Is More Always Better? - the ACCORD Study Results

The big medical news today was that the intensive treatment arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study will be stopped because a preliminary analysis revealed that patients given intensive treatment to lower their blood sugars were more likely to die than those given less intense treatment. The trial and these results were summarize in a news release from the National Institutes of Health:

In this trial of adults with type 2 diabetes at especially high risk for heart attack and stroke, the medical strategy to intensively lower blood glucose (sugar) below current recommendations increased the risk of death compared with a less-intensive standard treatment strategy. Study participants receiving intensive blood glucose lowering treatment will now receive the less-intensive standard treatment.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study enrolled 10,251 participants. Of these, 257 in the intensive treatment group have died, compared with 203 within the standard treatment group. This is a difference of 54 deaths, or 3 per 1,000 participants each year, over an average of almost four years of treatment.

The intensive treatment group had a target blood sugar goal, measured by hemoglobin A1C, of less than 6 percent.

In ACCORD, intensive treatment group participants achieved, on average, A1C values lower than standard treatment group participants. Half of the participants in the intensive treatment group achieved an A1C of less than 6.4 percent, and half of the participants in the standard treatment group achieved an A1C of less than 7.5 percent.

These results shocked quite a few distinguished experts.

• "Its striking that more is not necessarily better. You'd think that lowering blood sugar more would give better results, but it's exactly the opposite" - Dr Douglas Weaver, Co-Director, Heart and Vascular Institute, Henry Ford Hospital, President-Elect, American College of Cardiology (via USA Today).
• "It's confusing and disturbing that this happened. For 50 years, we've talked about getting blood sugar very low. Everything in the literature would suggest this is the right thing to do." - Dr James Dove, President of the American College of Cardiology (via the New York Times).
• "It's profoundly disappointing. This presents a real dilemma to patients and their physicians. How intensive should treatment be? We just don't know." Dr Richard Kahn, Chief Scientific and Medical Officer, American Diabetes Association (via the Washington Post).

Actually, what is striking is that these results should have come as such a surprise. There has never, repeat never been good evidence that intensive treatment to lower glucose provides clinical benefits that outweigh the harms for patients with type 2 diabetes. (Type 2 diabetes is the most common type of diabetes that begins in adulthood, and that does not require insulin treatment for patients to survive.) Thus, the notion that there was 50 years of evidence that "more is better" in terms of treatment of this kind of diabetes using existing drugs and methods was little more than a myth.

For review of the existing evidence about the benefits and harms of intensive treatment, see the Appendix below.

As McCormack and Greenhalgh noted,(1) there are psychological reasons why people, even highly trained professionals, tend to believe more is better. Unfortunately, these reasons have been abetted by the influence of financial incentives.

A lot of people make a lot of money from intensive diabetes treatments. Drug-makers sell more drugs and biologics, device-makers sell more diabetes tests, and doctors are paid for more office visits. Pharmaceutical, biotechnology, and device companies have marketed diabetes tests and treatments with great enthusiasm.

Also, these companies have fostered conflicts of interest that may have influenced how physicians, academics, and organizational leaders think and act. These companies have paid physicians and academics as consultants, speakers, advisors, etc. These companies have also lavishly contributed to professional societies and not-for-profit organizations that are positioned to influence diabetes care. For example, the American College of Cardiology and American Diabetes Association, whose leaders were quoted above, have received considerable funding from pharmaceutical companies that make diabetes drugs and related products (see report by the Center for Science in the Public Interest here for older data, and the ADA 2006 annual report here, which included $1 million plus contributions from Abbott/Abbott Diabetes Care, BD Medical Diabetes Care, Eli Lilly and Company, GlaxoSmithKline, Merck & Co., Inc., Novo Nordisk, Pfizer Inc, sanofi-aventis, and Takeda Pharmaceuticals North America). Is it any surprise that individuals and organizations receiving pharmaceutical/ biotechnology/ device companies' largesse are less likely to question the prevailing wisdom that more treatment is always better?

I strongly hope that the results of the ACCORD study prompt a re-examination of what we really know about treating diabetes, our general acceptance that more, more intense, more high-tech, more recent, more invasive, more expensive is always better, and our laissez faire notions about financial transactions between companies which make profits by selling goods and services and professionals whom the public trusts to put patients' welfare first.

Appendix - Quick Review of Evidence About Intensive Glucose Lowering Treatment for Type 2 Diabetes

Although there have been a multitude of studies of type 2 diabetes treatment, nearly all of them only assessed surrogate or secondary endpoints. None assessed the development of complications of diabetes that could affect how patients feel, function, or survive.

There really have only been two large-scale, prospective controlled trials of the clinical effects of treatment (critically summarized in two articles in the British Medical Journal). (1-2). The first major controlled trial to assess the clinical effects of more and less intense treatment of diabetes was the University Group Diabetes Program Study (UGDPS), reported in 1970. That trial's counter-intuitive result was that treatment with the major class of oral drugs used at that time, the sulfonylureas, seemed to increase mortality. After the study was published in 1970, there seemed to be a tremendous effort to explain away its findings. I remember the study being dismissed as controversial, if not discredited, when I was in medical school. Almost no one seemed to take its results seriously.

The UKPDS study, reported in 1998, was the only other large, prospective, long-term, randomized controlled trial of intensive treatment of type 2 diabetes. It did show one benefit of intensive treatment.(3) Such treatment lowered the rates of surrogate endpoints related to microvascular (small vessel) complications of diabetes, that is, the rates of performance of laser treatment of retinal disease, retinal changes on examination, and increased albumin excretion in the urine. However, intensive treatment did not decrease the risks of clinical endpoints related to microvascular disease, that is, endpoints that would affect how patients feel or function, such as loss of visual acuity, blindness, or kidney failure. Intensive treatment also did not lower the rate of any macrovascular (large vessel) clinical complications, i.e., of myocardial infarction (heart attack), heart failure, stroke, need for amputation, or death.

On the other hand, patients taking intensive therapy continuously were subject to the risk of hypoglycemia (low blood sugar). Risks of serious hypoglycemic events were 0.6% per year for patient taking oral glucose lowering drugs, and 2.3% for patients taking insulin.

Thus, from this study, it is not clear that the only clear benefits produced by intensive therapy that might affect how patients feel or function, reducing the need for laser treatments of retinal disease, were worth the risks of severe hypoglycemia, which can result in confusion, falls, accidents, or even death.

However, as McCormack and Greenhalgh noted, the results of the UKPDS study were widely mininterpreted as "convincing evidence that tight blood glucose control is an important goal for type 2 diabetes," and that the main finding of the study was "intensive treatment of type 2 diabetes is beneficial."

References

1. McCormack J, Greenhalgh T. Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data. Brit Med J 2000; 320: 1720-3.

2. Shaughnessy AF, Slawson DC. Blowing the whistle on review articles: what should we know about the treatment of type 2 diabetes? Brit Med J 2004;

3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853.

ADDENDUM (7 February, 2008) - See also comments on DBs Medical Rants.