Title: Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT)
Funder: Department of Health (England)

Abstract: DESIGN: We plan to undertake a pilot and feasibility phase of an individually-randomised double-blind pragmatic parallel group trial of slow-release metformin compared with placebo in people with non-diabetic hyperglycaemia (NDH) at high CVD risk. SETTING: General practices will be recruited via Diabetes and Primary Care Research Networks in East Anglia and South East Midlands. TARGET POPULATION: For the pilot phase we plan to recruit 500 men and women with NDH aged 40 years and above with an estimated 10-year CVD risk >/= 20% and no history of CVD. High CVD risk participants will be recruited via three complementary methods including the NHS Health Checks programme existing research registers and using routine data directly from participating general practices. Eligible participants will be invited to local clinical research facilities for a health check including blood pressure HbA1c and total cholesterol. Those with a 10-yr CVD risk of >/= 20% and an HbA1c >/= 5.5% but <6.5% will be invited to participate in GLINT. Exclusion criteria: (i)history of T2DM or CVD event; (ii) pregnancy or lactating; (iii) serious illness (life expectancy <5 years); (iv) a psychotic illness or disability precluding informed consent; (vi) contraindication to metformin; and (vii) eGFR<45ml/min. HEALTH TECHNOLOGIES BEING ASSESSED: Participants will take 1 tablet daily (500 mg slow-release metformin/placebo) increasing to 2 and then 3 tablets daily. Individuals with baseline eGFR 45-60ml/min will have renal function monitored at 3 and 6 months and annually thereafter. Evidence from DPP in similar participants suggests that hypoglycaemia is not expected and serious adverse effects will be very rare. Adherence to therapy is expected to be similar to DPP in which 72% of participants took >80% of prescribed dose. At baseline health assessment all participants will receive best practicelifestyle advice and their GPs will be advised to provide usual care for other CVD risk factors. SAMPLE SIZE: We require 500 participants in the pilot phase to demonstrate the feasibility of the proposed trial and to provide accurate estimates of key trial parameters (for example recruitment retention and adherence rates) as detailed in the draft protocol. For the main trial EPIC-Norfolk data suggests that 10% of individuals screened by the NHS checks programme will have a CVD risk >20% and an HbA1c between 5.5% and 6.5% and annual CVD event rate of 2.2%. If 25% agree to participate and 16% arelost to follow-up we would require 473360 screened and 11834 participants randomised to detect a 17% CVD relative risk reduction (85% power p=0.05). Uncertainty concerning these parameters will be reduced by the pilot. Treatment effect is estimated from observed CVD risk reductions in T2DM (15-30%) and expected risk reductions (9-13%) due to changes in HbA1c BMI lipids and blood pressure in NDH. We currently estimate that a full trial of this size would also have >99% power to detect a 31% reduction in incident diabetes (DPP) and a 36% reduction in incident cancer. MEASUREMENT OF COSTS AND OUTCOMES: For the pilot phase the outcomes are demonstration of feasibility of studyset up recruitment and retention and estimation of key parameters that will inform the main trial. The main trial five year outcomes are: PRIMARY ENDPOINTS - a composite of the following (first event only): Cardiovascular mortality; Cardiovascular morbidity including non-fatal myocardial infarction and non-fatal stroke. SECONDARY ENDPOINTS: Time to first CVD event; death due to any cause; time to first non-melanoma cancer diagnosis; death due to a non-melanoma cancer cause; physician diagnosed diabetes; patient satisfaction with treatment; functional status; health utility. EXPLORATORY ENDPOINTS: Confirmed hospital admission for congestive heart failure: confirmed hospitalisation for unstable angina; confirmed coronary cerebrovascular or peripheral revascularisation; medical resource utilisation during the trial. The followingdata will also be collected at a baseline assessment visit: 1. Anthropometric variables: height weight BMI waist circumference body fat percentage; 2. Non-fasted bloods: total cholesterol LDL and HDL cholesterol LFTs renal function creatinine HbA1c. 3. Blood pressure; 4. Spot urine for albumin:creatinine ratio (microalbuminuria); 5. Short questionnaire including self-reported CVD events prescribed medication SF8 EuroQol patient costs / health service use data. Our main outcomes will be identified prospectively by sensitive electronic searches of primary and secondary care medical records(England) the Information Services Division (Scotland) and patient questionnaire. When a possible event is highlighted relevant notes will be extracted and anonymised by a researcher blind to study group allocation and reviewed by an independent endpoint committee. NHS automated systems will trace participants who move during follow-up. Mortality will be tracked using ONS tagging. Baseline health assessment visits will be done at local DRN clinical research facilities or local practices with support from research networks. A health service perspective cost-effectiveness analysis will include measures offunctional status health utility and health service use. All analyses will be by intention-to-treat for all participants with outcome data. PROJECT TIMETABLES INCLUDING RECRUITMENT RATE: The pilot phase is for 30 months and this will run into the main trial which is projected to begin in January 2016. All participating centres have proven ability to recruit local GP practices into research studies and our well-established links with the research networks suggest that the pilot phase is a sufficient time to recruit 500 participants from two centres.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;6.1 PHARMACEUTICALS
Health categories: STROKE;METABOLIC AND ENDOCRINE;CARDIOVASCULAR