Methods

•Carotid Atherosclerosis: Metformin for insulin Resistance7

•RCT of metformin vs. placebo in non-diabetic participants with coronary disease and on statins•No change in carotid IMT (10 outcome) or routine lipids (20 outcome)•↓HOMA-IR, ↓weight 3.2 kg, ↓fat mass (20 outcomes)•n=173 (86 metformin [850 mg bd], 87 placebo)•Plasma was collected at 0, 6, 12 and 18 months•Advanced lipoprotein profiling (ALP) was performed by quantitative NMR spectroscopy

• Samples were mixed with NMR buffer and analysed using a 500 MHz NMR at 310 kelvin8,9

• Concentrations of 14 lipoprotein subclasses (XL-VLDL, L-VLDL, M-VLDL, S-VLDL, XS-VLDL; IDL; L-LDL, M-LDL, S-LDL; XL-HDL, L-HDL, M-HDL, S-HDL) and sizes of 3 lipoprotein particles (VLDL, LDL and HDL) obtained

•Statistics: repeated measures analysis or by visit as appropriate

Introduction•Metformin reduces risk of developing T2DM: 25-30% in individuals with IGT1

•Metformin has also been associated with reduced CVD in T2DM - independent of improved glycaemic control2,3,

•Metformin has been reported to reduce total cholesterol (TC), LDL-cholesterol (LDL-c) and triglycerides (TG) in individuals with T2DM4

•Metformin therapy for one year decreased small, dense LDL-particle number (LDL-p), increased small-HDL-p and large-HDL-p5 •Patients with the same LDL-c can have different particle concentrations (LDL-p). The LDL-p in these cases correlates better with CVD outcome6

Acknowledgments•Supported by Chief Scientist Office, Scotland •Metformin and placebo provided free by Merck Serono•Figure 1 attributed to Press-office City of Muenster, Germany•Figure 2 includes image from Ala Korpela et al., 2007•The CAMERA RCT was conducted by DP, RH, PW, SL, and NS•ALP was performed by PS, AK and MAK

Results•Baseline lipoprotein concentrations similar in both groups •Treatment with metformin over 18 months vs. placebo:

• ↓XXL-VLDL at 6 months by 213% (95%CI -401 to -32; p=0.02)• ↑S-HDL at 18 months by 2.2% (95%CI 0.6 to 3.7; p=0.006)• ↑LDL size at 6 months by 0.4% (95%CI 0.1 to 0.6; p=0.014)• No significant changes at other time points• No differences in other 3 HDL subclasses; 5 VLDL subclasses;

or any of the 4 LDL subclass concentrations (including IDL)• No significant differences in the VLDL or HDL size

•No associations between any particle concentrations or the 3 particle diameters, with change in HOMA-IR•M-VLDL, S-VLDL, L-HDL and mean particle size associated with change in weight•L-HDL, M-HDL and HDL diameter associated with change in fat mass

Naomi Rankin1,2, Suzanne M Lloyd3, Naveed Sattar2, Paul Welsh2, Rury R Holman4, Antti J Kangas5, Pasi Soininen5,6, Mika Ala-Korpela5-7, and, David Preiss2

1Glasgow Polyomics, University of Glasgow, Glasgow, UK, 2BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK, 3Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK, 4 Diabetes Trials Unit, University of Oxford, Oxford, UK, 5Computational Medicine, Institute of Health Sciences, University of Oulu and Biocentre Oulu, Finland, 6NMR

Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland, 7Computational Medicine, School of Social and Community Medicine and the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK

The effect of metformin on lipoprotein profiles in the CAMERA trial

References

Aim: to determine if metformin changes circulating lipoprotein sub-fractions

Discussion & Conclusion•Although changes in some lipid measures reached significance at individual time points on metformin, none were consistently significant •The magnitude of observed changes was small and unlikely to be clinically significant•Strengths: comparably large RCT, double-blind, 18 month duration, participants not on other glucose-lowering therapies•Limitations: Participants did not have diabetes, all patients were already on a statin

Figure 3: the effect of metformin on lipoprotein profilesPercent change in particle number/diameter over 18 months

Figure 2: 1H NMR spectra of human serum: NOESY optimised for lipoproteins10 Methyl and methylene 1Hs in PL, TC, CE and C give broad peaks at apx 0.8-0.9 and 1.2-1.4 ppm respectively. Exact chemical shift

depends on diameter of the lipoprotein11.

Figure 1: is it better to measure passengers or vehicles?Measuring cholesterol content of lipoproteins has been likened to measuring passengers – perhaps it would be better to measure the lipoprotein concentration (cars, busses etc.) itself to monitor lipoprotein remodelling (traffic)

6.Otvos et al., J Clin Lipidol, 2011 5:1057.Preiss et al., Lancet Diabetes Endocrinol, 2013 2:1168.Inouye et al., Mol Sys Biol, 2010 6:4419.Soininen et al., Analyst, 2009 134:178110.Rankin et al., Atherosclerosis, 2014 237:28711.Ala-Korpela et al., Artherosclerosis, 2007 190:352

1.Knowler et al., New Engl J Med, 2002 346:3932.UKPDS group. Lancet, 1998 352:8543.Kooy et al., Arch Intern Med, 2009 169:616-6254.Wulffele et al., J Intern Med, 2004 256:15.Goldberg et al., 2013. J Clin Endocrin Metab, 2013 98:3989

Treatment with metformin in patients with established CHD already on statins had little impact on the profile of circulating lipoproteins in

patients without T2DM

  

Time (months)

 

Metformin group (mean %

change; SD) 

Placebo group (mean % change;

SD) 

Treatment effect (metformin - placebo)

 

effect (95%CI) p value

6 -19.1 (92.0) 201.1 (704.7) -212.5 (-392, -32.4) 0.021XXL VLDL-p  12 -4.3 (124.1) 163.2 (625.0) -159.5 (-342, 23.3) 0.087

  18 95.3 (400.9) 87.8 (390.1) 6.8 (-170.7, 184.4) 0.940  6 0.7 (5.1) 0.7 (5.9) -0.2 (-1.8, 1.4) 0.792

S HDL-p 12 2.6 (5.1) 1.1 (4.5) 1.5 (-0.1, 3.1) 0.068  18 3.5 (5.6) 1.1 (5.6) 2.2 (0.6, 3.7) 0.006  6 0.1 (0.9) -0.3 (1.0) 0.4 (0.1, 0.6) 0.014

LDL size 12 -0.1 (1.1) 0.03 (1.0) -0.1 (-0.4, 0.2) 0.525  18 -0.2 (1.1) -0.1 (1.0) -0.2 (-0.4, 0.1) 0.255