Clinical trial NCT07017127: Remission of Type 2 Diabetes With Lifestyle Intervention
Official title: Remission of Type 2 Diabetes With Mediterranean Diet, Physical Activity and Psychological Support: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Diabetes Mellitus Type 2
Obese Diabetics
Keywords: diabetes remission
Mediterranean diet
physical activity
stress
weight loss
healthy lifestyle
Lead sponsor: University of Split, School of Medicine
Sponsor class: OTHER
Collaborators: name: Croatian Science Foundation
First posted: 2025-06-12
Enrollment: 120
Sex: ALL
Minimum age (years): 20
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to achieve diabetes type 2 (DM2) remission using intensive lifestyle intervention.

The main questions it aims to answer are:

* Does intensive lifestyle intervention (including Mediterranean diet with a caloric deficit, daily physical activity, increase in stress resilience and group support) lead to DM2 remission (HbA1c\<6.5%, without medications)
* Can intensive lifestyle intervention (including Mediterranean diet with a caloric deficit, daily physical activity, increase in stress resilience and group support) result to weight loss of \>15 kg
* Does intensive lifestyle intervention result in any side effects (secondary outcome)

Researchers will compare intensive lifestyle intervention to the usual clinical care (control group).

Participants in the experimental group will:

* eat Mediterranean diet with a caloric deficit
* perform daily physical activity
* increase their stress resilience with psychosocial support of the group
* enroll weekly in individual and group counseling and workshops for 6 months, following with 1.5 years of follow-up

Detailed description: Type 2 diabetes (diabetes mellitus type 2, DM2) is a leading clinical and public health problem, with a global prevalence that is rapidly increasing and reaching pandemic proportions. According to the International Diabetes Federation (IDF), 537 million adults between the ages of 20 and 79 in the world have type 2 diabetes (DM2), and it is predicted that this number will increase to 643 million by 2030 and 783 million by 2045. According to the data of the National Register of Persons with DM2 (CroDiab) 337,774 persons with DM2 type 2 were registered in Croatia in 2022.

DM2 increases the risk for cardiovascular diseases, blindness, kidney failure and amputation of the lower limbs, thereby significantly affecting the quality of life of the patients. Additionally, it is well known that people with DM2 often have obstructive sleep apnea (OSA). Therefore, active screening for an OSA diagnosis and its treatment in patients with DM2 is extremely important for the prognosis and successful treatment of DM2, especially since it has been shown that CPAP treatment, along with body weight reduction, is associated with a reduction in HbA1c in morbidly obese patients with severe OSA.

The increased prevalence of DM2 is inextricably linked to the change in lifestyle and the transition to a "western" lifestyle, which implies an abundance of energy-rich foods and reduced physical activity, with a subsequent increase in obesity. Looking at individual components of the diet, it has been shown that sweetened beverages, refined grains and processed meat increase the risk of developing DM2. On the other hand, green leafy vegetables, dairy products, whole grains, nuts, legumes, moderate amounts of alcohol and coffee are associated with a reduction in this risk. Considering not only the individual nutrients in the diet but the entire nutrition pattern, the Mediterranean diet stands out with its numerous protective effects on the health of the organism. Epidemiological and interventional studies have shown the protective effect of the Mediterranean diet in chronic inflammation, insulin resistance, and metabolic syndrome. The Mediterranean diet is best known for its protective cardiovascular effect, which has been shown in a number of studies, meta-analyses and systematic reviews. Among other things, this type of diet supports healthy aging (reaching the age of 70 and over without chronic diseases, such as DM2, kidney disease, respiratory diseases, cancer or Parkinson's disease, and without significant decline in mental and cognitive function).

Losing excess body weight is a key factor in achieving remission of DM2, therefore it is important to look at the evidence of how different dietary patterns can promote weight loss. Comparing low-carbohydrate, low-fat, and Mediterranean diet showed that both the Mediterranean diet and the low-carbohydrate diet were superior in achieving weight loss compared to the low-fat diet. Moreover, these two dietary patterns also showed significant metabolic benefits, such as reduced CRP, reduced fasting glucose and increased insulin sensitivity. In the PREDIMED study, it was shown that a Mediterranean diet supplemented with nuts or extra virgin olive oil reduces the risk of death from stroke by 30%. In addition, there was a significant reduction in the incidence of DM2 in subjects on the Mediterranean diet, independent of weight loss or the subjects' physical activity. Hence, besides weight loss, the quality of nutrition is a valuable factor in the prevention of DM2. The Mediterranean diet is based primarily on unprocessed food of plant origin (vegetables, fruits, legumes, whole grains, nuts). Moderate consumption of fish, seafood and dairy products is encouraged, as well as avoiding red and processed meat. The main source of fat in the Mediterranean diet is extra virgin olive oil. Apart from water as the main drink, wine can be enjoyed in moderation with a meal.

DM2 is considered to be an incurable, chronic and progressive disease. However, several studies recently showed that it is possible to achieve a remission of the disease. It is considered that the remission of DM2 has been achieved if Hba1c is less than 6.5%, without the use of blood glucose-lowering drugs for at least 3 months. Body weight control is the most important aspect of DM2 treatment, with weight reduction leading to reduced morbidity and mortality in these patients. The results of several studies have shown that weight loss of at least 10-15 kg leads to normalization of blood glucose levels in people who were relatively recently diagnosed with DM2. The DIRECT study showed that an intensive and structured weight management program delivered in primary care can result in significant weight loss and diabetes remission among adults with newly diagnosed diabetes. Remission of DM2 was achieved in 46% of subjects who lost an average of 10 kg, after one year. After two years, 36% of subjects were still in remission, with an average of 8 kg lost.

Another study achieved excellent DM2 remission results using dietary modification. The Diabetes Intervention Accentuating Diet and Enhancing Metabolism (DIADEM-I) study followed the effect of a 12-month intensive lifestyle intervention, which consisted of complete meal replacement, in subjects who were younger than 50 years and had been diagnosed with DM2 in the previous 3 years. DM2 remission was achieved in 61% of subjects who lost 15% of their initial weight.

Procedures:

Two groups of subjects will be included in the study: an experimental group and a control group, using the same criteria for the inclusion and exclusion.

Experimental group: the intervention will consist of the following elements:

1. Mediterranean diet - personalized nutritional recommendation based on the modern pyramid of the Mediterranean diet, additionally adjusted based on the current nutritional status of the subjects (tested through anthropometric and body composition parameters), and considering the level of physical activity during free time and professional requirements
2. Physical activity - emphasis on reducing sedentary behavior and including a daily regime of aerobic exercises, and exercises for muscle strength and endurance 2 times a week
3. Psychological support and intervention - group and individual counselling of subjects on effective ways of coping with stress
4. Positive and supportive interpersonal relationships - implementation of the intervention in small groups, which will be formed primarily as support groups (12 subjects per group) - weekly meetings, counselling and workshops, group exercise (walking), during which education and counselling on nutrition, physical activity and psychological determinants of health will take place.

Detailed description of the intervention, consisting of changes in lifestyle habits in four domains:

The nutritional intervention will consist of the exclusion of highly processed food products and beverages containing free simple sugars, along with the introduction of a diet according to the modern pyramid of the Mediterranean diet. In addition, subjects will be recommended to reduce (and when possible, to exclude) the use of plastic drinking containers, plastic containers for food preparation and storage, in order to reduce exposure to endocrine disruptors. For each subject, the nutritionist will create a personalized nutritional recommendation, with a moderate reduction in caloric intake, in order to ensure a gradual loss of body weight. The required level of caloric reduction will be quantified by calculating the basal metabolism and ideal body mass of each subject of the experimental group (based on anthropometric measurement and determination of body composition), and the whole day's energy consumption will be determined, considering the physical activity of the person and energy necessary for digestion and assimilation of nutrients. The goal of this part of the intervention is to achieve a weight loss of at least 0.5 kg every week, or approximately 2 kg per month, which will be achieved by reducing caloric intake by 300-500 kcal. Personal preferences of the subjects towards certain foods will be considered, all in accordance with the Mediterranean diet pyramid. The nutritionist will create sample menus throughout the day, for 30 days, to make it easier for subjects to follow this part of the intervention. In addition, each subject of the experimental group will receive a total of six liters of extra virgin olive oil (one liter per month, during the six months of the intervention), considering that olive oil is an indispensable element of the Mediterranean diet, in order to avoid financial burden on the subjects. Investigators expect this will increase the subjects' compliance.

Physical activity intervention: Participants will be involved in aerobic activities expertly guided by kinesiologist (Nordic walking) every day for 45-60 minutes, spent in nature or indoors in case of unfavorable weather. Along with Nordic walking, participants will be involved in organized muscle strength and endurance exercises twice a week for 60 minutes with the use of external loads (elastic bands, small weights), and mobility, balance and coordination will also be developed. All training programs will be conducted by trained kinesiologists who will instruct, monitor and correct participants in order to perform the exercises correctly and get the maximum effect on the targeted motor skills. Nordic walking, resistance exercise, and a combination of aerobic activity and resistance exercise have been shown to be effective in improving cardiometabolic parameters, physical fitness, and quality of life in people with DM2.

Psychological intervention will consist of support groups, where of mental health topics and encouraging change through the adoption of healthy lifestyle habits will be discussed. In addition to the psycho-educational component, participants in the stimulating group environment will have the opportunity to share personal experiences, motivation and become aware of emotions and resistance, which is crucial in achieving and maintaining change. The specific topics of individual group meetings will be: stress and stress management, relaxation techniques (breathing techniques, autogenic training, progressive muscle relaxation techniques and guided fantasies), emotion management (recognition of negative beliefs and thought patterns, awareness and management of emotional reactions), interpersonal skills in the function of self-care (awareness and communication of one's own needs through assertive communication techniques), self-care through the adoption of healthy habits (motivation, adoption of habits and planning), conscious eating and the alike. Each subject will create for himself a list of SMART goals that she/he wants to achieve during his participation in the project (Specific, Measurable, Achievable, Relevant, and Time-Bound).

Positive and supportive interpersonal relationships can result in more sustainable effects on behaviors change in patients with chronic non-communicable diseases, and are an important component of chronic disease self-management, and can be an effective resource in patients trying to lose excess weight.

Control group: subjects of the control group will receive a short brochure that will be created for the purposes of this project on the importance of healthy lifestyle habits in people diagnosed with DM2, as well as advice and recommendations from a specialist for practicing healthy eating and physical activity. Furthermore, the subjects of the control group will receive regular clinical care within the framework of the health care system. At the same time intervals as the subjects of the experimental group, these subjects will be invited for a clinical examination, carrying out all measurements and tests, filling out questionnaires and providing biological samples (fasting blood and urine).

Eligibility criteria: Inclusion Criteria:

* type 2 diabetes diagnosis
* incident cases or diagnosed not more than 7 years ago
* body mass index of 27-45 kg/m²

Exclusion Criteria:

* mobility restriction
* use of mobility aids
* insulin therapy
* HbA1c \>12%
* TSH \>10 mU/L
* heart failure (NYHA III, NYHA IV)
* use of obesity pharmacotherapy (orlistat, GLP-1 receptor agonists, GLP-1/GIP dual agonists) for less than 6 months
* weight loss greater than 5 kg in the last 6 months
* chronic kidney disease and estimated glomerular filtration rate \<30 ml/min/1.73 m2
* active treatment of proliferative diabetic retinopathy with anti-VEGF
* heart attack or stroke in the past 1 year
* active malignant disease diagnosed in the past 1 year
* eating disorders
* pregnancy or pregnancy planning
* substance abuse
* learning disabilities
* acute episode of severe depression
* current use of antipsychotics
* food allergy

Primary outcomes:
measure: Remission of diabetes mellitus type 2
timeFrame: 24 months
Secondary outcomes:
measure: Weight loss
timeFrame: 24 months
measure: Adverse events
timeFrame: 24 months
Other outcomes:
measure: Additional benefits
timeFrame: 24 months
measure: Additional benefits
timeFrame: 24 months
Locations:
city: Split
country: Croatia
facility: University of Split School of Medicine
Study officials:
affiliation: University of Split, School of Medicine
name: Ivana Kolčić, Prof, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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