Remission Evaluation of Metabolic Interventions in Type 2 Diabetes in Primary Care (REMIT-Prime)

Type 2 diabetes (T2D) is a major health problem in Canada, affecting 11 million Canadians. Individuals with diabetes have a greater risk of developing blindness or being hospitalized with cardiovascular disease, end-stage renal disease, and lower limb amputations compared to the general population. Currently, T2D management involves lifestyle modification and glucose-lowering medications in response to rising glucose levels and failing therapeutic regimens. This approach leads to frequent self-blood glucose monitoring (SBGM), clinical appointments, and chronic polypharmacy, all of which are associated with increased risk of adverse effects, non-adherence to medications, and poor quality of life.

Evidence that T2D can be completely or partially reversed is now challenging the traditional approach to its management. Strategies combining dietary interventions, intensive metabolic and pharmacotherapy strategies, or bariatric surgery have been shown to induce diabetes remission. However, extremely low-calorie diets or bariatric surgery is not acceptable to many patients and not scalable for primary care, where diabetes care is primarily delivered.

Over the past 7 years, our investigators of Canadian multidisciplinary health care providers, patient partners, physicians, and researchers have identified and tested non-surgical remission-inducing therapeutic regimens in people with T2D. The Remission Evaluation of Medical Interventions in T2D (REMIT) program comprises 1 pilot study, 3 completed pan-Canadian multicentre (8 sites) trials, and one ongoing trial. For all the trials, the paradigm tested was one of a 3 to 4-month remission-induction period, followed by a 1-year follow-up period to detect relapse. All 5 trials tested the efficacy of an induction period during which normoglycemia was targeted to reduce glucotoxicity with frequent health coaching (focused on self-efficacy, weight reduction, and physical activity), metformin and basal insulin. These trials also included additional metabolic therapy with either: a) dapagliflozin (SGLT2 inhibitor); b) sitagliptin (DPP-4 inhibitor); c) lixisenatide (GLP-1 receptor agonist); or d) liraglutide. In all 5 trials, glucose-lowering drugs were stopped after 3-4 months. Participants with a glycated hemoglobin (A1C) \<7.3% were classified as being in possible remission and followed for relapse. Following the pilot study, all 3 completed trials observed a lower hazard of relapse in the intervention group with hazard ratios of 0.60 (95% CI 0.39, 0.95) for the sitagliptin trial, 0.57 (95% CI 0.39, 0.81) for the dapagliflozin trial 0.57 (95% CI 0.40, 0.81) for the lixisenatide trial.

The findings from the previous trials suggest that a short-term intensive intervention with passive follow-up is a viable alternative to achieving remission. Research is needed to test the implementation of an intensive short-term remission approach in real-world settings such as primary care. Therefore, the REMIT-Prime study will use an implementation-effectiveness evaluation approach to assess the REMIT short-term metabolic intervention on the real-world effectiveness and understand implementation barriers and facilitators in primary care settings. This proposed study seeks to simultaneously test the clinical effectiveness and an implementation strategy in one partnering site (Escarpment Health Centre, in Hamilton, Ontario \[EHC\]), to inform additional implementation sites. Ultimately, the program of REMIT-Prime will inform the future scale, spread and sustainability of the REMIT intervention in primary care.

1.2 What are the principal questions to be addressed?

1.2.1 Primary Research Question: Among patients in primary care settings with T2D diagnosed within the past 5 years, does a 16-week multimodal intensive metabolic program (health coaching for lifestyle changes plus basal insulin, metformin and either an SGLT2 inhibitor, DPP4 inhibitor, or GLP1 receptor agonist titrated to a dose that rapidly achieves normoglycemia) reduce the hazard of diabetes relapse (A1C ≥6.5%) up to 1 year after all drugs are stopped?

1.2.2 Secondary Research Questions: a) Does the REMIT program improve the proportion of patients at 28, 40, 52 and 68 weeks who: i) have relapsed; and ii) achieve and maintain 5% total body weight loss? b) Does the REMIT program improve health-related quality of life (HRQoL), as measured by the European Quality of Life 5 Dimension Scale and Visual Analogue Scale (EQ-5D) at 16, 40 and 68 weeks? and c) Does the effectiveness of the REMIT program depend on baseline participants' demographic variables such as age, sex, gender, ethnicity, diabetes duration or baseline diabetes medications use?

2.0 DESCRIPTION OF POPULATION

2.1 What are the inclusion and exclusion criteria? 2.1.1 Inclusion Criteria: Adults aged 30-80 years with: a) T2D diagnosed ≤ 5 years; b) stable T2D drug regimen in the 8 weeks before consent; c) A1C 6.5-9.5% on no glucose-lowering drugs or 6.5-8.0% on 1-2 glucose-lowering drugs or 6.5-7.5% on basal insulin; d) BMI ≥ 23 kg/m2; e) ability to perform SBMG; f) access to a telephone; and g) ability to read, write, and provide informed consent in English.

2.1.2 Exclusion Criteria: Individuals will be excluded if: a) coaching may not be appropriate (e.g., impaired cognition); b) pregnant (or planning pregnancy) at the time of recruitment; c) cohabiting with a participant in the study (to reduce contamination); c) have an underlying medical condition that may limit one's participation in the study (e.g. history of cardiovascular disease, injury, or contraindication to any study medication (e.g. metformin)); (d) history of bariatric surgery, or planned bariatric surgery in the next 1.5 years; (e) history of any major illness with a life expectancy of \< 3 years; (f) history of injury or any other condition that significantly limits participant's ability to achieve moderate levels of physical activity; (g) excessive alcohol intake, acute or chronic; or (h) inability to take the study medications.

Because the safety of the study drugs for a newborn is unknown, participants who intend to become pregnant, are pregnant or are breastfeeding, cannot participate in this study. They must agree to use a reliable form of birth control (either the birth control pill \[14 days prior\], hormonal injections or implants, an intrauterine device \[30 days prior\], or a combination of spermicide and condoms) to prevent any pregnancy during the study. Women of childbearing age will be counselled about the possibility of becoming pregnant on these drugs and urine pregnancy tests will be offered at baseline (which is also the final screening visit) and week 12 of the intervention (while on medications). Beyond these timepoints, the participants are not on these medications. If the baseline visit is more than three months from the time the participant starts the trial, then a repeat pregnancy test will be offered. If they become pregnant despite these precautions, they must notify the study team immediately.

2.2 What is the proposed trial sample size and justification for it? The sample size calculation is based on the estimated proportion of patients achieving diabetes remission of 12% in the control group. Assuming \~ 80% follow-up, a total sample size of 118 participants from the primary care site will provide 80% power to show an absolute risk difference of ≥20% (i.e. 68% versus 88%) in diabetes relapse between treatment groups and 90% power to show an absolute risk difference of ≥25%.

3.0 THE PROPOSED STUDY AND OUTCOMES

3.1 What is the proposed study design? The investigators propose an implementation-effectiveness (hybrid type 2) study, where the aim is to simultaneously evaluate the REMIT program in a primary care setting and to understand the context for implementation. This design blends effectiveness and implementation goals (adoption and fidelity) to provide a more rapid translation and valid estimate of real-world effectiveness. The effectiveness component will be a single-site, single-arm study of the effect of the REMIT program on rates of diabetes relapse. The implementation component (embedded within the study) will explore the mechanisms by which the program is delivered (context) and identify potential implementation barriers and facilitators (from the participant and provider perspective) and inform an implementation strategy for additional primary care sites. The implementation component has commenced and is being led by a graduate trainee (Hamilton's Integrated Research Ethics Board - #17376).

Figure 1: REMIT-Prime Study Design

3.2 What is the planned trial intervention, including screening and consent? Pre-screening: All primary care doctors at EHC are aware of the study and have engaged in previous presentations or discussions with the study researchers and health coach to discuss the study and the T2D Remission program. Brochures and posters will be available in the health care provider's offices and the waiting area. Therefore, patients may self-refer, or they can be referred by their primary care provider, by communicating with the health coach.

Screening and Consent: At the initial appointment with the health coach, they will review the study information package and ask if they have any questions. Written consent will be obtained, and confirmation of study eligibility will be determined by the health coach. Consent is sought first to obtain consent to access the electronic medical record (EMR); for example, laboratory confirmation related to A1C value and timing of the latest blood work. Following confirmation of eligibility, study participants will complete all baseline assessments, including demographic questionnaire, quality of life, BMI (height and weight) and A1C.

Eligible participants will either receive the T2D remission program immediately or at the next available appointment (e.g., waitlisted) based on health coach availability. The waitlist group will receive usual care and diabetes educational resources related to healthy eating and increasing physical activity, mimicking real-world waitlist scenarios, while they wait for the program. If participants are waiting for more than 3 months, a recent A1C will be collected and used as a comparator group. The T2D remission program / REMIT program is a 16-week intensive metabolic intervention comprising: i) health coaching to promote behaviour change for diet (caloric reduction of 600 kcal/day) and physical activity (increase intensity for 30 minutes per day); and ii) combination pharmacotherapy aiming for a fasting capillary glucose of 4-5.3 mmol/l. As the intensity of care is a key feature of the REMIT program, those who have started the program will have more frequent interactions during the first 16 weeks than the waitlist care group.

T2D Remission Program:

The Induction Phase - Weeks 1 to 16: Participants who have started the program will have twice-weekly visits (telephone or in-person) for the first 6 weeks and visits every week for the last 10 weeks. At every interaction, a health coach (registered dietitian and certified diabetes educator) will help participants (with the support of a personal workbook that is not meant for data collection or recording of data for study purposes) with: a) tailoring lifestyle changes including a modified diet targeting a weight loss of \>5%, and physical activity targeting \>150 min of activity/week; b) review of SBGM levels; c) hypoglycemia prevention and treatment; and d) drug titration and adherence. All glucose-lowering drugs except metformin will be stopped when participants begin the program. The regimen will include basal insulin, metformin and a choice of an SGLT-2 inhibitor, DPP-4 inhibitor or GLP-1 receptor agonist, determined by the primary care lead and patient, and all used according to their label. As the REMIT trials with these classes of medications showed a similar effect on the relapse outcome, attention to

• Weight [Срок оценки: At baseline, intensive period (16 weeks) and at the end of the study (68 weeks)]