Personalised Medicine in Pre-diabetes and Early Type 2 Diabetes (PREDICT)

Personalised Medicine in Prediabetes - Towards Preventing Diabetes in Individuals At Risk

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Pre Diabetes
• Intervention / Treatment: Drug: Metformin + Healthy diet; Drug: Metformin + Personalized diet

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • Garvan Institute of Medical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Metformin + Healthy diet; Metformin (1500 mg/d, Extended Release) + Healthy, low fat diet	Drug: Metformin + Healthy diet; Metformin (1500 mg/d, Extended Release) + Healthy, low fat diet; Other Names: Metformin + Healthy (low fat) diet
Active Comparator: Metformin + Personalized diet; 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; Metformin (1500 mg/d, Extended Release) + Algorithm-based personalized diet

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut microbiome (exploratory)	Difference in gut microbiome features between the groups	6 months

Collaborators and Investigators

• Sponsor: Garvan Institute of Medical Research
• Collaborators: Weizmann Institute of Science
• Investigators: Principal Investigator: Dorit Samocha-Bonet, PhD, Garvan Institute of Medical Research; Principal Investigator: Jerry Greenfield, MD, PhD, Garvan Institute of Medical Research; Principal Investigator: Eran Elinav, MD, PhD, Weizmann Institute of Science; Principal Investigator: Eran Segal, PhD, Weizmann Institute of Science

Publications and helpful links

General Publications

• Htet TD, Godneva A, Liu Z, Chalmers E, Kolobkov D, Snaith JR, Richens R, Toth K, Danta M, Hng TM, Elinav E, Segal E, Greenfield JR, Samocha-Bonet D. Rationale and design of a randomised controlled trial testing the effect of personalised diet in individuals with pre-diabetes or type 2 diabetes mellitus treated with metformin. BMJ Open. 2020 Oct 10;10(10):e037859. doi: 10.1136/bmjopen-2020-037859.

Helpful Links

• Study protocol paper

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2018
• Primary Completion (Actual): December 15, 2023
• Study Completion (Actual): July 23, 2024

Study Registration Dates

• First Submitted: June 5, 2018
• First Submitted That Met QC Criteria: June 5, 2018
• First Posted (Actual): June 15, 2018

Study Record Updates

• Last Update Posted (Actual): October 31, 2024
• Last Update Submitted That Met QC Criteria: October 29, 2024
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Insulin resistance; Metformin; Gut microbiota; Type 2 Diabetes Mellitus; Pre Diabetes
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Hyperglycemia; Diabetes Mellitus, Type 2; Diabetes Mellitus; Prediabetic State; Glucose Intolerance; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: SVH 17/080

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No