Normalized Glucose Levels in Type 2 Diabetes With Carbohydrate or Caloric Restriction

Study Overview
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Brief Summary
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This is a randomized controlled trial to determine whether a low-carbohydrate (LC) diet can lead to normalized blood glucose levels in patients with short duration of type 2 diabetes (T2D). Previous studies have shown that caloric restricted diet leading to weight loss can normalize blood glucose levels in approximately 50% of patients with a short duration of diabetes type 2. However, caloric restriction is difficult to maintain. Less restrictive approaches are needed. The hypothesis in this study is that Low carbohydrate diet can results in normalized blood glucose levels in T2D and can be an alternative to caloric restriction diet, both in the shorter term (3 months) and longer term (15 months). The outcome of this study leading to reduction of HbA1c is important for prevention of diabetes complications.

Detailed Description
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Background Overweight and obesity raise the risk of hyperglycemia which is among the strongest risk factors for morbidity and mortality globally, linked to type 2 diabetes (T2D) as well as, e.g., cardiovascular diseases (CVD), several cancers, dementia, complicated pregnancies and non-alcoholic fatty liver disease.1 The link between obesity, T2D and CVD is partially explained by the visceral adiposity and ectopic (e.g., hepatic) fat associated with insulin resistance, glucose intolerance, arterial stiffness, high blood pressure and dyslipidaemia constituting the metabolic syndrome.2,3 Recent studies have demonstrated that diet-induced weight loss, averaging just over 10 kg at 12-months, can effectively normalize blood glucose levels in T2D in a large proportion of patients. While energy-restrictive diets can enable rapid weight loss, any restrictive diet can be difficult to maintain over time. Strict weight loss diet is difficult to follow. Less restrictive approaches that can be adopted as part of a healthy lifestyle would be ideal. Cardiovascular complications are the leading cause of morbidity and mortality among patients with diabetes. 29 The mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood. Hyperglycemia has been shown to cause increased oxidative stress arising from oxi-dative degradation of glucose metabolites. Similarly, advanced glycosylation endproducts (AGEs), which are the result of intracellular hyperglycemia, have been shown to be involved in mediating vascular damage. Furthermore hyperglycemia has been reported that to lead to a hypercoagulable state.29 Low carbohydrate diet has recently gained popularity. Rresearch questions remain on if LC diet with low GI can lead to normalization of blood glucose levels and decrease cardiovascular risk markers. The ideal energy percentage (E%) of carbohydrate in the diet for optimal glucose levels is unclear. Caloric restriction diet has shown best results for normalisation of blood glucose levels. There are no previous studies comparing LC diet with caloric restricted diet in regard to normalization of blood glucose levels. The main goal of this study is to evaluate if LC with low GI can lead to normalization or improvement of blood glucose levels in type 2 diabetes (T2D) and to explore the mechanism for normalization of blood glucose levels after LC diet and caloric restricted diet. Hypotheses The main hypothesis in this study is that Low carbohydrate diet can results in normalization or improvement of blood glucose levels in patients with T2D with short duration of disease both in the shorter term (3 months) and longer term (15 months). Project description 3.1 Description of dietary interventions 300 patients with type 2 diabetes will be included in this study. Patients will be randomized to one of the following diet arms. Dietary arm 1: Continuous ad libitum LC diet (Low Carb diet): During the first 3 months, participants will have to restrict carbohydrate (CHO) intake to < 30 g per day. For the following 12 months (3-15 months), participants will be asked to restrict CHO intake to <80 g per day. Participants will receive recipes to follow. As a rescue plan if participants will not be able to follow strict LC diet, they will be offered to continue the study and follow a moderate LC diet. Dietary arm 2: Caloric restriction diet (Low Calori diet): During the first 3 months, participants will be asked to use a total diet replacement, providing  850 kcal/day (59 E% CHO, 13 E% fat, 26 E% protein, 2 E% fiber), followed by 2-8 weeks of food reintroduction towards a long-term weight loss maintenance phase (45-50 E% CHO, 35 E% fat, 15-20 E% protein). Total energy intake during the maintenance phase is 1,500-2,000 kcal/day tailored to the individual patient needs. As rescue plan if participants find it difficult to follow the diet they will be offered to continue with intermittent fasting (5:2 diet). Endpoints Primary endpoints: Rate of patients with normal glucose levels, defined as no use of glucose-lowering drugs and HbA1c <48 mmol/mol (<6.5%) at 3 and15 months. Secondary endpoints: Number of patients with HbA1c <48 and <42 mmol/mol at 3, 9 and 15 months, both on and off anti-diabetes medication (e.g. metformin). Changes in HbA1c and fasting glucose concentrations (treatment targets in current clinical practice), changes in fasting insulin concentration and insulin resistance (HOMA2-IR); general medication usage. 3.2 Power calculations Previous study on caloric restriction diet (DIRECT trial) showed normalization of blood glucose levels in 46% of participants after 12 months. Previous studies on LC diet have shown different results on blood glucose levels based on differences in study design. The greater the carbohydrate restriction, the greater glucose lowering effect. There is a lack of studies reporting normalisation of blood glucose levels. Therefore, it was assumed that LC dietary strategies can result in normalization of blood glucose levels in 30% of patients with T2D after 3 and 15 months. Using an online sample size calculator for a study power of 80% and alpha value of 0.05 the sample size was calculated to 143 participants in each group. 3.3 Randomization Eligible participants will be randomized to one of the two arms. We will use stratified randomization method, stratifying by sex. 3.4 Inclusion and exclusion criteria Inclusion criteria: HbA1c > 48 mmol/mol (with or without medical treatment); less than 6 years since the diagnosis of T2D; both genders; age 24-70 years (adult onset); BMI ≥ 27 kg/m2 (≥ 25 kg/m2 for Asians). Exclusion criteria: Insulin deficiency. HbA1c concentration of 12% or more (≥108 mmol/mol), treatment with sulphonyl urea or sodium-glucose-cotrasporter2-inhibitor (SGL2-i), myocardial infarction, severe or unstable heart failure or other severe diseases including cancer, psychiatric/eating disorders, severe depression and substance abuse, conditions that may affect the ability of patients to participate in the study. 3.5 Data collection, measurements and analysis Anthropometric data and blood samples will be collected at baseline and after 3 months (initial weight loss and remission) months (continued weight loss and remission), and 15 months (weight maintenance). For security reason Hb1c and lipid status will be analyzed after changes in medication. For Standardized measurement protocols, instruments (e.g., for anthropometrics), collection tubes, etc. will be used. HbA1c, glucose, lipids and other standard biochemical variables will be measured directly on the day of the visit at the laboratories, or, for substances sensitive to batch effects (e.g., serum insulin), after collection and freezing at -80°C. Samples that are not analyzed immediately will be stored in a biobank for later use. The study will be performed in accordance with GCP. 3.6 Body composition Body composition will be measured at base line, 3 and 15 month using bio impedance (BIA). 3.7 Diet effect on insulin release At baseline and after 3 and 15 months, the B-cell capacity of insulin release will be investigated by a glucagon stimulated test (GSCT). GSCT will be performed by collecting blood samples before and 6 minutes after an intravenous injection of 0.5 mg glucagon. Secured serum samples will be analysed for C-peptide, insulin and proinsulin. 3.8 Development of user-friendly electronic tools for healthy eating We will use an online database of hundreds of recipes. The platform will furthermore include online support for both cooking and behavioral modification, interactive communication through, e.g., a chat service and weekly newsletters with reminders, educational videos covering topics such as how to prepare foods, meal planning, food addiction, food, and mood, and dining out. The electronic platform/app and digital information will be available in different languages for the different study centers. We will ask the participants to fill in 3 days diet register online on the platform before the start of the study and after 3 and 15 months. 3.9 Questionaries Participants will be asked to fill in Questionnaires EQ-5DL, AUDIT and questionaries for satisfaction with the diet before the start of the study and after 3 and 15 months. 3.10 Statistics A statistician will perform the statistical analyses for the primary outcome of the study. Statistics for the secondary outcomes as well as exploratory analyses will be done by the study centers. 3.11 Insurance National patient insurance policy will cover patients participating in the study. 4 Clinical relevance Controlled diet that leads to weight reduction can reverse type 2 diabetes or delay the diagnosis of T2D. According to the report from the Swedish Institute for Health and Healthcare Economi (IHE) decreasing the blood sugar levels in patient with T2D will spare 800 cases of heart infarction, 500 cases of stroke, 450 cases of kidney failure and 20 cases of blindness. Delaying the diabetes diagnosis is beneficial for the patients since the diabetes complications are directly correlated to the diabetes duration. Patient with type 2 diabetes who change their diet with less carbohydrate have shown to need less insulin. The cost of diabetes disease is affected by the cost of medications and the cost of complications of diabetes. Improved knowledge about which diet can reverse T2D and improve glucose levels will in the end affect the cost for the type 2 diabetes. Dietary intervention which effectively improve blood sugar levels will have significant positive health economic effects. The result from this study will be used for diet recommendation for patients with T2D. 5 Sex and gender perspective Both men and women will be included in the study. Sex will also be one of the factors in randomisation to assure both groups have equal percent of men and women. Gender is considered a risk factor for obesity. Previous studies have shown that being female doubles the chance of becoming overweight. It is known that lifestyle intervention programs are effective in the prevention of type 2 diabetes mellitus in high-risk populations. However, most studies report poorly about the influence of sex and/or gender effectiveness of these interventions. Male sex is acknowledged as a diabetes risk factor. Men are marginally higher affected by diabetes all over the world. They are diagnosed at younger age and at lower levels of overweight/obesity. Women on the other hand are the majority of participants in weight loss studies (This was also observed this in our study investigating the effect of intermittent fasting). Women show greater weight control involvement and thus seek medical help for weight loss therapy/surgery earlier. It is not known if men and women have different preference for LC-diet or caloric restriction as strategies for weigh maintenance. The power of this study enables us to investigate if there are sex differences in regard to preference to different diet. We will be able to compare the remission rate for T2D in men and women.

Official Title
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Normalized Glucose Levels in Type 2 Diabetes With Carbohydrate or Caloric Restriction: a Randomized Controlled Trial (CarborCal)

Conditions
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Diabetes Mellitus Type 2 in Obese

Intervention / Treatment
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* Other: Low carbohydrate diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HbA1c > 48 mmol/mol (with or without medical treatment); less than 6 years since the diagnosis of T2D BMI ≥ 27 kg/m2 (≥ 25 kg/m2 for Asians). Exclusion Criteria: Insulin deficiency. HbA1c concentration of 12% or more (≥108 mmol/mol), treatment with sulphonyl urea or sodium-glucose-cotrasporter2-inhibitor (SGL2-i), myocardial infarction within the previous 6 months, severe or unstable heart failure other severe diseases including cancer, psychiatric/eating disorders, severe depression - substance abuse, conditions that may affect the ability of patients to participate in the study

Ages Eligible for Study
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Minimum Age: 24 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Carb diet<br>Participants will have acces to a plattform with recepies containing 30 g carbohydrate / day during the first three months and thereafter recepies containing 80 g carbohydrate/ day during the remaining 12 months | Other: Low carbohydrate diet<br>* Low carbohydrate compared to low Calori diet<br>* Other names: Low calori diet;|
| Placebo Comparator: Low Calori diet<br>Participants will be asked to by low caloric diet replacement containing 850 kCal/day during the first 3 months, aiming for a weight loss of 10 kg during and thereafter will have access to recepies containing less calorie for weight maintenance during the remaining 12 months | Other: Low carbohydrate diet<br>* Low carbohydrate compared to low Calori diet<br>* Other names: Low calori diet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| non-diabetic HbA1c | HbA1c below 48 mmol/mol without antidiabetic medication | After 3 months | 
| non diabetic HbA1c | HbA1c below 48 mmol/mol without antidiabetic medication | After 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in HbA1c | Changes in HbA1c from base line to 3 and 15 months | After 3 and 15 months | 
| Percent of participants with HbA1c below 48 and 42 mmol/mol | Number of participants with HbA1c below 48 and 42 both on and without antidiabetic medication | After 3 and 15 months | 
| Changes in Fasting glucose levels | Changes in fasting plasma glucose levels after 3 and 15 months | After 3 and 15 months | 
| Changes in HOMA-IR | Changes in HOMA_IR afte 3 and 15 months | After 3 and 15 months | 
| Changes in Insulin secretion | Changes in Insulin secretion measured by glucagon stimulation test | After 3 and 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus Type 2, Diet, Carbohydrate-Restricted, Caloric restriction