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SAN FRANCISCO, June 6 -- Not only was ultra-tight glucose control linked to excess deaths in the star-crossed ACCORD trial, but it was no more effective than standard therapy in reducing cardiovascular events among patients with type 2 diabetes, researchers said here.

Intensive treatment was also associated with significantly higher rates of hypoglycemia requiring assistance and with weight gain of more than 10 kg, according to Hertzel Gerstein, M.D., of McMaster University in Hamilton, Ontario, at a press briefing at the American Diabetes Association meeting.

A formal report on the 10,251-patient Action to Control Cardiovascular Risk in Diabetes (ACCORD) study by Dr. Gerstein and colleagues in the New England Journal of Medicine was released early online to coincide with the briefing.

ACCORD was intended to show whether extremely tight glucose control would reduce cardiovascular events in diabetic patients at high risk for them.

The intensive-treatment arm of ACCORD had been halted in February after interim analysis revealed the increased mortality. (See: Deaths Force NHLBI to Drop Intensive Glucose-Lowering Strategy in Type 2 Diabetes)

With mean follow-up of 3.5 years -- out of a planned five years -- the hazard ratio for deaths with intensive treatment versus standard therapy was 1.22 (95% CI 1.01 to 1.46).

Moreover, there was no significant difference between groups in the study's primary endpoint, a composite of nonfatal heart attack, nonfatal stroke, and death from cardiovascular causes, Dr. Gerstein said.

He reported a hazard ratio of 0.90 for intensive versus standard therapy (95% CI 0.78 to 1.04).

In ACCORD, patients with type 2 diabetes at high risk for cardiovascular complications -- because of multiple risk factors or confirmed pre-existing disease -- were randomized 1:1 to the two arms.

The intensive-treatment arm used a mix of drugs -- including insulin -- and lifestyle modifications to bring glycated hemoglobin levels below 6%.

With standard therapy, the glycated hemoglobin goal was 7% to 7.9%.

The same drugs, representing all major classes of anti-diabetic medication, were available to both groups, but higher doses were used in the intensive-treatment arm. That arm also had more frequent contacts with study investigators.

After a year of treatment, median glycated hemoglobin was 6.4% with tight control (interquartile range 6.1% to 7%) and 7.5% with standard treatment (IQR 7% to 8.1%).

The report confirmed that the excess deaths with intensive treatment were mainly from cardiovascular causes, with 41 more patients dying from strokes, heart attacks, congestive heart failure, arrhythmia, or invasive interventions than in the standard therapy group (135 versus 94 deaths, HR 1.35, 95% CI 1.0 to 1.76). The cardiovascular deaths appeared to be spread evenly among the different specific causes.

Nonfatal heart attacks, however, were significantly less common with intensive treatment (HR 0.76, 95% CI 0.62 to 0.92).

Intensive therapy also showed disadvantages or no benefit on other outcomes:

• Hypoglycemic events requiring any assistance: 16.2% versus 5.1% (PFluid retention: 70.1% versus 66.8% (PWeight gain of more than 10 kg: 27.8% versus 14.1% (P

  
  

  Mean diastolic and systolic blood pressure was lower with tight control, but the differences were only about 1 mm Hg.

  
  

  Today's press briefing also included a report on ADVANCE, another major trial that examined the effects of extremely tight glucose control. (See ADA: Tight Glucose Control No Help for Cardiovascular Risk in Type 2 Diabetes)

  
  

  The ADVANCE investigators also reported no advantage in preventing cardiovascular events. However, their intensive treatment strategy, which differed from that used in ACCORD, did result in lower rates of nephropathy.

  
  

  In an editorial accompanying the reports in the New England Journal of Medicine, William T. Cefalu, M.D., of the Pennington Biomedical Research Center in Baton Rouge, La., suggested that the 6% glycated hemoglobin goal for intensive control may have been too aggressive.

  
  

  "A target glycated hemoglobin level of approximately 7% may be appropriate in this high-risk population, especially when the use of aggressive pharmacologic therapy is under consideration," he wrote.

  
  

  He also pointed out that both ACCORD and ADVANCE included only high-risk patients, putting their generalizability to the broader population of type 2 diabetic patients in doubt.

  
  

  "Whether achieving glycemic targets below 7% will be beneficial to the vast majority of patients with type 2 diabetes and a low risk of cardiovascular disease remains another unanswered question," Dr. Cefalu said.

  
  

  In a separate commentary, Harlan M. Krumholz, M.D., of Yale University, and Thomas H. Lee, M.D., of Partners Healthcare System in Boston, said the ACCORD and ADVANCE results showed that focusing treatment on measures of risk factors, rather than clinical outcomes, may be a mistake.

  
  

  "The assessment of net clinical benefit should be based on events averted or lives improved," they wrote.

  
  

  Drs. Krumholz and Lee also argued that treatment guidelines should link treatment goals, such as target levels of glycated hemoglobin or blood lipids, with specific strategies proven to achieve them safely.

  
  

  "Guidelines and performance measures should reflect the evidence about interventions that are known to be beneficial," they wrote.

  
  

  
  

  ACCORD was funded by the National Institutes of Health, the CDC, and General Clinical Research Centers. Medications, equipment, and supplies were provided by Abbott, Amylin, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline, King, Merck, Novartis, Novo Nordisk, Omron, sanofi-aventis, and Schering-Plough. Dr. Cefalu reported relationships with Eli Lilly, Amylin, Pfizer, and Merck. No other potential conflicts were reported.

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