In the last couple of decades, the number of people deemed to have diabetes or its precursor, “pre-diabetes,” has boomed, right along with sales of diabetes drugs. But an investigative report last month shows how the new drugs haven’t improved outcomes, that conflicts of interest were front and center and that the FDA’s stamp of approval might have been misguided.
The report, published jointly by the Milwaukee Journal Sentinel and MedPage Today, reviewed how, in 1997, the American Diabetes Association changed the definition of type 2 diabetes to a lower blood sugar threshold. That move immediately classified 1.9 million Americans as having diabetes. Then, in 2003, the Diabetes Association widened its disease net with a new definition of pre-diabetes that ensnared another 25 million more Americans. (See our blog, “The Escalating – and Useless – Diagnosis of ‘Pre-Diabetes.'”)
So of course, with a ballooning consumer market for drugs that would lower blood sugar, pharmaceutical companies pounced, introducing 30 new drugs between 2004 and 2013. And the drugs were popular, because the ravages of diabetes can include cardiovascular (heart) disease, stroke, blindness, kidney failure and amputation of limbs due to poor circulation. And nobody wants any of that.
The frenzy was stoked in 2008, the reporters explained, when two endocrinology groups declared that pre-diabetes could be treated with drugs if diet and exercise didn’t lower blood sugar levels. The lifestyle changes generally are advised for patients who might be candidates for developing diabetes.
Diabetes is diagnosed when levels of blood glucose, or blood sugar, are too high. In type 1 diabetes, the body doesn’t make enough of the hormone insulin necessary to deliver sufficient energy to cells, a condition that usually develops when you’re young. Type 2 diabetes is more common, and develops later in life, when the body doesn’t make enough insulin or doesn’t use what it makes properly. It’s often promoted – and controlled – by lifestyle habits.
Last year, according to the reporters, sales of diabetes drugs were $23 billion. But between 2004 and 2013, they wrote, “none of the 30 new diabetes drugs that came on the market were proven to improve key outcomes, such as reducing heart attacks or strokes, blindness or other complications of the disease, …”
“Instead, the U.S. Food and Drug Administration approved the drugs based on their ability to lower blood sugar levels, what is termed a surrogate measure. Many of the new drugs have dubious benefit; some can be harmful.”
Treatment of diabetes is about controlling blood sugar. But because diabetes isn’t well understood, is difficult to control and can’t be cured, relying on hard-and-fast glucose numbers can be misguided, and dangerous.
As Dr. David Newman explained in the Journal/MedPage story, “We’ve called a sign of the disease the disease, but there are no rigorous studies that prove we understand how to treat the illness rather than its symptoms.” Newman is director of clinical research for emergency medicine at Icahn School of Medicine at Mount Sinai Hospital in New York. He founded theNNT.com, an independent group of physicians who analyze the effectiveness of medical therapies.
NNT refers to “number needed to treat,” a statistical measure of how many people need to receive a certain drug, test or treatment for one person to benefit. The lower the number, the better. ( See Patrick’s newsletter, “The One Medical Statistic You Need to Know.”)
Although diabetes is associated with obesity, lack of exercise and age, the number of people diagnosed with either diabetes or pre-diabetes “who are candidates for drugs has been magnified by organizations and doctors with financial ties to drug companies,” said the Journal/MedPage story.
The professional organizations that changed the blood-sugar numbers reap millions of dollars a year from pharmaceutical companies, as do many of the individual doctors who sit on the panels that make the recommendations. In one case, according to the Journal/MedPage, 13 of 19 members of a 2013 committee received more than $2 million in speaking and consulting fees since 2009 from companies that make diabetes drugs.
Many of the new drugs approved by the FDA have side effects, including heart problems, cancer and overdoses that lead to dangerously low blood sugar. One analysis showed that in about 3,300 patient deaths, diabetes drugs approved since 2004 were considered to be the “primary suspect.” Another study found that 20,000 hospitalizations occurred because of the drugs’ use.
“We may be using drugs that are great for lowering glucose but don’t do anything for cardiovascular risk,” Dr. Clifford Rosen told the Journal/MedPage. He’s an endocrinologist and professor of medicine at Tufts University School of Medicine.
Rosen also said that many of the newer drugs haven’t been proved to prevent other diabetes complications, including blindness and amputations.
But drug approval from the FDA has hinged on the surrogate measures (lowered glucose), which aren’t necessarily the best measure for safety. For example, to measure effectiveness in heart disease, an acceptable surrogate measure might be improved cholesterol blood levels that might not necessarily result in fewer heart attacks – the “number” is a surrogate for what actually might be happening, which, of course, is far more important.
An acceptable surrogate measure for cancer treatment might show tumors getting smaller, but not necessarily result in increased survival rates.
“Clinical trials that would prove new drugs prevent heart attacks and other diabetes complications require larger numbers of patients, take longer and are more costly than simply showing an improvement in blood sugar,” the reporters explained.
To address concerns that diabetes drugs posed a cardiovascular risk, in 2008 the FDA started requiring companies whose drugs were approved on surrogate measures to conduct follow-up studies. You have to wonder why, because the studies weren’t required to show improved heart health. All the drug makers have to show is that their wares don’t increase cardiovascular risks by more than 1.3 times.
Most of the follow-up studies, according to the Journal/MedPage, continue, but the one that has finished found a serious problem.
The drug Onglyza was approved in 2009. Last year, a study published in the New England Journal of Medicine showed that it increased the rate of hospitalization for heart failure by 27%.
It’s still on the market. The FDA says it is investigating.
The FDA has claimed that a couple of clinical trials in the 1990s showed drugs lowered glucose and reduced many complications of diabetes. But one of those studies involved people with type 1 diabetes. Type 2 diabetes is a different disease. The other study found significant reductions in blood vessel problems such as strokes or eye damage, but its results have not been replicated in further research, some of which showed significantly higher death rates from cardiovascular causes among people with type 2 diabetes whose blood sugar was brought under intensive control.
Cardiovascular disease is the cause of death for as many as 8 in 10 people with type 2 diabetes.
Although the diabetes treatment establishment has deemed tight blood sugar control key to controlling the disease, recent research has demonstrated that attempting to control high blood sugar so intensively can increase the risk of dangerously low blood sugar, known as hypoglycemia. It can cause seizures, unconsciousness or death.
In 2014, a study in JAMA Internal Medicine showed that 404,000 Medicare patients were admitted to the hospital because of dangerously low blood sugar levels between 1999 and 2011, compared with 280,000 for dangerously high blood sugar levels. About 20,000 of them died within 30 days of their hypoglycemia admission.
As Newman told the Journal/MedPage, “Treating a sign or a symptom rather than the disease is not the science patients believe their treatments are based on.”
Consider Victoza, a drug that lowered blood-sugar levels that the FDA approved despite concern about serious side effects and objections from its own advisors. Three FDA doctors recommended against approving it, according to the Journal/MedPage, because of concerns about an increased risk of thyroid cancer and cardiovascular safety. Two cardiologists on an FDA advisory committee voted against approving it.
But the FDA approved it and three more drugs in the same class, all of which carried serious risks. Known as GLP-1 receptor agonists, they all bear the agency’s most stringent “black box” warning because they cause thyroid tumors in rodents. Victoza and some other diabetes drugs also have been linked to serious inflammation of the pancreas and pancreatic cancer.
Public Citizen, a patient advocacy group, petitioned the FDA in 2012 to remove Victoza from the market. Last year, the FDA denied the petition. Now, its manufacturer, Novo Nordisk, is seeking approval for a higher-dose of the injectable drug to be used for weight loss, with an eye toward the pre-diabetes consumer market.
Clearly, overmedicating people who might have or be predisposed to diabetes is dangerous. And even drugs that might benefit some people are being too widely applied. None of the drugs the FDA approved from the 2008 and 2013 panels to treat diabetes was approved to treat pre-diabetes. But lots of doctors prescribe them for that purpose in what’s known as “off-label” use. It’s not illegal for practitioners to prescribe off-label, but it is for drug makers to promote them for that purpose.
“The logic of treating pre-diabetes with drugs is basically nuts,” James McCormack told the Journal/MedPage. He’s a pharmacist and professor of pharmaceutical sciences at the University of British Columbia, and has studied diabetes drug research. “We treat 100% of people with pre-diabetes with a drug to prevent roughly 15% of people from getting diabetes, a condition for which they may need a drug.”
As detailed on AboutLawsuits.com, the number of lawsuits by patients harmed by newer diabetes drugs is high, and climbing.
If you have been diagnosed with diabetes, understand that diet and exercise are not only the safest treatment, but have been proved to be much more effective at preventing pre-diabetes from becoming diabetes. If you do need drugs, make sure to discuss with your doctor all their risks and benefits, especially if they are relatively new. Dealing with diabetes is difficult enough without complicating it with drug side effects.