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Diabetes Drugs: A Disappointing Tale of Broken Promises

Billions of dollars are spent on diabetes drugs every year. Patients have been led to believe that these medications will protect them from the ravages of elevated blood sugar: heart attacks, strokes, blindness, kidney disease, nerve damage (neuropathy) and possibly even Alzheimer’s disease.

Do Diabetes Drugs Prevent Complications?

The Food and Drug Administration and researchers seem to have far lower expectations. Research in the New England Journal of Medicine (October 3, 2013) demonstrated how investigators can seemingly make a silk purse out of a sow’s ear.

The headlines are confusing:

“New Diabetes Drugs Don’t Raise Heart-Attack Risk” (Wall Street Journal)

“New Diabetes Drug Seems Safe for Heart, Study Finds” (HealthDay)

“Doctors Get Good and Bad Safety News on Diabetes Drugs” (Reuters)

“Diabetes Drugs No Help for Heart” (MedPage Today)

Are you baffled by these contradictory messages? That’s hardly any wonder, since such mixed messages are indeed mystifying. And this research has been followed by more bad news about these medications.

What Is the Straight and Skinny on These “New” Diabetes Drugs?

We’re talking about a class of medications called DPP-4 (dipeptidyl peptidase-4) inhibitors specifically. Also known as “gliptins,” this kind of medicine has become very popular for controlling blood sugar. That’s because they are considered highly effective and well tolerated. The drugs are alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza) and sitagliptin (Januvia).

How Well Do the Gliptins Work?

The key issue is all about the definition of effectiveness. All such drugs lower blood sugar. One might assume that is the key to success. Sadly, though, we have learned from past diabetes drugs that just lowering glucose in the blood stream does not necessarily produce the desired outcomes outlined above, ie, fewer heart attacks and strokes and improved longevity.  Rosiglitazone (Avandia) was reported to cause an increased risk of heart attacks and strokes in May, 2007 (New England Journal of Medicine). It and a similar drug called pioglitazone (Actos) increase the risk for heart failure…big ooops.

Heart Attack Prevention Fizzles:

The newer gliptin drugs were supposed to be better when it comes to the heart. The two drugs reported in the research published in the New England Journal of Medicine were alogliptin and saxagliptin. First, we will analyze the NEJM studies and then delve deeper into the safety of many of the newer diabetes drugs referred to as incretin mimetics or GLP-1 inhibitors. (This larger class includes the DPP-4 inhibitors.)

One of the studies titled SAVOR TIMI53 [The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI)] involved 16,492 people with diabetes who were diagnosed with cardiovascular disease or were at high risk for heart disease. They were randomly assigned to receive either Onglyza or placebo and were followed for over two years. Blood sugar levels were substantially lower in the patients getting Onglyza. But (and this is important!), there was no difference in the really important outcomes: heart attacks and deaths. In our opinion: This drug was a fizzle.

At the end of the stud,y 613 patients in the Onglyza group had had a heart attack or stroke compared to 609 patients in the placebo group. 1059 patients on the diabetes drug suffered one of the following: death from cardiovascular causes, nonfatal heart attack, nonfatal stroke, hospitalization for severe chest pain, bypass surgery or stenting or heart failure. 1034 patients on placebo experienced these events. In fact, more patients on the drug were hospitalized for heart failure compared to those on placebo.

The authors conclude:

“DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes.”

In other words, these high-risk patients (like canaries in the coal mine) did not experience any measurable cardiovascular benefit from this medication and actually had a higher incidence of heart failure.

The other study was called Examine [Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care]. Over 5,000 people with diabetes who had experienced a heart attack or serious heart complications were recruited into this trial. They were randomized to receive either Nesina or placebo. At the end of the trial there was no increase in major cardiovascular events compared to placebo.

The researchers seemed OK with this result, but we find it disappointing to say the least. Shouldn’t we have expected that patients getting the diabetes drug to have experienced fewer heart attacks, strokes and deaths than those getting a sugar pill?

Real-World Experience:

Both Onglyza and Nesina cost hundreds of dollars a month. Patients have a right to assume that an investment in such drugs would reduce the likelihood that they would experience serious complications of diabetes. We think doctors should demand such proof before prescribing these medications.

A recent study demonstrates that these medications may not even lower blood sugar well enough to justify the expense. It is titled “Real-World Evaluation of Glycemic Control Among Patients with Type 2 Diabetes Mellitus Treated with Canagliflozin versus Dipeptidyl Peptase-4 Inhibitors” (Current Medical Research and Opinion, online March 3, 2016). Unlike the studies reported several years ago in The New England Journal of Medicine, this study was not a double-blind placebo-controlled experiment. Instead, the researchers reviewed insurance claims and lab data from more than 5,000 people with type 2 diabetes. At the beginning of the study period, the average HbA1c values were similar-just over 8.5%. The patients who were prescribed canagliflozin (Invokana) were more likely to get this important measure of blood sugar over time down below 8%.

Now, that might suggest that canagliflozin is simply a better bet for people with type 2 diabetes. Last year, however, the FDA issued a strong warning that this medication can reduce bone mineral density and increase the risk of fractures. So, maybe not so wonderful.

A national study in Taiwan that lasted several years found that the gliptin drugs were less likely to be associated with heart attacks or strokes than the other medicines used to treat type 2 diabetes-except for metformin, a very old drug and our first choice for treating this metabolic disorder (Cardiovascular Diabetology, March 1, 2016).  See below for more information on metformin.

What about Cancer?

In addition, there has been a cancer cloud hanging over the entire class of new diabetes drugs called GLP-1 agonists or incretin mimetics. Although there was no increase in pancreatic cancer (or pancreatitis) in the NEJM study of Onglyza, the trial lasted just over two years. That may not have been enough time to detect a problem.

In 2013, the FDA issued a Drug Safety Communication for the following medications:

  • Bydureon
  • Byetta
  • Janumet
 (sitagliptin & metformin)
  • Janumet XR
 (sitagliptin & metformin)
  • Januvia
  • Jentadueto
 (linagliptin & metformin)
  • Juvisync (sitagliptin & simvastatin)
  • Kazano
 (alogliptin & metformin)
  • Kombiglyze XR (saxagliptin & metformin)
  • Nesina
  • Onglyza 
  • Oseni
 (alogliptin & pioglitazone)
  • Tradjenta (linagliptin)
  • Victoza (liraglutide)

The FDA offered the following on March 14th, 2013:

“The U.S. Food and Drug Administration (FDA) is evaluating unpublished new findings by a group of academic researchers that suggest an increased risk of pancreatitis, or inflammation of the pancreas, and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics.”

“FDA has not reached any new conclusions about safety risks with incretin mimetic drugs. This early communication is intended only to inform the public and health care professionals that the Agency intends to obtain and evaluate this new information. FDA will communicate its final conclusions and recommendations when its review is complete or when the Agency has additional information to report. “

“At this time, patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.”

As usual, such safety alerts leave everyone in the lurch. Millions of people who are taking these new diabetes drugs are in a terrible bind. These are pricey medications and yet there is little evidence that they reduce the really serious problems associated with type 2 diabetes such as heart attacks, strokes, premature death, nerve damage, blindness or Alzheimer’s diasease. And we do not yet know how safe these drugs are in the long term.

The Bottom Line:

We encourage people with type 2 diabetes to become as informed as possible about ALL options involving blood sugar control. In our Guide to Managing Diabetes we discuss many non-drug options. You will learn about the Low-Cal vs. Low-Carb controversy and get practical recommendations on the best vegetables to keep blood sugar under control. Find out about the role of cinnamon, vinegar and supplements such as vitamin D, selenium and chromium as well as herbs like bitter melon, fenugreek and nopal cactus.

Pros and Cons of Old Metformin:

You will also learn about the pros and cons of metformin. Not only does this drug help control blood sugar without the usual weight gain associated with many other medications, it has been linked to a lower risk of cancer!

In June, 2012 a study published in the Journal of Clinical Oncology had some very good news about metformin:

“In a large population of postmenopausal women, use of oral metformin was associated with lower incidence of invasive breast cancer…Our results inform future studies evaluating use of metformin in the management and prevention of breast cancer.”

This isn’t the first time metformin has been linked to a lower risk of cancer. A comprehensive review of the medical literature published in Cancer Prevention Research (Nov. 2010) revealed that metformin was associated with a 31% reduced risk of cancer in general compared to other diabetes treatments. In particular, the reduction in rates of pancreatic and liver cancer were statistically significant. A more recent study, however, found that although people treated for pancreatic cancer had better survival rates if they took metformin rather than placebo, the difference was not statistically significant (PLOS One, March 11, 2016).

Cancer researchers have even given metformin to people who don’t have diabetes. In one randomized, controlled trial, the people who took metformin for a year had fewer precancerous colon polyps or adenomas than those on placebo (Lancet Oncology, online March 2, 2016).

More Information:

To learn more about metformin’s benefits and risks as well as other practical ways to manage diabetes and prediabetes, we hope you will find our Guide to Managing Diabetes worthwhile. Even if you have not been diagnosed with elevated blood sugar, we think the dietary suggestions in this guide will make sense for you and those your love. You may also find our section on diabetes in the book, Top Screwups Doctors Make and How to Avoid Them of interest. The key to success in managing this complicated condition is good communication with your heatlh care provider, knowledge about the latest research and a dedication to making lifestyle changes that can help control blood sugar. To do that you will need a team approach and great coaching from family, friends and health professionals who know how to help motivate and maintain healthy behavior.

Please let us know how you mange your blood sugar by commenting below.

Revised 3/14/16

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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
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