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Type 2 Diabetes, Evidence-Based Medicine & The Reign of Confusion

Evidence-based medicine (EBM) is getting a lot of attention these days. Like most topics, it has its ardent fans and die-hard opponents. To some, EBM is cookbook medicine, with too many rules and too little room for individual clinical judgment. On the other side of the controversy are EBM proponents who feel that arming physicians with guidelines, best practices and protocols brings a much needed dose of standardization into the Wild West world of healthcare decision making.

Why the sudden attention to EBM? The rising cost of healthcare expenditures–along with health care reform-means insurers want to be certain of the value of the pharmaceutical treatments they pay for. Clinicians, living in a post-Vioxx world, want assurance that the medications they prescribe are safe and effective. While the FDA tells us that drugs are efficacious compared to placebo (or as Jerry Avorn jokingly says, ‘probably better than nothing’), there is often little or no evidence that these new treatments are effective clinical interventions (e.g. able to reduce disease morbidity and mortality).< What some physicians do not realize is that many drugs are approved on their ability to improve surrogate endpoints – markers such as LDL-cholesterol, hemoglobin levels or HbA1c. Proving that a drug actually saves lives or prevents disease complications is another matter all together. This is one reason why large-scale epidemiological studies that look at the impacts of clinical interventions on disease progression, disease complications and mortality rates wind up causing so much confusion. These study findings, along with their interpretation and the subsequent recommendations regarding treatment, often come into conflict with the medical status quo, either by contradicting clinical standards promulgated by thought leaders and medical associations and/or the marketing messages of pharmaceutical and medical device companies whose products, although improving surrogate endpoints, do not necessarily impact survival. One example of this was the assumption that intensive glucose-lowering regimens can reduce the incidence of cardiovascular mortality, the leading cause of death in patients with type 2 diabetes. Up till recently, standard thinking was that intensive glucose control - targeting the HbA1c to around 6.5% or 7% - would prevent development of cardiovascular complications in people with type-2 diabetes at high-risk of heart disease. Intensive treatment (vs standard treatment which lowers HbA1c to 7.0% or 7.5%) often involves higher doses and/or combinations of hypoglycemic medications, as well as more frequent glucose monitoring at home. In the last five years, evidence from 5 large-scale epidemiological studies turned the world of type 2 diabetes upside down when they suggested that intensive treatment does not reduce cardiovascular mortality. These studies include: UKPDS (United Kingdom Prospective Diabetes Study), ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), PROActive (PROspective PioglitAzone Clinical Trial In MacroVascular Events), and VADT (Veterans Affairs Diabetes Trial). These studies followed patients, in some cases up to 10,000 patients for up to 10 years, in order to compare cardiac death rates for standard vs intensive treatment.

In one of the studies, ACCORD, there were actually more cardiac deaths in patients assigned to intensive therapy. The median HbA1c level achieved was 6.4% for the intensive treatment group and 7.5% for standard treatment. The trial was stopped after 3.5 years because 41 more patients in the intensive treatment arm (median HbA1c of 6.4%) had died from strokes, heart attacks, congestive heart failure, and arrhythmia than in the standard therapy group (median HbA1c of 7.5%). These results have engendered debate as researchers try to understand the factors behind the increased death rate in patients on intensive therapy with hypoglycemia, weight gain and fluid retention being possible contributing factors. (Note: Since clinical trial interpretation is highly complex and requires in-depth knowledge of study design and sub-group analysis, I will leave more detailed analysis of these trials to clinical thought leaders)

While everyone agrees that managing plasma glucose is important, the question is how tightly? Years ago, an HbA1c around 8% was considered acceptable. In more recent years, clinical guidelines from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) have recommended tighter glycemic targets, in some cases as low as 6.5%. In a market-driven healthcare system, these recommendations have serious financial implications for pharmaceutical companies, insurers and consumers.

The determination of the HBA1c target, for example, dramatically impacts the sales of drug and device companies because a shift in HBA1c targets as small as .05% translates into gains (or losses) worth billions of dollars to the drug and device companies that produce type 2 diabetes medications as well as monitors and glucose test strips used for self-monitoring at home.Emphasis on tight glucose control, for example, is a major reason why we have seen a near doubling of annual costs of prescription diabetes drugs in the past decade. According to a 2008 article, published in Archives of Internal Medicine, expensive medications such as glitazones, Januvia (sitagliptin) and Byetta (exenatide) have driven up costs for treating patients with type 2 diabetes – from $6.7 billion in 2001 to $12.5 billion in 2007.

While older, generic drugs such as metformin or glipizide cost less than $20.00 for a 30-day supply, newer drugs can be 8 to 12 times that. For example, a 30-day supply of Januvia is $194, a month’s supply of Actos (pioglitazone ) is $149.00 and a 30-day supply of Byetta, $245.00. (Pricing Information: Epocrates Rx and drugstore.com)

A recent editorial in the Canadian Family Physician points out that the culture of tight glycemic control “tyrannizes patients with little gain”. A December 2009 article published in Circulation states, “based on limited evidence, self- monitoring [in type 2 diabetes] has failed to show consistent benefits in terms of quality of life, patient satisfaction, hypoglycemia, long-term complications of diabetes and mortality.”

I doubt whether the average physician has heard much about the intensive therapy debate. Pharmaceutical companies spend millions of dollars promoting evidence that supports use of their products. When the evidence could hurts drug sales, companies tend to say little. Therefore, do not hold your breath waiting to see Lilly or Merck “twittering” about the risks of intensive treatment. It is more likely that the industry spinmeisters will be spending their money warning doctors of the risks of ‘cookbook medicine’.

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