Mixed Results From ACCORD: Study Found No Overall Reduction In Cardiovascular Risk, But Benefits To Eyes, Kidneys And Nerves

Five-year results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study confirm that neither more intensive lowering of blood glucose (sugar) levels, more intensive lowering of blood pressure, nor treatment of blood lipids with a fibrate and a statin drug reduce cardiovascular risk in people with established type 2 diabetes who are at severely high risk for cardiovascular events. However, the study did find improvements to microvascular conditions, such as progression of diabetic eye disease (retinopathy), visual acuity, and renal and nerve function. The landmark study is sponsored by the federal government through the National Institutes of Health (NIH).

Speaking at the American Diabetes Association’s 70th Scientific Sessions®, the ACCORD Study Group cautioned that any potential benefits must be weighed against the increased risk of mortality and episodes of seriously low blood glucose that were seen to accompany intensive lowering of blood glucose levels — which in ACCORD was focused on achieving normal A1C levels in the study population. They emphasized that both the positive and negative results of the study apply only to this population of middle-aged or older people with type 2 diabetes for an average of 10 years, who also had a history of cardiovascular disease (CVD) or at least two risk factors for CVD.

“These results underscore the importance of patient-centered care that stresses individual treatment choices made in consultation with a physician,” said Denise Simons-Morton, MD, Ph.D, Director of the Division for the Application of Research Discoveries at the NIH’s National Heart, Lung and Blood Institute (NHLBI), the primary sponsor of the study. “Within this group, it’s important for patients and doctors to decide the highest priority for the patient,” she said. “Is improved eye health worth a higher risk of death and low blood sugar episodes? That’s a question only a fully informed patient can answer.”

The ACCORD researchers set out to investigate whether cardiovascular risk in people with type 2 diabetes could be reduced using one of the following strategies, each compared with standard treatment: intensive lowering of blood glucose to near-normal levels (target A1C less than 6%), intensive lowering of blood pressure to near-normal levels, or treatment of blood lipids with a combination of fibrate and statin drugs. It also looked at how each of these treatments would affect other outcomes such as mortality and microvascular outcomes (e.g., eye, kidney and nerve complications).

NHLBI prematurely halted the intensive blood-glucose lowering strategy after 3.5 years, in February 2008, due to safety concerns caused by an unexpected higher incidence of death in the intensive glucose lowering treatment group compared with the standard treatment group. Patients in the intensive treatment arm of the study were transitioned into the standard treatment arm for the remainder of the trial’s five years, which has now concluded.

Intensively Lowering Blood Glucose: Increased Mortality and No Cardio Benefit, But Possible Benefits to Eyes, Kidneys and Nerves

Results of intensive glucose lowering on microvascular outcomes were published today in the Lancet and presented at a symposium at the American Diabetes Association’s 70th Scientific Sessions in Orlando.

The study examined patients who underwent intensive glucose-lowering treatment for 3.5 years (increased medication aimed at lowering A1C levels to less than 6 percent) and were then given standard treatments (aimed at achieving A1C levels of 7.0-7.9%) for the remaining 1.5 years, compared with standard treatment for the duration of the study. The intensively treated patients did not see a reduced incidence of cardiovascular disease.

In addition, the groups did not differ in overall measures of microvascular health, for example, in the progression rates to kidney failure, major vision loss, or advanced peripheral neuropathy, a common nerve problem in diabetes that usually begins as tingling or numbness in the feet. However, there were some microvascular improvements noted, such as a reduced incidence of albuminuria (protein in the urine, a marker of kidney disease) in the intensive group, compared to those receiving standard treatment, along with fewer cataract extractions during the study period. Visual acuity (sharpness of vision) and nerve function scores were also better for the intensive group than for the standard-treatment group, suggesting that intensive lowering of blood glucose may also help prevent eye and nerve damage.

“Patients who develop macroalbuminuria are prone to renal failure and cardiovascular events,” said Faramarz Ismail-Beigi, MD, Ph.D, of Case Western Reserve University and the lead researcher on this portion of the study. “Less protein in the urine is a very good sign.”

Though the visual acuity tests were somewhat subjective, Ismail-Beigi said, they could indicate that intensive glucose lowering helps to prevent eye damage.

Intensively Lowering Blood Glucose, Treating Lipids: Slows Retinopathy Progression

That finding is further supported by a substudy of ACCORD chaired by Emily Chew, MD, chief of the Clinical Trials Branch of the Division of Epidemiology and Clinical Applications at the NIH’s National Eye Institute (NEI). Results of the study were published online in the New England Journal of Medicine today. Chew and her colleagues investigated whether each treatment arm of the ACCORD trial — blood glucose, blood pressure, and blood lipids — would reduce the progression of diabetic eye disease (or retinopathy) in a subset of about 3,000 ACCORD study participants, compared to that treatment’s standard approach. Disease progression was identified through retinal photographs that indicated blood vessel changes or by the need for laser or vitrectomy surgery to treat abnormal blood vessels.

The study found that people in the intensive blood glucose lowering arm, as well as those who received a combination of a fibrate and a statin for blood lipids, experienced slower progression in diabetic retinopathy than those in each standard treatment arm. Those who were in the intensive blood pressure lowering arm did not see a reduction in eye disease progression when compared to people receiving standard blood pressure control.

Compared with standard blood glucose control, intensive control decreased the progression of diabetic retinopathy by about one-third, from 10.4 percent to 7.3 percent, over four years. Participants in the intensive control group had a median blood glucose level of 6.4 percent hemoglobin A1C — a level close to values in people without diabetes. The standard blood glucose control group maintained a median level of 7.5 percent.

In addition, compared with simvastatin treatment alone, combination lipid therapy with fenofibrate plus simvastatin also reduced disease progression by about one-third, from 10.2 percent to 6.5 percent, over four years. No prior clinical trial has shown that the combination of fenofibrate and simvastatin reduces diabetic eye disease progression.

Contrary to predictions, there was no difference in diabetic retinopathy progression among participants treated to an intensive systolic blood pressure (the top number in a blood pressure reading) target of less than 120 mm Hg, compared with those treated to a standard target of less than 140 mm Hg.

“The results of the ACCORD Eye Study indicate that intensive blood sugar control and combination fibrate plus statin treatment of lipids independently reduce diabetic retinopathy progression,” Chew said. “However, patients and their doctors should work together to develop an individual treatment plan, taking into account the potential risks of intensive glucose treatment.”

Combination Lipid Treatment: No Cardio Benefits Overall, But Subgroup May See Reduced Risk

Combination lipid therapy with a statin plus a fibrate did not help lower cardiovascular risks overall, but the results did suggest that a subgroup of the study — those with high triglycerides and low HDL (the so-called “good” cholesterol) — may benefit by such treatment.

In this subpopulation of the investigation, which included about 15 percent of the 5,518 people studied in the ACCORD Lipid Trial, those who had triglyceride levels of more than 200 and HDL levels below 34 saw a reduced incidence of cardiovascular events of 30 percent. These findings are supported by similar findings of subgroup populations in several large previously published clinical studies.

“If it were an isolated finding in our study I’d be less enthusiastic,” said Henry Ginsberg, MD, Irving Professor of Medicine and Director of the Irving Institute for Clinical and Translational Research at Columbia University. “But this finding is in line with subgroup analyses in several other trials.”

A second subgroup analysis of this arm of the study found that women and men respond differently to combination lipid therapy, Ginsberg said. Though overall the study found no cardiovascular benefits for the study population, when broken down by gender, the results showed men experienced a 20 percent reduction in cardiovascular events, while women experienced a 38 percent increase in cardiovascular events.

However, when examined for statistical significance, “the data for men showed a strong indication that they benefitted, while the data for women were not as conclusive,” Ginsberg said. “This raises possibilities that need to be further examined.”

These results were published in the April 29, 2010, issue of the New England Journal of Medicine.

Intensively Lowering Blood Pressure: No Cardio Benefits, But Suggested Reduction in Stroke

Results from the intensive blood pressure control arm of the study were also published in April in the New England Journal of Medicine. In this treatment arm, participants lowered blood pressure levels to “normal” levels of less than 120 mm Hg, to see if doing so would reduce major cardiovascular events, compared with standard treatment of levels less than 140 mm Hg. No significant reduction in overall CVD events was found.

The study did find a significant (41 percent) reduction in stroke, which was consistent with other BP-lowering clinical trials. However, because this was not the primary focus of the study, and because the overall rate of stroke was low, the researchers are hesitant to recommend a strategy of lowering blood pressure to this degree without further study.

“Older patients with known cardiovascular disease, higher blood pressure to begin with, and African Americans may benefit from such a treatment plan,” said William Cushman, MD, of the Memphis Veterans Affairs Medical Center, “but we’re going to have to do further analyses.”

The NHLBI is the primary sponsor of ACCORD, with additional funding and scientific expertise contributed by the National Institute of Diabetes and Digestive and Kidney Diseases. Other components of the NIH — including the National Institute of Aging — as well as the Centers for Disease Control and Prevention, support substudies. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare Inc., GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals, Inc., Novo Nordisk, Inc., Omron Healthcare, Inc., Sanofi-Aventis U.S., and Takeda Pharmaceuticals, Inc.

American Diabetes Association

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