The ACCORD ( Action to Control Cardiovascular Risk in Diabetes ) study was a large clinical trial of adults with type 2 diabetes who are at especially high risk of cardiovascular disease ( CVD ) ( myocardial infarctions, strokes, and deaths from conditions of the heart and blood vessels ).

The ACCORD study was primarily composed of three clinical trials, which tested treatment approaches to determine the best ways to decrease the high rate of major CVD events among people with type 2 diabetes who are at especially high risk of having a cardiovascular event.
These three treatment approaches were: intensive lowering of blood sugar levels compared to a more standard blood sugar treatment; intensive lowering of blood pressure compared to standard blood pressure treatment; and treatment of multiple blood lipids with two drugs—a fibrate plus a statin – compared to one drug, a statin alone.

The study began enrolling participants in 2001 and took place in 77 clinical sites across the United States and Canada. A total of 10,251 adults with established type 2 diabetes participated in ACCORD. At enrollment, study participants were between the ages 40 and 79 ( average age 62 ), had diabetes for an average of 10 years, and were at especially high risk for CVD events because they already had pre-existing CVD, evidence of subclinical CVD, or at least two CVD risk factors in addition to type 2 diabetes.

ACCORD Lipid Clinical Trial

People with type 2 diabetes very often have a combination of high blood levels of LDL cholesterol, low HDL cholesterol, and high triglycerides.

Statin medications are very effective at reducing the levels of LDL cholesterol.
Many clinical trials have shown that treatment with statins lowers the rates of heart attacks and cardiovascular death. On the other hand, fibrate medications are used to increase the blood levels of the HDL cholesterol as well as reduce triglycerides.
Unlike the statins, which are used to lower LDL cholesterol, there was no definitive evidence from previous clinical trials that using a fibrate to increase HDL cholesterol and decrease triglyceride levels in combination with a statin to control LDL cholesterol would reduce the risk of heart attacks and strokes in patients with type 2 diabetes.

The statin drug simvastatin ( Zocor ) was given to all participants as necessary to control their level of LDL cholesterol according to current treatment guidelines.
Participants were randomly assigned to receive either the fibrate drug fenofibrate ( Tricor or Trilipix ) or a matching placebo.

There were no specific target levels for HDL or triglycerides. However, there were significant differences between the levels of HDL cholesterol and triglycerides between the group that received the Fenofibrate as compared to the group that received the placebo. So in this way the trial achieved its goal of a difference in multiple blood lipids between the two groups.

Overall, the fibrate and the placebo groups did not differ in the rates of the combined outcome of heart attacks, strokes, or cardiovascular death. The results, however, have suggested that men may benefit from this treatment, but there was a trend toward more cardiovascular problems in women receiving the combination therapy compared to those who received statins only. Also, the group of patients who at the start of the trial had the lowest level of HDL cholesterol combined with the highest level of triglycerides ( which represented only 17% of the ACCORD participants ) may have benefitted from this combined drug treatment. However, when there is no difference overall, any positive result on a subgroup of patients must be interpreted with a lot of caution as it could occur by chance alone.

ACCORD Blood Sugar Clinical Trial

A large body of research in which adults were followed for several years had shown that diabetes increases the risk of developing CVD. However, most studies were observational, rather than more rigorous randomized clinical trials that test interventions or treatments, so they do not prove whether lowering blood sugar levels reduces CVD risk.

Some clinical trials, have tested the effects of reducing blood sugar through medical treatments. The United Kingdom Prospective Diabetes Study ( UKPDS ), the NIH-supported Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications ( DCCT/EDIC ) study, and other clinical trials have demonstrated benefits of lowering blood sugar in persons with diabetes. Such studies have shown, for example, that for every percentage point drop in A1C blood test results ( from 8.0 percent to 7.0 percent, for example ), the risk of diabetic eye, nerve, and kidney disease is reduced by 40 percent. Lowering blood sugar reduces these microvascular complications in both type 1 and type 2 diabetes.
Intensive blood sugar control in people with type 1 diabetes ( average HbA1C of 7.4% ) reduces the risk of any CVD event by 42 percent and the risk of heart attack, stroke, or death from CVD by 57 percent.
In adults with more recent onset of type 2 diabetes than the ACCORD participants, the UKPDS showed a trend toward reduced CVD events, particularly heart attacks. However, the results are not considered conclusive. However, no previous major clinical trial had studied whether lowering a raised blood sugar level to a level similar to that of people without diabetes reduces the risk of CVD. In addition, no previous clinical trial had studied the effects of intensive blood sugar lowering in people with longstanding type 2 diabetes who already have CVD or have multiple risk factors for CVD in addition to diabetes.

All major classes of drugs approved by the FDA ( Food and Drug Administration ) to treat diabetes were used to treat blood sugar in both groups of the ACCORD blood sugar trial – those in the intensive strategy group that targeted a near-normal blood sugar level as well as those in the standard blood sugar strategy group.

Medications used included ( in order of frequency of use ): Metformin; thiazolidinediones ( Rosiglitazone, Pioglitazone ); injectable insulins; sulfonylureas ( Gliclazide, Glimepiride, Glipizide, Glyburide ); Acarbose and Exenatide. Combinations of medications could be used to achieve the A1C goals.

The type, number and dosages of these drugs varied, depending on participants’ individual needs and their A1C goals. For example, Metformin was used in about 95% of intensive-group participants, and in about 87% of standard group participants. Insulin was used in about 77% of intensive-group participants, and in about 55% of standard-group participants.

Participants in the intensive group were more likely to be on combinations of drugs than participants in the standard group. For example, 52% of participants in the intensive strategy group were on three oral medications as well as Insulin, compared to 16% of those in the standard group.

In its regular review of the available study data, the ACCORD Data and Safety Monitoring Board ( DSMB ) noticed an unexpected increase in total deaths from any cause among participants who had been randomly assigned to the intensive blood sugar strategy group compared to those assigned to the standard blood sugar strategy group. The data analyses showed that over an average of 3.5 years of treatment ( ranging from about 2 years to about 7 years ), 257 participants in the intensive group died, compared to 203 in the standard group – a difference of 54 deaths, or an excess of about 3 deaths per 1,000 participants treated for a year. This translates to a statistically significant 22% higher rate of death in the intensive than the standard group.

There was a trend toward lower ( 10% lower ) rate of primary outcome events, primarily nonfatal heart attacks, in the intensive compared to the standard treatment group. However, the DSMB recommended discontinuing intensive blood sugar treatment because the harm of the intensive strategy outweighed the potential benefit. NHLBI accepted the DSMB’s recommendation and decided to transition all participants to the standard blood sugar strategy.

On the whole, the death rates in both blood sugar strategy groups were lower than those seen in similar type 2 diabetes patients with similar characteristics. That is, although the death rate was higher in the intensive treatment group than the standard group, it was still lower than death rates reported in other studies of type 2 diabetes.

In general, intensive-group participants achieved lower blood sugar levels than standard-group participants. An HbA1C level less than 6.4% was achieved in half of the intensive-group participants and a level less than 7.5% in half of the standard group participants. These levels were maintained over the average 3.5 year study period.

ACCORD researchers have extensively analyzed the available data and have not been able to identify to date any specific cause for the higher death rate among the intensive blood sugar treatment group. Based on analyses done to date, there is no evidence that any medication or combination of medications is responsible for the higher risk. In addition, although the number of severe hypoglycemic events was greater in the intensive blood sugar strategy group, this does not appear to account for the difference.

ACCORD Blood Pressure Clinical Trial

Many observational studies have shown that there is a continuous relationship between blood pressure level and risk of cardiovascular disease, such as heart attacks or stroke. This relationship goes all the way down to levels of blood pressure considered normal – below 120 mm Hg of systolic blood pressure. In other words, there were data suggesting that lower systolic blood pressure is better for patients with type 2 diabetes. However, there was no evidence from randomized clinical trials of treatment interventions to definitely show that lowering systolic blood pressure to such normal levels would reduce cardiovascular events in patients with diabetes and elevated blood pressure. It was necessary to conduct a rigorous randomized clinical trial to compare a lower goal to a more standard goal that was consistent with prior evidence.

ACCORD used all classes of FDA-approved blood pressure lowering medications. These included common classes of blood pressure lowering medications such as diuretics, angiotensin converting enzyme inhibitors, beta-blockers, and calcium channel blockers. Most patients in ACCORD needed several medications to control their blood pressure to the levels being targeted.

Patients were randomly assigned to the intensive or the standard blood pressure treatment groups. In the intensive group, an average systolic blood pressure of less than 120 mm Hg – the goal for treatment – was achieved at the end of the first year of treatment and stayed under 120 for the rest of the trial. In the standard group, systolic blood pressure averaged around 134 mm Hg – consistent with the goal of less than 140 mm Hg. So, the standard group was treated similar to current standards, and the intensive group was treated to about a 14 mmHg lower level.

Serious adverse effects were relatively uncommon. However, there were more cases of hypotension and bradycardia in the intensive group. Also, there were more cases of low and high blood potassium levels, which can cause severe heart rhythm problems, as well as more cases of changes in kidney function. But there was no increase observed in the number of cases of dialysis or kidney failure in the intensive group compared to the standard group during the study.

There was no significant difference in the primary study outcome between the intensive and standard blood pressure treatment groups. The primary outcome was the time to first occurrence after randomization of a heart attack, a stroke, or a cardiovascular death. Thus, the primary hypothesis of the ACCORD BP trial was not supported. There was, however, a significant reduction in the rate of strokes, although the numbers were relatively small. This reduction in stroke was consistent with previous blood pressure lowering trials. Overall, however, the findings from the ACCORD blood pressure trial suggest that, on average, the standard treatment for blood pressure lowering treatment was just as good as the intensive lowering treatment for cardiovascular outcomes.

Source: NHLBI, 2010

XagenaMedicine_2010


Link: Xapedia - Medical Encyclopedia