The People's Perspective on Medicine

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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I would like to know more about the drug, Glyxambi & any serious issues & any recent studies.

Only one that works for me w/out negative side effects – can’t tolerate Metformin.

Glyxambi is a combination of empagliflozin–the same drug in Jardiance–and linagliptin, aka Tradjenta. It was initially approved in 2015 as an add-on to metformin but is now prescribed on its own.

I’m and 85 year old female who has had type II diabetes for some 35 years. The only medication I have ever used is Prandin (now generic repaglinide). Its problem has always been proper dosage since it is affected by exercise. Take too much= dangerous lows, take too little = higher than I want. Nevertheless I have maintained an A1C between 5.6% and 6.2% on this drug. A couple of years ago, I developed painful peripheral neuropathy for which I use 600mg. a day of benfotiamine.

Dr. Richard Bernstein, an 82 or so year old Type 1 diabetic, says to take only the original Metformin and not generics. Maybe there are some that really are equivalent.
So if you have trouble with a specific generic, ask your pharmacist for a different manufacturer or change drug stores.

I live in Mexico and manage my blood sugar levels with local products that assist a lot, like nopal cactus.
My last HgbA1c about a month ago was 5.53. So with some watching, I am keeping it down.

I had JANUVIA prescribed and took is for several weeks. After a while Severe pain in the bones in my hands woke me up in the early morning. Januvia was stopped and the pain went away.

You wrote “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?”

“Sugar pill” is commonly used as a synonym for “placebo” but it shouldn’t be used in an article pertaining to diabetes. It’s misleading.

Diabetes drugs induce epigenetic effects just like statins.

All the articles I have read don’t mention drinking water! A diabetic needs to drink a lot of water. I drink a gallon a day, exercise and watch what I eat. I still have an occasional drink and some candy before the craving gets too bad. Taking cinnamon in a glass of water helps keep my sugar under control.

LA, I also had breast cancer, surgery and radiation. It was not the breast cancer that forced your doctor to take you off metformin, it was the state of your kidney. Right after my radiation was done, we found I had two kidney cancers; my endo immediately discontinued the met. As I was on insulin, I had to increase it by 50% to make up the difference. Now, as you do, I have one kidney and, after 30+ years of diabetes, while I am 75, it is about 100. If the kidney does not clear met from the body in a timely manner, something that may be hard for your kidney and mine, it can build up and create a condition called lactic acidosis. While some is normal, for instance after exercise, too much can be fatal.
I found, almost three years ago, that lipitor was pushing up my bgs, and when I discontinued it, on my own, I fell back to the same insulin I was using when still on the met. Are you taking a statin for cholesterol?
All diabetes drugs, including insulin, can make you hungry – except the incretins like byetta. It actually has helped many people lose weight and normalize blood sugars. There are risks there too; but sometimes one has to balance risk against benefit and see which is stronger.
From what you wrote about having to consume carbs to keep up with the medication says to me, as commented previously, that you would do well on a low carb diet. Usually within the first week, cravings are gone, weight goes down, as weeks go on, and, eventually, medication can be much lowered or eliminated. Triglycerides, which are fats in the blood, go down too.
Readings in the 70s are good; you may be experiencing difficulties at that level because your body is used to higher numbers. An A1c of 6.4 translates to readings well above the 70s. These lower readings are a good sign, not a bad one, and with the appropriate changes in lifestyle, yes, even in your 70s, you and your pancreas may achieve an A1c in the 5s, better for you, better for your kidney.

bdc, yes, sounds like some neuropathy. At the very beginning, there is a chance the nerves will heal if you achieve tight control. At the risk of sounding like a broken record: has anyone discussed changes in lifestyle with you? Losing weight, if necessary, even some weight loss can make a difference in your insulin sensitivity. Exercise can take up glucose from the blood and put it into the muscles, even in the ABSENCE of insulin. Glipizide forces more insulin out of your pancreas, a low carb diet means you need less insulin.
Please join a diabetes online support group.
PS You can try benfotiamine for your neuropathy. Look it up on line for studies and prescribed amounts. This is widely used in Germany and other countries to treat neuropathy.

You cannot lump all people into the same bag. I have friends on metformin who eat the right portions and eat right and they still have problems. Without insurance to help pay for these drugs and able to see a doctor where would they be? You seem frustrated when you speak about people on diabetic drugs. My understanding is diabetes can run in families.

Since I have been on glipizide–about 2 month–I have been experiencing a burning sensation under the toes on my left foot. Someone suggested diabetic neuropathy.
How do they treat that, or do they.

I have some questions and hope you may be able to help. I was diagnosed w/Diabetes 2, 4 years age. I am 72 years old and my mother and many relatives from her side of the family have died from it, or from complications because of it.
At first my doctor had me on Metformin, than I had breast cancer and after two surgeries and 33 radiation treatments, my doctor took me off Metformin and for the last year I have been on Glimepiride Tab 1 mg.
This drug makes me very hungry. I have to say that I do not like sweets that much, I go for the savory foods and have to force myself to eat enough carbs, to counteract the Glimepiride, or I start to feel sick in the afternoon. My A1C is 6.4. Sometimes when I check my bloodsugar it is as low in the 70s.
I also have to tell you, that I am in Kidney failure, my Nephrologist says my kidney function is at about 64 %. I had kidney cancer and I am living with one kidney. Did my doctor take me off Metformin to protect my kidney? I liked it better, because I did not have to strugle with being overweight.
Would it be safe to ask to go back on Metformin?

I have been taking glimpiride for type-2 diabetes for 10+ years. Over the last year my numbers have been slowly increasing but that may be due to a change in diet because I moved into a senior living center and they provide a huge lunch and desserts. Prior to my move, my A1C hovered between 5.7 and 6.0. Now it’s 6.1. My heart is fine and most of my other problems can be attributed to mistakes that my back surgeon made.

I just turned 66. 3 years ago I had a routine blood test (first in many years) and my blood sugar showed at 330; didn’t do an A1C at that time. I immediately cut out all sugars and simple carbs (even fruit), reduced my total carbs from well over 200 a day (over 250 most days) to around 120-130, started eating smaller meals every 3-4 hours (to keep blood sugar at a more constant and steady level), and started working out 30 minutes 6 days a week (3 days weight training, 3 days treadmill). No drugs. 4 months later my average blood sugar was around 115 and my A1C was 5.7. You can do it people, and you don’t need to go down to 50 carbs a day; just eat the right kind and space them out. The 65% carb diet (and the type of carbs) the ADA recommends is criminal; I don’t see how they aren’t being ridiculed and shamed for their ridiculous recommendations.

My husband was diagnosed with Type 2 four months ago…we found out in the ER, since he was having a heart attack. His A1C was 13.4 (Yes, that is correct.), and he had triple bypass surgery a few days later. He was only 10 pounds overweight, has exercised 3-4X a week for years, has never smoked, and rarely drinks alcohol. BUT, he loves carbs of every stripe, especially candy. I read everything I could find on the subject and I soon realized that by following the ADA nutritionists’ advice to consume 60% of calories in carbs was going to keep him chained to insulin for the rest of his life, so I make sure he doesn’t exceed 40% of carb calories at any meal…also never eats even one carb without balancing it with protein and/or “good fat” of some kind. It’s been hard for him, after a life-time of carb dependency, BUT he no longer injects insulin 4X a day! With Metformin 2X daily, 15 units of Lantus, and careful fat/carb/protein balance, his pre-meal BG never exceeds 115. Everyone’s situation is different, I know. However, as I tell my husband, “Your BG won’t spike unless it’s provoked!” ;-)

A couple of things left out of the article. Metformin costs $10 for a 90 days supply at WalMart. Compare that price with the non-generic Diabetes medications.
I follow the literature on diabetes drugs and Metformin has consistently been associated with numerous health benefits in various studies over the years. For those for whom it is effective, it is the greatest bargain in Diabetes care. What the FDA does not do and what it should do when it approves new medications is compare them with existing medications to see whether there is any substantial benefit to the new medication. This is particularly the case if the new medication will be expensive and old medication(s) are generic and inexpensive.

I was diagnosed with type2 diabetes 30 years ago, suffered with it for much longer than that. Treating diabetes with diet and exercise is fine at the beginning. As time goes on, the pancreas beta cells, those making insulin, continue to change, producing less and less insulin. This is why diabetes is a progressive disease. Far easier to PREVENT than treat. When I had to stop the other drugs (still taking metformin), I had to go to insulin for control. In 2008 I was diagnosed with kidney cancers, goodbye metformin. I now control with insulin only; which has its own problems.
The drugs are really not about preventing heart disease, etc; they are about controlling blood glucose. High bgs lead to other complications that tight control either eliminates or pushes off so indefinitely, they might as well be eliminated. Compared to actos, avandia and rezulin, it is a relief to find the new drugs do not increase heart disease. Tight control can save your nerves, your eyes, your kidneys.
ONLY, diabetes education in this country is a farce. There should be no controversy between low carb and low cal. The more carbs you eat, the more medication you need. OTOH, the more you exercise, the more carbs you can eat. Unfortunately, most diabetes educators push a high carb diet; just as they learned in school. However, there is a lot of information on the net, plus many support groups where the emphasis is on low carb.
Many low calorie foods are high in carbs; if you need to lose weight, and you are very resistant, you may have to go both. Unless you are very conversant about nutrition, you will probably need professional help. Remember, your doctor knows nothing about nutrition, nor does he have the time to learn anything. The best best, as mentioned above, is the internet.
If we had true education, I am sure many people would elect using diet and exercise far more than they do now. That means, also, education about frequent monitoring to assess how diet and exercise affect your body.

I almost died taking actos. It’s a horrible drug, yet is still on the market. A couple of the responders talk like its so easy to change ones’s diet. A diabetic can do all the right things and still have health issues. Another wrong assumption is that only the obese get diabetes type two. That is also a fallacy. There are drugs that can raise one’s blood sugar as a side effect. Diabetes is a disease that so many think they know about, but in fact is a hard to understand and fatal disease.

I’ve had Type II diabetes for almost thirty years and have been using Prandin tabs for about twenty-five years. I test four times a day in order to predict my dosage, which can vary between 3.5 and 5mgs daily depending on my level of physical activity. The action of this drug kicks in fifteen minutes after ingestion.
I stick to a mostly vegetable diet, my staples being small red beans, kale, fresh tomatoes, romaine lettuce, raw carrots, celery, olive oil, Bragg’s cider vinegar, brown rice, apples, oranges, steel cut oats, blueberries, yogurt, whole eggs a couple of time a week, both sugar free Activia and regular fat free, Ezekiel sprouted grain salt free bread, brisling sardines, albacore, occasional Stilton cheese, low salt Triskets and other crackers, pistachios, walnuts, almonds, cashews and rarely, peanut butter.
I have found highs and lows with this drug difficult to manage, but have managed to maintain an A1c around 6%. I wish I could take Metformin, but renal impairment precludes this because of the risk of lactic acidosis. I fast walk for twenty minutes after breakfast and lunch for a total of forty minutes a day as well as gardening and other activity. I’ve been using Benfotiamine for over two years and seem to be holding my own in the neuropathy department.

Karen you hit the nail kiddo! People don’t want to change their lifestyle. Pop a pill, that will take care of the problem.

Cold bloodedly, “Millions of people who are taking these new diabetes drugs are in a terrible bind…” because they want to continue to eat the way they have always been eating, without any nasty side effects like high blood sugar. That’s kinda like wanting to smoke the way you always smoked, but without the nasty hacking cough. Or drinking the way you always drank, without passing out at the dinner table.
Every other addiction requires abstinence as part of treatment.
Why is it that we treat an addiction to a high-carb diet with medications that our insurance covers?
Don’t eat the high-glyclemic load carbs, and most people will be amazed at how easy it is to manage blood sugars.

I have been taking Metformin for about 15 years – – controlling blood sugar just fine, but I did develop cardiovascular disease. Prior to Metformin I was taking Avandia. Considered going natural but have never really been serious about it.

Article was very done and informative. I would like to see a similar article which discusses the positive aspects of some diabetes drugs such as the metformin discussion in this article.

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