Improvement of Cardiovascular Risk Profile by Metformin

During the last two decades a number of studies showed beneficial effects of metformin on traditional and non-traditional cardiovascular risk factors [11,47-58]. Metformin reduces fasting and postprandial insulin levels [3], insulin resistance [4-6] and has beneficial effects on lipids, thrombosis and blood flow. Metformin has a weight-lowering effect [11,13,15] and reduces hypertriglyceridaemia [11], elevated levels of PAI-1 [47], factor VII [49], C-reactive protein [51,52,54] and intact proinsulin and des 31,32 proinsulin concentrations [48]. In randomized head-to-head comparisons (Fig. 2) of oral anti-diabetic drugs metformin treatment reduced triglycerides by 10% and increased HDL-cholesterol by 7%, whereas pioglitazone reduced triglycerides by 19% and increased HDL-cholesterol by 14% [11]. By contrast, LDL-cholesterol decreased by 4% under metformin therapy, but increased by 8% under pioglitazone. Remarkably, HbA1c improvement was very similar and the prognostically important total cholesterol/HDL-cholesterol ratio was reduced identical by 8% (Fig. 2) in both treatment arms [11]. Recent studies indicate that metformin has direct effects on fibrin structure/ function and stabilizes platelets, two important components of arterial thrombus [55]. In addition, metformin has been shown [56,57] to reduce soluble vascular cell adhesion molecule-1 (sVCAM-1) and migration inhibitory factor (MIF). Metformin also reduces methylglyoxal, a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications in a dose-dependent fashion and minimizes the effect of worsening glycaemic control on methylglyoxal levels [50].

A recent Cochrane Systematic Review [59] about all available studies with metformin arrived at the following conclusion: Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated weight, lipids, insulinaemia and diastolic blood pressure. Sulfonylureas, alpha-glucosidase inhibitors, thiazolidendiones, meglitinides, insulin and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.

Changes in Lipid Concentrations: Pioglitazone versus Metformin (Quartet)

Schernthaner et al (J.Clin.Endocrin.Metab 2004; 89:6068)

% Change from Baseline 25 -

d Pioglitazone d Metformin

Triglycerides

HDL-Cholesterol

LDL- TC/HDL Ratio Cholesterol

FFAs

Triglycerides

HDL-Cholesterol

LDL- TC/HDL Ratio Cholesterol

FFAs

mmol/L

mmol/L

mmol/L

Ratio

mmol/L

pio met

pio met

pio met

pio met

pio met

Baseline

2.64 2.61

1.13 1.13

3.56 3.56

5.34 5.34

0.66 0.66

Week 52

2.03 2.31

1.29 1.21

3.83 3.44

4.92 4.92

0.54 0.62

Fig. 2. Changes in lipid concentrations: pioglitazone versus metformin (QUARTET) (Schernthaner et al. J Clin Endocrinol Metab 2004;89:6068 [11]).

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