Cut Down on Carbohydrate in the Dietary Therapy of Type 2 Diabetes - The Meal Box Study

Study Overview
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Brief Summary
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The cornerstone in the initial treatment of type 2 diabetes (T2D) is lifestyle modification, involving-among other things-a healthy diet. However, scientific evidence regarding optimal nutrition therapy for patients with T2D is insufficient. This clinical study will examine the effect of a carbohydrate-reduced high-protein (CRHP) diet compared to a conventional diabetes (CD) diet for 12 months on metabolic function and body weight in patients with T2D. The hypothesis of the study is that the CRHP diet will improve metabolic control and the cardiovascular risk profile of patients with T2D to a greater extent than the CD diet. In particular, the expectation is that, compared with the CD diet, the CRHP diet will: Reduce diurnal and postprandial glycemia measured by continuous glucose monitoring (CGM) and thereby facilitate a significant reduction of glycated hemoglobin (HbA1c) Reduce body weight Reduce ectopic fat deposition in the liver and the pancreas Improve the blood lipid profile Reduce or not affect blood pressure with no adverse effect on heart rate variability Increase insulin sensitivity and secretion Decrease inflammatory markers in the blood Improve satiety Reduce or not affect the need for antidiabetic, antihypertensive and/or lipid-lowering medications

Detailed Description
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Methods: This is a 12-month investigator-initiated, randomized, controlled, open-label, superiority trial with two parallel groups. The study examines the effect of a CRHP diet (which is reduced in carbohydrate and increased in protein and fat) compared with a CD diet (which follows the currently recommended macronutrient intake for patients with T2D). The study will include 100 T2D patients with overweight or obesity. The macronutrient intake in the CD diet and the CRHP diet is 50 percentage of energy (E%) and 30 E% from carbohydrate, 17 E% and 30 E% from protein, and 33 E% and 40 E% from fat, respectively. The CD diet and the CRHP diet do not principally differ in the quality of carbohydrate, protein, and fat; they both comprise of nutritious, organic, and sustainable food items. Participants will be randomized in a 1:1 ratio to either the CD diet or the CRHP diet for 12 months. About 2/3 of the total calculated energy requirements on both diets will be delivered to the participants free of charge, as meal box solutions containing breakfast meals, snack meals, and dinner meals to optimize compliance and adherence to the assigned diet. The daily energy requirements for body weight maintenance will be calculated by multiplying resting energy expenditure using the Mifflin-St Jeor equation, with an estimated physical activity level (estimated by using a physical activity questionnaire at the beginning of the study). Based on the calculated daily energy requirements, participants will be divided into one of three energy level groups; in all groups, the amount of recommended total daily energy intake will exceed the amount required for weight maintenance and subjects will be instructed to consume the diets ad libitum until satiety is achieved. The dietary interventions are implemented under the guidance of registered clinical dietitians (RCDs) in a free-living setting without any instruction or requirement for weight loss or increased physical activity level. Participants will be instructed to eat until satiety is achieved and allowed to consume alcoholic beverages within the recommendations from the Danish Health Authorities. Dietary advice and counselling regarding food choices and preparation of food concerning the allocated diet, especially the self-prepared lunch meals and how to navigate at special occasions, will be given under the guidance of RCDs. Medication will be kept unchanged during the study, if possible. Rescue medication will be commenced if a HbA1c target of 58 mmol/mol is not reached after six months. If study participants obtain a HbA1c below 48 mmol/mol antidiabetic medication will still be kept constant. Diurnal urine samples, fasting blood samples, dietary records and questionnaire responses will be collected every third month of the study. In addition, at baseline and 12 months, participants will undergo a standardized test battery including magnetic resonance imaging (MRI) and spectroscopy (MRS) for measurement of abdominal subcutaneous and visceral adipose tissue, and ectopic fat in the liver and pancreas, dual X-ray absorptiometry (DXA) scans for body composition, handgrip strength and 30-second chair-stand for muscle strength, oral glucose tolerance test (OGTT), continuous glucose monitoring (CGM), Holter-recording, diurnal blood pressure measurement, and dietary records. Analysis: The primary outcome will be tested by a constrained linear mixed model (CLMM) with inherent baseline-adjustment. Diet group, time and their interaction will be included as fixed effects and participants as random effect. Secondary analyses will furthermore adjust for potential confounders in multivariate CLMMs. The secondary and explorative outcomes will be tested for significance using CLMMs for continuous data (including changes in blood lipid profiles, body weight and hepatic fat content) and Chi-squared tests for proportions (including proportion of the participants who increase their need for glucose lowering medications from baseline to 12 months). Secondary and explorative outcomes will be tested at a significance level at 0.05 without correction for multiplicity, but interpreted according to their secondary and explorative nature. Missing data will be evaluated in regards to whether they can be assumed to be missing at random, and in that case handled implicitly by maximum likelihood estimation in the CLMMs, which is the optimal approach statistically. Intention-to-treat analyses will be performed including all available data. Per protocol analyses of the diet groups will be performed to support the primary analysis. Ethics and dissemination: The National Committee on Health Research Ethics of the Capitol Region of Denmark has approved the trial (H-21057605). The study will be conducted in accordance with the Declaration of Helsinki II. Results will be submitted for publication in international peer-reviewed scientific journals, regardless of being positive, negative or inconclusive.

Official Title
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Cut Down on Carbohydrate in the Dietary Therapy of Type 2 Diabetes Mellitus - The Meal Box Study

Conditions
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Diabetes Mellitus Type 2, Overweight and Obesity

Intervention / Treatment
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* Other: Carbohydrate-reduced high-protein (CRHP) Diet
* Other: Conventional diabetes (CD) Diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or postmenopausal women aged 18-75 years. Menopause is defined as >12 months without menses Overweight or obesity with Body Mass Index (BMI) >25 kg/m2 Type 2 diabetes with HbA1c between 48 mmol/mol and 75 mmol/mol (6.5%-9.0%) Treated with or without Metformin, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and/or glucagon-like peptide 1 receptor agonists (GLP-1RA) Nonsmokers or having quitted smoking >1 year before the study Acceptance of regulation of antidiabetic, antihypertensive, and lipid-lowering medications by Cut-DM endocrinologists only Exclusion Criteria: Ongoing insulin or insulin analog therapy Severe gut disease as evaluated by the principal investigator e.g. Crohn's disease, Ulcerative colitis, Celiac disease etc. Extensive surgery to the gut e.g. bariatric surgery, colectomy etc. Severe heart disease as evaluated by the principal investigator e.g. angina pectoris, coronary heart disease, congestive heart failure (NYHA III-IV) Severe renal impairment (eGFR<45 ml/min/1.73 m2 or urine albumin / creatinine ratio > 300 mg/g) Severe hepatic impairment as evaluated by the principal investigator (measure of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) Cancer within the last 5 years (except basal cell skin cancer or squamous cell skin cancer) Psychiatric disease, e.g. a history of major depressive or other severe psychiatric disorders Systemic corticosteroid treatment, e.g. prednisolone Reported or documented food allergy, food intolerance, or strong food preferences Reported or documented alcohol consumption exceeding the recommendations from The Danish Health Authorities Ongoing treatment with sulfonylureas and/or thiazolidinediones due to the risk of hypoglycemia unless discontinuation is possible, in which case a >3-month wash-out is mandatory Hemoglobin <7 mmol/L for men and <6 mmol/L for women Inability, physically and/or mentally, to comply with the procedures required by the study protocol, as evaluated by the principal investigator Weight change ≥5% the preceding 3 months of screening Participation in other on-going clinical trials

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Experimental: Therapeutic Diet: CRHP Diet<br>Carbohydrate-reduced high-protein (CRHP) dietary intervention. Intervention: Therapeutic Diet: CRHP Diet. | Other: Carbohydrate-reduced high-protein (CRHP) Diet<br>* Macronutrient intake of 30 percentage of energy from carbohydrate, 30 percentage of energy from protein and 40 percentage of energy from fat.<br>|
| Active Comparator: Therapeutic Diet: CD Diet<br>Conventional diabetes (CD) dietary intervention. Intervention: Therapeutic Diet: CD Diet. | Other: Conventional diabetes (CD) Diet<br>* Macronutrient intake of 50 percentage of energy from carbohydrate, 17 percentage of energy from protein and 33 percentage of energy from fat.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glycated hemoglobin (HbA1c) after 12 months on the CRHP diet compared with the CD diet | HbA1c will be measured in fasting blood samples at baseline, 3, 6, 9 and 12 months. HbA1c will be expressed in mmol/mol. | Baseline, 3, 6, 9 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total body weight after 12 months on the CRHP diet compared with the CD diet | Total body weight will be measured at baseline, 3, 6, 9 and 12 months. Total body weight will be expressed in kilograms (kg). | Baseline, 3, 6, 9 and 12 months | 
| Change in hepatic fat content after 12 months on the CRHP diet compared with the CD diet | Hepatic fat content will be assessed by magnetic resonance imaging/spectroscopy (MRI/MRS) at baseline and 12 months. | Baseline and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus Type 2, Nutrition Therapy