ADVANCE: Perindopril/indapamide for all type 2 diabetes patients?

September 02, 2007

For a follow-up discussion of the ADVANCE trial, see ADVANCE reinforces message to aggressively treat blood pressure in diabetics

Vienna, Austria - Routine administration of a fixed-dose combination of perindopril and indapamide (Servier) to a broad range of patients with type 2 diabetes was associated with reduced risks of major vascular events, including death, in the ADVANCE study[1].

The study, which is being presented today at the European Society of Cardiology Congress 2007, is also published online in the Lancet. The authors say that if the benefits seen in ADVANCE were applied to just half the population with diabetes worldwide, more than a million deaths would be avoided over five years, and there is thus a case for considering routine treatment with perindopril/indapamide for patients with type 2 diabetes.

But in an accompanying comment published in the Lancet[2], Dr Norman M Kaplan (University of Texas Southwestern Medical Center, Dallas) cautions against overinterpretation of ADVANCE and suggests that other drugs that lower blood pressure as much and do not have metabolic side effects would be just as protective.

In the paper, the ADVANCE authors, led by Dr Anushka Patel (University of Sydney, Australia), note that blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes but that traditional strategies set arbitrary blood-pressure levels at which treatment is initiated, which neglects those diabetic patients without what is typically defined as hypertension. They also point out that this strategy is resource-intensive, needing multiple patient visits, careful monitoring of both blood pressure and side effects, and the coordination of complex drug regimens.

They suggest an alternative approach—adding a fixed-dose combination of blood-pressure-lowering drugs irrespective of initial blood-pressure level or the use of other antihypertensive drugs. They say that while this approach might not produce the largest blood-pressure reductions possible, it will shift the entire distribution of blood-pressure values down in patients with diabetes, with minimum requirements for titration and, potentially, with fewer side effects.

To investigate this idea, they conducted the ADVANCE trial, in which 11 140 patients with type 2 diabetes underwent a six-week active run-in period and were then randomized to treatment with a fixed combination of perindopril and indapamide or matching placebo in addition to current therapy. The combination therapy was given at a dose of perindopril 2 mg and indapamide 0.625 mg for the first three months, and then the dose of both agents was doubled. The use of concomitant treatments during follow-up, including blood-pressure-lowering therapy, remained at the discretion of the responsible physician, with two exceptions—the use of thiazide diuretics was not allowed, and open-label perindopril, to a maximum of 4 mg a day, was the only ACE inhibitor allowed, thus ensuring that the maximum recommended dose of 8 mg for perindopril could not be exceeded by patients randomly assigned to active treatment.

The primary end points were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, nonfatal stroke or nonfatal MI, and new or worsening renal or diabetic eye disease; analysis was by intention to treat. The macrovascular and microvascular composites were analyzed jointly and separately.

Results showed that after a mean of 4.3 years of follow-up, compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was significantly reduced by 9%. The separate reductions in macrovascular and microvascular events were similar but were not independently significant. Death from cardiovascular and from any cause was also reduced in the active-treatment group.

ADVANCE study major results

End point Active (n=5569) (%) Control (n=5571) (%) HR 95% CI p
Major macrovascular or microvascular event 15.5 16.8 0.91 0.83-1.00 0.04
Macrovascular event 8.6 9.3 0.92 0.81-1.04 0.16
Microvascular event 7.9 8.6 0.91 0.80-1.04 0.16
CV death 3.8 4.6 0.82 0.68-0.98 0.03
Death from any cause 7.3 8.5 0.86 0.75-0.98 0.03

The authors say there was no evidence that the effects of the study treatment differed by initial blood-pressure level or concomitant use of other treatments at baseline. They add that by the end of follow-up, antihypertensive drugs were being used by more than three-quarters of participants, and more than 90% were taking one or more glucose-lowering agents.

They add that the results suggest that for every 66 patients commencing long-term treatment with perindopril and indapamide, one patient would avoid at least one major vascular event in five years as a direct consequence of study treatment. They note that the major contributor to the 9% overall reduction in the risk of major macrovascular or microvascular events was an 18% reduction in the risk of death from cardiovascular disease, and from the results of ADVANCE, it seemed that over five years, one death would be averted in every 79 patients commencing treatment with the study drugs.

The ADVANCE authors also report that the fixed combination regimen was well tolerated, with only 3.6% of patients withdrawn because of suspected side effects during the prerandomization run-in period. At the end of the study, adherence to active treatment was 73%, only 1% less than adherence to placebo. They point out that this finding indicates that a short course of active treatment identifies the small proportion of patients who are intolerant, which means that only one follow-up visit would be needed to establish a patient's suitability for long-term treatment with this regimen. "This simple strategy, with its attendant reductions in vascular events and death, should prove practical and affordable in most clinical circumstances and might have special relevance in those primary healthcare settings where there are practical barriers to providing individually titrated treatment regimens for patients with diabetes," they say.

They conclude: "These results support the provision of treatment, not on the basis of arbitrary cutoffs for blood pressure, but rather on assessment of vascular risk, which is raised in patients with type 2 diabetes, even in the absence of hypertension."

Kaplan's caveats

In his comment, however, Kaplan raises several caveats about the study. He says that while the discontinuation rate on the fixed combination appears very low, 43% of participants were already taking an ACE inhibitor before the trial, and such an infrequency of cough would not be seen if ACE inhibitors were started in ACE-inhibitor-naive patients.

He also questions the validity of the claim that better outcomes could be attributed solely to the intake of perindopril and indapamide. "Perindopril and indapamide are surely not that much stronger than other antihypertensives in view of the almost equal efficacy of all antihypertensive agents in moderate doses," he writes. "I believe that other drugs—if they lower blood pressure as much and do not have metabolic side effects—would be as protective as this combination treatment. As has been said many times before by many experts: in most circumstances, lowering the blood pressure is what counts, not the way by which it is lowered."

ADVANCE was funded by grants from Servier and the National Health and Medical Research Council of Australia . Kaplan says he has no conflicts of interest.

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