ACCORD, ADVANCE, and the VADT: What Do They Mean, and for Whom?

“Psssst. Have you heard? Three large clinical trials presented this month show that lowering your blood sugar to near-normal levels produces no cardiovascular health benefits and may even be harmful.”

“Psssst. Have you heard? Even the reputable New York Times had a front page article called “Tight Rein on Blood Sugar Yields No Heart Benefits.”

These are the type of misleading headlines circulating after the presentation of results from three large clinical studies involving about 23,000 patients at this year’s ADA meeting in San Francisco. But what do these three trials really mean, and for whom? The answer is not as simple as it appears in sensationalized headlines and the studies actually raise many more questions than they answer.

what are ACCORD, ADVANCE, and the VADT?

First, some background: ACCORD, ADVANCE, and the VADT were three large clinical trials that compared the rates of heart disease in patients receiving either “intensive” diabetes treatment (targeting near-normal average blood glucose levels - A1c closer to 6%), or “conventional” diabetes treatment (targeting somewhat higher blood glucose levels - A1c closer to 7.5%). ACCORD was designed to test 10,000 people in North America and Canada over eight years, half with an A1c goal of 6%, the other half with a 7.5% goal in the diabetes part of the trial. ADVANCE tested 11,1400 people over six years in Australia of whom half had a 6.5% A1c goal and half targeted 7%. VADT included almost 2,000 veterans in the US with an A1c goal of less than 6.0% for half of the participants, and 8.0-9.0% for the other half. These studies were designed to test the theory that extremely tight control of BG would help reduce heart disease.

As a reminder, the A1c is a measure of average blood glucose. An A1c of 7.0% is equivalent to an estimated average blood glucose level of 154 mg/dl (8.5 mmol/l), whereas an A1c of 6.0% is equivalent to an average blood glucose level of 126 mg/dl (7 mmol/l). Roughly two-thirds of people with type 2 diabetes die from heart disease, a much higher rate than in the general population. As such, researchers for these three studies wanted to see if reducing blood sugar to near-normal levels would reduce the risk of heart disease. For more background, see diaTribe issue #9 What We’re Reading.                                                                                            

The three trials differed in the precise blood glucose levels targeted, as well as in their patient populations. Patients were mostly over 60 years old with a long duration of type 2 diabetes. Thus, the results may not be relevant to people less than 60 years of age, people with type 1 diabetes, or people with either newly diagnosed or well-managed type 2 diabetes. If you have type 2 diabetes and are at high risk of heart disease, or have had a heart attack, then these results are more likely to relate to you.

Contrary to many researchers’ expectations, none of the three trials showed a clear benefit of tight glucose control on heart disease risk over the study periods. In ADVANCE, which lasted five years, and the VADT, which lasted seven and a half years, the rate of heart attacks, stroke, and heart disease was similar between the intensive and standard glucose arms of the studies. Even though both studies went to completion, some doctors believe that a longer study would have shown greater benefits of intensive glucose control on heart disease.

In contrast, the intensive glucose control arm of the ACCORD study was famously discontinued in February, long before its expected completion date. This happened after a committee responsible for overseeing the study found that the intensive glucose control arm had significantly more deaths than the standard control arm (257 versus 203).

so what is (are) the answer(s)

Why was intensive glucose control associated with poorer outcomes in ACCORD, but not the in other two studies? Nobody knows for sure, but several speakers at the ADA meeting offered explanations. One theory is that glucose was lowered too quickly in the ACCORD trial. Whereas average glucose levels were lowered slowly in ADVANCE and the VADT, glucose levels were lowered very quickly and aggressively in ACCORD – from an average of 8.3% to 6.4% in four months. Some research presented at the meeting by Dr. Eric Kilpatrick (Hull Royal Infirmary, UK) and colleagues suggests that rapid changes in average blood glucose may increase the risk of heart disease. Patients in the intensive treatment arm of the ACCORD trial were also treated to reach a blood glucose level below current international guidelines – many think this was too aggressive. Whereas the ADA recommends that patients try to achieve an A1c level of less than 7.0%, patients in ACCORD were treated to target an A1c level of less than 6.0%.

According to diaTribe advisory board member, Dr. Barry Ginsberg, there were actually fewer cardiovascular deaths in both ACCORD patient groups (intensive and standard) than expected, possibly due to the better overall control of blood pressure, cholesterol, and blood glucose. He noted that a number of doctors and researchers believe a longer study would have shown greater benefits of intensive glucose control on heart disease. He pointed out that the assumption that having more people in a study allows you to run the study for a shorter time was a potential design flaw.

To achieve lower blood glucose levels, many patients in ACCORD were treated with multiple medications that cause significant weight gain, including Avandia or Actos, sulfonylureas, and insulin. Whereas patients in ADVANCE did not gain weight, almost 30% of patients in the intensive treatment arm of ACCORD gained 10 kg (22 pounds) or more during the study. This weight gain may have contributed to the increased incidence of heart failure in the intensive arm of that study.

Another theory proposed is that unrecognized or “silent” hypoglycemia (possibly due to insulin or sulfonylurea use) may have occurred more often in the intensive treatment arm of the study, leading to more heart disease and increased deaths. This easily gets very complicated since it’s impossible to study something that can’t really even be identified.

No medication in the ACCORD study was associated with poorer health outcomes. This included Avandia, which some previous studies have suggested could be linked to increased heart attacks (see Learning Curve in diaTribe issue #6). Notably, the drug Byetta was linked to significantly fewer deaths than any other medication. This was especially significant in our view because Byetta is not usually associated with hypoglycemia or weight gain – in fact, it is known to cause weight loss. That said the study was not designed to assess the safety of different drugs, so it is difficult to draw conclusions about any specific drug in the study. It would be very enlightening if these drug effects were formally studied.

what does all of this mean? and for whom?

Here is our list of conclusions – and as always, we remind readers that we aren’t medical doctors, so please consult your healthcare team before making any changes:

• For older patients with a long duration of type 2 diabetes who are at high risk for heart disease, aggressive treatment of blood glucose may not necessarily reduce heart disease risk over the span of a few years. It remains unclear whether aggressive treatment of blood glucose will reduce heart disease risk over a longer time frame. Previous studies have suggested that the benefits of tight glucose control may not become apparent until much later.

• For patients with a shorter duration of type 2 diabetes at lower risk for heart disease, it is unclear what message (if any) to take from these studies. Arguably, many experts believe that the studies highlight the importance of treating diabetes earlier and more aggressively. By doing so, these experts suggest, it might be possible to prevent the later stages of diabetes (and complications) when aggressive interventions are less effective and potentially harmful.

• It is impossible to draw any conclusions from these studies for patients with type 1 diabetes, since only type 2s were studied. The DCCT and EDIC studies (both type 1 studies) showed conclusively that tight control of blood glucose significantly reduced both microvascular and macrovascular complications. In EDIC and STENO 2 (a trial investigating multiple interventions in reducing heart disease risk in type 2s), the benefit it took far longer than the average five years of ACCORD, ADVANCE, and VADT for the benefit of intensive glucose control to be shown. For more on DCCT and EDIC, see http://diabetes.niddk.nih.gov/dm/pubs/control/.

• Treating blood glucose to current guidelines is safe and conclusive evidence has shown such treatment to be very important for reducing microvascular complications like nerve, kidney and eye disease. As such, these studies should not be viewed as supporting less aggressive guidelines. At the same time, lowering blood glucose well below treatment guidelines may not make sense for patients with longstanding diabetes at high risk for heart disease.

• Blood glucose, as measured by A1c, is only one of several aspects of diabetes management. Managing cholesterol levels and blood pressure is also a critical part of heart disease prevention. According to 2007 CDC diabetes statistics, blood pressure control can reduce the risk of heart disease by 33% - 50%, and the risk of microvascular complications by 33%. Control of so called “bad” cholesterol can reduce cardiac risk by 20% - 50%.

We look forward to the completion of the intensive blood pressure and cholesterol management segments of the ACCORD trial, which will continue for another seven years as originally planned. Researchers will also continue to monitor patients in the intensive glycemic control arm of the study that was discontinued to see long term effects of this intervention.