MetfoRmin and Its Effects on Myocardial Dimension and Left Ventricular Hypertrophy in Normotensive Patients With Coronary Artery Disease
Phase: PHASE4
Conditions: Left Ventricular Hypertrophy, Insulin Resistance, Coronary Artery Disease, PreDiabetes
Sponsor: University of Dundee

Metformin and its effects on myocardial dimension and left ventricular hypertrophy in 
normotensive patients with coronary heart disease (MET-REMODEL study) 
 
Analysis Plan 
22nd August 2017 
 
Prof Chim C Lang 
Chief Investigator                         
 
Mr Mohapradeep Mohan 
Research fellow  & Principal Investigator                          
 
 
MET-REMODEL study is a double blinded placebo controlled trial, funded by British Heart 
Foundation (Grant number: PG/14/4/30539). In this pragmatic “proof of concept” study, we will 
investigate the efficacy of Metformin to cause a favourable effect on left ventricular hypertrophy 
(LVH), either regression or less increase in left ventricular mass in non-diabetic patients with 
documented coronary artery disease and who are insulin resistant and/or prediabetic. Further 
information regarding the MET-REMODEL study can be found in the approved trial protocol and 
also from the published rationale and design paper (1). This analysis plan relates to the MET-
REMODEL trial protocol Version 5.4 dated 20th October 2016. 
 

Background 
Left ventricular hypertrophy (LVH) is a common and independent risk factor for cardio-vascular 
events in patients with coronary artery disease (CAD) [2]. Controlling blood pressure is the 
standard approach to the management of LVH, but this is only partially effective as LVH also 
persists in normotensive patients [3]. Apart from blood pressure (BP), other main risk factors 
associated with LVH are insulin resistance (IR) and central obesity [1]. The diabetic medication, 
Metformin, reduces IR and aids weight loss and may therefore regress LVH [4].  
In this single-centre, phase IV, double-blind, randomized, placebo-controlled trial, we propose to 
investigate the efficacy of Metformin to regress LVH in patients with a 68 non-diabetic patients 
with CAD who are insulin resistant and/or prediabetic. Participants will be randomized into two 
groups to receive, either Metformin XL or placebo.  
The primary end-point of this trial is to investigate any change in left ventricular mass index 
(LVMI) measured using cardiac magnetic resonance imaging (cMRI). Secondary endpoints 
include changes to LV mass (LVM) and function measured using cMRI, insulin resistance 
measured using fasting insulin resistance index (FIRI), changes in glycaemic index measured 
using HbA1c, abdominal obesity measured using MRI, improvement in endothelial function 
assessed using flow mediated dilatation (FMD) and blood-borne biomarkers such as IL-6 
(inflammation), NT-pro BNP (wall stress), Soluble ST2 (wall stress & fibrosis) and TBARs 
(oxidative stress). As blood-borne biomarkers can offer objective and biologically relevant and 
mechanistic insights that complements the findings of study specific end points, we propose to 
include these 4 biomarkers of distinct mechanisms that contribute to the pathophysiology of left 
ventricular hypertrophy.  

A positive result will assist clinicians to identify a new mechanism for LVH regression by 
administering Metformin XL. This may also lead to investigating the mortality benefit of 
Metformin in patients with CAD and LVH. 
Research question 
Compared to placebo, does metformin improve cardiac parameters such as LVH regression, LV 
ejection fraction, LV systolic and diastolic volumes, endothelial function, blood-borne 
biomarkers, insulin resistance/glycaemic index and abdominal obesity? 
Study Objectives 
Primary Objective   
To study the efficacy of metformin to cause regression of left ventricular mass index (LVMI) 
in participants with coronary artery disease (CAD) who are insulin resistant/pre-diabetes 
and on optimal current evidence based therapy for IHD.   
Secondary Objectives   
• 
To assess if metformin has effects on cardiac parameters LVM, LVEF, LVSV, 
LVEDV, LVESV as measured by cardiac MRI.    
• 
To study whether metformin improves insulin resistance/HbA1c in patients with 
CAD.    
• 
To assess whether metformin will reduce abdominal obesity in this patient group 
as measured by MRI     
• 
To examine any differences following treatment with metformin in blood borne 
biomarkers such as NT pro BNP, IL-6, Soluble ST2, TBARs and any other 
markers of interest.   
• 
To assess whether metformin will improve endothelial function as assessed by 
flow mediated dilatation.  
 

STATISTICS AND DATA ANALYSIS   
SAMPLE SIZE CALCULATIONS   
For the primary outcome of LVMI regression using cardiac MRI, the study has been powered 
for an absolute change in LV mass based on previous studies conducted in the department of 
Clinical Pharmacology, Ninewells Hospital. In this group’s recently published study of LVH 
regression using allopurinol in patients with ischaemic heart disease it was found that 
allopurinol significantly reduced LV mass by -5.2± 5.8 grams compared to placebo -1.3±4.5 
grams (p<0.007) [5].  For an 80% power at a 5% significance level (α=0.05), to detect a similar 
change in LV mass, 29 subjects per group (N=58) will be required.  Previous studies have 
shown a 15% dropout rate. Therefore, accounting for this, a total of 68 participants will be 
required (34 per group).   
 
Although we have shown above that this study has the potential sample size to achieve an 
adequate statistical power to detect a reasonable change in LVMI, we acknowledge that the 
overall sample size of the study is small. Furthermore, a limitation of our sample size 
calculation is that it is based on a single outcome and may not reflect the effects on other study 
endpoints. If the observed effect sizes for other end points in this study are small (i.e. less than 
ES of 0.4) then we acknowledge we will not have adequate statistical power to detect such 
effects in this study. In summary, given the relatively small sample size of this study, inferential 
between group comparisons are likely to be exploratory rather than definitive 
 
 
 
 
 
 
 
 

 
 
 
Outcomes 
 
Variables 
Baseline 
12-13 months follow-up 
Cardiac Parameters 
 
 
LV Mass Index & LV mass (LVMI&LVM) 
X 
X 
LV end systolic volume(LVESV) 
X 
X 
LV end diastolic volume(LVEDV)  
X 
X 
LV Ejection fraction (LVEF) 
X 
X 
LV Stroke Volume (LVSV) 
 
 
Abdominal Obesity 
(Subcutaneous Abdominal 
Tissue [SAT] & Visceral Adipose 
Tissue [VAT]) 
X 
X 
Endothelial Function 
 
 
Flow mediated dilation 
X 
X 
Research Biomarkers 
 
 
IL-6 
X 
X 
NT pro BNP 
X 
X 
Soluble ST2 
X 
X 
TBARs 
X 
X 
Biochemical Analysis 
 
 
Fasting Insulin Resistance Index 
X 
X 
HbA1c 
X 
X 
 
 

PROPOSED DATA ANALYSES   
The primary analysis will be based on a between-group, intention-to-treat principle using the 
outcome data collected at baseline and 12-13 months’ follow-up. The primary outcome 
comparison will be based on modified intention-to-treat analysis, i.e. all participants 
who had baseline measurements and took at least one dose of IMP will be analysed as 
part of the group to which they were randomized. Missing post-baseline values will be 
imputed using the baseline observation carried forward (BCOF) approach. However, to 
provide a true estimate of the efficacy of intervention, a per-protocol analysis was also 
performed. 
Descriptive statistics in the form of means and standard deviations for continuous variables and 
percentages and denominators for categorical variables will be tabulated at baseline and for 
each visit. As outcomes are continuous, the comparison between arms of the trial will be 
assessed using the 2-tailed t test while categorical variables were analysed using chi-square 
test. Continuous variables not normally distributed are presented as medians with their 
interquartile ranges (IQRs). If normality could not be assumed, data underwent log 
transformation to convert it to a normal distribution. Correlation will be performed using 
Pearson’s or Spearman’s method. A sensitivity analysis using ANCOVA (analysis of 
covariance) will be performed adjusted for relevant covariates to evaluate the robustness of the 
effect of treatment on the outcome parameters. All between group outcome results will be 
presented as means and 95% confidence internals.  A p value <0.05 will be considered 
significant.     
MISSING DATA   
The primary analysis will be based on the modified intention-to-treat. The extent of missing 
data will be examined and the reason for drop-out ascertained. Missing post-baseline values 

will be imputed using the baseline observation carried forward (BCOF) approach.. Given the 
relatively small sample size of this study, we regard the results of the between group 
inferential analyses as exploratory and hypothesis generating. All analyses will be conducted 
by the trial statistician blinded to group allocation, using R Software (version 3.3.2, R core 
development team) or SPSS 22.0 (IBM Corp, Armonk, NY, USA). 
 
References 
(1) Mohan M, McSwiggan S, Baig F, Rutherford L, Lang CC. Metformin and its effects 
on myocardial dimension and left ventricular hypertrophy in normotensive patients 
with coronary heart disease (the METREMODEL study): rationale and design of the 
MET-REMODEL study. Cardiovasc Ther 2015; 33(1): 1-8. 
(2) Ang DS, Pringle SD, Struthers AD. The cardiovascular risk factor, left ventricular 
hypertrophy, is highly prevalent in stable, treated angina pectoris. Am J Hypertens 
2007;20(10):1029-35.   
(3) Mancia G, Carugo S, Grassi G, Lanzarotti A, Schiavina R, Cesana G, et al. 
Prevalence of left ventricular hypertrophy in hypertensive patients without and with 
blood pressure control: data from the PAMELA population. Pressioni Arteriose 
Monitorate E Loro Associazioni. Hypertension 2002;39(3):744-9.   
(4) Srinivasan S, Ambler GR, Baur LA, Garnett SP, Tepsa M, Yap F, et al. Randomized, 
Controlled Trial of Metformin for Obesity and Insulin Resistance in Children and 
Adolescents: Improvement in Body Composition and Fasting Insulin. Journal of 
Clinical Endocrinology & Metabolism 2006;91(6):2074-80. 

(5) Rekhraj S, Gandy SJ, Szwejkowski BR, Nadir MA, Noman A, Houston JG, et al. 
High-dose allopurinol reduces left ventricular mass in patients with ischemic heart 
disease. J Am Coll Cardiol 2013;61(9):926-32.