www.removalstudy.org Double Diabetes Metformin In T1D Use of - - PowerPoint PPT Presentation

www.removalstudy.org Alicia Jenkins

On behalf of REMOVAL Aust. team including: Peter Colman, David O’Neal, Tony Keech, Greg Fulcher and Steve Twigg

Double Diabetes

Metformin In T1D

Use of Metformin in T1D

• UK registry - 29% with T1D have had metformin script

J Petrie, H Colhoun personal communication

• Local use @ RPAH 15% , SVH 9.5%

A Jenkins, G Tun, D O’Neal, G Ward, M McGill, A Januszewski, J Wong, S Twigg et al

Metformin in T1D in the Literature

Minor benefits metabolic control

• Over 192 clinical studies in people with T1D
• Meta-analysis - 9 RCTs, 1 wk - 1 yr, median 4 Month
• Metformin (1 – 2.5 g) vs placebo associated with:
• ↓Insulin 6.6 IU/day (5.7-10.1 IU/day in 6 of 7 studies)
• Non-significant ↓ 0.11% in HbA1C (0.6-0.9% in 4 of 7 studies)
• Weight 1.7-6.0 kg in 3 of 6 studies
• Total cholesterol 0.3-0.41 mmol/L in 3 of 7 studies
• Trend to more hypoglycaemia
• CGM study - no change glycaemic variability

Vella, Petrie Diabetologia 2010

Metformin and Vascular Health?

REversing with MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes

6 Countries - 23 Sites

Australia (CTC) A Jenkins AC Keech

RPAH Steve Twigg / Greg Fulcher SVH David O’Neal RMH Peter Colman

Canada London, Ontario Ottawa Scotland Glasgow Dundee Edinburgh Denmark Netherlands England Newcastle Durham Salford Manchester Hull Aintree London Plymouth Exeter

• Steno

Maastricht Chief Investigator: John Petrie (Glasgow) Deputy: Helen Colhoun (Dundee)

Study Outline

• double-blind randomised, placebo-controlled trial
• T1DM aged ≥40 years, HbA1c ≥ 7- 10% and ↑ CVD risk.
• 3 or more of 10 risk factors:
• three years metformin 1000 mg b.d. or placebo (as tolerated)

added to titrated insulin [towards HbA1c 7.0% (53 mmol/mol)]

Target: n = 500 (BMI > 27 kg/m2; current HbA1c > 8.0% (64 mmol/mol); CVD/PVD; current smoker: eGFR < 90

ml/min per 1.73 m2: micro- or macroalbuminuria; hypertension (BP ≥ 140/ 90 mmHg or on BP drugs; dyslipidaemia [TC≥5.0 mmol/L ; or HDL-C <1.0 mmol/L; or trigs≥1.7 mmol/L; or on lipid drugs); strong family history CVD; T1D > 20 yrs)

Males and females with T1DM, aged > 40 years, HbA1c>7.0 <10%; not on metformin, three or more CVD risk factors. Eligibility/ informed consent: metabolic, anthropometric assessments Carotid IMT, retinal images, metabolic/ anthropometric assessments Metformin 500mg daily, titrating to 1 g bd over 4 weeks with supported insulin dose titration to target HbA1c 7.0% Matching placebo, titrating over 4 weeks with supported insulin dose titration to target HbA1c 7.0% 3-6 monthly dispensing, tablet checks, insulin dose and hypoglycaemia recording Three annual repeat visits for carotid IMT, metabolic/ anthropometric assessments; repeat retinal images at final visit. Study close-out after three years for each participant 3-month run-in: optimise insulin and CV risk factor management RANDOMIZATION

AUSTRALIAN SUBSTUDY Echocardiogram and WBC AMPKinase Activity (baseline, years 1 and 3)

Design

Primary endpoint: carotid IMT

High resolution B-mode ultrasound

Bots ML. Carotid intima-media thickness measurements in intervention studies design options, progression rates, and sample size considerations. Stroke 2003; 34: 2985-2994.

Averaged mean far wall common carotid artery intima-media thickness

Secondary endpoints:

(i) HbA1c; (ii) LDL-C; (iii) albuminuria & eGFR (iv) retinopathy stage (ETDRS and retinal vessel calibre); not all sites (v) weight (vi) insulin dose; (vii) endothelial function “EndoPat” (not all sites). 2 or more specified as clinically significant

2 1

OD-Fields 1 and 2 OS-Fields 1 and 2

1 2

Tertiary endpoints

(i) hypoglycaemia; (ii) treatment satisfaction; (iii) markers of endothelial function (t-PA, sE-selectin, sICAM-1, others; (iv) progression of mean maximal distal common carotid artery IMT (v) vitamin B12

Australian Sub-Studies

• Participation in multi-country retinal studies (camera)
• Participation in multi-country vascular function studies (EndoPat)

60 T1D and 45 age and gender matched non-diabetic subjects

• Echocardiogram – incl. cardiac function and cardiac backscatter

(software)

• AMPKinase activity – WBC prep.

Progress

Started 2012 Recruitment end July 2014 About 500 subjects T1D recruited and about 450 randomised Close out 2017 Australian Substudy (Echos and AMPK) 60 Australians with T1D No major safety signals

2 1

OD-Fields 1 and 2 OS-Fields 1 and 2

1 2

Advantages of JDRF CRN Support

Increased international profile

(other studies, other grants)

Increased local profile with T1D community Reduced funding gap

What can we improve on?

• Greater closure of the funding gap
• Outreach to adult T1D community
• Contracts

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Acknowledgements REMOVAL Aust. Investigators

Melbourne

SVH

• David O’Neal and team including
• Alicia Jenkins
• Bala Krishnamurthy
• Jodie Horsburgh
• Sue Kent
• Catherine Peeler

RMH

• Peter Colman and team including
• Alison Nankervis
• Spiros Fourlanos
• Lee-anne Lynch
• Anne Doran
• Jennifer Nairn

Core resources (Vic)

• John Vrazas
• John Donelan
• Bronwyn Parslow
• Andrew Wilson
• Joss Dimock
• Amanda Rebbecchi

Sydney

RPAH

• Steve Twigg and team, including
• Connie Luo / Rebecca Denner
• Belinda Brookes
• David Celermajer
• Seamus O’Meagher – Echocardiographer
• Greg Fulcher and Rachel McGrath (RNS)

CTC

• Anthony Keech
• Wendy Hague
• Helen Pater
• Andrzej Januszewski
• Liping Li

REMOVAL Group Meeting (RCP) Edinburgh 2013

REMOVAL Study Participants Acknowledgements