DM: Protein (2007)

Citation:

Pijls LTJ, de Vries H, van Eijk JThM, Donker AJM. Protein restriction, glomerular filtration rate and albuminuria in patients with type 2 diabetes mellitus: a randomized trial. Eur J Clin Nutr. 2002;56:1200-1207.

PubMed ID: 12494305
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To determine if protein restriction beneficially influences glomerular filtration rate (GFR) and albumin excretion rate (AER) and thus plays a role in the prevention or delay of renal disorders in type 2 diabetes mellitus

Inclusion Criteria:
  • type 2 diabetes mellitus.
  • microalbuminuria (30-300 Mg/24 h) or detectable albuminuria (> 20 mg/24 h) or diabetes duration > 5 years.
  • age <79 years
Exclusion Criteria:
  • Baseline protein intake < 0.8 g/kg/d
  • Low compliance in keeping prestudy appointments
  • In a period of recovery from severe morbidity
  • Protein-losing enteropathy, venous leg/pressureulcer, malignancy, psychiatric/serious psychosocial problems
  • Clinically obvious nephropathy
  • Reluctant to change diet or to understand diet information
Description of Study Protocol:

Recruitment

46 general practitioners selected all their patients with type 2 diabetes who met inclusion criteria and not exclusion criteria.

Design

Comparison of a protein-restricted diet (0.8g/kg/d) vs usual dietary guidelines (The Netherlands guidelines) in patients with type 2 diabetes at baseline and every six months (average of 28 months), with primary outcome measures being GFR and AER. 

Blinding used (if applicable)

 Physician-blinded

Intervention (if applicable)

Both groups received baseline counseling from a dietitian on usual dietary guidelines, focusing on restriction of saturated fat; during the study both groups were provided the same "amount of attention"

Only the protein restricted diet group received information about how to decrease dietary protein intake to 0.8 g/kg/d by partially replacing it, isocalorically, with unsaturated fat and carbohydrates (especially dietary fiber). 

Intervention included 30 min meetings with the dietitian at months 1 and 3 after baseline, and then every 3 months till end of study. Consultation included feedback based on repeated dietary interviews and on protein intake estimated from 3-month measurements of 24h urinary urea excretion.  Subjects were provided individually designed daily menus, plus variation lists indicating foods that contain equivalent amounts of protein, and a food composition table and recipes (note: not clear if this is just for the protein restricted group, or for both groups)

General practitioners continued to be responsible for treatment of diabetes and medications.

Statistical Analysis

  • 2-sided t-test (for differences between the 2 study groups
  • x2-test (difference in categorical variables)
  • Intention-to-treat analysis
  • Best-case analyses
  • Note: no power calculations provided
Data Collection Summary:

Timing of Measurements

Baseline, 1 month, 3 months, and then every 3 months until end of study 

Dependent Variables

  • GFR (cimetidine-influenced creatinine clearance as an estimate)
  • AER (Beckman Instruments)

Independent Variables

  • Comparison of a protein-restricted diet (0.8g/kg/d) vs usual dietary guidelines (The Netherlands guidelines) in patients with type 2 diabetes at baseline and every six months (average of 28 months), with primary outcome measures being GFR and AER. 

  • Both groups received baseline counseling from a dietitian on usual dietary guidelines, focusing on restriction of saturated fat; during the study both groups were provided the same "amount of attention"
  • Only the protein restricted diet group received information about how to decrease dietary protein intake to 0.8 g/kg/d by partially replacing it, isocalorically, with unsaturated fat and carbohydrates (especially dietary fiber). 
  • Intervention included 30 min meetings with the dietitian at months 1 and 3 after baseline, and then every 3 months till end of study. Consultation included feedback based on repeated dietary interviews and on protein intake estimated from 3-month measurements of 24h urinary urea excretion.  Subjects were provided individually designed daily menus, plus variation lists indicating foods that contain equivalent amounts of protein, and a food composition table and recipes (note: not clear if this is just for the protein restricted group, or for both groups)
  • General practitioners continued to be responsible for treatment of diabetes

 

Control Variables

  • Date of diabetes diagnosis
  • Ethnic origin
  • Gender
  • 24-h urinary urea (BM/Hitachi 747/737) + Maroni formula to estimate compliance with protein intake
  • Systolic and diastolic blood pressure (mean of second and third reading;Hawksley random-zero meter)
  • use of medications
  • HbA1c
Description of Actual Data Sample:

Initial N: 160: 81 protein-restricted diet (47 men, 34 women); 79 usual diet (41 men, 38 women) 

Attrition (final N):

  • 131 completed a follow-up of at least 12 months: 63 protein-restrictied diet (40 men, 23 women); 68 usual diet (36 men, 32 women).  Gender difference is nonsignificant (p=0.19)
  • 94 with complete 24-m follow-up: 50 protein-restricted diet; 44 usual diet

Age: mean 63-65 ± 8yrs

Ethnicity: caucasian except for 2 non-caucasian in each group at baseline

Other relevant demographics: duration of diabetes (6.7 yrs for protein restricted diet-; 7.2 for usual diet)

Anthropometrics : weight (81 kg, both groups); BMI (27.4 for protein restricted diet; 28.2 for usual diet);

Location: Amsterdam, The Netherlands 

Summary of Results:

 

Variables

Protein-restricted diet group, baseline n= 131 mean±SD or geometric mean with 25th and 75th percentiles

Protein-restricted diet group, 24 mo n= 94 mean±SD

Usual diet group, baseline n= 131 mean±SD or geometric mean with 25th and 75th percentiles

 

Usual diet group 24 mo n= 94 mean±SD

Dietary protein intake (g/kg/d)

1.18±0.24

1.11+0.20

1.15±0.26

1.19+0.29

GFR (ml/min/1.73m2)

 82±19

74

 85±23

 75

AER (mg/24 h)

 21.2 (10,41)

16

 20.5 (8,42)

 14

 Other Findings

  • Average duration of intervention and follow-up was 28 +/- 7 months.
  • At 6 months, albuminuria decreased in the experimental group by 12% (0.08 g/kg/day) and increased in the control group by 16% (p = 0.02) but at 12 months there were no differences.
  • After first six months, annual decline in GFR in protein-restricted diet group was 4.8±12 ml/min/1.732; in the usual diet group, 6.46±14 (NS).  Effect estimate not influenced by adjustment for baseline levels of GFR, albuminuria, blood pressure, age, gender, use of ACE inhibitors, or duration of follow-up
  • Best-case analysis (patients in protein-restricted diet group with at least 0.20 g/kg/d decrease in protein intake; patients in usual diet group with no decrease) did not indicate a slower rate of decline in GFR in the experimental group compared to the control group.
  • Intention to treat analysis showed no clear effect on GFR (because no substantial protein restriction was achieved)
Author Conclusion:
  • In patients with type 2 diabetes and no clinically obvious nephropathy, protein restriction for an average period of 28 months is neither feasible nor efficacious
  • It is very unlikely that, had substantial protein restriction been achieved, an effect on renal function would have been observed. 

 

Funding Source:
University/Hospital: Vrije University, University of Maastricht
Reviewer Comments:
  • No power calculations provided in statistics section
  • Less than 60% of subjects completed the 24 month follow-up
  • Subjects did not (were not able to) decrease protein intake, even with good nutrition education techniques.  Consequently even use of specialized statistics (intention-to-treat and best-case analysis) did not show a beneficial effect on GFR/AER of protein reduction.
  • Cross-reference other articles about this study:
    •  published baseline and 6 and 12 mo data (Pijls LTJ et al, Nephrology Dialysis Transplantation 1999;14:1445-1453)
    • compliance data (Pijls LTJ et al, Eur J Clin Nutr 2000;54:347-352)
    • determinants of albuminuria (Pijls LTJ et al, Diabetes Res Clin Pract 2001;52:133-143) 
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) No
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? ???
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes