Diabetes, PreDiabetes, Metabolic Disease, Hyperglycemia, Diet Modification, Glucose Intolerance, Glucose Metabolism Disorders (Including Diabetes Mellitus), Endocrine System Diseases
Conditions
Keywords
Prediabetes, Diabetes, Low-Carbohydrate Diet
Brief summary
The proposed randomized controlled trial will test the effect of a low-carbohydrate diet on hemoglobin A1c among individuals with elevated hemoglobin A1c that are within the range of prediabetes or diabetes. Results may provide evidence about the role of carbohydrate restriction in individuals with or at high risk of type 2 diabetes.
Detailed description
In the short-term, among patients with type 2 diabetes, low-to-moderate carbohydrate diets have a greater glucose-lowering effect than do high-carbohydrate diets. However, compared with usual diet, the effect of a behavioral intervention promoting a low-carbohydrate/high-unsaturated fat and high-protein dietary pattern among individuals with prediabetes or untreated type 2 diabetes is not well understood. The overall goal of this randomized controlled trial is to study the effect of a behavioral intervention promoting a low-carbohydrate/high-unsaturated fat and high-protein dietary pattern compared with usual diet on hemoglobin A1c (HbA1c) and other metabolic risk factors among individuals with or at high risk of diabetes (HbA1c 6.0-6.9%). A total of 150 participants with HbA1c 6.0-6.9% will be recruited and randomly assigned to either a 6-month behavioral modification program designed to reduce carbohydrate intake (initial target \<40 g digestible carbohydrates, final target \<60 g digestible carbohydrates) or to usual diet in a 1:1 randomization ratio. The primary outcome will be the difference between the active intervention and control groups for change in HbA1c from baseline to 6 months. Secondary outcomes will be fasting glucose, systolic blood pressure, total-to-high-density lipoprotein-cholesterol ratio, and body weight. Findings from this study may provide evidence about the role of carbohydrate restriction in individuals with or at high risk of type 2 diabetes.
Interventions
BEHAVIORALLow-Carbohydrate Diet
Behavioral modification to reduce carbohydrate consumption. Target \<40 g net carbohydrates per day for first 3 months; \<60 g net carbohydrates per day for months 4 onwards. The intervention will consist of 4 weekly individual counseling sessions, followed by 4 group sessions held every other week, with phone follow-ups in between group sessions. For the last 3 months of the study, there will be 3 monthly group sessions and 3 telephone follow-ups. At baseline, participants will receive written information with standard physical activity recommendations.
Sponsors
National Institute of General Medical Sciences (NIGMS)
Tulane University School of Public Health and Tropical Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Men or women ages 40 to 70 years * HbA1c 6.0-6.9% * Willing and able to provide informed consent
Exclusion criteria
* Diagnosed type 1 diabetes mellitus * Use of agents affecting glycemic control (medications for diabetes, oral glucocorticoids) within the past three months prior to enrollment * Medical condition in which low-carbohydrate diet may not be advised: estimated glomerular filtration rate (eGFR) ≤45 mL/min/1.73 m²; self-report of liver disease due to hepatitis or alcohol; osteoporosis; untreated thyroid disease; gout; cancer (other than non-melanoma skin cancer) requiring treatment in the past year, unless prognosis is excellent * Factors that may affect HbA1c: hemoglobin \<11 mg/dL (cutpoint for moderate-to-severe anemia, which could lead to falsely elevated or lowered HbA1c); recent blood donation or blood transfusion (self-report, past 4 months); human immunodeficiency virus (self-report) * Self-reported history of intensive care unit stay due to Coronavirus Disease 2019 (COVID-19) in the past three months, as severe COVID-19 may affect blood glucose levels * Allergies to nuts * For women, current pregnancy, breastfeeding, or plans to become pregnant during the study * Consumption of ≥21 alcoholic drinks per week or consumption of ≥6 drinks per occasion * Current or planned residence making it difficult to meet trial requirements (due to distance from study site and/or challenges regularly traveling to site) * Current participation in another lifestyle intervention trial or a pharmaceutical trial * Participation of another household member in the study; employees or persons living with employees of the study * Other concerns regarding ability to meet trial requirements, at the discretion of the principal investigator or study coordinator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin A1c | Baseline and six months | 6-month change in Hemoglobin A1c comparing low-carbohydrate arm with usual diet arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight | Baseline and six months | 6-month change in body weight comparing low-carbohydrate arm with usual diet arm |
| Change in Fasting Plasma Glucose | Baseline and six months | 6-month change in fasting plasma glucose comparing low-carbohydrate arm with usual diet arm |
| Change in Systolic Blood Pressure | Baseline and six months | 6-month change in systolic blood pressure comparing low-carbohydrate arm with usual diet arm |
| Change in Total-to-HDL-cholesterol Ratio | Baseline and six months | 6-month change in total-to-HDL-cholesterol ratio comparing low-carbohydrate arm with usual diet arm |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin | Baseline and six months | 6-month change in fasting insulin comparing low-carbohydrate arm with usual diet arm |
| Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | Baseline and six months | 6-month change in HOMA-IR comparing low-carbohydrate arm with usual diet arm. HOMA-IR was calculated as fasting insulin (μIU/mL) x fasting glucose (mmol/L)/22.5. |
| Change in Diastolic Blood Pressure | Baseline and six months | 6-month change in diastolic blood pressure comparing low-carbohydrate arm with usual diet arm |
| Change in Waist Circumference | Baseline and six months | 6-month change in waist circumference comparing low-carbohydrate arm with usual diet arm |
| Change in Estimated Atherosclerotic Cardiovascular Disease Risk | Baseline and six months | 6-month change in estimated 10-year atherosclerotic cardiovascular disease risk comparing low-carbohydrate arm with usual diet arm. The estimated 10-year cardiovascular disease risk was assessed by 2013 American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease Risk Score, known as the Pooled Cohort Equations. The Pooled Cohort Equations estimate the 10-year primary risk of ASCVD (atherosclerotic cardiovascular disease) among patients without pre-existing cardiovascular disease who are between 40 and 79 years of age. Variables included in the risk score include: gender, age, race, total cholesterol, HDL cholesterol, systolic blood pressure, treatment for blood pressure, diabetes, and smoking status. Reference: Goff DC, Lloyd-Jones DM et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American college of cardiology/American heart association task force on practice guidelines. Vol. 129, Circulation. 2014. |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred from September 2018 through December 2020. Participants were recruited from the greater New Orleans, Louisiana area, primarily by mass mailing
Pre-assignment details
After ascertaining eligibility, staff obtained randomization assignment in either a sealed envelope from or by telephoning the methodology unit at the time of randomization.
Participants by arm
| Arm | Count |
|---|---|
| Low-Carbohydrate Diet Behavioral modification to reduce carbohydrate consumption. Target \<40 g net carbohydrates per day for first 3 months; \<60 g net carbohydrates per day for months 4 onwards. The intervention will consist of 4 weekly individual counseling sessions, followed by 4 group sessions held every other week, with phone follow-ups in between group sessions. For the last 3 months of the study, there will be 3 monthly group sessions and 3 telephone follow-ups.
At baseline, participants will receive written information with standard physical activity recommendations.
Low-Carbohydrate Diet: Behavioral modification to reduce carbohydrate consumption. Target \<40 g net carbohydrates per day for first 3 months; \<60 g net carbohydrates per day for months 4 onwards. The intervention will consist of 4 weekly individual counseling sessions, followed by 4 group sessions held every other week, with phone follow-ups in between group sessions. For the last 3 months of the study, there will be 3 monthly group sessions and 3 telephone follow-ups.
At baseline, participants will receive written information with standard physical activity recommendations. | 75 |
| Usual Diet No dietary intervention.
At baseline, participants will receive written information with standard dietary advice and standard physical activity recommendations. | 75 |
| Total | 150 |
Baseline characteristics
| Characteristic | Total | Usual Diet | Low-Carbohydrate Diet |
|---|---|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 7.9 | 58.6 years STANDARD_DEVIATION 8.8 | 59.3 years STANDARD_DEVIATION 7 |
| Body weight | 99.5 kg STANDARD_DEVIATION 20.9 | 96.4 kg STANDARD_DEVIATION 19.6 | 102.6 kg STANDARD_DEVIATION 21.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 139 Participants | 71 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin A1c | 6.16 % STANDARD_DEVIATION 0.3 | 6.14 % STANDARD_DEVIATION 0.3 | 6.17 % STANDARD_DEVIATION 0.31 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 85 Participants | 49 Participants | 36 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 57 Participants | 24 Participants | 33 Participants |
| Region of Enrollment United States | 150 participants | 75 participants | 75 participants |
| Sex: Female, Male Female | 108 Participants | 54 Participants | 54 Participants |
| Sex: Female, Male Male | 42 Participants | 21 Participants | 21 Participants |
| Waist circumference | 113.9 cm STANDARD_DEVIATION 15 | 111.8 cm STANDARD_DEVIATION 15 | 115.9 cm STANDARD_DEVIATION 14.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 75 |
| other Total, other adverse events | 2 / 75 | 2 / 75 |
| serious Total, serious adverse events | 4 / 75 | 3 / 75 |
Outcome results
Primary
Change in Hemoglobin A1c
6-month change in Hemoglobin A1c comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Data were analyzed using intention to treat. For the primary outcome (net 6-month change in HbA1c), we used linear mixed effects models with HbA1c as the dependent variable. This model included a random intercept with an unstructured covariance matrix, indicator variables for time and study group, and group by time interaction terms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Hemoglobin A1c | -0.26 percentage |
| Usual Diet | Change in Hemoglobin A1c | -0.04 percentage |
p-value: <0.0595% CI: [-0.32, -0.14]linear mixed effects model
Secondary
Change in Body Weight
6-month change in body weight comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Body Weight | -6.4 kg |
| Usual Diet | Change in Body Weight | -0.5 kg |
p-value: <0.0595% CI: [-7.4, -4.4]linear mixed effects model
Secondary
Change in Fasting Plasma Glucose
6-month change in fasting plasma glucose comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Intention to treat analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Fasting Plasma Glucose | -8.4 mg/dL |
| Usual Diet | Change in Fasting Plasma Glucose | 1.9 mg/dL |
p-value: <0.0595% CI: [-15.6, -4.9]linear mixed effects model
Secondary
Change in Systolic Blood Pressure
6-month change in systolic blood pressure comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Systolic Blood Pressure | -4.9 mm Hg |
| Usual Diet | Change in Systolic Blood Pressure | -1.6 mm Hg |
p-value: <0.0595% CI: [-7.3, 0.9]linear mixed effects model
Secondary
Change in Total-to-HDL-cholesterol Ratio
6-month change in total-to-HDL-cholesterol ratio comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Total-to-HDL-cholesterol Ratio | -0.54 ratio |
| Usual Diet | Change in Total-to-HDL-cholesterol Ratio | -0.41 ratio |
p-value: <0.0595% CI: [-0.31, 0.05]linear mixed effects model
Other Pre-specified
Change in Diastolic Blood Pressure
6-month change in diastolic blood pressure comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Diastolic Blood Pressure | -3.2 mm Hg |
| Usual Diet | Change in Diastolic Blood Pressure | -0.6 mm Hg |
p-value: <0.0595% CI: [-5.2, 0]linear mixed effects model
Other Pre-specified
Change in Estimated Atherosclerotic Cardiovascular Disease Risk
6-month change in estimated 10-year atherosclerotic cardiovascular disease risk comparing low-carbohydrate arm with usual diet arm. The estimated 10-year cardiovascular disease risk was assessed by 2013 American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease Risk Score, known as the Pooled Cohort Equations. The Pooled Cohort Equations estimate the 10-year primary risk of ASCVD (atherosclerotic cardiovascular disease) among patients without pre-existing cardiovascular disease who are between 40 and 79 years of age. Variables included in the risk score include: gender, age, race, total cholesterol, HDL cholesterol, systolic blood pressure, treatment for blood pressure, diabetes, and smoking status. Reference: Goff DC, Lloyd-Jones DM et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American college of cardiology/American heart association task force on practice guidelines. Vol. 129, Circulation. 2014.
Time frame: Baseline and six months
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Estimated Atherosclerotic Cardiovascular Disease Risk | -1.7 estimated % |
| Usual Diet | Change in Estimated Atherosclerotic Cardiovascular Disease Risk | -0.9 estimated % |
p-value: <0.0595% CI: [-1.8, 0.3]linear mixed effects model
Other Pre-specified
Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
6-month change in HOMA-IR comparing low-carbohydrate arm with usual diet arm. HOMA-IR was calculated as fasting insulin (μIU/mL) x fasting glucose (mmol/L)/22.5.
Time frame: Baseline and six months
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | -1.6 no units |
| Usual Diet | Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 0.8 no units |
p-value: <0.0595% CI: [-3.7, -1.1]linear mixed effects model
Other Pre-specified
Change in Insulin
6-month change in fasting insulin comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Insulin | -4.0 μIU/L |
| Usual Diet | Change in Insulin | 2.3 μIU/L |
p-value: <0.0595% CI: [-10.5, -2]linear mixed effects model
Other Pre-specified
Change in Waist Circumference
6-month change in waist circumference comparing low-carbohydrate arm with usual diet arm
Time frame: Baseline and six months
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-Carbohydrate Diet | Change in Waist Circumference | -5.2 cm |
| Usual Diet | Change in Waist Circumference | -0.5 cm |
p-value: <0.0595% CI: [-6.7, -2.6]linear mixed effects model