April 29, 2009

News You Missed: Actos Strongly Linked to Retinopathy

I mentioned this in my "Updates to Blood Sugar 101" blog, but because that blog doesn't get a lot of traffic, I think it is worth repeating here.

A new study has disturbing news for people who switched to Actos thinking it was a safe drug. This study was published in an Ophthalmology journal, rather than a diabetes journal, and seems to have been completely ignored by the diabetes press.

Here's the study:

Glitazone Use Associated with Diabetic Macular Edema Donald S. Fong. Am J Ophth Volume 147, Issue 4, Pages 583-586.e1 (April 2009)

This study analyzed the records of 170,000 people with diabetes treated by Kaiser Permanente Southern California. The researchers found that
In 2006, there were 996 new cases of ME. Glitazone users were more likely to develop ME in 2006 (odds ratio [OR], 2.6; 95% confidence interval [CI], 2.4 to 3.0). After excluding patients who did not have the drug benefit, did not have an eye exam, and had a HgA1c <7.0, glitazone use was still associated with an increased risk of developing ME (OR, 1.6; 95% CI, 1.4 to 1.8).

It's worth noting, too, that the Science News report of this study adds, "Most of the glitazone users in the study were taking pioglitazone (Actos)."

Since the whole point of lowering blood sugar in diabetes is to avoid blindness, this study gives yet another reason to avoid Actos (and Avandia). Slightly more than one person out of every 200 in this huge group of patients developed macular edema. And those taking Actos or Avandia (but mostly Actos) were more than two and a half times as likely to develop retinal swelling leading to vision loss than those not.

This was true even in those with very well controlled blood sugar--A1cs below 7%.

I've been receiving a steady stream of angry, hostile comments from an anonymous poster (the tone suggests one person) whenever I post about TZD-related issues. This may be an investor--this blog is often cited in posts on investment discussion boards when I discuss new drug side effects. But I'll give them the benefit of the doubt and assume this is someone who is getting very good blood sugars on one of these drugs.

The person has never put anything in their comment which casts doubt on the research I cite. Mostly they express fury that I'm threatening their beloved drug. I don't post the comments that contain only personal attacks or cites to old drug-company supported research "proving" the safety of the drug without examining the new side effects that more recent research has discovered.

But let me say here that I do understand that a few people see much better blood sugars while taking Avandia or Actos and that this might make someone respond strongly to research findings that make it clear that these drugs are dangerous. That person may say, "I've looked at the risks and it's worth it to me to take this drug." Perhaps it is.

But a lot of us learned some very interesting about risk during last year's stock market meltdown. People who invest in the stock market always claim to understand the risks. Always. The problem is that studies always show that people assume that the "risks" they can accept will happen to someone else. It is only when they lose their life savings in a risky investment that they finally understand that while risk may be expressed in percentages, when you get whatever it is you are risking, you get it 100%.

So when you consider the "risk" of a side effect from a drug, if that risk is high enough to be taken seriously--i.e. much more likely than, say, being struck by lightning or being elected president--you have to imagine yourself sitting in the doctor's office being told you've got that side effect.

Which is why when you consider this new research you have to ask yourself, is your better blood sugar worth the loss of your optic nerve?

And you also have to ask yourself, is your doctor even aware of this possible side effect? The otherwise excellent doctor who prescribed Avandia to me several years ago had never heard that it caused edema or heart failure, though at the time this was very well documented. He brushed off my concern that it might have any negative impact on the heart, though this doctor was the one who sent me for test after test looking for heart disease because I'd had diabetes long enough he was certain I must have it. (I didn't) Shortly after our discussion, Avandia's connection with heart attack became known.

So if your doctor assures you that Actos (or Avandia) is safe, ask him if he's heard about the major Kaiser study published by Dr. Fong linking these drugs to macular edema. If he brushes this question off without giving you a very good reason why can be certain you aren't at risk of it, you need to spend spend sometime thinking about what "risk" really means and you need to ask yourself if the benefits you are getting from this drug would thrill you, even if you ended up losing your vision.

You might also want to ask your doctor what the warning signs of macular edema are--and whether your once a year appointment with the eye doctor is sufficient to protect you from it.



Anonymous said...

First off, I want to thank you, as always, for the tremendous service you provide in bringing to light all the clinical data and empowering diabetics to improve their care. I read your blog not to evoke hostility but to inform myself, and have never been interested in personal attacks. I do take the aforementioned drug along with metformin and byetta and am very happy and well controlled with this regimen. As for this study, ME is worrisome yet you have stated in the past that "what is missed here is that the study found association, not causation. And this is an important point" (on insulin use with dementia). Any epidemiologic or meta analysis study is hypothesis generating in nature. That is not to say no risk exists. One study I would love to hear more about is NICE SUGAR where tighter control in critically ill patients through insulin increased their death rate (via cardiovascular events) compared to moderate control in the same patients; it was robust, significant and surprising. I would also be curious if you or your readers had any thoughts on a recent lecture published in Diabtes Journal about the pathophysiology of type 2 diabetes as given by the recent recipient of the Banting Medal (given for lifetime achievement in diabetes research). Here is a link: http://diabetes.diabetesjournals.org/cgi/content/extract/58/4/773
Thanks Jenny and sorry for any misunderstanding.

Jenny said...

The study found an association, but this is not the first study I've read that flagged the issue. It's just the largest.

We already know that these drugs cause edema in other contexts--and that's not an association, it's a known side effect.

The biggest issue with tight control in hospital situations is the way insulin is dosed--without reference to incoming carbs, but using the "sliding scale" method notorious for causing hypos. Also--and I know this from personal experience--hospitals often use meters that are highly innaccurate which further raises the possibility of hypo.

Finally, some severe medical crises cause hypos independent of diabetes and using insulin in those situations is even more complicated. This isn't all that relevant for people in normal health.

Dr. DeFronzo's article (which I don't have full text access to)reads pretty much the standard intelligent endocrinologist line except that he's pitching the standard treatment with the argument that it's goal is to try to avoid beta cell death.

I'm baffled at how he can state that TZDs save beta cells as that idea was pretty much debunked thanks to the follow up of the DREAM study.

There is no oral drug (or Byetta) that has been shown to preserve beta cells in humans. Lots of claims for that based on questionable animal studies, but no human result. And the fact that over time Byetta patients like Avandia patients see worse blood sugars not better, really makes it unlikely any of these drugs are preserving cells in the people taking them, no matter what they do in mice.

Anonymous said...


Jenny said...

The cell culture study is well known, but it is a huge leap from cell cultures to people. Avandia looked good in cell cultures too, but over time, people who took it saw their beta function decrease, not increase and there is zero evidence of beta regrowth with TZDs or Byetta.

The point of regrowing beta cells is to to increase insulin secreting capacity. If that capacity drops rather than rises after years of using a drug, any theoretical increase in beta cells is moot.

The incretin drugs are being prescribed with that sales pitch, but there is no human evidence to support it. Unless we see humans sustaining blood sugar control improvements even after stopping these drugs it's very unlikely anything has been rejuvenated beyond drug company bottom lines.

This isn't the place to debate incretin drugs. The discussion is about Actos/Avandia and macular edema.

Trinkwasser said...

TZDs have turned into something of a disappointment. They attacked insulin resistance through a different process than metformin, but oh dear don't they seem to adversely affect other systems?

So what's left to attack IR? Gosh, reducing carbs! The Horror! Side effects include hugely improved lipids and reduced BP and general reduction in all cardiovascular risk factors.

I suspect there's a lot of individual (genetic) variation with drug treatment, TZDs may well be excellent drugs IF you don't have whatever factors lead to the side effects. By the time you find out whether or not you're in that part of the population it may be too late. :(

Is there a similar sub-population for which carb restriction doesn't work? Probably, but it seems to be very tiny.

Jenny said...

There is a population for whom carb restriction doesn't work. They are usually people who require several hundred units a day of insulin (up to 500!) to get near normal numbers.

Two people I know who fall into that category have done extremely well on Byetta, but on nothing else.

"Diabetes" is really many different disorders with a common symptom, high blood sugars.

And of course, people diagnosed as Type 2 who are insulin deficient rather than IR will need insulin no matter what diet they eat.

Anonymous said...

interestingly enough, insulin and meglitinde also showed an increased risk of macular edema - while metformin and acarbose showed they didn't increase the risk. This is from a study in the journal of opthamology in feb 2009. the increased risk of fractures in post menapausal women seems to be the real risk in the tzd class when the doctors use these drugs appropriately

Trinkwasser said...

"Diabetes" is really many different disorders with a common symptom, high blood sugars.

Indeed, and sometimes the BG doesn't actually have to be that high to induce a lot of diabetic symptoms, particularly the dyslipidemia.

Once again there appears to be a small population for whom Byetta simply doen't work. Probably all drugs work for some and not for others and in the Big Picture it's good that so many alternatives exist.

The bad thing is when drugs are touted as a cure-all and prescribed to people for whom they are at best useless and at worst dangerous, cf. statins which seem to be beneficial in a small sub-population but are prescribed to everyone else as well.

Mookie said...

After taking actos for only two days I started experiencing all the symptoms of someone with congestive heart failure - extreme shortness of breath, fatigue, a dry cough and wheezing. I could not walk from my kitchen to the bathroom without being out of breath. Dressing and bathing were ordeals. Has anyone else had such a rapid negative response to this drug? I just wanted to tell someone -I want to have this documented in some way.
After consulting with the doctor on call, I stopped taking the Actos at the end of that week -two days ago - but I am still out of breath and fatigued. Is this side effect permanent? Do you know of anyone who has recovered from this effect?
Thanks for letting me vent.

Don said...

This may come up as anonymous, but I am Don. I wanh all to know that i am not hiding behind anything.
I took Actos Plus Met for almost 2 years. After two months I was diagnosed with a Central Retinal Vein Oclusion in the right eye. Two months later, same thing in the left eye. I informed my doctor who promptly increased my Actos dose. My HA1c was 5.7. Long story short. After 3 years of fighting, I am virtually blind and my career is over. I have had 21 Intravitral Injections of Kenalog, Cataract surgery in both eyes and , last month, a Vitrectomy and Membrain peel in the left eye. I get to look forward to another Vitrectomy on the right eye in December. I have been a diabetic for 20 years and never had any vision problems until taking Actos. Now I take nothing. Through diet and excersise I have managed to loose 64 pounds and am now HA1c of 5.2. All through this, my highest was 5.7. And yet I am legaly blind. I can no longer drive or read for pleasure. After an 9 hour day of working on the computer (I am an engineer, or was) I have eye strain the feels like they are on fire. I don't go out and I don't have people in. I am being treated for depression. For me there is much more than an "association" between Actos and Macular Edema. I live it.
Thank you for your time Jenny, you are a real inspiration to me.

Jenny said...


Your story is so tragic. My own experience with serious side effects is that doctors are so scared of law suits they will become very dishonest when a serious side effect occurs.

You might consider contacting a good personal injury attorney because you need the services and adaptive devices that could let you continue to be productive. Find someone who specializes in drug-related injury. In this particular case, the data pointing to this problem has been available for years and the drug company has done nothing to warn doctors about it so they could take people off the drug at the slightest sign of problems.

My own experience with a relative who suffered serious harm with liability was that a good personal injury attorney will also be able to hook you up with the best doctors and rehabililtation specialists all paid out of the proceeds of the case if he thinks you have a case. It's worth a try. That's the ONLY way the drug companies pay any attention to the harm they wreak on the patients who enrich them.