ADVANCE Reinforces Message to Aggressively Treat Blood Pressure in Diabetics

September 04, 2007

September 4, 2007 (Vienna, Austria) - The ADVANCE trial, showing a reduction in major events (including death) with the fixed-dose combination antihypertensive perindopril/indapamide (Servier) in a broad range of type 2 diabetic patients regardless of their blood pressure at baseline, was well received when reported at the European Society of Cardiology (ESC) Congress 2007 today.

But while the study investigators say the results justify giving this fixed-dose combination drug as blanket therapy to all diabetic patients, other experts said they interpreted the data as giving more solid evidence to treat blood pressure in diabetics down to the 130/80 mm Hg target now recommended in most national guidelines.

Presenting the trial at a hotline session, Dr Steven MacMahon (University of Sydney, Australia) explained that the previous UKPDS study had established that reducing blood pressure produced benefits in diabetics. Blood pressure was lowered from 155 systolic to 145 systolic in UKPDS, and the ADVANCE study extended these findings to patients with lower pressures, he noted. In ADVANCE, which with 11,140 patients is the largest-ever trial of the prevention of diabetes complications, the average blood pressure at baseline was 145/81 mm Hg, and this was reduced to 135/75 mm Hg in the active-treatment group vs 140/77 in the placebo group over the 4.3-year follow-up.

This better reduction pressure in the active-treatment arm was associated with significant reductions in outcomes, with one major vascular event prevented for every 66 patients treated for five years, one death prevented in every 79 patients, one coronary event in every 75 patients, and one renal event in every 20 patients. "By any standards, these are large benefits," MacMahon said. These benefits were achieved on top of aggressive ancillary drug therapy, with the majority of patients in both arms also taking other blood-pressure-lowering agents.

MacMahon told heart wire that this is the first trial that has shown the importance of lowering blood pressure for all diabetic patients, regardless of whether they are hypertensive or not. "We didn't see any problems with low blood pressure, and we believe antihypertensive treatment should now be considered for all diabetics."

Speaking at a Servier press conference, Dr Giuseppe Mancia (University of Milan, Italy), who was also involved in the ADVANCE trial and is chair of the European Society of Hypertension/ESC hypertension guidelines committee, said the study provided much-needed new evidence to support the recommendations already in the guidelines for lower target blood pressures in diabetic patients. But he said was not advocating ignoring blood pressure completely. "All diabetic patients should still have their blood pressure measured, and treatment should be given to those with pressures above 130/80."

While MacMahon believes that it is probably the blood-pressure reduction that produced the benefit in this trial rather than the specific agents used, he says the idea of giving everyone a fixed-dose combination drug such as the one used in ADVANCE is in the logistics. "This is a very simple strategy. Getting patients down to blood-pressure goals is notoriously difficult and involves titrating multiple drugs over many different consultations, with many patients ending up on just one treatment. Giving everyone a combination drug straight away works well to achieve aggressive blood-pressure reduction, and we have shown that this particular combination is well tolerated," he commented to heart wire . ADVANCE co-principal investigator Dr John Chalmers (University of Sydney) added: "The simplicity of a single combination tablet given to all diabetic patients will make a huge difference in lowering blood pressures across the board. It will enable many more patients to get treated than do currently. It would be a bit like taking an aspirin a day if you have CHD."

Other experts not involved in the ADVANCE study were also impressed with the results but were less convinced about the necessity of using this one combination agent in all patients.

Discussant of the study at the hotline session, Dr Sydney Smith (University of North Carolina, Chapel Hill), said it was a very important trial. "There is a major increase in diabetes occurring, particularly in the developing world, and this trial included 45% of its patients from countries with developing economies and showed important benefits in cardiovascular death," he noted.

Filling the evidence gap

Smith said he was "somewhat surprised" that there was no benefit in ADVANCE in cerebrovascular disease, and he said he "took issue" with the idea that the benefits were also seen in the nonhypertensive population. "Hypertension seems to have been defined in this study as a blood pressure of 140/90 or above, but in diabetics it should be defined as 130/80. That is the target for high-risk patients, and diabetics are high-risk patients. But although the guidelines do now recommend that blood pressure be lowered to 130/80 in this population, until now we did not have good evidence for this systolic pressure. So that is why this trial is important for me. I see it at providing that evidence." Smith said more evidence was needed on target blood pressure in diabetics, and more will come from the ACCORD trial, which is reporting soon, and is looking at targets of 120 to 140 mm Hg.

Blanket therapy or treat to target?

Smith added that he would also be cautious about the idea of giving blanket therapy to all diabetics. "To me, it seems that the typical person who benefited in this trial was a 55-year-old who had had diabetes for several years and had a systolic blood pressure at entry of about 145 mm Hg. I can't see much evidence in this study that a 35-year-old diabetic with blood pressure of 130/80 would benefit much from more drug therapy." Another issue that Smith said remain to be resolved was whether ACE inhibitors have benefits other than blood-pressure lowering in diabetics, adding, "I would think that the benefits in this trial are primarily related to the blood-pressure reduction."

Chair of the session, Dr Raymond Gibbons (Mayo Clinic, Rochester, MN), agreed with many of Smith's comments. "This is a very important study. It supports the idea of that we can achieve lower mortality rates with lower blood pressures in diabetic patients. ADVANCE shows we need to make more effort to control blood pressure to targets in diabetic patients," he commented to heart wire . "The national guidelines already state that blood-pressure targets are lower for diabetics (130/80) than the normal population (140/90), and this trial reinforces that concept. The message I take home from this trial is that we should be treating diabetic patients aggressively to get their blood pressure down to 130/80. This is a simple message, but it's not being done. This trial should help get that message across," he added.

Gibbons says he does not believe that this one particular combination agent has to be used. "Yes, this trial shows the tolerability and benefits of this particular drug combination, but one would hope that the link between reducing blood pressure and improving mortality will be generalizable to other antihypertensive medication. I personally am not bothered about how we lower the blood pressure to these levels--there are many different options, in my view."

Dr Freek Verheugt (Nijmegen University, the Netherlands) echoed this view. He commented to heart wire : "For me, as a general cardiologist, this trial is telling me that the lower the blood pressure, the better for diabetic patients.I would not think that it has to be lowered necessarily with these particular drugs. But the 130/80 target for diabetics certainly seems a lot more solid after this study. They have a large trial with a lot of beautiful data. I'm sure we will see much more interesting information from these data in future publications."

MacMahon and Chalmers have received research grants from Servier for the ADVANCE study, which were administered through the University of Sydney, and MacMahon, Chalmers, and Mancia have received honoraria from the company for speaking at meetings.

The complete contents of Heart wire , a professional news service of WebMD, can be found at, a Web site for cardiovascular healthcare professionals.


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