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Controversies With the Prediabetes Diagnosis

Did you know that the issue of prediabetes and what it actually means for health is controversial among some physicians and medical groups? Elevated blood sugar was once considered a risk factor for type 2 diabetes, but now it has been elevated into a pre-disease called prediabetes. We are now told that 1 out of 3 Americans are pre-diabetic and 90 percent of us don’t even know it. The main issues are: What does a prediabetes diagnosis mean? Does prediabetes lead to diabetes? How frequently does this occur? Should one treat it with medications? When one thinks about risk factors - then they can usually be modified (e.g. diet, weight loss, exercise), but when something is called a pre-disease - then one thinks treatment (e.g. medicines).

Yes, we all agree that type 2 diabetes is a very serious health problem. But what about prediabetes? What is alarming to some researchers is that the definition of prediabetes has been broadened over the years to include millions more Americans. Also, what is considered prediabetes in the US may not be considered prediabetes in other countries. Keep in mind that the people most involved with promoting a broadening definition of prediabetes and promoting drugs to treat it, have a number of conflicts of interest (financial and scientific).

The site Health News Review covered the topic of prediabetes in Jan. 2017 in a post by Dr. Michael Joyce: BMJ:Can we trust the numbers that define pre-diabetes? Some quotes from that post: "...meta-analysis of the progression rates of pre-diabetes shows the majority of people did NOT go on to develop diabetes a decade later."  "...in an article published in the BMJ, the accuracy of screening for pre-diabetes with fasting blood sugar and glycated hemoglobin is brought into question." ... “Our research looked at both these tests for pre-diabetes and found that neither of them was accurate,” says lead researcher Dr. Trisha Greenhalgh .... "In short, both our ability to predict diabetes with blood tests alone, and do so accurately in people with borderline elevated blood sugars, is questionable. Nonetheless, results from these tests – sometimes interpreted without clinical context – are being used to medicalize a risk factor and create a new medical condition."  Yikes!

This past week another thought-provoking article discussed the topic of prediabetes. Note that some experts call the focus on aggressively treating prediabetes as "scaremongering", especially because those promoting aggressive treatment the most are those with conflicts of interest. Centers for Disease Control and Prevention (CDC) data show that progression from prediabetes to diabetes is actually less than 10% in 5 years, and other studies show even slower (lower) rates. And a comprehensive 2018 Cochrane review of studies found that "up to 59% of prediabetes patients returned to normal glycemic values over 1 to 11 years with no treatment whatsoever". (see below) Wow! Excerpts from the article by Charles Piller in the journal Science:

Dubious Diagnosis

A war on "prediabetes" has created millions of new patients and a tempting opportunity for pharma. But how real is the condition?

The most common chronic disease after obesity, afflicting 84 million Americans and more than 1 billion people worldwide, was born as a public relations catchphrase. In 2001, the PR chief of the American Diabetes Association (ADA) approached Richard Kahn, then the group's chief scientific and medical officer, for help with a vexing problem, Kahn recalls. ADA needed a pitch to persuade complacent doctors and the public to take seriously a slight elevation in blood glucose, which might signal a heightened risk of type 2 diabetes. Raising the alarm wasn't easy, given the condition's abstruse name, impaired glucose tolerance, and lack of symptoms

Kahn invited half a dozen diabetes thought leaders to brainstorm at a National Institutes of Health cafeteria in Bethesda, Maryland. Surrounded by hungry federal employees, many enjoying the kinds of fatty foods and sugary drinks tied to the diabetes epidemic, they landed on a then–little-used term that seemed sure to scare patients and doctors into action: prediabetes.

“We went back to the ADA office right after lunch and started the change. Within a relatively short period of time we … eliminated ‘impaired fasting glucose’ and ‘impaired glucose tolerance’ and substituted ‘prediabetes’ in all of our literature,” Kahn says. Soon, the term was enshrined in the Arlington, Virginia, group's standards of care—widely regarded as the bible of diabetes. ADA and the Centers for Disease Control and Prevention (CDC) in Atlanta declared war against prediabetes, with CDC diabetes prevention chief Ann Albright, an ADA board member from 2005 to 2009, leading the charge. The two groups labeled prediabetes a first step on the road to diabetes, which can lead to amputations, blindness, and heart attacks.

In medicine, prevention is usually an unalloyed good. But in this case, other diabetes specialists argue, medical and epidemiological data give weak support, at most, for increasingly dire prediabetes admonitions. “Nobody really thought at the time, how ‘pre’ is prediabetes for all these people?” says Kahn, who left ADA in 2009 and is now at the University of North Carolina in Chapel Hill. The World Health Organization (WHO) in Geneva, Switzerland, and other medical authorities have rejected prediabetes as a diagnostic category because they are not convinced that it routinely leads to diabetes or that existing treatments do much good. John Yudkin, a diabetes researcher and emeritus professor of medicine at University College London, describes the ominous warnings about prediabetes from ADA and CDC as “scaremongering.”

Yet ADA, a nonprofit that funds research, issues treatment standards, and raises public awareness, has gradually broadened its definition of prediabetes to encompass more people. “The public needs to know that right now, in the United States … one out of three may have some aspect of glucose abnormality,” says William Cefalu, ADA's current chief scientific and medical officer. ...

CDC has followed ADA's lead, because “they set the primary standards of care in the U.S.,” Albright wrote in a statement to Science. (Albright declined interview requests, and CDC would not permit Edward Gregg, Albright's top epidemiologist, to comment for this story.) ... Indeed, CDC's own data show progression from prediabetes to diabetes at less than 2% per year, or less than 10% in 5 years. (Other studies show even slower rates.)

To lower blood sugar, ADA has increasingly advocated more aggressive measures, such as prescription drugs—a push that has opened it to charges of conflicts of interest. Science found that the group and its experts who promote aggressive treatment of prediabetes accept large amounts of funding from diabetes drugmakers. So far, no drugs have been approved specifically for prediabetes, meaning that doctors are limited to prescribing diabetes drugs or other medications “off label” to treat the condition. But drug companies are testing dozens of drugs aimed at prediabetes in hopes of tapping a potential worldwide market of hundreds of millions of people.

ADA's current definition of prediabetes was born in 2009, after the group, along with the European Association for the Study of Diabetes (EASD) and the International Diabetes Federation (IDF), convened an expert committee to review research on a diagnostic blood sugar test, A1c. It improves on prior tests because it requires no fasting. Hemoglobin A1c is a form of the red blood cell protein bound to glucose; its level indicates a person's average blood sugar over the preceding 3 months. The expert committee urged that people with A1c readings of 6% or higher should be considered for preventive interventions. But it unanimously rejected the term prediabetes, saying it implies that prediabetic patients eventually will get diabetes and everyone else won't—“neither of which is the case.

ADA went in the opposite direction. It kept the term and ratcheted down its prediabetes A1c threshold from 6.1% to 5.7%—a move its two partners in the expert report never embraced. Evidence favored the lower figure, Cefalu says, noting that prediabetes comprises a “continuum of risk,” with higher A1c readings warranting more aggressive treatment. ADA's new A1c standard, combined with its adoption of a similarly broad standard on a different blood sugar test a few years earlier, created about 72 million potential new prediabetes patients in the United States alone—and could create hundreds of millions more if embraced worldwide.

The broadened definition of prediabetes has triggered far-reaching changes in the medical landscape. CDC's budget for diabetes prevention jumped from $66 million in 2010 to $173 million in 2017—a 123% rise, in constant dollars. (At the same time, the agency's cancer prevention budget plummeted.) Many people diagnosed with prediabetes visit doctors more often for blood sugar tests and advice on diet and exercise. And a major marketing opportunity has opened up. Companies have pressured the Food and Drug Administration (FDA) for a seal of approval on foods or supplements—such as coffee, dairy products, and sugar substitutes—that they say can help prevent diabetes. A cottage industry of specialty fitness coaches emerged to serve a multitude of worried prediabetes patients. ... As the market expands, individual patients and society as a whole face a steep price tag.

Many scientists, however, question the need to identify and treat prediabetes as ADA defines it. All endorse healthy diets and regular exercise and say substantially elevated glucose levels can lead to diabetes. But researchers diverge over crucial questions: How often and how quickly does prediabetes progress to diabetes? Does prediabetes itself cause harm, particularly when a person's average glucose levels are at the low end of the test result spectrum as defined by ADA?

On one side are CDC and ADA, powerful financial gatekeepers and opinion leaders. ADA journals are the field's most influential, and the two organizations fund much of the nation's research and programs on diabetes prevention. On the other side are public health and primary care authorities, including WHO, the U.K. National Institute for Health and Care Excellence, EASD, and IDF. Those groups either do not use or do not emphasize the term prediabetes, and they normally advise treatment only when blood sugar levels approach those of frank diabetes.

Researchers skeptical of the ADA definition point to a comprehensive 2018 review of 103 studies by the Cochrane Library in London, which showed that most people who qualify as prediabetic never progress to diabetes over any period studied. People who do progress usually start out at the higher end of the ADA prediabetes test range. The review also noted that studies of people labeled prediabetic often fail to account for weight, age, and physical activity, which can all affect glucose, as can daily stress, inflammation, and other factors. According to the review, up to 59% of prediabetes patients returned to normal glycemic values over 1 to 11 years with no treatment whatsoever. “Doctors should be careful about treating prediabetes because we are not sure whether this will result in more benefit than harm,” the Cochrane authors concluded, “especially when done on a global scale.”

Kahn adds that even people whose elevated blood sugar does lead to diabetes progress slowly. “If you screen for diabetes every 3 to 5 years, you're fine,” he says. Prediabetes itself does not raise the risk of cardiovascular disease or other complications of diabetes, says former ADA President Mayer Davidson, a physician now at Charles R. Drew University of Medicine and Science in Los Angeles.

While the scientific dispute simmers, drug companies are racing to fill the demand created by ADA's prediabetes definition. The federal registry ClinicalTrials.gov lists human tests for more than 100 drugs, supplements, and other prediabetes remedies, including devices such as gastric bands. Drugmakers, ADA, and others have funded trials for at least 10 classes of drugs.

Any drug for prediabetes would likely have to be taken for years, perhaps a lifetime, so such modest benefits must be weighed against the potential harms of continual treatment. And several prediabetes options described by ADA and others present serious hazards. Pioglitazone, a drug to lower blood sugar developed by the Tokyo-based Takeda Pharmaceutical Company under the brand name Actos, carries on its label a “black box” side effect warning of the risk of congestive heart failure.... 

Yudkin says the growing emphasis on drugs for prediabetes reflects in part a false sense of urgency about its health risks. WHO's Roglic also doubts that the benefits of taking a diabetes drug for prediabetes outweigh the risks. “It seems counterintuitive to take a medicine in order to prevent something for which you would take that medicine. The reasoning is a bit twisted.”

The push for drug treatments for prediabetes takes place in an environment rife with financial conflicts of interest. For years, ethicists have criticized ADA for financial dependence on diabetes drugmakers. In recent years, ADA says, it has received $18 million to $27 million annually from drug companies, including many donations of $500,000 to $1 million per year. The group also gets up to $500,000 annually from each of more than a dozen other firms in the diabetes and prediabetes markets, including makers of consumer and medical products, testing labs, insurance companies, and drug retailers.

Many prominent physicians who now recommend drugs for prediabetes also received large payments in recent years from companies whose sales could be affected by such endorsements. ... Many physicians who wrote the 2018 ADA standards of care for prediabetes, which recommend that doctors consider prescribing those same three drugs, also received large sums from drugmakers. Seven of the 14 ADA experts got between $41,000 and $6.8 million between mid-2013 and 2017 from makers of diabetes drugs or candidate prediabetes medicines or devices. The payments covered consulting, travel, and research and included an average of $276,000 for personal fees.

John Ioannidis, a physician and expert on evidence-based medicine at Stanford University in Palo Alto, California, calls prediabetes a classic example of how clinical guidelines from groups such as ADA can escalate costs to society, to the benefit of specialty practitioners and drug companies. “You have a combination of two forces. One is to expand the definition of disease and to get more people classified as being sick or in need of treatment. And second, direct endorsement of specific interventions that [guideline authors] have direct conflicts of interest with,” he says. “It's really very worrisome.”

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