June 11, 2009

Research Updates: Avandia, Actos and Byetta

UPDATE (April 2, 2013): Before you take Byetta, Victoza, Onglyza, or Januvia please read about the new research that shows that they, and probably all incretin drugs, cause severely abnormal cell growth in the pancreas and precancerous tumors. You'll find that information HERE.

Original Post:

One nice thing about writing this blog lately, is that people have started sending me press releases and full text versions of new research studies that relate to topics I have blogged about. They also send me a lot of commercial spam and offers of free samples in exchange for my promise to blog about their diabetic-exploiting product which I ignore. But keep sending the studies!

Right now there are four studies that you need to know about. Three were presented at last week's ADA session.

Byetta Does Not Increase The Incidence of Pancreatitis

The first is a study that should put to rest fears that Byetta causes pancreatitis. The people at Medco a huge prescription management company ran a database analysis to answer the question of whether the incretin drugs might be causing pancreatitis and their findings are encouraging.

The methodology was to analyze "pharmacy and medical claims from the National Medco Integrated Database."
A total of 123,621 patients were divided into three groups: 9,260 patients were taking exenatide, 2,143 patients were on sitagliptin and 112,218 were in the control group. Patients were followed for 540 days to measure the incidence of acute pancreatitis....A total of 123,621 patients were divided into three groups: 9,260 patients were taking exenatide, 2,143 patients were on sitagliptin and 112,218 were in the control group. Patients were followed for 540 days to measure the incidence of acute pancreatitis.
The finding was that "Only 41 patients (.44%) on exenatide, 6 patients (.28%) on sitagliptin and 438 (.39%) in the control group had pancreatitis during the study period."

While this is a very short term study--less than two years--it looks like the incidence of pancreatitis is not statistically significant compared to controls. Pancreatitis does occur in the general population for reasons not entirely understood. Another recent study discussed HERE finds smoking to be strongly dose-related to pancreatitis incidence, heavy drinking somewhat related, and mentioned that there is probably a genetic component involved too.

So that's good.

What is NOT good is the news about the TZDs, the evil twins Actos and Avandia.

Confirmed: Avandia Doubles Heart Failure Risk and Causes Osteoporosis

Two studies have confirmed earlier findings that these drugs cause an elevated risk of fractures and heart failure. But so strong is the power of the drug companies, that you might not know this if you read the studies--and headlines describing the studies--that proved this.

The study, presented at last week's ADA conference is being reported like this:

Overall Cardiovascular Safety of Rosiglitazone [Avandia] Confirmed in 5 and 1/2 Year Study

UPDATE 6/19: You can read the published study here:

Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Philip D Home, et al. The Lancet, The Lancet, Volume 373, Issue 9681, Pages 2125 - 2135, 20 June 2009. doi:10.1016/S0140-6736(09)60953-3

Sounds like great news, doesn't it. Until you read this:
...the only adverse finding was a doubled risk of heart failure [emphasis mine], but positive findings in other areas – especially CV death and stroke – almost exactly balanced out the total numbers for the primary outcome, thus meeting the criterion of non-inferiority for rosiglitazone (hazard ratio 0.99: CI 0.85, 1.16).
Reading further, we find:
The key secondary outcome, mentioned above, is a composite of CV death, stroke, and heart attack, in which the result was slightly but not statistically significantly in favor of rosiglitazone versus its metformin and sulfonylurea comparators, with a hazard ratio of 0.93 (CI 0.74, 1.15).
The "slightly but not statistically significant" phrase tells you just how low these people will go to confuse their readers. Not statistically significant means that there is no way this result means Avandia was better than the other drugs. "Statistical significance" often means that there is only a very tiny difference, but when there is none it means the items being compared, statistically are absolutely equivalent. To phrase the finding in this way is to attempt to get around this by influencing statistically ignorant readers--which are 99% of all readers including most physicians whose one statistics course was decades in the past

So what this study really found is that the very expensive drug, Avandia, doesn't work any better than cheap $4 a prescription metformin or the sulfonylureas, but doubles the risk of heart failure. Which is a condition that shortens life dramatically and does very bad things to quality of life while the person is alive.

But the findings of this study get even worse. Here's a quote from the chief researcher.
“We have also confirmed that it is not wise to prescribe rosiglitazone for older women who are fragile and at risk of falling because the risk of arm and lower leg fractures is doubled in women,” said Home. This finding confirmed results in the ADOPT study and was statistically significant.
The only statistically significant finding here is that this drug which doesn't do anything metformin doesn't do also causes severe osteoporosis. And when you realize that fractures are a leading cause of death in older women you have to realize just how important this finding is.

UPDATE 6/19/2009 : Note that this study was funded entirely by GlaxoSmithKline plc, UK, makers of Avandia.

Note also that not only was the risk of "Heart failure causing admission to hospital or death" much higher, but that the incidence of "Heart failure causing admission to hospital or death" was extremely high. Sixty-one out of 321, or one out of every five people in this study who were taking Avandia ended up in the hospital or dead thanks to heart failure. In the control group the incidence was 9 out of 100.

One in Five dead or hospitalized gives you worse odds than does Russian Roulette.

UPDATE: In reviwing these statistics about Avandia, it is very important to keep in mind that both heart failure and fractures are what are known as "Class Effects" of the TZD drugs, which means that they occur in both Avandia and Actos because they occur in direct response to the way they affect PPAR-gamma.

But there was more news about fractures and TZD drugs presented at the ADA sessions, which did not make press coverage.

Avandia and Actos Cause Significantly Higher Rate of Fractures in Women and Men

Another MEDCO database study presented confirmed that both TZD drugs, Avandia AND Actos cause fractures, and in everyone, not just in older women.

The methodology here was similar to the Byetta study.
The sample, consisting of 144,399 people, was divided into two cohorts; one group was made up of 69,047 patients who were taking a TZD, and the other included 75,352 patients who were not prescribed a TZD. The average age for both groups was 56. Fracture rates were also compared between a subset of subjects who were prescribed a TZD for the first time during the study period (n=11,738) and 13,563 patients who were newly prescribed one of the other diabetes treatments but not a TZD. The analysis also compared fracture rates according to gender; women made up 49% of the sample and men 51%. A logistic regression model was adjusted for age and conditions including COPD, asthma, osteoporosis, stroke and prior fracture, and was used to compare fracture risks between diabetes patients prescribed TZD and those not taking TZD.
The finding was chilling:
Among patients taking a TZD, there were a total of 3,346 fractures, a 43% higher rate than those not taking a TZD. The risk was the same no matter if the patient was on rosiglitazone or pioglitazone. When analyzed by gender, both men and women had an increased risk associated with a TZD. Women on a TZD were 55% more likely to have a fracture than females not using the drug, and men on a TZD had a 26% higher likelihood of a fracture than the male control group. [emphasis mine]

While women who were new to TZD treatment were at a 40% higher risk for a fracture within 18 months of initiating therapy than females new to treatment but not on a TZD, men newly started on TZD treatment showed no difference than those not taking a TZD.

WHY Avandia and Actos Cause Heart Failure Discovered: It's the PPAR-Gamma

And finally, another study was published last week that was not presented (as far as I know) at the ADA sessions. It was published in German, unfortunately, it explains why TZD drugs cause heart failure. You can read about it in Science Daily:

Stopping Fatty Change in Heart Cells

This study found that that. "A healthy heart burns fat. But the abnormally enlarged heart cells burn sugar in the form of glucose because this form of energy is quickly available. The protein HIF1-alpha is responsible for this conversion to sugar combustion." Furthermore "One of the genes regulated by HIF1-alpha is known as PPARgamma. It causes the cardiac cells to produce and store fat. This results in the cells becoming fatty and dying off. Myocardial contraction is disrupted and this can lead to fatal heart failure." When you put this together with the fact that the mechanism by which the TZD drugs work is by stimulating PPAR-gamma it all falls into place.

The Science Daily report explains
"...some diabetics are given PPARgamma-promoting medicine to help muscles and other organs better respond to insulin. Clinical studies have shown that these patients have a higher risk of dying from heart failure. This research by Krishnan and Krek has shown why these drugs may be risky.
There you have it folks. TZD drugs double your chances of developing heart failure and raise the risk that you will break bones--because they divert osteoclasts (baby bone cells) and turn them into baby fat cells. You can read the research that explains this HERE.

These drugs do not prevent the most serious complication of diabetes any better than metformin or sulfonylureas. So why would you put them in your body?

Byetta, on the other hand, is looking a lot better. It is starting to generate safety studies that are compelling and though it only works for one out of three people who take it, for those for whom it works, it works very well.


Anonymous said...

the bari 2d study which was a 2x2 factorial design presented at the ada looked at both medical therapy and revascularization found that theinsulin-sulphonylurea combo increased heart failure and bone fractures equivalent to the metformin-tzd combination. Known effects of both inuslin and tzds. Metformin and byetta are looking great! Try to avoid insulin until your c-peptide or insulin levels are low and start with a basal insulin.

Jenny said...

Link please? Without a link it is hard to know what you are describing.

Sulfonylurea and insulin is a very poor combo for many reasons, and Sulfs are not great for the heart due to their potential to stimulate a heart muscle receptor.

Generic advice about insulin ignores the fact that everyone's diabetes may have a unique pattern requiring a unique solution.

Some people retain fasting control long after meal time control is gone and for them meal time insulin without basal is a much more effective approach using much less insulin.

Basal doesn't have any impact on meals, and it is high blood sugars after high carb meals that cause most of the damage to organs.

Anonymous said...

I understand your long standing concern with the glitazones but I continue to disagree with your positioning of most recent data. I do think these drugs are linked to serious side effects and should be used with caution as all drugs should. You suggested that these drugs cause the heart muscle to retain fat but failed to mention this was a rodent study. Most research suggests the opposite, that glitazones reduce LPL activity and pull fat from the liver, pancreas and muscle tissues. There is no question that these drugs lead to plasma expansion through the re absorption of sodium in the distal tubule of the nephron (this has been documented in humans). This leads to diastolic failure as numerous glitazone studies have found. The key point here is that diastolic failure is not causing permanent muscle damage and can be reversed (whereas systolic tends to stem from a low EF). Many LARGE human trials have shown just this (DREAM [IGT patients-relatively healthy]and PROactive [CAD patients-very sick]) where there were indeed more HF cases of patients at the max dose of these drugs, but no increase in death from the resultant HF suggesting it was reversed. Now you have argued that these 3 year trials were insufficient to find true survival of SHF; but patient level data shows the same result in epidemiologic studies. I doubt anyone is arguing that HF is good it just means finding the right patient. As for bone fracture risk the same applies- find the right patient. Here is a link showing how PPI's especially in diabetics caused a 30% increase in large bone (HIP) fractures yet no mention by you?
My final comment would be that if these drugs were so evil, then why would the largest drug company in the world risk coming out with one of its own?
As much as I am a fan of byetta, I find it surprising how people can claim safety after just 4 years of data. Avandia took 7 years to find its problem...Thanks Jenny

Health Advocate said...

Eye opening statistics...really helps to know the facts sometimes...great post.

Trinkwasser said...

Here you go!