A Feasibility Study of Optimal Non-Pharmacological Lifestyle Modifications in People With Type 2 Diabetes

A Feasibility Study of Optimal Non-Pharmacological Lifestyle Modifications in People With Type 2 Diabetes (ON LiMiT)

The overall aim of this study is to examine the feasibility of a 12-month, two-arm lifestyle intervention to induce and maintain remission of type 2 diabetes (T2D). The findings from the feasibility study will inform the recruitment, design and delivery of the interventions in a 5-arm, 24-month randomised controlled trial.

Studies on T2D remission have reported varying rates of remission, often around 50% in intervention groups. These studies typically involve individuals with a recent T2D diagnosis, usually within six to ten years of diagnosis, with intervention periods most commonly lasting between twelve and twenty-four months, though durations have ranged from six to sixty months. Lifestyle interventions combining dietary changes and increased physical activity generally yield modest remission rates, but maintaining adherence over time remains challenging. Trials that include an initial phase of a very low-calorie diet, followed by ongoing structured support, tend to report higher remission rates. This emphasizes the critical role of significant and sustained weight loss. However, the most effective combination of dietary, exercise, and behavioral support strategies remains to be determined.

In addition to calorie restriction, changes in dietary composition may influence the underlying mechanisms of T2D. For instance, reducing carbohydrate intake can promote ketone production, affecting liver glucose production and improving glycemic control. Higher protein intake has been linked to an improved insulin response. Replacing saturated fats with polyunsaturated fats and increasing dietary fiber may also support glucose metabolism. However, it remains unclear whether carbohydrate-reduced or carbohydrate-rich diets are more effective in supporting long-term remission following initial weight loss.

Physical activity, particularly high-intensity exercise, plays a key role in reducing the risk of T2D, supporting weight management, and improving remission rates when combined with dietary interventions. Significant improvements in blood glucose control are usually seen with regular moderate-to-high-intensity exercise.

Moreover, there is considerable variation-or sometimes an absence-in the inclusion of key lifestyle intervention components, such as specific dietary and exercise protocols, as well as levels of supportive activities. This inconsistency complicates effective care provision for healthcare professionals and makes it difficult for individuals with T2D to adhere to non-pharmacological management recommendations.

Despite the known benefits of lifestyle modifications, initiating and maintaining these changes is challenging due to barriers such as a lack of support, motivation, and knowledge about nutrition and portion sizes. Involving individuals with T2D in designing and evaluating interventions may improve adherence, reduce participant burden, and increase the feasibility and scalability of lifestyle programs for wider implementation.

The overall aim of this study is to examine the feasibility of a 12-month, two-arm intervention designed to induce and maintain remission of T2D. After baseline measurements, participants will be randomized to one of two groups: Group A: Very-low-calorie-diet (VLCD)/weight loss followed by a carbohydrate-reduced (CH-reduced) diet combined with high-intensity exercise. Group B: VLCD/weight loss followed by a carbohydrate-rich (CH-rich) diet combined with high-intensity exercise. Participants and study staff will be blinded to the intervention arm during the VLCD phase.

To determine the optimal macronutrient composition of the Mixed Meal Tolerance Test (MMTT) for subsequent testing, participants will undergo three different MMTTs consisting of 550 kcal in random order at baseline; a low-carbohydrate meal (27/30/43 energy percentage (E%) from carbohydrate/protein/fat), an intermediate-carbohydrate meal (40/23/37 E%), and a high-carbohydrate meal (53/17/30 E%). Postprandial responses to the intermediate-carbohydrate meal will be evaluated against those to the low- and high-carbohydrate meal in terms of glucose, insulin, C-peptide, free fatty acids, and triglycerides during 240 minutes. If the responses are deemed sufficiently favorable, the intermediate-carbohydrate meal will be selected for MMTTs conducted at weeks 12, 18, and 52.

Feasibility will be evaluated based on the recruitment process, intervention acceptability, and participant adherence. This includes assessing whether the intervention components and outcome measurements are delivered and conducted as intended. Additionally, the study will examine how these elements perform in a real-life setting among individuals with T2D. Findings from this feasibility study will inform recruitment strategies, study design, and implementation of a subsequent five-arm, 24-month randomized controlled trial.

Specific aims:

1. To study the recruitment process (including recruitment of general practitioners and participants) and identify related barriers and facilitators.
2. To investigate retention, adherence, and acceptability of the interventions (carbohydrate-reduced or carbohydrate-rich diet combined with high-intensity exercise), including participant experiences with the intervention components and data collection procedures.
3. To assess whether the intervention is delivered as intended, covering supervised/unsupervised sessions, study visits, online support, and group education.
4. To evaluate the effectiveness of safety procedures in responding to changes in participants' glycemic control, blood pressure, physical injuries, and related risk markers.
5. To determine the optimal macronutrient composition and sampling schedule for the Mixed Meal Tolerance Test (MMTT).
6. To explore the potential impact of the two interventions on T2D remission rates and related metabolic outcomes such as body weight, body composition, blood pressure, vascular function, glycemic control, lipid profile, beta-cell function, and inflammation.

Building on previous findings from T2D remission studies involving VLCD interventions, the study include individuals with recently diagnosed T2D who are overweight or obese and not receiving insulin therapy. This subgroup has demonstrated the greatest benefit from significant weight loss. Participants using GLP-1 receptor agonists (GLP-1 RAs) are eligible, provided their weight has been stable for at least three months prior to inclusion. Individuals on insulin therapy will be excluded. Allowing GLP-1 RA use enhances the study's generalizability, as approximately 29% of people with T2D in Denmark are currently treated with these medications.

Inclusion Criteria:

• Diagnosis of T2D. Treatment lifestyle changes, oral anti-diabetic medication including metformin, and/or sulfonylureas and/or DPP-4 inhibitors and/or SGLT2 inhibitors and/or incretin-based medication
• HbA1c between 36-86 mmol/mol
• T2D duration of ≤6 years
• BMI ≥27 kg/m2
• Body weight changes over 3 months ≤3 kg

Exclusion Criteria:

• Insulin treatment within 6 months prior to screening (any type)
• Heart failure (ejection fraction ≤40%) and treated with SGLT-2i (current or planned)
• Cardiovascular disease, including previous heart attack or stroke, for which incretin-based therapy and/or an SGLT-2i has been prescribed.
• Kidney disease (eGFR <60 ml/min/1,73m² and/or albuminuria (≥30 mg/g) for at least three months) and treated with SGLT-2i (current or planned)
• Physical comorbidity, which precludes the physical activity during intervention
• Dietary restrictions or allergies making the participant unable to adhere to the dietary interventions
• Unable to comply with trial procedures and/or interventions
• Alcohol/drug abuse
• Planned or present pregnancy/fertility treatment, or lack of contraception during reproductive age
• Unstable psychiatric disease that is deemed to impede participation in the project
• Diagnosed with binge eating disorder
• Participation (present or planned) in other clinical trials including lifestyle or pharmacy trials for any condition
• If HbA1c ≥60 mmol/mol and the participant is on 2 or more anti-diabetic drugs and has a positive GAD65 and/or stimulated C-peptide <800 pM