A parallel arm randomised controlled trial to achieve remission in patients with type 2 diabetes mellitus through dietary and behavioural interventions: a study protocol

BACKGROUND (6a)

Non-communicable diseases (NCD) are the leading cause of death globally and disproportionately affect individuals in low- and middle-income countries, where they account for 80% of all deaths and 90% of premature deaths.³ In absolute terms, out of 56 million global deaths, 38 million (67.8%) are directly attributable to NCD [1].

According to the ICMR-INDIAB study the prevalence of diabetes in India is 7.3% with a wide regional and an urban-rural variation [2]. Given this context, the economic burden of managing NCD and their complications poses a substantial challenge for policymakers when allocating resources and funds for their diagnosis and treatment. The challenge is exacerbated by the need to prioritize funding for traditional public health concerns, such as communicable diseases and maternal and child health, which remain at the top of the agenda. This prioritization further strains the limited resources available [3][4].

The rationale for conducting the study

As life expectancy rises, India faces a dual health challenge: widespread communicable diseases alongside the growing burden of NCD compounded by an aging population and strained healthcare infrastructure [5]. Evidence suggests that lower socioeconomic groups are more prone to alcohol and tobacco use and insufficient consumption of fruits and vegetables, increasing their NCD risk [6].

Management of type 2 diabetes mellitus (T2DM) and other lifestyle diseases has relied on pharmacological interventions, like oral hypoglycaemic agents (OHAs) to achieve normoglycaemia [7]. Along with medication treatment lifestyle changes are integral components of achieving T2DM remission. Recent evidence such as from the DiRECT Trial, highlights the potential for T2DM remission through structured weight management programs [8][9]. However, these findings need to be validated in a number of diverse settings, particularly in low- and middle-income countries where data is limited to case reports [10]. The study evaluating the effects of dietary and behaviour interventions in achieving remission in patients with T2DM in low- and middle-income countries is acutely needed in order to develop a more efficient strategy for these patients.

The rationale behind choosing dietary and behaviour interventions to achieve remission in patients with T2DM (6b)

Lifestyle changes have a positive impact on managing T2DM. In a retrospective review the complete and partial remission rates in patients 6 years after bariatric surgery were found to be 24% and 26% respectively [11]. By contrast, another study showed that weight loss through calorie restriction can also induce remission of T2DM in a dose-dependent manner, with a 15kg reduction achieving remission in 80% of patients [12]. Moreover, weight loss is cost effective and could significantly reduce out-of-pocket expenses on medications and laboratory tests [13].

In low- and middle-income countries such as India, dietary and behavioural interventions are favoured for achieving remission in patients with T2DM due to their cost-effectiveness, feasibility, and accessibility. Regular physical activity plays a crucial role by enhancing glucose uptake by skeletal muscles, improving insulin sensitivity, and facilitating weight management. Our hypothesis is that a combination of diet and exercises, tailored to the patient’s lifestyle and activity level, will contribute to achieving T2DM remission. Our core focus is based on three outcomes: (1) aerobics exercises (brisk walking, jogging) to boost endurance; (2) yoga to improve flexibility [14]; (3) resistance exercises to enhance strength.

The rational for choosing a low carbohydrate diet (6b)

The ICMR (Indian Council of Medical Research) 2018 guidelines for patients with T2DM recommend consuming 55–60% of energy from carbohydrates, prioritizing complex over refined carbohydrates.⁴ This dietary approach aims to improve glycaemic control by regulating caloric intake, optimizing macronutrient distribution, and promoting fibre-rich foods. Based on ICMR-NIN (Indian Council of Medical Research National Institute of Nutrition) 2024 guidelines, patients will receive tailored diets focusing on balanced nutrition, with specific energy and macronutrient recommendations for individuals below and above 60 years.⁵

Traditional Indian diets, mainly rice- and wheat-based, should be reconsidered due to the rising burden of T2DM and other NCD in India [15]. Millets such as finger millet (ragi), pearl millet (bajra), and foxtail millet, have a low glycaemic index, leading to a gradual rise in blood glucose levels essential for T2DM management. Rich in fibre, protein, and essential nutrients like magnesium and iron, millets improve satiety, enhance insulin sensitivity, and support gut health [16][17], establishing their value in T2DM dietary strategies.⁶

The rationale for a 9-month follow-up period

A 9-month follow-up period was selected based on the study design. Weight loss through dietary interventions tends to be slower than achieved via bariatric surgery. Kim et al. showed that sustained lifestyle changes can lower glycated haemoglobin (HbA1c) within 6 months [18]. With regular monitoring and gradual tapering of OHAs based on glycaemic status, significant outcomes are expected within 9 months. This timeframe also balances clinical relevance with practicality, reducing dropout rates while preserving data quality and participant engagement.

Objectives (7)

Primary objective

To evaluate the effect of dietary and behavioural interventions in achieving remission in patients diagnosed with T2DM.

Secondary objectives

1. To assess patients’ acceptability of adopting dietary and behavioural interventions through in-depth interviews.
2. To evaluate the impact of dietary interventions on patients with T2DM having co-morbidity such as arterial hypertension.

Trial design (8)

The study is a parallel two-arm randomised control trial (allocation ratio 1:1). Patients will be randomised into an intervention arm (dietary and behavioural intervention) and a control arm receiving standard care (fig.). There will be five measurement timepoints: baseline, 2^nd, 4^th, 6^th and 9^th months post-randomisation.

METHODS

Study setting (9)

The 9-month community based randomised control trial will implement dietary and behavioural interventions for adults ≥18 years with T2DM in the Indira Colony Urban Enclave, the field practice area of the Department of Community Medicine and School of Public Health at Post Graduate Institute of Medical Education and Research Chandigarh [19], Northern India, with a population of 25,000 as per the census conducted in 2011.⁷ The sampling frame comprises T2DM cases from a 2018 house-to-house survey (unpublished). Considering changes in morbidity and mortality, investigators will update the database through a new house-to-house survey.

Inclusion criteria (10)

1. Confirmed diagnosis of T2DM per HEARTS-D module criteria.⁸
2. Age ≥18 years.
3. Patients providing informed consent (26a).
4. Patients with systolic blood pressure ≥140 mm Hg and / or diastolic blood pressure ≥90mm Hg as per 2016 primary hypertension guidelines by India’s Ministry of Health and Family Welfare.⁹

Exclusion criteria

1. Patients not providing informed consent.
2. Patients with type 1 diabetes mellitus.
3. Age < 18 years.
4. Patients with impaired fasting glucose and glucose tolerance.¹⁰
5. Insulin-treated patients.

Definition of remission

Diabetes remission is defined using specific HbA1c, fasting, and postprandial glucose thresholds maintained without OHAs. The American Diabetes Association classifies remission as complete, partial, or prolonged [20]. The Association of British Clinical Diabetologists and Primary Care Diabetes Society define remission as glycaemia below diagnostic thresholds for ≥6 months without glucose-lowering therapy [21]. This study adopts the American College of Lifestyle Medicine’s definition: HbA1c < 6.5% for at least 3 months without surgery, external devices, or active glucose-lowering medication [22].

Intervention (11a)

Intervention arm

Customised diet plan per Dietary Guidelines¹¹

Carbohydrate intake will be restricted to <50% of total calories, replaced with fibre-rich, non-starchy foods and green leafy vegetables, alongside increasing vegetable salads in the diet [23]. Millet will be incorporated flexibly into participants’ diets as porridge, chapati (Indian millet flat bread), or traditional Indian millet snacks. While millet will not fully replace other grains, it will be promoted as a healthier alternative, prioritized over refined grains like white rice and refined wheat. The intervention aims to shift dietary patterns toward millet-based options as a primary grain.

Physical activity plan

Physical activity recommendations are tailored to the patient’s fitness level, age, and any physical limitations.¹² Exercise plans will be customised according to patient’s age. For patients who undertake a moderate amount of activity, the regimen will aim to sustain their activity through aerobic exercises, resistance training, and yoga. For sedentary patients, a gradual initiation into physical activity will be encouraged, starting with light exercises such as walking. Progress will be closely monitored, and plans will be adjusted based on patient response. Daily activity charts will be provided to track time spent on physical exercises.

Standard medication

Patients will receive OHAs for the first six months of the trial. After this period, OHAs will be gradually tapered for patients with HbA1c levels below 6.5%. Patients weaned off OHAs will monitor blood glucose levels using finger-prick tests. If any patient struggles with the reduced dosage, their original medication regimen will be reinstated. The day a patient is completely weaned off OHAs marks the start of a three-month follow-up period. Patients showing symptoms of dysglycaemia will be reviewed and consulted with an endocrinologist to determine whether OHAs should be resumed.

The package of intervention in our study is summarised in Table.

Control arm

Patients in control arm will continue to receive OHAs as prescribed by their physician. No dietary and behavioural interventions will be made in the control arm.

Participant timeline (13)

At each timepoint, HbA1c, waist circumference, weight and body mass index will be measured.

Additionally for patients in the intervention group, investigators will conduct weekly visits to address challenges in adopting lifestyle changes, monitor diet adherence, review self-recorded capillary blood glucose diaries, and provide personalized support. A WhatsApp group will be created for participants in the intervention arm, where investigators will share motivational voice notes and video vlogs to encourage adherence.

Data collection will include a peer-reviewed, Delphi-validated questionnaire designed with input from subject experts to capture demographic profiles and dietary habits through a Food Frequency Questionnaire, assessing daily and weekly consumption patterns [25]. Additional tools include questions to identify barriers and facilitators of healthy dietary and physical activity transitions, the World Health Organisation STEPS (STEPwise approach to NCD risk factor surveillance) questionnaire for dietary and physical history,¹³ and the EuroQol EQ-5D-5L questionnaire for quality of life assessment [26].

Criteria for discontinuing the trial (11b)

Parents may withdraw from the trial at any time without prejudice or in case of frequent episodes of hypoglycaemia.

Strategies to improve adherence to the study protocol (11c)

Informative booklets and pamphlets with colourful info graphics will address local dietary habits, cultural beliefs, and misconceptions about T2DM, offering practical guidance on diet and exercise in simple, engaging language. Adherence cards will be provided to each patient in the intervention arm to help track physical activity, monitor dietary patterns, and make adjustments as needed.

To enhance compliance, investigators will conduct weekly visits to review adherence cards, providing constructive feedback to both patients and their family champions on gaps and strategies to achieve targets. This approach emphasizes open, two-way communication. The term family champion refers to a key family member who actively supports the participant during the study in adhering to dietary and behavioural interventions. This role is crucial in fostering accountability, motivation, and creating a supportive home environment, which is essential for sustainable lifestyle changes and effective T2DM management.

The selection of the family champion follows four key principles:

1. Emotional and practical support. The family champion provides encouragement, assists with meal planning, and supports daily routines, improving adherence to lifestyle changes.
2. Close relationship with the patient. Ideally a spouse, sibling, or adult child with a trusting bond, empathy, and open communication to provide reliable support.
3. Consistency and accountability. A consistent presence, the family champion helps maintain adherence by gently reminding patients of the importance of prescribed interventions.
4. Cultural and household dynamics. In Indian households where families play a central role in health decisions, the family champion leverages this cultural strength, embedding support within the broader family network.

The intervention includes focus group discussions to enhance social support by encouraging the sharing of challenges and successes, peer influence through positive behaviour, group norms to establish shared expectations, accountability via regular check-ins, shared goals by celebrating achievements, and collaborative problem-solving to address barriers effectively.

Sample Size (14)

The total recruitment target is 228 patients (114 per arm), calculated with a 95% confidence interval and 80% power. The sample size estimation was based on a study reporting remission rates of 57% in patients with T2DM following dietary intervention, compared to 31% in the control group [27]. Accounting for a 20% non-response rate, the adjusted sample size was calculated as 285. However, for simplicity, a sample size of 290 (145 per arm) was chosen. The calculation was performed using OpenEPI software, version 3, for a randomised control trial.

Recruitment of participants (15)

The first step involves baseline recruitment where investigators will visit households to enroll patients in the trial. To prevent contamination bias [28], only patients who provide informed consent will be recruited.

Allocation (16a) and concealment (16b) of participants will be managed through sealed envelopes, with a neutral third party assigning patients to each trial arm. The initial recruitment will include all 290 patients, followed by block randomisation in blocks of 4, 6 and 8 into either of the arm. Varying block sizes was shown to have several advantages over one single block including increased unpredictability of the allocation sequence, thereby reducing selection bias. This approach minimizes risks of manipulation or subversion of the allocation process, enhancing the trial’s integrity and robustness.

Outcome measures (12)

Primary outcome

The number of patients achieving remission of T2DM through behavioural and dietary interventions.

Secondary outcomes

1. The number of patients with hypertension as co-morbidity achieving normal blood pressure.
2. Assessment of acceptability and identification of barriers to adopting dietary interventions, particularly the inclusion of millets.

Data collection (18)

Demographic data, medication information, clinical symptoms, data on primary and secondary outcomes, laboratory tests (fasting and post prandial blood glucose, HbA1c), physical examinations (weight, body mass index, waist circumference), and validated questionnaires assessing dietary intake, quality of life will be collected at each timepoints. For promoting data quality outcome measurements will be taken by using pre-formulated standardized protocols. To minimize measurement error, duplicate measurements will be taken where applicable (e.g., blood pressure), and the average of the readings will be recorded.

Statistical methods (20)

Data analysis will be performed using IBM SPSS version 25 (released 2017, IBM Corp., USA).

Statistical methods for analysing primary and secondary outcomes (20a)

Univariate analysis will be conducted to compare the demographic data of patients in the intervention and control groups. McNemar’s test or paired t-tests will be performed for pre- and post-intervention comparisons in patients with arterial hypertension. A logistic regression model will be utilized to identify factors associated with blood pressure normalization. Kaplan-Meier survival analysis will be performed to estimate the proportion of patients achieving remission over time, with remission treated as a time-dependent variable at the 9^th month.

Methods for additional analyses (20b)

We will conduct focus group discussions and semi-structured interviews to explore patients’ perceptions of dietary changes, particularly concerning millet consumption. Content or thematic analysis will be used to identify common barriers, including cost, accessibility, taste, or unfamiliarity with millets.

Subgroup and adjusted analyses

A separate analysis of primary outcome and effect estimates will be performed for physical activity level, gender, age, and fruit and vegetable intake.

Confidentiality (27)

Data confidentiality will be ensured through de-identification and anonymization, with minimal use of identifiers. Prior to collecting any personal data, written informed consent will be obtained from participants. During this process, participants will be informed about the type of the data to be collected, its intended use, and the measures implemented to protect their privacy.

Declaration of interests (28)

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the trial.

Access to data (29)

The principal investigator will be custodian of the data. In the trial, access to the final dataset will be managed to ensure both data integrity and participant confidentiality.

DISCUSSION

Achieving remission in T2DM requires a comprehensive management plan alongside OHAs treatment. This includes the supervised and systematic de-prescription of existing antihyperglycaemic medications and the gradual introduction of lifestyle changes, such as a calorie-restricted diet supplemented with a millet-based component [29]. We propose that T2DM remission is an achievable clinical goal. Our study gains relevance from its alignment with the declaration of 2023 as the International Year of Millets, focusing on this “wonder grain”.¹⁵

However, challenges exist regarding the acceptance of millets among participants. These include an underdeveloped supply chain, limited availability in retail outlets, higher costs compared to rice and wheat [30], and societal perceptions that undervalue millets as an investment in future health [31]. Despite these barriers, we anticipate significant improvements in participants’ quality of life upon achieving remission. Benefits may include enhanced mental and physical health, fewer work-loss days, reduced hospitalizations, and potentially lower risks of complications associated with T2DM [32][33].

The novelty of this trial lies in its community-based approach, diverging from the typical clinical or hospital-based frameworks. By leveraging accessible and sustainable interventions, it empowers T2DM patients to pursue remission. The intervention integrates dietary and behavioural changes into the cultural, socioeconomic, and dietary contexts of the community, facilitating the adoption and long-term maintenance of lifestyle changes essential for remission.