Hyperglycaemia precedes the development of PAD, peripheral neuropathy and lower extremity amputation in patients with diabetes (Adler etal., 2002). In a study involving elderly Dutch patients, a 1% increase in HbA1c was associated with a 35-42% increased risk for ABPI <0.9 or obstructed crural arteries (Beks etal., 1995; Hoogeveen etal., 2000). In the UKPDS, the effect of intensive blood glucose control was investigated in 3867 patients with newly diagnosed type 2 diabetes. Patients who were allocated to the tight glycaemic control group showed a clear trend towards a reduction in deaths from PAD (relative risk 0.26, P = 0.12) and fewer amputations (relative risk 0.61, P = 0.099), although neither endpoint achieved statistical significance (UK Prospective Diabetes Study (UKPDS) Group, 1998a). Treatment of obese patients with metformin had a favourable effect on cardiovascular outcomes overall, but there was no evidence of a specific effect of metformin on amputation rates (UK Prospective Diabetes Study (UKPDS) Group, 1998b). Nevertheless hyperglycaemia in the UKPDS seems to be more strongly linked with PAD than coronary heart disease. (Figure 8.1) In the Diabetes Control and Complications trial (DCCT), tight glucose control (mean HbA1c 7.2% vs. 9.1%) resulted in a 22% relative risk reduction in major lower limb complications and a 42% relative risk reduction for the combined endpoint of coronary and peripheral arterial events, neither of which reached statistical significance (Diabetes Control and Complications Trial (DCCT) Research Group, 1995). Thus, in large randomised clinical trials, tight glycaemic control seems to have a more profound impact in the prevention of small-vessel rather than large-vessel disease. Increasingly, PAD is also thought to have a significant microvascular component. Microvascular disease, for example, has been shown to increase peripheral resistance and accelerate atherosclerosis. Data from the UKPDS support the likelihood of a shared pathogenesis of PAD with retinopathy (UK Prospective Diabetes Study (UKPDS) Group, 1998a). In addition, a histological study of lower limb small vessels from patients with diabetes and PAD showed that 80% had proliferative changes, with only 5% having atheromatous changes (Blumenthal etal., 1966).
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