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Evidence-based Medicine, Type 2 Diabetes, & the Reign of Confusion

Evidence-based medicine (EBM) has gotten a lot of attention in recent years, as have questions pertaining to the importance of intensive glucose lowering in type 2 diabetes.

Like most topics, EBM has its ardent fans and its 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 healthcare reform—means insurers want proof of the value of the pharmaceutical treatments they pay for. These insurers want to see clear evidence that an intervention saves lives, reduces morbidity, or prevents disease. 

Many disagree, however, about the legitimacy of the evidence backing up many of our standard medical practices. Many treatments and even accepted guidelines are based on minimal or questionable evidence. Clinical trials may generate evidence of effectiveness based on comparing a new medication with a placebo. Industry-funded clinical trials also frequently use non-clinically relevant endpoints called surrogates. Surrogate endpoints are measurements like HbA1C, blood pressure, or FEV1. Many drugs are approved based on changes in surrogate endpoints. Proving that a drug actually saves lives or prevents disease complications using clinical endpoints like reduced mortality, fewer heart attacks, or reductions in pain is much harder. 


The Marketing of Intensive Glucose Lowering

Industry marketing contributes to overutilization by emphasizing certain target endpoints, even when academic researchers question the clinical relevance of those endpoints. 

During the 1990s and early 2000s, pharmaceutical companies popularized a surrogate endpoint, A1C, a measure of blood glucose averaged over a 3-month time period. Companies launching new medications for type 2 diabetes sponsored “educational” campaigns urging all patients with diabetes to “aim” for an A1C of <7%. The American Diabetes Association (ADA) and the American Association of Endocrinology (AACE)—with funding from industry—adopted guidelines recommending patients achieve an A1C <7 or lower. As a result, medical care emphasized intensive glucose control, targeting A1C levels of around 6.5% or 7%. 


Intensive Treatment Good for Many, Not for All

Pharmaceutical companies did such a thorough job of promoting intensive treatment that many doctors came to believe that it would prevent heart disease in patients with type 2 diabetes. However, subsequent large-scale studies showed that intensive glucose lowering did not reduce cardiovascular mortality. In fact, in many cases, lowering A1C too much led to increased deaths. These interventional and epidemiological studies were 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). 

In ACCORD , more cardiac deaths occurred in patients assigned to intensive therapy. The median A1C 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 A1C of 6.4%) had died from stroke, heart attack, congestive heart failure, and arrhythmia than in the standard therapy group (median A1C of 7.5%). 

Today, we know that the benefits and risks of intensive glucose lowering depend on various patient characteristics, such as age, diabetes duration, previous glucose control, presence of cardiovascular disease, and risk of hypoglycemia. While everyone agrees that managing plasma glucose is important, the question is how tightly? Years ago, an A1C around 8% was considered acceptable. 

Because of excessive industry influence, tighter glycemic targets—in some cases as low as 6.5%—have become the norm. Intensive treatment, especially in those on insulin and sulfonylureas, is risky for seniors and those with comorbidities. The human cost of increased falls, ER visits, hospitalizations, and long-term care placements due to drug-induced hypoglycemia is disturbing. However, as a society with limited resources, we must also consider the excessive costs of overtreatment. 


Economic Harms of Intensive Treatment
In 2016, payers spent $51.5 billion on diabetes medications for those with type 2 diabetes. Polypharmacy has become standard as healthcare practitioners try to get people’s A1C as low as possible. A 2016 article reported that the US annual cost of insulin- and sulfonylurea-induced hypoglycemia in older type 2 diabetic adults attaining very tight glycemic control was more than $500 million. The authors concluded that avoiding intensive treatment with insulin and sulfonylureas in seniors with type 2 diabetes could save the US healthcare system up to $1 billion annually by reducing costs associated with unnecessary diabetes medications and hypoglycemia complications.

Promoting surrogate endpoints like A1C targets dramatically impacts sales for drug and device companies. A shift in A1C targets as small as .05% translates into gains (or losses) worth billions of dollars to the companies that produce type 2 diabetes medications, home self-monitoring devices, and glucose test strips. 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 an article published in Archives of Internal Medicine, expensive medications such as glitazones, Januvia® (sitagliptin) and Byetta® (exenatide) drove up costs for treating patients with type 2 diabetes from $6.7 billion in 2001 to $12.5 billion in 2007.

An editorial in 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.” Unfortunately, older patients continue to be overtreated to achieve unnecessarily low A1C. 

Pharmaceutical companies spend millions of dollars promoting evidence based on surrogate endpoints. Do not hold your breath waiting for Eli Lilly, Novo Nordisk, or Merck to use continuing medical education, PR, or advertising to inform us about the limitations of surrogate endpoints or the need for relaxed targets for certain subsets of patients. Companies will emphasize the value of achieving very low endpoints, while continuing to debate, contradict, and argue with any evidence that interferes with their profit margins.

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