Personalised Medicine in Pre-diabetes and Early Type 2 Diabetes

Study Overview
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Brief Summary
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Prediabetes is a common condition in overweight individuals affecting approximately 35% of American adults and 30% of Australian adults. Like diabetes, prediabetes is a serious risk factor for cardiovascular disease, eye, kidney and liver disease, and some types of cancer. Appropriate blood glucose control is crucial in preventing pre-diabetes complications and onset of diabetes, yet clinical practice, backed by randomised trials, reports that many patients treated with standard dietary guidelines or with the first-line treatment of diabetes patients, metformin, do not improve blood glucose control sufficiently. The overarching goal of the present project is to improve the efficacy of metformin mono-therapy in pre-diabetes and early type 2 diabetes.

Detailed Description
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Prediabetes is common in overweight and obese individuals and, as with frank diabetes, it is a risk factor for cardiovascular disease, cognitive dysfunction, fatty liver, kidney, ophthalmic, renal and neuropathic disease, and cancer. Effective management of dysglycemia in pre-diabetes and diabetes and prevention of diabetes in individuals at risk reduce the risk of organ damage and associated co-morbidities and improves the affected individuals' quality of life. Metformin, an oral biguanide, is the first-line treatment of newly-diagnosed type 2 diabetes patients, and the pharmacological choice for preventing diabetes in individuals with pre-diabetes. Metformin is an ideal medication to initiate for diabetes prevention, due to its excellent safety profile (lack of hypoglycemia), neutral to marginally beneficial effect on body weight, evidence of cardio-protection, and low cost. However, clinical practice, backed by randomised clinical trials, suggests that metformin mono-therapy fails to achieve glycemic goals in 20-40% of type 2 diabetes patients and to prevent diabetes in approximately 20% of individuals with pre-diabetes. While the mode of action of metformin is still being investigated, the liver and the gastrointestinal tract are thought to be the main targets responsible for the improvement in glycemia. An increasing body of evidence suggests that the gut microbiota play an important role in obesity, prediabetes and diabetes, and alterations in gut microbial composition have been described in individuals with type 2 diabetes and pre-diabetes. Interestingly, metformin-treated diabetes patients have a healthier gut microbial composition compared with treatment-naïve diabetes patients, and changes in gut microbial composition with metformin treatment has been suggested to contribute to the therapeutic effect of the medication. Randomised, clinical study with parallel assignment and single-masking will be performed in treatment-naïve individuals with pre-diabetes or early type 2 diabetes (diagnosed in the last 6 months) aiming to compare the effect of metformin (extended release [XR]) 1500 mg/d administered with personalized diet (based on the Weizmann Institute Personalized Nutrition Project) or administered with a healthy (low fat) diet.

Official Title
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Personalised Medicine in Prediabetes - Towards Preventing Diabetes in Individuals at Risk

Conditions
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Pre Diabetes, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Metformin + Healthy diet
* Drug: Metformin + Personalized diet


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Individuals with pre-diabetes or newly-diagnosed (in the last 6 months) with type 2 diabetes, fulfilling the following criteria: Impaired fasting glucose (IFG, plasma glucose [PG]- 5.6 - 6.9 mmol/L, ±0.2 mmol/L) and/or impaired glucose tolerance (IGT, 2-h PG 7.8 - 11.0 mmol/L, ±0.2 mmol/L) with or without elevated HbA1c (up to 8.0 %). Willingness to provide written informed consent and willingness to participate and comply with the study. Exclusion Criteria: Females planning a pregnancy during the course of the research or 3 months after completion of the research project. Patients with type 1 diabetes, chronically active inflammatory disease, neoplastic disease in the previous 3 years, chronic gastrointestinal disorders, including inflammatory bowel disease or celiac. Liver enzymes ALT and/or AST>3-times normal range limit. Abnormal renal function as measured by (eGFR<45 mL/min/1.73m^2). Individuals with a history of a psychological illness or condition that may interfere with the individual's ability to understand the requirements of the study. Normo-glycaemia. HbA1c>8.0% Cardiovascular event in the previous 6 months. Current or recent (within 24 months) treatment with a glucose lowering medication (i.e. GLP-1 receptor agonist, SGLT2 inhibitor, thiazolidinedione, sulfonylurea, DPP-4 inhibitor or insulin). Current or recent (within 3 months) treatment with metformin. Treatment with an oral steroid. Treatment with antibiotics/antifungal in the last 3 month. Treatment with immunosuppressive medications. Alcohol or substance abuse. Participants who had received an investigational new drug within the last 6 months. Participants involved in another clinical study. Participants who actively lose weight. Participants who had a bariatric surgery.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Metformin + Healthy diet<br>Metformin (1500 mg/d, Extended Release) + Healthy, low fat diet | Drug: Metformin + Healthy diet<br>* Metformin (1500 mg/d, Extended Release) + Healthy, low fat diet<br>* Other names: Metformin + Healthy (low fat) diet;|
| Active Comparator: Metformin + Personalized diet<br>Metformin (1500 mg/d, Extended Release) + Personalized diet based on an algorithm developed at the Weizmann Institute of Science (Zeevi et al, Cell 2015) | Drug: Metformin + Personalized diet<br>* Metformin (1500 mg/d, Extended Release) + Algorithm-based personalized diet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in glycated haemoglobin (HbA1C, %) from baseline | Difference in the reduction of HbA1C between the groups | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total daily time of interstitial glucose levels below 7.8 mmol/L (140 mg/dL) | Difference in the time (minutes) per day with interstitial glucose measured below 7.8 mmol/L (140 mg/dL) between the groups | 6 months | 
| Glycaemic variability | Difference in the glycaemic variability as derived from CGM between the groups | 6 months | 
| Body weight | Difference in the magnitude of weight loss between the groups | 6 months | 
| Body fat mass | Difference in body fat mass composition as assessed using dual-energy X-ray absorptiometry (DXA) between the groups | 6 months | 
| Abdominal visceral fat volume | Difference in the abdominal visceral fat volume as assessed using DXA between the groups | 6 months | 
| Serum low-density lipoprotein (LDL)-cholesterol concentration | Difference in serum LDL-cholesterol between the groups | 6 months | 
| Serum high-density lipoprotein (HDL)-cholesterol concentration | Difference in serum HDL-cholesterol concentration between the groups | 6 months | 
| Serum triglycerides concentration | Difference in serum triglycerides between the groups | 6 months | 
| Blood pressure | Difference in diastolic and systolic blood pressure between the groups | 6 months | 
| Liver fat | Difference in liver fat measured by the Fibroscan's controlled attenuation parameter (CAP) function between the groups | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pre Diabetes, Insulin resistance, Metformin, Gut microbiota, Type 2 Diabetes Mellitus