Dietary Strategies for Remission of Type 2 Diabetes (CARBCOUNT)

Karolinska Institutet, University of Glasgow, University of Copenhagen, Technical University of Munich

In this project, the investigators will perform a multicenter randomised controlled trial to determine whether advice to consume a moderate, whole food-based low-carbohydrate high-fat (LCHF) ad libitum diet (CarbCount program) can produce and maintain equal remission rates of type 2 diabetes (T2D) as a nutritionally complete very-low-calorie formula diet followed by a energy-restrictive (i.e., calorie counting) diet (DiRECT principles). Within the principles of each approach, the dietary goals and change will be adjusted according to individual needs/capabilities conducive to long-term adherence. Furthermore, the investigators aim to determine whether the rate of diet-induced remission is reflected in/can be predicted by baseline or diet-induced changes in glucose variability (e.g., time-in-range measured by continuous glucose monitoring) and other factors such as anthropometric changes and genetic susceptibility. Each center will also conduct locally-lead standalone mechanistic research, including analyses of intra-abdominal/hepatic fat accumulation, adipose tissue biopsies and/or measurements of energy metabolism. Additionally, changes in medication use, nutritional status, cardiovascular disease risk, as well as adverse events, will be monitored.

At least 588 patients with T2D will be recruited, approximately 120-150 men and women at each research center. The participants will be randomised to 1) a nutritional complete formula diet for 3 months followed by an energy restricted diet for 12 months or 2) a very low-carbohydrate high-fat (VLCHF) diet for 3 months, followed by a low-carbohydrate high-fat diet (LCHF) for 12 months. Each of the diets will cover all basic requirements for essential nutrients including amino acids, fatty acids, vitamins and minerals. Participants will be encouraged to consume at least 200 g of vegetables per day. Furthermore, we will emphasize high-quality, minimally processed foods. In arm 2 they will receive advice to eat specific fat sources such as extra virgin olive oil, butter and high-fat cheeses. The DiRECT trial showed remission in 46% of participants after 12 months. Assuming that both the DiRECT program and LCHF dietary strategies yield a 45% chance of T2D remission after 15 months, it is calculated (using nQuery v8) that each group needs 235 participants to complete the trial. This sample size yields 90% statistical power to conclude, with respect to the primary outcome, whether the CarbCount Program is no more than 15% more or less effective than the DiRECT principles (equivalence study, one-sided p-value at 0.025). To allow for expected loss to follow-up (estimated at 20%), each of the arms needs at least 294 participants for a total of 588. Participants will have access to electronic platforms that include an online database of recipes (breakfast, easy-to-cook lunches, snacks, dinners, and food for special occasions). The platforms will facilitate planning of week menus, and include an e-learning course covering topics such as how to cook and prepare foods, meal planning, dining out, sleep and individual aspects that challenge habit change. If the participants are failing in their efforts to establish or maintain lifestyle change, they will be encouraged to seek possible solutions in the e-learning courses or to contact one of the study's health educators and/or dietitians. Specific rescue plans involving direct contact with study staff will be implemented if a participant regains more than 2 kg or experiences T2D relapse. After individual assessment by a doctor, the participants will be taken off diabetes medication upon starting the diet, and be asked to self-monitor blood sugar changes during the first 2 weeks on the diet, followed by a consultation that includes evaluation of these changes. The need of reintroduction of medication will be done in consultation with the study doctor at least every 3 months. Between visits, the participants will complete dietary assessments and an e-learning course, and at least once a month have follow-ups with dietitians/health educators and/or online group workshops. The study will enroll eligible participants to the study continuously, until the total number of participants needed for the study is reached. Each participant will follow their own timeline, and attend visits at the study center at baseline, 3, 9 and 15 months. During 2 weeks before each visit, participants will wear a continuous glucose monitor (CGM) and record food intake for at least 3 consecutive days during this period. Measurements during visits will include anthropometric variables/body composition and energy expenditure, blood, saliva, urine and stool samples will be collected, and participants will be asked to fill out questionnaires on physical activity, sleep pattern, meal frequency, quality of life, problem areas in diabetes, eating efficacy and eating behaviors. They will also have a consultation with a registered dietitian and meet with the study medical doctor when needed. A blinded statistician will perform the statistical analyses for the primary outcome of the study.

Diabetes Mellitus, Type 2, Overweight and Obesity, Hypertension, Glucose Intolerance, Insulin Resistance, Dyslipidemia Associated With Type II Diabetes Mellitus

Low-carbohydrate high-fat diet, Energy restricted diet, Lifestyle change, Ketogenic diet, Total meal replacement

We will use an independent statistician who will analyse the data anonymously and be blinded to information regarding dietary arms.

A nutritional complete formula diet for 3 months followed by an energy restricted diet for 12 months.

A very low-carbohydrate high-fat ketogenic diet (VLCHF) diet for 3 months, followed by a low-carbohydrate high-fat diet (LCHF) for 12 months.

Very low-carbohydrate high-fat ketogenic diet (VLCHF) diet followed by a low-carbohydrate high-fat diet (LCHF)

Number of patients with diabetes remission, defined as no use of glucose-lowering drugs and HbA1c <48 mmol/mol (<6.5%) at 15 months

Number of patients with HbA1c <48 and <42 mmol/mol at 3, 9 and 15 months, both on and off anti-diabetes medication (metformin etc.)

HbA1c and fasting glucose concentrations (treatment targets in current clinical practice) measured in fasting blood samples

The HOMA2-calculator (https://www.dtu.ox.ac.uk/homacalculator/download.php) is used to estimate insulin resistance and beta cell function based on fasting glucose and C-peptide concentrations

The number of diabetes- and antihypertensive medications used/reintroduced by each study visit counted and compared between groups

Eating behaviour measured by the The Weight Efficacy Lifestyle Questionnaire - Short form (WEL-SF). The questionnaire contains 8 items on a 10-point response scale (ranging from not at all confident/very confident). Responses to each item are given a score between 0-10, summed together and transformed to percentages. Changes in these scores will be compared between the study groups for the respective time-points throughout the intervention.

Eating self-efficacy assessed by the Three-Factor Eating Questionnaire (TFEQ), which measures 3 aspects of eating behaviour: cognitive restraint, uncontrolled eating, and emotional eating. The questionnaire consists of 18 items on a 4-point response scale ( ranging from definitely true/mostly true/mostly false/definitely false). Responses to each item are given a score between 1 and 4 and and total scores are summed by the 3 measured aspects mentioned above. The raw scale scores are transformed to a 0-100 scale. Changes in these scores will be compared between the study groups for the respective time-points throughout the intervention.

Quality of life measured by the EQ-5D-5L questionnaire, which includes 5 dimensions: mobility, self-care, usual activities, pain /discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The levels are scored with a 1-digit number and the digits for the five dimensions are combined into a 5-digit number that describes the patient's health state. We will compare change at all timepoints between groups using both the 1-digit and the 5-digit number. The questionnaire includes the patient's self-rated health on a Visual analog scale (VAS) ranging from 0-100. The endpoints are labelled "The best health you can imagine" and "The worst health you can imagine". The scale will be transposed into percentages and the percent change will be compared between the study groups.

Polygenic risk scores are calculated based on the latest GWAS data for T2D, and rates of remission compared between patients with the top 20% high- and top 20% low scores, for all participants combined and the respective diets separately

Body fat measured by MRI (abdominal adipose tissue distribution, hepatic-, intramuscular-, pericardial- and pancreatic fat)

Alanine transaminase (ALT), C-reactive protein (CRP) and other markers of liver function measured in fasting blood samples

Circulating concentrations of selected markers of inflammation measured in fasting blood samples by ELISA

NORRISK calculated by the most current NORRISK calculator (https://hjerterisiko.helsedirektoratet.no/)

Changes in total-, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and very-low-density (VLDL) cholesterol concentrations from baseline

Lipoprotein particle numbers and sizes (small/medium/large LDL, IDL, HDL, VLDL) measured in fasting blood samples

Ghrelin and ketones measured in fasting blood samples, and correlations in the change of ghrelin and ketones (beta-hydroxybutyrate and acetoacetate) from baseline.

Inclusion Criteria: HbA1c ≥48 mmol/mol (with or without medical treatment) Less than 10 years since the diagnosis of T2D BMI ≥27 kg/m2 (≥25 kg/m2 for Asians) Exclusion Criteria: Treatment with insulin >25 IU HbA1c concentration of 12% or more (≥108 mmol/mol) Insulin to C-peptide ratio <0.8 (indicative of insulin deficiency) Myocardial infarction within the previous 6 months, and severe or unstable heart failure or other severe diseases including cancer, psychiatric/eating disorders, severe depression and substance abuse