A week ago, the media was all abuzz about a new study published in the New England Journal of Medicine showing that the oral drug Actos can prevent diabetes. At first we at the ‘Mine didn’t pay much attention, because of course we’re more concerned with what happens to people who already have diabetes. But the buzz didn’t stop. Forbes blogger Matthew Herper wrote a great piece about why side effects make this a bad idea.
So we’ve been chewing on this news all week, and just couldn’t resist adding our 2 cents on why this study is dumb. Errr, 10 cents that is:
1. The study was financed by the company that makes this drug! No surprise it came out in their favor! Talk about your self-fulfilling prophecies.
2. It’s counter-intuitive (and counter-productive) to treat type 2 diabetes with a drug that clearly causes weight gain.
3. Pre-diabetes is defined as elevated fasting glucose. If you give folks any glucose-lowering drug (metformin, glipizide, or insulin!), their fasting glucose levels go down. So how is this prevention? Isn’t giving people Actos for high BGs just basic treatment for diabetes?
4. This drug is in the same class as Avandia, which has been known to cause serious complications in individuals and has already been banned in Europe, and has been greatly restricted in the US!
5. The European Medicines Agency has opened a study investigating whether Actos is linked to cancer. They’re in the middle of a 10-year study. So you want patients to take their pick of diabetes or cancer risk?!
6. Other research suggests that about three out of every 100 people who take Actos or Avandia develop heart failure as a result!
7. The study doesn’t address how long patients have to stay on Actos to avoid “full-blown diabetes.” Just a year? Or indefinitely? Again, is this really prevention or just garden variety treatment?
8. According to Kelly Close of the diabetes consultancy Close Concerns, seeking FDA approval for this use of Actos is a “non-starter”:
“This class of drugs is going generic in 2012… (and) no companies have yet tried to get approval for a drug specifically for pre-diabetes. It would take so long that these drugs will go generic before that, and then the companies will lose interest because they can’t make money off it.”
9. In the meantime, encouraging docs to use this drug for pre-diabetes would constitute “off-label use.” (evil!)
10. At the core of it: do we really want to encourage people to med up unnecessarily? Wouldn’t diet and exercise be healthier than embarking on a potential lifetime of “prevention” medication?
And… Bonus reason: This is so old news (2008)!
btw, were you thinking April’s Fools here? Think again!!
Thanks for this great post, Amy. I actually blogged about another stupid study that was apparently done by researchers over in Italy… Not sure what is going on this time of year for these wastes of time and money, but it’s mind-boggling that these are happening. Gave you a shout-out in my post today, too!
Excellent points! From what I’ve read, intensive counseling and support for diet and exercise are more effective than any med. Trouble is, insurance companies won’t pay for it. They’d rather pay for complications.
Amy –
THANK YOU for writing about this ACTNOW study…your points are all excellent and need to be said again and again. As a dietitian/diabetes educator it is so frustrating to see these types of studies garner headlines and yet studies showing the benefits of lifestyle changes merit merely a blip on the media radar screen (DPPOS, Look AHEAD).
And Natalie makes a critical point. But to clarify, Natalie, the studies showing effectiveness with lifestyle intervention also include a great deal of support “intensive” by trained interventionists. People need support during lifestyle change and throughout time to maintain these changes and relatively minimal weight loss. People might find it interesting to read this blog on my website http://www.hopewarshaw.com/blog/lip-service-lifestyle-change-prediabetes. This provides a bit more detail on how these studies are designed. Reality is these drugs aren’t studied fair and square against lifestyle.
PS: Speaking of old – can you replace “diet and exercise” with healthy lifestyle behaviors or….
Fabulous post! Appreciated! A study just came out proving how well lifestyle changes work to prevent type 2 diabetes. Here is a link about it:
http://thediabetesclub.com/major-proof-that-you-can-prevent-type-two-diabetes/
Couldn’t disagree more.
Please see my blog post as a counter argument
http://drmintz.blogspot.com/2011/04/using-actos-to-prevent-diabetes.html
@Dr. Mintz – just had a look at your post, and couldn’t disagree more either. IMHO, on a societal level, giving up on healthy lifestyle, shrugging our shoulders at obesity trends, and throwing lots of pills at people is a bad choice on many, many levels.
Not to mention, how do you as a doctor define “manageable side effects”??
As per my post, I am far from suggesting that we should be “giving up on healthy lifestyle, shrugging our shoulders at obesity trends.” This is clearly important and the best way to go. However, in clinical practice, it is only effective the minority of the time. The ADA recongized this in established type 2 diabetics, and changed their treatment recommendations from diet/exericise first followed by metformin, to diet/exericse plus metformin as initial therapy.
I strongly believe that we should not only advise patients on diet and exericse but push the insurance companies to pay for things like nutritionists, gym memberships, personal trainers, etc. We also need to ask our politicians to support public health efforts. When a pint of berries at the grocery store costs as much as a full course dinner at McDonalds, Americans are going to continue to struggle to maintain a healthy diet.
I am not giving up on stressing the importance of diet and exericse. However, I can not give up on my patients when my recommendations and support for lifestyle changes don’t work. The reality unless they lose a substantial amount of weight, they will progress to diabetes. During those few years it takes them to reach an A1c of 6.5% or fasting glucose of 126, their triglycerides are going up, HDL is going down, blood pressure is going up, atherosclerosis is progressing, and we now know that even microvascular complications happen before over diabetes. Should I just let this happen for the majority of my patients where diet an exercise will fail, especially when I know their are medications to prevent this?
@Dr. Mintz : not saying you shouldn’t treat patients with meds when there’s real evidence it will help. BUT you could help them just as well with metformin, insulin, etc. Our core issue here is the publicity stunt by the company behind Actos, a drug that has some serious drawbacks.
Also, regarding manageable side effects:
1. Edema- this is usually mild, and tolerable by patients. Diuretic blood pressure medicines usually resolve this. Since most patients with diabetes or metabolic syndrome often need blood pressure control as well, including a diuretic as a choice usually resolves the edema.
2. Weight gain- this is managed by diet and exercise. Again, I never stop focusing on this. There is a study, though Takeda sponsored and in diabetics not pre-diabetics, which shows that if you have a good diet and exercise, you don’t gain weight on Actos.
3. Heart failure- patients with heart failure should not take Actos. Patients with long standing high blood pressure and thus at risk for heart failure should have a work up (EKG, echo) before starting a TZD.
I have written many prescriptions for TZD’s over many years. I do not believe I caused one heart attack or heart failure. I have seen a few cases of edema which was usually managed by adjusting existing blood pressure medications. I have caused some weight gain, though I believe this risk of metabolic syndrome/diabetes far outweighs the extra few pounds.
P.S. A great example of just how frustrating treating obesity can be is your post on Victoza. Look how many responses you have gotten. Look at how thrilled some of your diabetic readers have been to finally have a medication which helps them lose weight. It’s not because they haven’t tried diet and exercise, and not because their doctor hasn’t suggested it. It’s because losing weight in our country is extremely difficult.
No. We are talking about using pharmacotherapy for patients with pre-diabetes. Insulin is not an option. Patients who are pre-diabetic have high levels of insulin. Insulin, because of it’s risk of hypoglycemia should be reserved for patients with progressive diabetes that can not be controlled with medications. As mentioned in my post, metformin does have evidence that it can prevent diabetes. In fact, the ADA recommends metformin for pre-diabetes. It does not recommend Actos.
However, though there is no comparative study the magnitude of the affect of Actos and Avandia was similar to diet and exercise in the DPP study (which showed metformin to be superior to placebo, but not diet and exercise), and the preliminary data from the first year of the DPP which had troglitazone (before it was pulled), showed the TZD to be superior to metformin and lifestyle intervention. Because the Actos will soon go generic, there will never be a study comparing metformin to Actos in the prevention of diabetes. However, the existing data suggests that Actos is superior to metformin and about the same as diet and exercise.
This is also not a publicity stunt by Takeda. They designed a trial to show Actos prevented diabetes, using standard definitions, and that study was a positive one. You are correct in being skeptical about industry sponsored studies. The reality is that most therapy studies are funded by the industry. I would love to see a non-industry sponsored study comparing metformin, diet and exercise and pioglitazone for the prevention of diabetes. I doubt that will ever happen.
Dr. Mintz makes some very good counterpoints.
I have to agree with Dr. Mintz that losing weight for some people is extremely difficult, and sometimes impossible. While I am not overweight myself, I have obese Type 2 friends, and I KNOW how hard they have tried, and how well they eat (better than me), and that they exercise within their capacities (exercise can be very difficult for an obese person, partly because they often have co-existing arthritis and other painful conditions). And they don’t lose weight. Obesity is a complex issue. Bariatric surgery may be an answer to Type 2 for some, but not all, especially late-stage Type 2′s who will never regain enough pancreatic function to be able to function without meds or insulin.
@Michelle – I had a long conversation with a well-respected endo friend of mine before writing this post. He made many of the points above. His main reaction to the study in question was: “I don’t know how it made it into the New England Journal. I was surprised. I don’t get it.” So not all dr’s see things equally, it seems
@ Amy T “So not all dr’s see things equally, it seems”
This is a good thing. Hopefully, disagreements from physicians lead to scientific studies that get us closer to the truth. However, we need to be clear about the true disagreements. There are essentially two issues here:
1. Is treating pre-diabetes really preventing diabetes/should we treat patients with medications for pre-diabetes? For this issue there is actually some consensus. Both the ADA and the AACE/ACE guidelines call for consideration of medication for the treatment of pre-diabetes. Thus, a study about a medication used to treat pre-diabetes has merit (which is why it was published in the NEJM and why it’s a little harsh to call the study “dumb.”)
2. Should Actos be used to treat pre-diabetes. This one is more controversial. We do not have a study that compares Actos to Meformin for pre-diabetes (though the first 9 months of the DPP where troglitazone was included gives a clue how this would turn out). Based on the available data, Actos is likely more effective than metformin for treating pre-diabetes. However, Actos has more side-effects. Thus, a patient with pre-diabetes has three options: diet and exercise (best choice, but not always practical), Actos (most effective, but with some side effects), and metformin (not as effective, but fewer side effects). This decision needs to be made carefully between each patient and their doctor. One must also consider that some patients will not be able to take/tolerate either metformin or Actos. Since Actos will soon go generic, cost will not be an issue soon.
Though some doctors may not feel that Actos is a good option given the risks and benefits, to completely discount this is unwise.
@ Dr. Mintz – Hmm, considering that Actos is expensive, it causes weight gain and other undesirable side effects, and potentially heart risk and cancer risk, it still may be a “dumb” choice for most people who’ve been told they have high fasting glucose.
@Amy T- Actos will be generic in months, so costs will soon not matter. CHF is a real but uncommon and preventable risk (and MI doesn’t seem to be an issue). Cancer risk is very questionable (unlike a cancer risk for insulin which seems to be a greater concern). In addition, Actos has many positive benefits (lowers blood pressure, raises good cholesterol), and is the only diabetes drug (granted, a secondary endpoint) to show PREVENTION of heart attack and stroke (PROACTIVE).
It is good to have choices, especially when weighing risks and benefits has a degree of uncertainty. You may personally feel that Actos would not be the right choice for you if you had elevated fasting glucose/pre-diabetes, but it may be a reasonable and even preferred option for others.
@Dr. Mintz – we still stand firm on two things: 1) these manufacturer self-funded drug studies are questionable to say the least, and 2) knowing what we do about this drug, we would not feel comfortable recommending it to family or friends, esp for a disease they supposedly don’t have yet. ‘Nuff said.
@Amy T
“these manufacturer self-funded drug studies are questionable to say the least.” Agree that healthy skepticism is good, but unfortunately most studies regarding medications, for any disease state, are funded by the drug companies. Can’t just throw these studies out given the lack of unbiased data available.
“knowing what we do about this drug, we would not feel comfortable recommending it to family or friends, esp for a disease they supposedly don’t have yet.” This is a valid opinion. As per my previous comments it boils down to making decisions between risks and benefits in the midst of uncertainty. Your opinion that the risks don’t outweigh the benefits in this case is perfectly reasonable. However, in my opinion, calling the study “dumb” went too far. I find myself too often convincing my patients to use well established, validated, guideline-based treatments because they”saw something on the internet” that said this was “bad.”
btw, @Dr. Mintz – Avandia was just pulled from market by the FDA “due to the cardiovascular risks it poses to patients” –
http://health.usnews.com/health-news/diet-fitness/diabetes/articles/2011/05/19/fda-to-pull-diabetes-drug-avandia-from-pharmacy-shelves
Ref “Dumb” point No. 4, above.
Avandia was not just pulled from the market. Back in July 2010, the FDA decided to severely restrict Avandia prescriptions. Yesterday, the FDA finally announced how they planned on doing this. One of the main reasons for their decision to severely restrict Avandia, is that they felt Actos did not seem to have the safety concerns Avandia did and since there was no real benefit of Avandia over Actos, Avandia should only be prescribed rarely if ever. Now, I disagree with this ( I think both Avandia and Actos are safe), but even though the Avandia decision was controversial, their was unanimous agreement based on a large amount of data presented at the advisory board (to scientist who are very, very critical of data) that Actos is safe. Thus, “Dumb” point No. 4 is not a very “smart” point.
@Dr.Mintz – considering thousands of lawsuits on Avandia ( http://www.aboutlawsuits.com/avandia-restrictions-in-us-18302/ ), it’s pretty likely that Actos will be next. Standing firm on what was stated earlier:
“1) these manufacturer self-funded drug studies are questionable to say the least, and 2) knowing what we do about this drug, we would not feel comfortable recommending it to family or friends, esp for a disease they supposedly don’t even have yet. ‘Nuff said.”
@Amy T: One of your recent posts “JDRF’s Insulin Initiative: Afrezza, Roche’s DiaPort, Smart Insulin and More” discuss some exciting new treatments for diabetes. Every single piece of evidence that supports these novel treatments are supported by industry sponsored studies. The government and other non-biased organizations simply do not do the same level of research that the industry does. This is not necessarily good or bad. It would be great if the NIH did even 25% of the therapeutic studies done by the industry. However, John and Jane taxpayer are unlikely to cover the several billion dollars in tax hikes this would require. Fortunately, industry studies are not entirely without regulation. Thus, in order to make decisions for our patients we need to rely on industry sponsored studies, making sure that we recognize the fact that having a sponsor is a limitation. Thus, “these manufacturer self-funded drug studies are questionable to say the least,” is not really an accurate statement, and if your really believe this to be true, you can’t pick and choose the industry sponsored studies you want to believe just because you like one company/product over another.
Regarding the lawsuits, GSK will settle many of these not as an admission of guilt, but to keep their shareholders happy. Regardless of what the FDA decided to do with Avandia, there is not one single randomized trial that showed Avandia causes heart attacks, and of those studies that were powered enough to see whether or not Avanida causes heart attacks, all of them showed not only no heart attacks, but improvements in A1c and other markers in those patients taking Avandia. Unfortunately, the FDA doesn’t make their decisions entirely on sound science.
Finally, regarding “esp for a disease they supposedly don’t even have yet,” the UKPDS (a non-industry European study) showed that Type 2 diabetics have lost 50% of their beta cell function at the time of their diabetes diagnosis. Men with 3 or more components of metabolic syndrome have more than double the risk of a heart attack or stroke, and women have more than 6 times the risk. Now, whether or not treating metabolic syndrome/pre-diabetes will have any impact on these outcomes has not been determined yet. However, you seem to suggest there is no rationale to treat these patients and that is simply not the case.
@Dr. Mintz – I really think you are missing our point from the patient perspective. Also starting to wonder why you insist on defending this particular drug so adamantly…?
@Amy T
Patients want to prevent disease and avoid complications, and despite the fact that many diabetics live happy and productive lives taking injectible insulin, most patients fear insulin more than any other therapy. Though patients would prefer not to take any medications at all, I think many patients would welcome the use of pioglitazone for pre-diabetes it will prevent complications and the future need for insulin.
My defense of Avandia is adamant because I feel that the medication’s bad name has more to do with political motivations of certain physicians and certain people within the FDA, and less to do about science. The Avandia fiasco not only affected GSK (Avandia’s maker), but has now made it much more difficult for ANY new diabetes treatment to be approved (and some other non-diabetes medicine, such as the recent obesity medications that have not been approved). Finally, pioglitazone will go generic very soon, yet many physicians and patients will likely be fearful of it’s use based on it’s similarity to Avandia ( your point #4) and not real science. Thus, the Avandia debacle will lead to an effective and soon to be inexpensive therapy not to being used.
Matthew L. Mintz, MD, has disclosed the following relevant financial relationships:
Served as an advisor for: GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Sunovion; Teva Pharmaceuticals USA; Mannkind
Served as a speaker or member of a speakers bureau for: GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Takeda Pharmaceuticals North America, Inc
would the above connections have something to do with his vehemence?
New data suggest that physicians with ties to the pharmaceutical industry may be more likely to write opinion pieces (I suppose Blogs and comments on other blogs count as these) supporting medications despite study results linking the treatments to adverse events. People who blog or comment who have drug company connections (not all doctors in the world have drug company connections) are more likely to endorse that company’s drugs.
It is “dumb” to prevent a disease caused by the Society (but interpreted in strict physiological terms by the doctors, read Paul Farmer, Physician Anthropologist if you want to learn about Society and its influence on diseases) by prescribing pills. An ethical doctor could work and struggle against the chemical burden in food, food insecurity in the society and a more equitable health care.
Seems like they wasted some fundings on this research. I wish they’d just used it for the more deserving ones.
But, Carol, what’s the definition of deserving? Who deserves more and who deserves less? That’s really a loaded question, and lots of disagreement about it. And the study really DID show something, even if it’s not what the authors claimed: it has been found that the high death rate occurred in the intensive group that DIDN’T meet their goals, not in the ones who did. At the AADE meeting last week, I really got an insight into how hard it is to study diabetes, and they definitely don’t have all the answers yet.