麻豆传媒

ATLANTA -- Intensive blood pressure and lipid managment does little against elevated cardiovascular risk in diabetes, according to results from the ACCORD study, again proving lower isn't always better.

Using a blood pressure target of 120 mm Hg rather than the general population standard of 140 did not reduce the primary outcome of nonfatal MI, nonfatal stroke, and death from cardiovascular causes (1.87% versus 2.09% per year, hazard ratio 0.88, P=0.20), reported William C. Cushman, MD, of the VA Medical Center in Memphis, Tenn.

Likewise, adding fenofibrate to standard statin therapy did not reduce the major adverse cardiovascular events (2.24% versus 2.41% per year, HR 0.92, P=0.32), according to Henry C. Ginsberg, MD, of Columbia University in New York City.

Both studies, part of the complex double two-by-two factorial ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, were presented here at the American College of Cardiology meeting and released simultaneously online in the New England Journal of Medicine.

In an unprecedented move, the FDA released a statement shortly after presentation of the results, saying it would review the indication for Abbott Laboratories' Trilipix delayed-release formulation of fenofibrate (fenofibric acid). (See ACC: FDA Announces Review of ACCORD Data)

The drug was approved in 2008 for combination use with a statin to lower triglycerides and LDL cholesterol and raise HDL cholesterol. (See Fibrate Wins Indication for Combination Therapy with Statins)

The new lipid and blood pressure results round out the negative portrait of aggressive risk factor management in diabetes patients, commented Brian O'Murchu, MD, of Temple University in Philadelphia, and a co-chair of the ACC's annual scientific sessions planning committee.

The intensive glucose lowering arm of the trial was prematurely halted in 2008 because of 22% excess mortality with a near normal blood glucose target of 6% hemoglobin A1c. Nor did it have any benefit against cardiovascular events compared with a standard target of 7% hemoglobin A1c.

In an interview with 麻豆传媒, O'Murchu echoed the concern voiced by diabetologists at the initial presentation of the blood glucose arm results: Pushing too hard may not help and may actually hurt in some cases.

In the lipid arm of the trial, women tended to have a significantly worse rate of major adverse cardiovascular events with the addition of fenofibrate to simvastatin (Zocor) -- 9.1% versus 6.6% among men.

The lesson is that "flexible goals should probably be applied to the control of hyperglycemia, blood pressure, and dyslipidemia in patients with type 2 diabetes, taking into account individual clinical factors of importance," wrote Peter M. Nilsson, MD, PhD, of the University Hosptial of Malmö, Sweden, in a editorial accompanying the NEJM paper.

However, he pointed out that other especially high-risk subgroups appeared to benefit.

Patients in Ginsberg's lipid study who had triglycerides over 204 mg/dL and HDL cholesterol of 34 mg/dL or less tended to have a reduction in major adverse cardiovascular events with fenofibrate (12.4% versus 17.3%).

"This finding is of potential impotance, since the ATP III guidelines define a high triglyceride level as 200 mg/dL or more and a low HDL cholesterol level as below 40 mg/dL," Nilsson wrote. "The role of fibrates for correcting dyslipidemia in high-risk patients with diabetes is still not settled."

That sentiment appears to mirror the hopes of Abbott Laboratories, which has been aggressively advertising its Trilipix delayed-release formulation of fenofibrate on banners around the ACC conference venue and on buildings and billboards around the host city.

O'Murchu called it perhaps a case of premature celebration.

Fenofibrates have been commonly added to statins for diabetes patients because statins do little if anything to improve HDL or triglycerides.

Physicians "want to feel that they're doing everything they can," O'Murchu told 麻豆传媒.

However, based on the ACCORD data, routine use of fenofibrates is not indicated and use overall will likely be restricted to the highest risk subgroup with combined HDL and triglyceride trouble, he said.

Ginsburg agreed that their results did not support the combination for patients with HDL cholesterol and triglycerides near the normal range.

It was notable that the ACCORD trial inclusion criteria were highly representative of the heterogeneous mild-to-moderate hypertension and dyslipidemia seen in clinical practice among diabetes patients, O'Murchu noted.

"These data are going to apply to the majority of patients," he said in an interview.

The lipid arm of ACCORD included 5,518 patients with high risk of cardiovascular events because of clinical or subclinical cardiovascular disease or at least two risk factors. LDL cholesterol had to be between 60 and 180 mg/dL, HDL under 50 mg/dL or 55 mg/dL for women and blacks, and triglycerides under 750 mg/dL if not on any therapy or 400 mg/dL otherwise.

They were randomized to double-blind treatment with fenofibrate (54 to 160 mg per day based on kidney function) or placebo in addition to open-label simvastatin (20 to 40 mg per day).

Over the mean 4.7 years of follow-up, lipids and triglycerides responded as expected.

But in addition to the negative primary results, there were likewise no significant benefits for the prespecified secondary endpoints:

• Major adverse cardiovascular events plus revascularization and hospitalization for heart failure (P=0.30)
• Nonfatal MI (P=0.39)
• Total stroke (P=0.80)
• Nonfatal stroke (P=0.48)
• Total mortality (P=0.33)
• Cardiovascular death (P=0.26)
• Fatal and nonfatal heart failure (P=0.10)

Cushman's blood pressure portion of ACCORD compared a stategy targeting systolic blood pressure to under 120 mm Hg to one of under 140 mm Hg in 4,733 diabetes patients with high risk of cardiovascular events because of clinical or subclinical cardiovascular disease or at least two risk factors.

Participants also had to have blood pressure of 130 to 160 mm Hg while on up to three antihypertensives, 161 to 170 mm Hg if on up to two medications, or 171 to 180 mm Hg if on no more than one blood pressure drug.

Two-drug combination therapy and further titration in the intensive treatment arm effectively lowered blood pressure to an average of 119.3 mm Hg compared with 133.5 mm Hg in the standard treatment arm.

But again, there was no impact on the primary outcomes or the following secondary results:

• Total mortality (P=0.55)
• Cardiovascular deaths (P=0.74)
• Nonfatal MI (P=0.25)

There was a significant reduction with more intensive blood pressure lowering in nonfatal stroke (0.30% versus 0.47% per year, HR 0.63, P=0.03) and total stroke (0.32% versus 0.53% per year, HR 0.59, P=0.01).

However, this was counterbalanced by a higher risk of serious adverse events (3.3% versus 1.3%, P<0.0001), Cushman noted.

These findings support the JNC 7 guidelines for blood pressure managment in diabetes, which recommend a treatment target of 130 mm Hg, O'Murchu said.

"We may have to assume that the 'sweet spot' is between 120 and 140 mm Hg," he told 麻豆传媒.