Remission of Diabetes With Lifestyle Intervention for Malaysian Patients

Malaysia is facing an epidemic of diabetes and despite public health efforts to increase awareness, screening and prevention, there is a continued rise in the prevalence of diabetes and its complications. A lifestyle approach for diabetes remission may be a solution to curb further rise in diabetes complications and be cost-effective.

Little is known about the transferability of diabetes remission lifestyle intervention into Malaysian primary care settings. This knowledge is important to understand whether DiRECT is feasible, actionable and acceptable to patients, clinicians and primary care settings given the original trial was developed overseas. Furthermore, local data on the economic burden of diabetes and the potential savings from remission are urgently needed to support evidence-based policymaking. This study will therefore include an economic evaluation using a cost-of-illness approach with a prevalence-based model, incorporating both direct and indirect costs from the societal perspective. In addition, the results from this proposed study will be important to see how we can increase acceptability of this approach in Malaysia and curb a disabling disease that is rapidly rising in Malaysia.

This study is a randomised, wait-list-controlled, dual-phase trial designed to evaluate the efficacy and cost-effectiveness of a structured lifestyle intervention for inducing remission of Type 2 Diabetes Mellitus (T2DM) in Malaysian adults. The protocol integrates a rigorous clinical trial framework with a comprehensive economic evaluation from a societal perspective.

The trial employs a randomised wait-list-controlled design, comprising two distinct phases:

• Randomised Controlled Trial (RCT) Phase: Eligible participants are randomised in a 1:1 ratio, using a computer-generated sequence via an online software (Sealed Envelope), to either the immediate intervention group or a wait-list control group. The structured intervention is undergo 12 weeks of total diet replacement course, followed by food reintroduction (12 weeks). The wait-list group will receive standard of care for the primary endpoint assessment at 24 weeks.
• Observational Follow-up Phase: Following the RCT phase, the intervention group enters a weight maintenance period. The wait-list control group crosses over to receive the identical structured intervention for 24 weeks. This phase provides longitudinal data on weight maintenance and diabetes remission sustainability in an enlarged cohort for up to 12 months.

Definition of three sequential phases are:

Total Diet Replacement (TDR) Phase (8-12 weeks) aims to rapid weight loss, targeting a 15% reduction from baseline body weight. This is achieved through a hypocaloric regimen of approximately 800-850 kcal per day. Support during this phase includes two face-to-face appointments in the first month, followed by monthly face-to-face/virtual contacts and bi-weekly phone calls with a study dietitian.

Food Reintroduction Phase (12-16 weeks) facilitates a structured transition from TDR to a solid-food-based diet for weight maintenance. Using a stepped protocol, the DSF is gradually replaced over several weeks with low-calorie, low-glycaemic index meals, increasing total daily energy intake from 1000 kcal to 1400 kcal. Participants are subsequently advised to titrate their intake by 200 kcal increments until a stable weight is achieved. Dietary counseling utilising motivational interviewing techniques is introduced to reinforce behavioural changes. Support includes two face-to-face appointments in the first month, followed by monthly face-to-face/virtual contacts and bi-weekly phone calls.

Weight Maintenance Phase (24 weeks) The focus shifts to sustaining lifestyle changes and preventing weight regain. Participants follow a healthy diet plan (1200-1500 kcal/day) and are offered one DSF serving daily as a dietary component. Physical activity of at least 150 minutes per week is recommended. Support is maintained through six face-to-face or virtual contacts with the dietitian.

Integrated Medical Management and Relapse Protocol will be chaired by certified Medical Officers. A critical and technically detailed component of the protocol is the systematic management of concomitant medications and weight regain. The medical is responsible and cover the below aspect.

• Medication Withdrawal: Upon TDR initiation, all oral hypoglycaemic agents (OHA), antihypertensives, and diuretics are withdrawn to mitigate risks of hypoglycaemia and hypotension, with reinstatement protocols based on strict systolic blood pressure (BP) and glycaemic thresholds.
• Hypertension Management: Antihypertensives are reintroduced in a defined sequence (ACE inhibitors → ARBs → Thiazides → etc.) if systolic BP exceeds 165 mmHg in the first two weeks, or >140 mmHg thereafter, with weekly dose titrations.
• Glycaemic Management Protocol: If troublesome hyperglycaemic symptoms or random capillary glucose >20 mmol/L persist after two weeks of TDR, glucose-lowering medications are reintroduced in a stepped manner
• Relapse Management: A "rescue plan" is activated for participant have trouble to reduce weight and blood glucose. Nevertheless, biomarkers rebound to a unsafe level. Medical team might consider revert the participants back to standard of care and reintroduction medications for controlling diabetes.

monitored via 3-day food records and daily DSF consumption logs, with compliance calculated as a percentage of actual versus expected intake.

A nested qualitative study uses semi-structured, theory-domain interviews to explore barriers and facilitators to diabetes remission. Patients are interviewed at four timepoints (Baseline, 12 weeks, 6 months, and 12 months). Additionally, a purposive sample of 10-15 healthcare professionals involved in intervention delivery will be interviewed to assess implementation barriers and facilitators.

Participants are closely monitored for Adverse Events (AEs). Blood pressure, postural symptoms, and capillary blood glucose will be All AEs are recorded and reported, with Serious AEs reported to the Ethics Committee within 48 hours. A clinical trial insurance will be secured for all participants.

Inclusion criteria

• Diagnosed diabetes for a duration of < 3 years (diagnosis based on 2 recorded diagnostic-level tests, HbA1C and/or blood glucose)
• Body mass index (BMI) > 25 kg/m2
• HbA1C level above > 6.5% to 9% as per the last routine clinical check within 6 months
• Currently being treated with one or more oral glucose lowering drugs

Exclusion criteria

• Type 1 DM
• Type 2 DM on basal or multiple insulin injections
• Recent routine HbA1C of > 9%
• Patients who in the past 6 months have weight loss exceeding 5 kg (such individuals may have difficulty losing additional weight)
• Recent (last 12 weeks) or current use of medications/meal replacements for weight loss
• Alcoholism or any substance abuse
• History of bariatric surgery, small bowel resection, or extensive bowel resection
• Chronic treatment with systemic corticosteroids. Use of hormone replacement therapy or oral contraceptives will not lead to exclusion
• Severe hypertension on multiple drugs treatment
• Currently pregnant or nursing and planning to get pregnant
• Requiring hospitalization for depression or are on antipsychotic medications
• Cancer requiring treatment for the past 5 years, except of non-melanoma skin cancers or cancers that have been clearly cured
• HIV- positive (self-report) due to effects or weight and body composition of HIV and medications treating HIV
• Cardiovascular disease (heart attack or procedure within past 3 months or participation in cardiac rehabilitation program within last 3 months, stroke or history/ treatment for transient ischemic attacks in the past 3 months, or documented history of pulmonary embolus for the past 6 months)
• Renal disease - eGFR < 60 ml/min (based MDRD) or currently receiving dialysis
• Proliferative retinopathy and other severe diabetes complications
• Diagnosed eating disorder or purging