Clinical trial NCT03558867: Personalised Medicine in Pre-diabetes and Early Type 2 Diabetes
Official title: Personalised Medicine in Prediabetes - Towards Preventing Diabetes in Individuals At Risk
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pre Diabetes
Type 2 Diabetes Mellitus
Keywords: Pre Diabetes
Insulin resistance
Metformin
Gut microbiota
Type 2 Diabetes Mellitus
Lead sponsor: Garvan Institute of Medical Research
Sponsor class: OTHER
Collaborators: name: Weizmann Institute of Science
First posted: 2018-06-15
Enrollment: 138
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean change in glycated haemoglobin (HbA1C, %) from baseline
timeFrame: 6 months
Secondary outcomes:
measure: Total daily time of interstitial glucose levels below 7.8 mmol/L (140 mg/dL)
timeFrame: 6 months
measure: Glycaemic variability
timeFrame: 6 months
measure: Body weight
timeFrame: 6 months
measure: Body fat mass
timeFrame: 6 months
measure: Abdominal visceral fat volume
timeFrame: 6 months
measure: Serum low-density lipoprotein (LDL)-cholesterol concentration
timeFrame: 6 months
measure: Serum high-density lipoprotein (HDL)-cholesterol concentration
timeFrame: 6 months
measure: Serum triglycerides concentration
timeFrame: 6 months
measure: Blood pressure
timeFrame: 6 months
measure: Liver fat
timeFrame: 6 months
Other outcomes:
measure: Gut microbiome (exploratory)
timeFrame: 6 months
Locations:
city: Sydney
country: Australia
facility: Garvan Institute of Medical Research
state: New South Wales
Study officials:
affiliation: Garvan Institute of Medical Research
name: Dorit Samocha-Bonet, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Garvan Institute of Medical Research
name: Jerry Greenfield, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weizmann Institute of Science
name: Eran Elinav, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weizmann Institute of Science
name: Eran Segal, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.