 12) and the differences between diet groups. Only the increase in fasting plasma glucose was less pronounced (0.2 (0.0–0.3) mmol l−1; P=0.011) in the HP compared with the LP group. For LDL cholesterol changes, a statistically significant interaction between protein content and GI was found (P=0.011), which was due to an increase in LDL cholesterol in the HGI group on a LP diet and a decrease in the HGI group on the HP diet. Plasma urea concentration increased more in the HP than in the LP groups (P=0.001). We found no differences in the other variables when comparing the protein or GI groups. If the change in body weight during the intervention was added to the model, HDL increased significantly more in the HP than in the LP groups (P=0.033).


The findings of the DIOGENES in the two highly controlled shop-based diet intervention centers indicate that an increase in dietary protein content (~7% of total energy intake) in the context of an ad libitum diet reduces weight regain over 12 months after weight loss induced by an energy-restricted diet. A modest increase in the GI of the diet (~5 units) was associated with less weight regain over 12 months in the completers analysis, but not in the ITT or sensitivity analyses, making this a less reliable outcome.

A major limitation of our study is obviously the high dropout rate during the intervention. This may be inherent to the type of trial, where part of the motivation of subjects to participate is likely to have been the provision of free foods during the first 6 months of the intervention. However, the effects of protein intake appear to be robust in all analyses, including or excluding dropouts. The HP/LGI diet group had the lowest dropout rate, suggesting that this may have been the most acceptable and/or palatable diet for the participants.

The reliability of dietary records with respect to macronutrient composition and GI of the diet can be questioned, as misreporting is a major issue.23 However, the differences in urinary nitrogen excretion and plasma urea concentration between the HP and LP diet groups confirm the difference in protein intake from dietary records between these groups in a qualitative sense. It has been suggested that serum fructosamine is a marker of glycemic load and dietary sugar intake in non-diabetic subjects.24,25 In this study we were unable to demonstrate differences in fructosamine concentrations between groups with HGI and LGI or glycemic load. Moreover, urinary C-peptide excretion, which has been shown to reflect GI of diets with identical macronutrient composition,26 did not differ between diet groups in our study. Thus, we are not able to objectively verify the reported difference in GI between the groups.

The 12-month effect of dietary protein content is in line with the previously reported 6-month results in all DIOGENES centers.14 Our data also confirm previous studies that showed better weight loss maintenance with ad libitum diets with a higher protein content by providing protein supplements.3, 4, 5 The LP groups had a dietary protein content that was similar to the habitual, baseline protein content (~16%), which shows that subjects in the LP groups did not reduce their protein intake to the target level of 10–15% of energy intake. The HP groups, on the other hand, increased their protein intake to the intended level. A weight loss study by Sacks et al.10 with similar group assignment (15 vs 25% of total energy from proteins in the context of an energy-restricted diet) attained a self-reported protein intake difference of 4% of total energy at 6 months and of 1 energy% at 24 months with no significant differences in weight loss between groups. Although the study designs were not completely comparable, a better adherence in our trial may have contributed to our finding of better weight maintenance on the HP diets. In addition, it has been suggested that HP diets may stimulate maintenance or accretion of muscle mass, thereby increasing energy expenditure and improving metabolic profile.6 Our data are in agreement with this, as changes in fat-free mass were not significantly different in the LP and HP groups despite the significantly lower body mass increase in the HP groups. However, the between-group difference in fat-free mass changes, as percentage of body weight change was not statistically significant, which may be due to the relatively small number of subjects in whom body composition data were available.

A higher-GI diet was associated with better weight maintenance in our study, although this was not supported by the ITT and sensitivity analyses and thus may have been a chance finding. Two meta-analyses came to different conclusions about the effect of GI on body weight.12,13 The 6-month analysis of the whole DIOGENES trial has indicated that less weight was regained in the groups consuming the LGI diet.14 The reasons for these inconsistent findings are not directly clear. They are not due to smaller self-reported differences in dietary GI in the two shop centers than in the other centers, which were very similar (5 vs 5 units). The HGI diet was accompanied by a significantly higher protein intake in the two shop centers and this may have confounded the GI effect, although the interaction between GI and protein content was not significant. It is also possible that the foods that contributed to the GI of the diet were different in the two centers in this analysis from those in the whole DIOGENES study population.

After 12 months, most cardiovascular risk factors still showed significant improvements compared with baseline (pre-LCD), except for total and LDL cholesterol. Diet composition hardly influenced these changes, only fasting glucose concentration increased significantly more in the LP than HP groups. The clinical relevance of this finding is not clear, as fasting plasma glucose levels remained in the normal range on both diets. In addition, measures of insulin resistance, C-peptide excretion and plasma fructosamine concentration were not different between protein groups. Thus, in this population of relatively healthy overweight adults, an increase in dietary protein content, which improves weight loss maintenance, was not associated with negative effects on the risk factor profile.

In conclusion, a moderate increase in dietary protein content helps to reduce weight regain after weight loss on an ad libitum diet over a 12-month period, without untoward effects on risk factors for cardiovascular disease and type 2 diabetes. The role of GI in prevention of weight regain remains uncertain.


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We gratefully acknowledge all food companies for their contributions of foods to the laboratory shops. The DIOGENES trial was funded by the European Commission, contract no. FP6-2005-513946. The funding source had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The majority of the food items in the shops were provided for free by a large number of different food companies. A complete list can be found on Food items to be offered in the shops were selected by the investigators. Companies were in no way involved in the planning, execution or analysis of the study.

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Correspondence to M A van Baak.

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Dr Astrup is currently member of advisory boards for McCain Foods, USA, Global Dairy Platform, USA, JennyCraig, USA, and McDonald’s, USA, and has received funding for other studies from about 100 food companies covering all food groups. Dr Saris is corporate scientist, Human Nutrition for DSM, The Netherlands, and received research grants and food donations from several food companies. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies this paper on International Journal of Obesity website

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Aller, E., Larsen, T., Claus, H. et al. Weight loss maintenance in overweight subjects on ad libitum diets with high or low protein content and glycemic index: the DIOGENES trial 12-month results. Int J Obes 38, 1511–1517 (2014).

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  • body weight changes
  • dietary proteins
  • glycemic index
  • risk factors

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