EAL

MNT: Disorders of Lipid Metabolism (2015)

Citation:

Yamada Y, Uchida J, Izumi H, Tsukamoto Y, Inoue G, Watanbe Y, Irie J, Yamada S. A non-calorie-restricted low-carbohydrate diet is effective as an alternative therapy for patients with type 2 diabetes. Internal Medicine. 2014; 53: 13-19. PubMed ID: 24390522

Study Design:

Randomized Controlled Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To examine the effectiveness of a non-calorie-restricted, low-carbohydrate diet for blood glucose and body weight management in Japanese patients with type 2 diabetes who were unable to adhere to a calorie-restricted diet.

Inclusion Criteria:

Type 2 diabetes diagnosis
Treated in a select outpatient clinic
Received guidance regarding calorie restriction at least once
Hemoglobin A_1C level was 6.9% to 8.4%
Written informed consent was provided.

Exclusion Criteria:

Proteinuria of more than one 1.0g per day
Serum creatinine level of more than 132umol per L for men or 106umol per L for women
Aspartate aminotransferase or alanine aminotransferase level of greater than three times the upper limit of normal
History of myocardial infarction or stroke within six months before study entry
Absolute change in hemoglobin A_1C of more than 1.0% within six months before study entry.

Description of Study Protocol:

Recruitment

Recruited from outpatient clinic.

Design

Enrolled patients were randomly allocated to receive either a non-calorie restricted, low-carbohydrate diet or calorie-restricted diet using a permuted randomized block of four patients per block. Patients received consultation every two months from a registered dietitian for six months.The effects of the two dietary interventions on hemoglobin A_1C levels, body weight, lipid levels, blood pressure, markers of atherosclerosis, renal function, liver enzyme levels and quality of life were compared at enrollment and at the end of the study.

Intervention

Type-of-diet face-to-face instruction was provided by registered dietitians
Calorie intake was defined based upon Japan Diabetes Society recommendations:
- Total kcal (ideal body weight times 25)
- 50% to 60% of kcal from carb
- 1g to 1.2g protein per kg (approximately 20%)
- 25% kcal from fat
- For low-carbohydrate diet, a limited daily carbohydrate intake to less than 130g per day (no less than 70g per day to prevent ketosis; 20g to 40g per meal to prevent hypoglycemia) was recommended.

Statistical Analysis

A total of 22 patients was needed for a=0.05 and power=0.9
Results presented as mean ± standard deviation
Mann-Whitney U-test used for within-group and between-group comparisons
Spearman's rank correlation test used to assess correlations between carbohydrate or calorie intake and outcomes
P<0.05 was considered statistically significant.

Data Collection Summary:

Timing of Measurements

Recorded every two months for six months:
- Hemoglobin A_1C level
- Laboratory blood tests
- Body weight
- Incidence of hypoglycemic episodes since previous visit
- Dietary intake over the three days prior to visit.
Demographic information, including age and gender as well as medication regimen collected at baseline
Effects of diet on quality of life was evaluated by patients completing the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Problem Areas in Diabetes (PAID) scale at enrollment and end of study.

Dependent Variables

Hemoglobin A_1C
Body weight
Lipid levels [total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C)]
Blood pressure
Markers of atherosclerosis [pulse-wave velocity (PWV), ankle brachial pressure index (ABI) and toe brachial pressure index (TBI)]
Renal function [urinary nitrogen (UN) creatinine (Cr), estimated glomerular filtration rate (eGFR) and albumin to creatinine ratio (ACR)]
Liver enzyme levels [AST, ALT, and y-glutamyl transpeptidase (yGTP)]
Quality of life
Nutrient intake.

Independent Variables

Diet regimen (calorie restricted vs. low carbohydrate diet).

Control Variables

Adverse events.

Description of Actual Data Sample:

Initial N: N=24 patients (12 females, 12 males)
Attrition (final N): N=24 patients
Age: Age for low-carbohydrate diet was 63.3±13.5 years, while it was 63.2±10.2 years for those on the calorie-restricted diet
Ethnicity: Japanese
Location: Japan.

Summary of Results:

Key Findings

Six months after starting the diet, the hemoglobin A_1Clevels were significantly lower than those observed at baseline in the low-carbohydrate group (baseline 7.6±0.4%, six months 7.0±0.7%; P=0.03), whereas there were no changes in the hemoglobin A_1Clevels in the calorie-restricted group [baseline 7.7±0.6%, six months 7.5±1.0%; not significant (NS)]
Fasting plasma glucose levels, body weight BMI and blood pressure did not change significantly in either group
TG levels significantly decreased in the low-carbohydrate group (baseline 141.7±76.2mg per dL, six months 83.5±40.6mg per dL; P=0.02), whereas no changes occurred in the calorie-restricted group (baseline 155.2±86.4mg per dL, six months 148.4±90.7mg per dL; NS) and the difference between the two groups was not statistically significant (P=0.08)
Other markers of lipid profiles were not altered in either group
Diet did not significantly affect markers of atherosclerosis
No changes in the markers of renal function in either group
ALT, a marker of liver function, tended to improve in the lower-carbohydrate group (baseline 28.6±12.5 U per L, six months 21.4±5.9 U per L; P=0.07)
Regarding quality of life, DTSQ score and PAID scores did not change in either group
Calorie intake at six months was similar in both groups with carbohydrate intake significantly lower (P=0.008) in the low-carbohydrate group compared to the calorie-restricted group
Correlations between carbohydrate or calorie intake and outcomes:
- Correlation analyses performed in 10 patients with nutrient intake data at baseline and end of study
- Change in body weight was significantly correlated with change in carbohydrate intake (R=0.764, P=0.0078) and the change in calorie intake (R=0.769, P= 0.0071)
- Change in hemoglobin A_1Clevel was significantly correlated with change in carbohydrate intake (R=0.670, P=0.0321) but not with the change in calorie intake (R=0.439, not significant).

Variable	Low-carbohydrate Diet			Calorie-restricted Diet			P-value
	Baseline	Six Months	P-value (For Within-Group Comparisons)	Baseline	Six Months	P-value (For Within-Group Comparisons)
Hemoglobin A_1C(%)	7.6±0.4	7.0±0.7	0.03	7.7±0.6	7.5±1.0	NS	0.03
Fasting blood glucose (mg per dL)	138±44	124±22	NS	155±46	163±26	NS	NS
Body weight (kg)	67±15.9	64.4±14.2	NS	68.1±7.7	66.7±7.0	NS	NS
BMI (kg/m²)	24.5±4.3	23.6±3.5	NS	27±3.0	26.4±2.2	NS	NS

Other Findings

Three patients treated with a sulfonylurea or insulin in the low-carbohydrate group experienced symptomatic hypoglycemia, which did not recur after medication adjustments
No patients developed ketonuria during the study.

Author Conclusion:

Significant improvements in hemoglobin A_1C level were observed in the low-carbohydrate group but not in the calorie-restricted group. Findings suggest that a low-carbohydrate diet is effective in lowering the hemoglobin A_1Cand triglyceride levels in patients with type II diabetes who are unable to adhere to a calorie-restricted diet.

Funding Source:

Other:

Not described; authors state that no conflicts of interest exist

Reviewer Comments:

Study limitations include:

Number of subjects enrolled was too small to detect significant differences in the between-group and within-group comparisons
Six-month study period may be too short to see long-term impacts of diets.

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.)	Yes
	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.)	Yes
	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?	Yes
	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?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	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?	No
	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)?	No
	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?	Yes
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