Reducing with Metformin Vascular Adverse Lesions in type 1 diabetes (REMOVAL)

The REMOVAL study aims to discover whether metformin, a drug with a proven effectiveness in safely improving cardiovascular function, can slow or prevent the development of cardiovascular complications in type 1 diabetes.

Metformin is an oral drug recommended for first-line treatment for people with type 2 diabetes to help control blood glucose levels, and has the added benefit of reducing the risk of heart attacks and strokes. Metformin is sometimes used in the treatment of type 2 diabetes to lower insulin requirements by reducing insulin resistance, and it may also help to reduce cholesterol levels.

The REMOVAL study is an international collaboration led by Professor John Petrie from the University of Glasgow, and Professor Alicia Jenkins from the University of Sydney is the Australian lead The study will use ultrasound to look at the blood vessels in the neck to track any changes that occur over time, and will also investigate whether metformin can affect the ability of blood vessels to contract and relax normally in people with type 1 diabetes. In addition, the study will look at whether metformin can improve blood glucose control, and whether it affects the development of other complications in type 1 diabetes such as eye and kidney damage.

The T1DCRN is funding the only sub-study of the international study, in recognition of the expertise of the Australian investigators in the proposed area of clinical and laboratory research. This Australian AMPKinase sub-study investigates areas of current ‘evidence-free zones’, such that any data regarding AMPKinase activity and subclinical cardiac structure and function studies would advance the global knowledge base in this area.

To find out about how you can participate in this project, contact: Helen Pater,

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Technical Summary
Metformin, an insulin sensitiser, is currently used as first-line pharmacological treatment for type 2 diabetes, and has also been recently associated with long-term benefit against complications in type 2 diabetes. Metformin has also recently been used in people with T1D who are overweight to manage insulin resistance, decrease insulin requirements and weight. Metformin has been shown to have beneficial effects increasing vascular function and blood flow, improving the lipid profile, and has anti-oxidant and anti-inflammatory properties. Metformin may act by increasing activity of the cellular energy sensor of 5’AMP-activated protein kinase (AMPK)] 2-fold. It may be beneficial to all people with type 1 diabetes and not just those who are overweight or obese.

REMOVAL is a phase III international multi-centre randomised controlled trial of metformin vs. placebo over three years in men and women with type 1 diabetes aged 40 years and over.

The REMOVAL international study is a phase 3, international randomised controlled trial with the following aims:
  1. To determine if relative to placebo metformin in adults aged >40 yrs with T1D will improve non-invasivemeasures of vascular structure and function.
  2. To determine if T1D in adults aged over 40 years is associated with worse cardiac structure and functionthan non-diabetic subjects, and in T1D patients improves with 3 years metformin (vs. placebo) treatment.
  3. To determine if monocyte AMPKinase activity differs in adults aged >40 yrs with vs. without T1D and isimproved in T1D by 3 years of metformin vs. placebo treatment.
  4. To determine if metformin intervention in addition to insulin in T1D improves traditional and novelvascular disease risk factors such as related to glycaemia, insulin resistance, lipids, adiposity, oxidativestress and inflammation.
This Australian AMPKinase sub-study of the trial will involve the simultaneous collection of Australian-specific measurements to assess damage to small blood vessels, a marker for cardiovascular disease. The studies all will bring a mechanistic component to the REMOVAL international study by informing how metformin may (or may not) act in people with Type 1 diabetes.

In Australia, 60 people were recruited for the main study, as well as for the Australian AMPkinase substudy.

Trial Design
The REMOVAL international study is a multi-centre randomised controlled trial of metformin vs. placebo over three years in men and women with type 1 diabetes aged 40 years and over Following the single-blind three month run-in period (taking placebo in the third month), participants will enter the double-blind period and remain on therapy as randomised for three years. The effects of three years metformin added to titrated insulin therapy (towards target HbA1c 7.0%/ 53 mmol/mol) will be assessed on progression of atheroma as measured by progression of averaged mean far wall common carotid artery intima-media thickness (cIMT) in adults with type 1 diabetes at risk of cardiovascular disease. Other cardiovascular changes will be monitoried including: change in: (i) HbA1c; (ii) LDL cholesterol; (iii) albuminuria and estimated glomerular filtration rate; (iv) retinopathy stage (two-field photographs); (v) weight; (vi) insulin dose; (vii) endothelial function. The Australian substudies runs in parallel to the international study and assessment include 1) echocardiogram studies including cardiac backscatter; 2) AMPKinase activity and 3) a contribution to the analysis an as yet unspecified biomarker from the international REMOVAL study, to be performed in Australia.

Principal Investigators
The Chief International Investigator is Professor John Petrie (University of Glasgow) and the Chief Australian Investigator is Professor Alicia Jenkins (University of Sydney).

International Funder: JDRF

Australian Funder: The Australian Type 1 Diabetes Clinical Research Network, JDRF

The study is being conducted in Australia at:
  • NHMRC Clinical Trials Centre, Sydney NSW
  • Royal Prince Alfred Hospital, Sydney NSW
  • St Vincent’s Hospital, Melbourne VIC
  • Royal Melbourne Hospital, Melbourne VIC
Primary Endpoint
Main study: Progression in carotid artery intima-media thickness (cIMT) with metformin treatment.

Australian substudy:
  • Changes in myocardial ventricular backscatter (indicates accumulation of Advanced Glycation End-Products (AGEs)
  • Changes in diastolic dysfunction as measured by the E/É ratio echocardiography
  • Circulating blood monocyte AMP kinase activity
Secondary Endpoints
Secondary endpoints include changes in clinical outcomes such as HbA1c, LDL-cholesterol, albuminuria, endothelial function and retinopathy staging as well as a variety of biomarkers.

Inclusion Criteria
  • Patients aged 40 years old or over with type 1 diabetes
  • Have blood sugar currently not well controlled
  • Have at least three cardiovascular risk factors
Exclusion Criteria
  • Pregnant and/or lactating or women of childbearing age not using effective contraception
  • Patients with diagnosed heart disease
  • Taken metformin for more than three months within last two years or allergies to Metformin
Anticipated Outcomes
The effects of 3 years metformin (or placebo) on vascular health in adults aged 40 years or more with Type 1 diabetes will be investigated. It is anticipated that treatment with metformin treatment will imporve vascular tissue health, retinal vessel calibre and a related biomarker in the international REMOVAL cohort, and improve cardiac structure and function, and AMPK activity in the Australian substudy. The resultant study outcomes will contribute to improvement of the lives of people living with T1D. The next generation of diabetes researchers will also be advanced.

Start/End Date
November 2012 – May 2015

Photo: Australian researchers working on the REMOVAL study.