ADVANCE-ON: Tight BP Control Lingers, Tight HbA1c Doesn't

Marlene Busko

September 22, 2014

VIENNA — Among older patients with longstanding type 2 diabetes, those who received about 4 years of intensive blood-pressure–lowering therapy as opposed to usual care had a lasting drop in their risk of MI, stroke, or death 6 years later, according to the new results from the follow-on of the ADVANCE study.

In contrast, after receiving intensive glucose-lowering therapy for about 4 years, the patients did not have any lasting survival or cardiovascular benefits, but they did have a lower risk of end-stage renal disease.

Sophia Zoungas, MD, PhD, and John Chalmers, MD, PhD, of the George Institute for Global Health, University of Sydney, Australia, presented these findings from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational Study (ADVANCE-ON), in the final session on Friday at the European Association for the Study of Diabetes 2014 Meeting. The study was simultaneously published in the New England Journal of Medicine.

"If your aim is to reduce end-stage kidney disease, then clearly intensive glycemic control is important, and the closer you can get to normal glycemia, the better," Dr. Zoungas commented to Medscape Medical News.

"However, we were unable to show any evidence that it actually leads to long-term effects for mortality or major macrovascular events."

In contrast to ACCORD, which "so prominently showed an increased risk" for death from cardiac causes [with intensive glycemic control], in ADVANCE, in a cohort with a similar age and history of diabetes, they found "certainly no harm, but benefits for microvascular outcomes (nephropathy)," she added.

"We've all been blinded by this increased signal that might not necessarily be a true effect, but may only be a chance effect," she said. In ACCORD, treatment was rapidly titrated to achieve an HbA1c of 6.5% within 6 months, whereas in ADVANCE, therapy was titrated more gradually to reach this target in a year, which more closely reflects clinical practice, she noted.

ADVANCE Showed Benefits of Tight BP, Glucose Control

As previously reported by Medscape Medical News, ADVANCE enrolled 11,140 individuals worldwide who had type 2 diabetes, were 55 or older, and at increased risk of cardiovascular disease.

The patients were randomized to standard care or intensive glucose control (aiming for an HbA1c of 6.5% or lower) with the sulfonylurea glicazide (Diamicron MR, Servier) and also randomized to placebo or the fixed-dose combination antihypertensive of 4 mg perindopril/1.25 mg indapamide (Preterax, Servier) daily.

In the intensive blood-pressure–lowering therapy arm, the patients initially had a mean BP of 145/81 mm Hg, which dropped to 136/74 mm Hg in the active-treatment arm and 140/75 mm Hg in the placebo arm.

In the glucose-control arm, the mean HbA1c went from 7.5% to 7.1% among patients who received standard care, and it dropped to 6.5% in patients who receive intensive glucose-lowering therapy.

At the end of ADVANCE, intensive BP control resulted in a 14% reduction in total mortality, an 18% reduction in cardiovascular death, a 9% reduction in major vascular events, a 14% reduction in total coronary events, and a 21% reduction in renal events.

Intensive glucose control resulted in a 10% reduction in combined macro- and microvascular events, a 14% reduction in microvascular events, a 21% reduction in new or worsening nephropathy, and a 65% reduction in end-stage kidney disease, but no reduction in total mortality.

Benefits Accrued During Intensive BP Lowering; Control Important

At the end of ADVANCE, patients went back to usual care, at the discretion of their treating physician.

ADVANCE-ON was designed as the posttrial follow-up to see what happened to these patients after intensive blood-pressure and glucose control were stopped: would the benefits go away or last, as time went by?

The researchers hypothesized that there would be "persistent and/or emerging health benefits in the ADVANCE participants that were initially assigned to the intervention groups," Dr. Zoungas said.

The ADVANCE-ON cohort consisted of 8494 participants from ADVANCE and was broadly representative of the original population.

In ADVANCE-ON, after a further 5.9 years of standard care, the BP readings in both groups converged to 137/74 mm Hg.

Patients in the original active-treatment group had attenuated but significant benefits on all-cause mortality, cardiovascular death, and major macrovascular events, suggesting that most of the benefits had accrued during the period of the intensive BP-lowering therapy and were carried forward.

"Blood-pressure lowering does confer real benefits," Dr. Chalmers said. Since the reductions were still evident, although lessened, "it is critically important to maintain blood-pressure" lowering to derive long-term benefits, he said.

Intensive Glycemic Control Benefits Kidney, Doesn't Cause Harm

At the end of the ADVANCE-ON study, the HbA1c levels converged to about 7.3% in both groups.

At the final posttrial visit, in both groups, about 54% were on metformin, about 40% were on glicazide or another sulfonylurea, about 10% were on another oral agent, and about 45% were on insulin. About half were taking a statin, and an equal number were taking aspirin.

The difference in HbA1c achieved during the ADVANCE trial was lost by the first posttrial follow-up visit and remained similar until the last posttrial follow-up, Dr. Zoungas noted.

The take-home message from the glucose-control arm is that "intensive glucose control is important for preventing serious renal complications and does not cause harm (does not increase the risk of mortality and cardiovascular events) in people with established type 2 diabetes," she said.

She went on to speculate that there were perhaps insufficient differences in glucose control or an insufficient period of intensive treatment to produce changes to the vasculature that would translate into long-term benefits.

What Does This Mean for Clinicians?

Assigned commenter, Joachim Spranger, MD, from Charité-Universitätsmedizin Berlin, Germany, boiled down his take on the ADVANCE-ON findings into 3 questions and answers:

  • Is a legacy effect supported by ADVANCE-ON? Yes.

  • Do the results change our HbA1c targets? No.

  • Do the results change our perspective on the medical treatment of patients with type 2 diabetes? Yes.

"The ADVANCE-ON trial was not made to investigate the question of which specific drug is successful in lowering risk. It was a target-driven trial," Dr. Spranger said.

However, the patients most often received the combination of metformin and sulfonylurea, plus insulin. "This is not Ib evidence,'s the best we have" and suggests this combination is safe.

"We urgently need novel drugs, because none of the trials show [therapy that provides] a substantial improvement or lowering of fatal cardiovascular disease risk. That would be the holy grail.

"In ACCORD, many patients had 3 or more oral therapies; that was different in the ADVANCE trial, and I think that may have contributed to the fact that in the ACCORD trial there was an increased risk of mortality," he concluded.

The study was supported by grants from the National Health and Medical Research Council of Australia, a joint grant from Diabetes UK and the British Heart Foundation, and an unrestricted educational grant from Servier International. Dr. Zoungas reports receiving fees for serving on advisory boards from Merck Sharp and Dohme, Bristol-Myers Squibb/AstraZeneca, Sanofi, Novo Nordisk, and Amgen; lecture fees from Servier, Merck Sharp and Dohme, and Bristol-Myers Squibb/AstraZeneca; and fees to her institution for research contract work with Bristol-Myers Squibb/AstraZeneca. Dr. Chalmers reports receiving lecture fees and travel support from Servier. Disclosures for the coauthors are listed in the article. Prof. Spranger has received consultancy fees from Bristol-Myers Squibb and Amgen. For preparing scientific CME events he has received honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp and Dohme, Berlin-Chemie, Sanofi, and Novo. He has also received funding from Sanofi.

European Association for the Study of Diabetes 2014; September 19, 2014. Oral presentations 1426, 1427, 1428, 1429.

N Engl J Med.Published online September 19, 2014. Article


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