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What does this study claim?
The Lancet published the results of the ADVANCE study on the 2nd September 2007. It examined the effect of a fixed combination of an angiotensin converting enzyme inhibitor (ACEI) and a diuretic on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus. The combination gave some benefits over placebo and is being suggested by the media as the preferred regimen in such patients
What were the details of the study?
This was a randomised controlled trial (RCT) of 11,140 patients aged 55 years and older and who had been diagnosed with type 2 diabetes at age of 30 or older. Patients also had to have either a personal history of cardiovascular disease (including stroke and MI) or at least one risk factor (including renal damage, retinopathy, blindness). 1,737 other patients who been recruited withdrew during the run-in phase, at least 29% of these due to adverse effects.
Active treatment with a combination of perindopril and indapamide (initially 2mg/0.625mg titrated to 4mg/1.25mg after 3 months) was compared with placebo. All concurrent medications were continued with the exception of ACE inhibitors, which were switched for open-label perindopril at 2mg or 4mg. Allocation concealment was not stated and this is a potentially large source of bias. At the end of the study, 74% the active treatment group and 83% of those taking placebo were also taking other blood pressure lowering drugs. This could have diminished the effects of the treatment by reducing the differences in blood pressure reduction seen between the groups.
The primary endpoints were major macrovascular events (death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction) and major microvascular events (new or worsening renal disease or new or worsening diabetic eye disease). The patients were followed up for a mean of 4.3 years with nearly 75% of patients remaining on the randomised treatment at the end of follow up.
The reported outcomes were as follows:
- Major macrovascular and microvascular events when combined were reduced by 1.3%, number needed to treat (NNT) = 77, a relative risk reduction (RRR) of 9% [hazard ratio (HR) 0.91, 95% CI 0.83-1.00, p=0.04.
- However, when major macrovascular events or major microvascular events were analysed separately, differences were not significant.
- Death from cardiovascular disease was reduced by 0.8%, NNT=125, a RRR of 18% (HR 0.82, 95% CI 0.68-0.98, p=0.03)
Death from any cause was reduced by 1.2%, NNT= 83, a RRR of 14% (HR 0.86, 95% CI 0.75-0.98, p=0.03)
How does this relate to existing evidence?
The United Kingdom Prospective Diabetes Study has already shown that tight blood pressure control reduces the risk of macrovascular and microvascular complications in type 2 diabetes. Similar evidence does NOT exist for tight control of blood glucose. National Institute for Health and Clinical Excellence (NICE) guidance for managing blood pressure in type 2 diabetes provides treatment thresholds, targets and provides advice on the choice of antihypertensive agent.
So what?
The authors of the paper conclude that, “routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death”. This is true. But so are other blood pressure lowering regimens. It is also notable that the study did not set a blood pressure target but simply added in the study drugs to existing therapy. The mean blood pressure in patients in the active arm differed from those patients in the placebo arm by 5.6/2.2mmHg and this was highly significant (p<0.0001). It is therefore possible that the differences observed were an effect of lower blood pressure rather than any drug specific action.
So this study confirms what we were already pretty sure about – lowering blood pressure in patients with type 2 diabetes reduces cardiovascular complications and deaths. NICE guidance on this should be followed with patients encouraged to try and control their blood pressure to the national targets or as close to this as possible while taking into effect adverse effects. Some have questioned the use of thiazides in people with type 2 diabetes – this study backs up the advice that a thiazide diuretic is a good first choice agent in most people.
You may find useful the educational resources on the diabetes type 2 and hypertension sections of NPC