The latest research

The latest research developments were presented at the recent conferences of the European Association for the Study of Diabetes and the European Cardiology Society. By Sharon Pickett and Sanjay Tanday


Liraglutide as add-on therapy in patients with type-2 diabetes
Latest results from the LEAD (Liraglutide Effect and Action in Diabetes) series of phase III studies with liraglutide have shown promise for the drug as add-on therapy to metformin and rosiglitazone in patients with type-2 diabetes.

In LEAD4, 533 patients aged 18-80 (mean age 55.1 years) in North America received the human glucagon-like peptide (GLP-1) analogue liraglutide (1.2mg or 1.8mg subcutaneous injection once daily) or placebo in conjunction with metformin 2g per day plus rosiglitazone 4mg twice daily.

At 26 weeks, more than half of the patients in the study group reached HbA1c <7% compared to 28 per cent in the placebo group, with 35 per cent reaching HbA1c ≤6.5% compared to 14 per cent on placebo.

Patients taking 1.2mg and 1.8mg liraglutide experienced statistically significant reductions in systolic BP of -6.7mmHg and -5.6mmHg respectively, versus -1.1mmHg control. They also experienced weight changes of -1.02kg and -2.02kg respectively versus +0.60kg control. Liraglutide is awaiting US Food and Drug Administration and European Medicines Agency approval and is expected to be launched in mid-2009. SP

Reducing the risk of CVD and renal complications in diabetes
Latest analysis of results from the Action in Diabetes and Vascular Disease (ADVANCE) trial show that combining BP control with intensive glucose lowering can reduce the risk of cardiovascular disease and renal complications in patients with type-2 diabetes.

The ADVANCE trial randomised 11,140 patients across 20 countries to either placebo or BP lowering using a fixed dosage of the ACE inhibitor perindopril and the diuretic indapamide. Patients in each group were then randomised to receive either standard blood glucose lowering or intensive treatment with gliclazide plus other drugs as required, to reach HbA1c ≤6.5%. The mean age of patients was 65.8 years.

Results of the BP-lowering arm were published in 20071 and those of the blood glucose lowering arm in 2008.2 According to researchers, combination therapy reduced the risk of death from cardiovascular disease by 24 per cent, risk of nephropathy by 33 per cent and all-cause mortality by 20 per cent. In addition, analysis of the results shows the effects of the two treatments are independent and additive for all clinical outcomes. SP

1. MacMahon S, Chalmers J, Neal B et al, ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829-40.
2. Patel A, MacMahon S, Chalmers J et al, ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24): 2560-72.

The benefits of early treatment in patients with type-2 diabetes
Researchers have backed the early treatment of type-2 diabetes after the UKPDS released 10-year post-trial monitoring data showing the long-term effects of glucose and BP control in patients with the condition.

The landmark UKPDS trial initially followed 5,102 patients from 1977 to 1997 and showed that complications of diabetes could be reduced by improving blood glucose and/or BP control.

On completing the trial, all surviving patients were returned to community or hospital-based diabetes care according to their clinical needs, but with no attempt or intervention to maintain them on their randomised therapies.

Over a further 10-year, post-trial monitoring period, patients continued to receive annual assessment at UKPDS clinics, where possible, for five years, followed by questionnaire-based assessment with input from patients' GPs to capture possible endpoints for an additional five years.

Results showed that between 1997 and 2007, after return to usual care, RR reduction for MI and all-cause mortality persisted in patients who received blood glucose control in the original trial. For MI, patients taking suphonylureas/insulin had an RR reduction of 16 per cent in 1997 and 15 per cent in 2007, while for all-cause mortality, these figures were 6 and 13 per cent, respectively. Patients taking metformin had RR reductions for MI of 39 per cent in 1997 and 33 per cent in 2007, and 36 and 27 per cent for all-cause mortality, respectively.

Those patients who received BP-lowering therapy during the UKPDS trial showed no 'legacy effect' and analysis of results suggested that the difference had gone after two years. The researchers said this finding suggests that changes made to usual care guidelines following announcement of the UKPDS results in 1997 were working and that BP-lowering treatments have their maximal beneficial effect early. SP

The effects of ARBs in treating diabetic retinopathy
Lancet Online September 2008 DOI:10.1016/S0140-6736(08)61412-9

ARBs may have a positive effect on diabetic retinopathy, according to researchers. The DIRECT trial aimed to examine the effects of candesartan on the incidence and progression of diabetic retinopathy in patients with type-1 and type-2 diabetes.

The trial consisted of three studies – primary and secondary prevention studies in normotensive patients with type-1 diabetes, and secondary prevention in either normotensive or treated hypertensive patients with type-2 diabetes.

A total of 4,500 patients were randomised to receive either 32mg candesartan or placebo for a period of three years at more than 300 centres worldwide.

The trial failed to reach its primary endpoints, but showed an 18 per cent reduction in incidence of diabetic retinopathy in patients with type-1 diabetes (p = 0.0508), and a 13 per cent reduction in risk of progression of retinopathy in patients with type-2 diabetes (p = 0.2). Regression of retinopathy was also increased by 34 per cent compared to placebo in patients with type-2 diabetes taking candesartan (p = 0.009). The authors concluded that treatment with candesartan might confer benefit for retinopathy in patients with diabetes. SP


Slowing down the heart rate can reduce the risk of MI
Fox K, Ford I, Gabriel Steg P et al on behalf of the BEAUTIFUL investigators. Lancet 2008; 372: 807-16

Taking the heart rate inhibitor ivabradine can reduce the risk of MI by 36 per cent in patients with stable coronary artery disease (CAD), UK research suggests.

This is the first time a study has shown that using a drug to lower heart rate can lead to a reduction in coronary events in patients already receiving optimal therapy.

The morbidity-mortality evaluation of the IF inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction (BEAUTIFUL) trial involved 10,917 patients with a resting heart rate of >60 beats per minute (bpm), with stable CAD and left ventricular systolic dysfunction. Patients were randomly assigned either 5mg of ivabradine daily or placebo. Some 87 per cent of the patients were already receiving treatment with beta-blockers.

After the 19-month follow-up, the researchers found that in patients with a heart rate >70bpm, ivabradine reduced the risk of hospitalisation for fatal and non-fatal MI by 36 per cent compared to placebo. The risk of coronary revascularisation was reduced by 30 per cent for these patients and the risk of angina by 22 per cent. ST.

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