ACCORD: No reduction in CV events with intensive BP, lipid therapies

Lower BP targets and combination lipid therapy failed to reduce the overall risk for CV events in patients with type 2 diabetes compared with standard treatment strategies, according to the results of two new Action to Control Cardiovascular Risk in Diabetes trials, leading many health care professionals to reason that intensive therapy may not be better in diabetes.

The landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is one of the largest studies ever conducted in adults with type 2 diabetes at especially high risk for CV events. The multicenter, clinical trial tested three potential strategies to reduce the risk for major CV events: intensive glycemic control, intensive BP control and intensive lipid control. In 2008, results of the ACCORD glycemia trial revealed an increased risk for death with intensive glycemic control compared with standard control. Now, new data suggested failed to show benefit of intensive control in the other two trials.

In the ACCORD BP trial, targeting therapy to achieve a BP of less than 120 mm Hg had no significant effect on the combined rates of nonfatal MI, nonfatal stroke or CV death compared with conventional BP control aimed at a systolic BP of less than 140 mm Hg. Similarly, intensive lipid therapy with fenofibrate (TriCor, Abbott) plus simvastatin (Zocor, Merck) failed to reduce the rate of fatal and nonfatal CV events compared with simva-statin monotherapy in the ACCORD lipid trial. Results were presented in March at the American College of Cardiology 59th Annual Scientific Session and simultaneously published online in The New England Journal of Medicine.

Despite the negative findings of both trials, “We need trials like ACCORD because it illustrates that our previous beliefs about preventing CV outcomes in patients with diabetes may not have been founded on the best evidence,” Bernard Zinman, MD, director of the Leadership Sinai Centre for Diabetes and professor of medicine at the University of Toronto, said in an interview.

Henry N. Ginsberg, MD, presented the results of the ACCORD lipid trial at the 59th Annual American College of Cardiology Scientific Sessions in Atlanta. Photo courtesy of: Columbia University

The data will provide evidence to help guide treatment recommendations for adults with type 2 diabetes who are at high risk for CVD, according to Susan B. Shurin, MD, acting director of the National Institute of Health’s National Heart, Lung, and Blood Institute, which funded the trial.

“This information provides guidance to avoid unnecessarily increasing treatment that provides limited benefit and potentially increases the risk of adverse events,” Shurin said in a press release.

Cardiology Today interviewed ACCORD researchers and experts in endocrinology and cardiology to provide insight on whether intensive therapy is better when considering CV outcomes in diabetes.

Optimal BP target

The ACCORD trial enrolled 10,251 high-risk patients aged 40 to 79 years with type 2 diabetes and CVD or CVD risk factors. All participants were randomly assigned to intensive or standard glycemic control for the ACCORD glycemia trial. In addition, 4,733 patients were also randomly assigned — in a two-by-two factorial design — to a strategy to target intensive (≤120 mm Hg) or standard (≤140 mm Hg) systolic BP control, using a variety of BP-lowering medications, for the ACCORD BP trial.

Intensive BP treatment did not reduce the overall risk for CV events compared with standard treatment. After one year of follow-up, systolic BP levels averaged 119.3 mm Hg in the intensive-therapy group compared with 133.5 mm Hg in the standard-therapy group during the course of the trial. After five years, the researchers observed no significant differences in the combined rate of nonfatal MI, nonfatal stroke or CV death in the intensive-therapy group (1.875%) vs. the standard-therapy group (2.09%; HR=0.88; 95% CI, 0.73-1.06). The rate of death from any cause was 1.28% with intensive therapy vs. 1.19% with standard therapy (HR=1.07; 95% CI, 0.85-1.35).

“Intensive therapy did not show a benefit in getting the systolic BP down to 120 mm Hg, even though there was an effect on a secondary outcome,” William C. Cushman, MD, chief of the preventive medicine section, Veterans Affairs Medical Center, Memphis, Tenn., said at a press conference.

At five years, the risk for stroke was significantly lower in the intensive-therapy group (36 strokes vs. 62 strokes). The annual rate of stroke was 0.32% in the intensive-therapy group vs. 0.53% in the standard-therapy group (HR=0.59; 95% CI, 0.39-0.89).

Cushman said the reduced stroke risk is consistent with that reported in previously published studies. “Since it was not a primary outcome, from a statistical perspective, it could have happened by chance. But we do think it is biologically plausible and shouldn’t be ignored.”

Franz H. Messerli, MD, a member of the Cardiology Today editorial board and director of the hypertension program at St. Luke’s–Roosevelt Hospital and professor of clinical medicine, Columbia University College of Physicians and Surgeons, New York, said he was surprised by the lack of emphasis given to the significant reduction in stroke rate with intensive BP treatment.

“Stroke is the most devastating complication of hypertension,” Messerli said. “Poll any physician audience if they would rather have a stroke or MI — nearly everyone will choose MI over stroke.”

Further, more serious adverse events were reported with intensive therapy vs. standard therapy (3.3% vs. 1.3%; P≤.001), including hypotension and hyperkalemia. In addition, some laboratory measures of kidney function were worse in the intensive-therapy group, but the researchers reported no difference in rates of renal failure.

“It seems that this is almost like déjà vu all over again,” Elijah Saunders, MD, head of the division of hypertension at University of Maryland School of Medicine, and a member of the Cardiology Today editorial board, said during a panel discussion at the ACC meeting. “Most of us have been teaching for many years that the lower the BP, the better the outcomes — therefore, seek to get the BP lower.

“The problem is the differences between what we see and observe epidemiologically. The data we have suggest that we still cannot recommend bringing BP down to ≤120 mm Hg as a way of reducing risk. We need to look further and see if we can find some differences in subgroups that may explain this non-positive result.”

Peter M. Nilsson, MD, PhD, of the department of clinical science medicine at University Hospital in Malmö, Sweden, wrote an editorial accompanying the ACCORD results that was published in The New England Journal of Medicine. “The main conclusion to draw from this study must be that a systolic BP target ≤120 mm Hg in patients with type 2 diabetes is not justified by the evidence,” he wrote.

The results do not resolve the issue of the optimal BP target for patients with diabetes. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommends a goal of less than 130 mm Hg. However, the ACCORD researchers said the goal of the study was not to test the BP goal of 130 mm Hg recommended in the JNC 7.

Effects of combination lipid therapy

The ACCORD lipid trial was the first large clinical trial to compare the CV effects of combination therapy with a fibrate plus a statin with statin monotherapy in patients with diabetes, according to Henry N. Ginsberg, MD, director of the Irving Institute for Clinical and Translational Research at Columbia University College of Physicians and Surgeons.

Ginsberg and colleagues evaluated a subgroup of 5,518 patients enrolled in ACCORD who underwent randomization, again in a two-by-two factorial design, to receive simvastatin plus fenofibrate or simvastatin plus placebo.

“Overall, the results of the ACCORD lipid trial do not support use of combination therapy with fenofibrate and simvastatin to reduce CVD in high-risk patients with type 2 diabetes,” Ginsberg said in a press release.

During a mean follow-up of 4.7 years, the researchers found that combination therapy was safe but did not significantly reduce the primary outcome of first occurrence of CVD death, nonfatal MI or nonfatal stroke compared with simvastatin alone (annual rate, 2.2% vs. 2.4%; HR=0.92; 95% CI, 0.79-1.08). Combination therapy also had no significant effect on secondary outcomes, including individual rates of CVD, nonfatal MI, nonfatal stroke, total mortality, fatal stroke, revascularization or hospitalization for congestive heart failure. The annual rate of death was 1.5% in the fenofibrate plus simvastatin group compared with 1.6% in the simvastatin alone group (HR=0.91; 95% CI, 0.75-1.10).

The baseline fenofibrate dose was 160 mg per day, but it was later adjusted according to the estimated glomerular filtration rate with use of the abbreviated Modification of Diet in Renal Disease equation because of a rise in serum creatinine levels in some patients receiving this dose.

Pre-specified subgroup analyses also suggested heterogeneity in treatment effect according to sex, with a benefit for men and suggestion of harm for women (P=.01). The researchers also noted that patients who had both triglyceride levels in the top one-third and HDL in the bottom one-third at baseline may have benefited from the combination therapy, compared with other participants. Although a similar effect has been reported in other studies, researchers said more research is needed on the effects in this subgroup, which comprised 17% of the ACCORD participants.

At the end of the study, mean LDL decreased from 100 mg/dL to 81.1 mg/dL in the combination therapy group and from 101.1 mg/dL to 80 mg/dL in the simvastatin monotherapy group. Mean HDL increased from 38 mg/dL to 41.2 mg/dL in the combination therapy group and from 38.2 mg/dL to 40.5 mg/dL in the simvastatin monotherapy group. Triglycerides decreased from a median value of 164 mg/dL to 122 mg/dL in the combination therapy group and from a median value of 160 mg/dL to 144 mg/dL in the placebo group.

“Although our analysis suggests that certain patients may benefit from combination therapy, this study provides important information that should spare many people with diabetes unneeded therapy with fibrates,” Ginsberg said in a press release.

However, “the lack of benefit from fibrates should not obscure the proven value of statins in preventing CVD, which is well established from earlier studies,” he said.

A potential criticism of the trial is that it did not examine a very dyslipidemic population. “The decision was made that we should have a study group from which the results could be widely extrapolated in a general diabetic population,” Ginsberg said at a press conference.

Previously published studies indicated that fibrate therapy reduced the rate of CHD events in patients with diabetes in the Veterans Affairs HDL Intervention Trial but not in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. A post-hoc analysis of the FIELD study suggested benefit for patients with elevated triglycerides and low HDL. However, previous fibrate studies have not addressed the role of fibrates in patients receiving statins.

Messerli said he is reluctant to use fenofibrates in a patient with diabetes.

“The patient with diabetes is usually on numerous medications to start with, and then to add a drug such as a fenofibrate, which is fairly expense and the benefits of which are not that well documented, is a bit of a stretch for the practicing physician,” he said in an interview.

Zinman said these data “really put fibrates at a lower priority in the context of anti-lipid therapies. Statins reign high — they are tried, true and proven, and almost every patient with type 2 diabetes should be taking a statin.”

On March 16, the FDA informed health care professionals that it will review the primary data from the ACCORD lipid trial.

Currently, the FDA has made no new conclusions or recommendations regarding the combination use of simvastatin or other statins and fenofibrate. The agency will conduct a thorough review of the primary ACCORD data as soon as they become available. The FDA will determine how the ACCORD data relate to the approved indication and labeling for fenofibric acid (Trilipix, Abbott), which was approved by the FDA in 2008 as an adjunct to diet in combination with a statin to reduce triglycerides and increase HDL in patients with mixed dyslipidemia and CHD to achieve LDL goals. In the meantime, patients should not stop taking their current medications, according to the FDA.

Risk factor control

Although the new ACCORD data do not resolve any issues, it “makes the picture of diabetes management more complete,” Nilsson wrote in his editorial.

“Owing to the factorial design of the overall ACCORD study and the inclusion and exclusion of criteria that were applied, the study’s statistical power was reduced and the event rate was lower than expected,” he wrote, adding that it is possible that a larger trial or a trial conducted in a higher-risk population may show a significant benefit.

Cushman said the ACCORD BP and lipid trials have a different implication than the glycemia trial, which found a 22% higher relative risk for death among patients assigned to intensive glucose lowering (HbA1c ≤6%) compared with standard glucose control (7% to 7.9%).

“Unlike the glycemic trial, neither the BP nor lipid trials suggest serious harm from the interventions tested, whereas in the glycemic trial, the intensive group actually had a significantly higher mortality, and that part of the study was stopped early,” he said.

Other experts said the hope is that these data do not result in health care professionals drawing the wrong conclusions.

“My concern is that some may jump to the conclusion that it doesn’t matter if hyperglycemia or CVD risk factors are not assiduously controlled in patients with diabetes — and that is incorrect,” Zinman said.

According to Denise G. Simons-Morton, MD, PhD, director of the National Heart, Lung, and Blood Institute division for the application of research discoveries, and former project officer for ACCORD, the ACCORD results indicate no need for intensive treatment over standard practice.

“The treatment strategies used in the ACCORD standard control groups have previously been shown to be effective,” Simons-Morton said in a press release. “So the findings in no way detract from the important point that controlling blood pressure and LDL cholesterol levels reduce CV risk — not only in patients with diabetes, but in all patients with elevated levels.”

Looking ahead

Most experts said the standards of diabetes care and control of CV risk factors have improved considerably over the past decade.

“Such progress is reassuring, but now we learn from the completed ACCORD study that flexible goals should probably be applied to the control of hyperglycemia, BP and dyslipidemia in patients with type 2 diabetes, taking into account individual clinical factors of importance,” Nilsson wrote in his editorial.

“A period of three landmark studies (UKPDS, ADVANCE and ACCORD) has now come to an end. New trials should be designed on the basis of our new understanding,” he said.

The ACCORD findings will also be of importance in determining whether it will be useful to proceed with the National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT), which will evaluate the same BP targets ( ≤120 mm Hg and ≤140 mm Hg) in patients without diabetes. The nine-year, $114 million study will be conducted at more than 80 clinical sites in the United States. The multicenter, randomized, clinical trial will enroll approximately 7,500 participants aged 55 years and older. Enrollment is expected to begin in the fall, and the study is projected to end in 2018.

“I would like to know whether the same ACCORD results hold true in the non-diabetic population,” Messerli said.

“If SPRINT also shows that there is benefit of a BP target ≤120 mm Hg, then we may be looking back to the ACCORD blood pressure trial in a few years,” Cushman said.

One hypothesis, he said, is that it may take more than five years to see the benefit of intensive interventions.

“We have gotten used to having five-year studies show dramatic benefits; it is possible that it would take longer to see these effects, but we have no way of proving that yet,” Cushman said.

Researchers for both trials will follow the participants after the study, but they will no longer be randomly assigned to any treatment.

“Whatever the answer is, it is what we need to know in order to take good care of our patients with diabetes,” Cushman said. – by Katie Kalvaitis

For more information:

• Cushman WC. LBCT I. Presented at: American College of Cardiology 59th Annual Scientific Session; March 13-16, 2010; Atlanta.
• Ginsberg HN. LBCT I. Presented at: American College of Cardiology 59th Annual Scientific Session; March 13-16, 2010; Atlanta.
• Nilsson PM. N Engl J Med. 2010;doi:10.1056/NEJMe1002498.
• The ACCORD Study Group. N Engl J Med. 2010;doi:10.1056/NEJMoa1001282.