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GPs with an interest in cardiovascular disease review papers of significance from research teams across the world.

Blood glucose control and vascular outcomes
Patel A, MacMahon S, Chalmers J, Neal B, The ADVANCE Collaborative Group. N Engl J Med 2008; 358(24): 2560-72
Debate continues about whether intensive glucose control confers a superior cardiovascular outcome compared to standard control in type-2 diabetes.

Given the significant burden diabetes poses on cardiovascular risk, reliable studies must be carried out to guide clinical decision-making. This large five-year prospective study involved more than 11,000 patients with type-2 diabetes and aimed to discover whether tight glucose control reduces both micro- and macrovascular disease.

Those achieving an HBA1c of 6.5% or less by modified-release gliclazide and additional drug therapy were considered to have intensive control. Micro- and macrovascular outcomes were measured. The average HBA1c in the standard control group was 7.3%. Pooled micro- and macrovascular events were reduced more in the intensive group compared to the standard control group (incidence 18.1 versus 20 per cent p = 0.01).

More detailed analysis, however, revealed the effect on vascular events was primarily due to a reduction in incidence of nephropathy (21 per cent RR reduction in the intensive group) and that there were no significant differences in retinopathy or macrovascular events between the intensive and the standard groups. The authors suggest that intensive glucose control achieved by drugs, including modified-release gliclazide, only acts to reduce diabetic nephropathy and the trade-off is an increased incidence of hypoglycaemia, which may be severe and require hospitalisation.
- Dr Raj Thakkar is a GP in Wooburn Green, Buckinghamshire, and a hospital practitioner in echocardiography at Stoke Mandeville Hospital, South Bucks NHS Trust

Direct renin inhibitors in diabetes and nephropathy
Parving HH, Persson F, Lewis JB et al for the AVOID Study Investigators. N Engl J Med 2008; 358(23): 2433-46
Direct renin inhibitors (DRI) are being prescribed in secondary care and there is a move towards GPs providing them in the community. The key question is, do they provide significant and favourable clinical outcomes?

This study aimed to assess whether DRIs offer an advantage when added to losartan in the management of diabetic nephropathy. The double-blind study involved nearly 600 patients with nephropathy secondary to type-2 diabetes. All were treated to achieve optimal BP control and were prescribed losartan 100mg once daily for three months.

After the three-month run-in period, randomisation took place to receive either placebo or aliskiren (150mg once daily for three months, then 300mg once daily). Both groups continued to take losartan in addition to their standard drugs.

Urinary albumin:creatinine ratio (U a:c) was measured at six months. Patients receiving DRIs achieved a 20 per cent (95 per cent CI 9-30, P <0.001) reduction in U a:c, compared to placebo. A quarter of patients in the treatment arm were found to have a 50 per cent fall in U a:c, whereas in the losartan-only group, just 12.5 per cent managed such a reduction. The BP difference was not statistically significant between the two groups. Data are now required on whether DRIs influence progress to end-stage renal failure and on the incidence of cardiovascular outcomes. This study, however, supports the use of DRIs in patients with type-2 diabetic nephropathy. RT

Effects of intensive glucose lowering in type-2 diabetes
Gerstein HC, Miller ME, Byington RP et al. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358(24): 2545-59

Eighty per cent of patients with type-2 diabetes will have cardiovascular disease (CVD) and are generally treated aggressively to minimise disease burden. This study asked whether intensive therapy to reduce HBA1c to normal levels actually conferred an advantage in cardiovascular outcomes.

Patients were selected if they had type-2 diabetes and either established CVD or another risk factor. More than 10,000 patients were included in the study.

Before intervention, the average HBA1c was 8.1%. Usual treatment aimed to reduce the HBA1c to 7.0-7.9%, whereas the intensive arm aimed to achieve an HBA1c of 6.0% or less. Real clinical end-points were measured, including fatal and non-fatal cardiovascular events. Perhaps counterintuitively, the study was stopped prematurely after 3.5 years because there were more deaths from any cause in the intensive group than in the standard treatment arm, although non-fatal cardiovascular event rates were not statistically significant between the two.

The excess deaths may not be directly attributable to the absolute HBA1c level. The rate of HBA1c decline and the treatment strategies used may be two of many factors under suspicion and until the culprit is found, this study should be interpreted with caution. RT

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