Actos and Avandia -- Dangerous Diabetes Drugs

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Avandia and Actos: Dangerous Drugs

Avandia and Actos are members of a drug family called the thiazolidinediones, abbreviated TZDs. This is a relatively new class of oral anti-diabetic drugs which were developed during the 1990s. Three of these drugs began their careers showing great promise in the treatment of insulin resistance, and hopes were raised by preliminary research that they might be able to rescue failing beta cells.

Unfortunately, over time all three were found to cause life-threatening side effects, the risk of which was far greater than the benefit these drugs provided.

The first of these drugs, was Rezulin. It is the one that endocrinologists tell me was by far the most effective. It was withdrawn after it was found to cause fatal liver failure in a small, but significant number of patients.

Avandia (Rosiglitazone) and Actos (Pioglitazone) came to market in the late 1990s with the promise that they did not cause liver failure--though post-marketing reports of liver failure associated with these drugs have emerged.

But it took almost a decade for the most significant problems with these drugs to surface, mostly because the manufacturer of one of the drugs intimidated whistleblowers in the medical community who called attention to their dangers.

How These Drugs Work

These drugs lower blood sugar by decreasing insulin resistance. They do this by causing the formation of new fat cells primarily on the arms, thighs, and butt. These new fat cells then take glucose out of the blood stream.

A Disappointing Effect on Lowering Blood Sugar

Like the other, safer, oral diabetes drugs discussed elsewhere on this site the manufacturers' own prescribing information makes it clear that these drugs produce only a modest change in blood sugar and insulin levels, though possibly a bit more than Metformin.

Studies funded by Takeda, the manufacturer of Actos, suggest that Actos may improve endothelial dysfunction--a factor in the development of vascular complications--and that it might decrease the kind of inflammation associated with coronary artery disease and improve high blood pressure.

Is treatment of insulin resistance beneficial independent of glycemia. Mayer B. Davidson. Diabetes Care, Nov 2003.

Redefining the clinical management of type 2 diabetes: matching therapy to pathophysiology.
J.E. Gerich; European Journal of Clinical Investigation 32(Suppl.3) 46-53

Other research showed that Actos preserves the beta cell islet structure in two strains of genetically diabetic mice which raised hope that it might do something similar for people.

Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes.
Diani AR, Sawada G, Wyse B, et al. Am J Physiol Endocrinol Metab, Jan 2004, 286(1) pE116-22

Beta Cell Rest Proves to be a MYTH in DREAM Study Follow up

Unfortunately, the hope that these drugs could rejuvenate beta cells was dashed by a the follow up to large-scale study in humans, DREAM. In the DREAM is study, people with prediabetes took Avandia for three years. The initial publication at the end of the study concluded that Avandia prevented diabetes. This was used to market the drug very heavily to doctors who prescribed it in record amounts.

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. DREAM Trial Investigators. Lancet 2006 Sep 23;368(9541):1096-105.

However, there was a follow-up study to DREAM which cast doubt on this finding. Diabetes in Control reported:
As yet unpublished results from a follow-up study which were presented at a medical conference in December [2006] showed that when people stopped taking rosiglitazone (sold as Avandia), they began to develop diabetes at the same rate as people in the study who had been given a placebo rather than a real drug. Those results dashed the dream that short-term use of the drug would do the trick.

"The only thing that it does is it prolongs the time before a doctor tells you 'You have diabetes,"' said Montori.
Had the drug been able to rejuvenate beta cells, these people should have had better blood sugars after years of taking the drug.

Waking up from the DREAM of preventing diabetes with drugs. Montori et al. BMJ 334(7599): 882.

Even so, more than a year since that study was published, many people report that their doctors still prescribe TZD drugs telling them that they will rejuvenate their beta cells.

Does Avandia Cause Heart Attacks?

Whatever the findings of the DREAM follow up study might have been about the effectiveness of Avandia in preventing diabetes, they were drowned out by the really bad news that emerged over the next year from the same study.

The DREAM study had been funded by the manufacturer, Glaxo-Smith-Wellcome, which hoped to prove that Avandia would prevent heart disease. But when researchers analyzed the DREAM data along with data from other studies, they found just the opposite.

According to a report published in the New England Journal of Medicine in May, 2007, The DREAM study found this:
Patients taking Avandia had 66 percent more heart attacks, 39 percent more strokes and 20 percent more deaths from cardiovascular-related problems. (Quoted from the New York Times report on the study published 5/21/07).
Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes.
Steven E. Nissen and Kathy Wolski, NEJM10.1056/NEJMoa072761

As the story unfolded, Glaxo-Smith-Kline, the maker of Avandia claimed in the press that another study would disprove the Avandia-heart attack link.

At the same time, the news came out that in 1999 Glaxo had silenced an early critic of Avandia who had uncovered the heart problems with threats of a lawsuit against the critic's university. The threat was effective. Details can be found HERE

On July 26, FDA drug reviewers published a report confirming that patients taking Avandia are more likely to suffer and die from heart problems than those taking Actos. The report cited Glaxo's threats against the whistle-blower and said that the May 21, 2007 claim made by Glaxo that another study would show Avandia was safe was false.

The New York Times story can be found HERE

Avandia with Insulin Most Dangerous

The most serious heart problems associated with Avandia appear occur when patients combine Avandia with Insulin, which is a combination that the drug company has been pushing as part of a three drug strategy (with metformin) which supposedly avoids weight gain. The combination with insulin increases the incidence of heart failure, which is a weakening of the heart muscle that leads, inexorably, to death.

Another Study Finds No Impact on Heart Attacks--But A Doubling of Heart Failure with Avandia

The study, presented at the 2009 ADA Scientific Sessions is being reported like this:

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

The Study was published a few weeks later in The Lancet and you can read it 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.Note that the published research paper discloses that this study was funded entirely by GlaxoSmithKline plc, UK, makers of Avandia.

The abstract of the published version of this study reveals just how devastating the research finding was about heart failure with Avandia. Not only was the risk of "Heart failure causing admission to hospital or death" much higher in people taking Avandia, 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 gives you worse odds than playing Russian Roulette.

It's also worth remembering that both heart failure and fractures are class effects of TZD drugs, which derive from the way they work on PPAR-gamma. You should expect to see similar statistics coming out of a study of Actos, too.

Avandia and Actos Double Heart Failure Risk even in Younger People without Previous Heart Failure.

The finding of the 2009 study confirmed an earlier finding which applies not only to Avanida but to Actos. The July 26 FDA report suggested that Actos is safer than Avandia, and indeed, many doctors had started to switch patients to Actos after the reports of Avandia's relationship to heart attack were made public. But given that the mechanism by with the two drugs work is very similar, the safety of Actos is also questionable.

Indeed, only a day later, another study was published in the printed journal, Diabetes Care suggesting both drugs cause heart failure in younger patients with no previous history of heart failure.

Thiazolidinediones and Heart Failure: A Teleo-Analysis
Sonal Singh, MD, Yoon K Loke, MBBS, MD and Curt D Furberg, MD, PhD.
Diabetes Care, published online ahead of print May 29, 2007

As reported by,
The analysis in the journal Diabetes Care projected that one in every 50 patients who takes Avandia or Actos over a 26-month period would be hospitalized for heart failure. The researchers found that one-fourth of cases occur in people younger than 60. Heart failure tends to affect older people. Glaxo, Takeda Diabetes Drugs Raise Heart-Failure Risk in Study

The Independent reporting on the same story added,
But the new study, carried out by experts at the University of East Anglia (UEA) and Wake Forest University in North Carolina, suggests an increased risk even for those who have never suffered heart failure.:

Yoon Loke, a clinical pharmacologist at UEA, who led the study said the findings meant the drugs "could have caused thousands of additional cases of heart failure.
The Independent: Diabetes drugs 'double risk of heart failure' No longer available online.

A Meta Study Suggests Avandia is dangerous and ineffective

As reported by Diabetes in Control A meta study published which was later published online on July 18, 2007, in the Cochrane Database of Systematic Review, which analyzed the results of 22 randomized clinical trials involving 6,200 patients with type II diabetes receiving Avandia concluded that:
Published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised (OR 2.27, 95% confidence interval (CI) 1.83 to 2.81). The single large RCT (ADOPT - A Diabetes Outcomes Progression Trial) indicated increased cardiovascular risk. New data on raised fracture rates in women reveal extensive action of rosiglitazone in various body tissues.
Rosiglitazone for type 2 diabetes mellitus. Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Cochrane Reviews, July 18. 2007.

Mechanism By Which TZDs Cause Heart Failure Discovered

This study was published in German, unfortunately, and has not been discussed much in the medical press but it is extremely important, because it explains why both Actos and Avandia 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, Avandia and Actos, 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.

Other Significant Problems with Avandia and Actos

The cardiovascular risk posed by these drugs should rule them out as legitimate treatments for diabetes, but doctors continue to prescribe them. Here are some further findings about these drugs that should make you think twice before taking them.

Actos and Avandia Cause New and Permanent Fat Cells to Form

It has long been known that all the drugs in the thiazolidinedione family cause weight gain. Because they also cause the water retention and swelling that now are linked with heart failure, it was first believed that this weight gain attributed to these drugs was caused solely by water retention.

When it was later determined that real fat was being deposited the drug companies spun this information by claiming that that in people taking the drug the hip/waist ration had changed and suggested that this might be because abdominal fat--the kind known to correlate with insulin resistance was decreasing, which would be a good thing.

However, when a group of researchers--once again funded by a drug manufacturer with a financial interest in the results--randomized a group of non-diabetic insulin resistant volunteers to either diet and exercise or Actos, they discovered that decrease in waist hip ratio that study subjects experienced while taking Actos was due to the increase in their hips, not a decrease in their waist In fact, Actos was causing an increase in the number of fat cells accumulating in what was euphemistically called "the lower body depot" in an area most of us would probably recognize better when called by its common name: the butt

Effects of Pioglitazone Versus Diet and Exercise on Metabolic Health and Fat Distribution in Upper Body Obesity Samyah Shadid, MD and Michael D. Jensen, MD (Mayo Clinic). Diabetes Care 26:3148-3152, 2003.

This is troubling, because once you add new fat cells, they do not go away even when you diet.

Calorie Restriction and Exercise Works Much Better than These Drugs

It is even more troubling because the Mayo Clinic study cited above also found that whatever gain the drug groups achieved in either blood sugar control or the decrease of insulin levels, could have been achieved with no such cost. The group of insulin resistant volunteers in this study who took no drug but cut 500 calories a day from their diet and exercised for 45 minutes achieved far better improvements in their fasting insulin levels, their fasting triglyceride levels, and their total cholesterol than did the Actos group, while losing weight from both their waists and their "lower fat depot."

Other, Non-Heart Related Side effects

Macular Edema Leading to Blindness

Another dangerous side effect was discovered by an alert eye doctor, Edwin Hurlbut Ryan, Jr., MD, who presented a paper at the 2003 meeting of the American Academy of Ophthalmology, discussing 30 cases in which the thiazolidione drugs his diabetic patients were taking apparently caused macular edema--swelling in the retina which leads to blindness. This swelling does not always resolve when the drug is discontinued.

That macular edema leading to vision loss is a "class effect" with both Avandia and Actos was demonstrated by a study published in Feburary of 2002 in the American Journal of Ophthalmology. Unfortunately, because this was not a diabetes journal, most family doctors will never hear about this study.

Glitazone Use Associated with Diabetic Macular Edema Donald S. Fong. Am J OphthVolume 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).
This means you are 60% more likely to develop retinal swelling leading to vision loss even with well controlled blood sugars if you take Actos or Avandia than if you don't.

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 makes it crystal clear that no person with diabetes should be taking Actos or Avandia.

Liver Toxicity

Finally, despite the original claim that they were not toxic to the liver, there have been a few reports of liver disease occurring in patients taking these drugs. While it does appear they are less damaging that Rezulin, they do raise the level of the liver enzymes usually interpreted to mean that liver damage is occurring. Experts suggest that monitoring liver enzymes may not be enough to prevent damage.

Rosiglitazone-induced granulomatous hepatitis. Dhawan M, Agrawal R, Ravi J, et al. J Clin Gastroenterol, May-Jun 2002, 34(5) p582-4

Hepatotoxicity of the thiazolidinediones. Tolman KG, Chandramouli J. Clin Liver Dis , May 2003, 7(2) p369-79

On Oct 29, 2008, the public advocacy group Public Citizen said its review of U.S. Food and Drug Administration data found 14 previously unpublished cases of severe drug-induced liver failure, including 12 deaths and called for Avandia to be taken off the market. The FDA said it would review the petition.

Reuters: Liver Risk, Death seen with Glaxo's Avandia

TZDs Cause Osteoporosis and Broken Bones in Women and Men

A study published in November of 2006 found some evidence that elderly women taking Avandia and Actos were more likely to suffer bone loss leading to more fractures.

TZDs Can Increase Bone Loss in Type 2 Women - Diabetes in Control

Type 2 Diabetes, Thiazolidinediones: Bad to the Bone? Nelson B. Watts and David A. D'Alessio. J Clin Endo & Metab Vol. 91, No. 9 3276-3278

This finding was reinforced by another study by Dr. Steven Kahn which was published The New England Journal of Medicine. It compared Avandia to Metformin and Glyburide and found twice as many bone fractures in the group of patients taking Avandia.

Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. Steven E. Kahn, for the ADOPT Study Group et al. NEJM Volume 355:2427-2443, December 7, 2006.Number 23

The mechanism by which these drugs cause fractures was discovered in a study published in November 2007. As reported HERE this study performed at the Salk Institute found that
Avandia also appears to affect a key cellular protein called the peroxisome proliferator-activated receptor (PPAR-gamma). In their study, the California team discovered that activating this receptor in mice also stimulates the production of osteoclasts, cells whose key function is to degrade bone.
Actos has also been found to cause a doubling of fractures in a group of patients taking it for a relatively short period--less than 3 years. To quote the Actos Prescribing Information "Side Effect" section:
Fractures: In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2.1% (37/1728). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.
Note that this study only lasted a few years. Over time it is likely that a higher incidence of broken bones and osteoporosis would be found with this drug. Men have thicker bones than women and it would take longer for bone thinning in males to be diagnosed.

In 2008, the ADOPT researchers published a research paper documenting that there was a significantly higher number of fractures with Avandia when it was taken for a median length of four years.

Rosiglitazone-Associated Fractures in Type 2 Diabetes: An analysis from A Diabetes Outcome Progression Trial (ADOPT).Steven E. Kahn,et. al. Diabetes Care31:845-851, 2008.

In this study women taking Avandia had almost twice as many fractures as those taking Metformin and almost three times as many as those taking glyburide. The researchers report,

The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs.
Note that these areas of fracture correlate to the areas where Avandia transforms bone stem cells into new fat cells.

A UK study analyzed ten years of data concerning 4,748 patients and found strong evidence that long term use of both Avandia and Actos increased the incidence of fractures, predominantly of the hip and wrist.

Use of Thiazolidinediones and Fracture Risk. Christian Meier et. al. Arch Intern Med. 2008;168(8):820-825.

Yet another meta analysis of TZD study data published in December 2008 concluded that use of Actos or Avandia doubles a woman's risk of fracture.

Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. Yoon K. Loke et al. CMAJ Early release, published at on Dec. 10, 2008.

The article reporting on this study published on Science DaiIy quoted one of the researchers, stating,
In absolute terms, Singh said, if thiazolidinediones (TZDs) are used by elderly, postmenopausal women (around 70 years) with type 2 diabetes for one year, one additional fracture would occur among every 21 women. Among younger women (around 56 years), use of the drugs for one year or longer would result in one additional fracture for every 55 women.
And if that isn't enough, yet another very large study found similar results.

Thiazolidinedione Use and the Longitudinal Risk of Fractures in Patients with Type 2 Diabetes Mellitus Zeina A. Habib et al. JClinEndo&Metab Vol. 95, No. 2 592-600 doi:10.1210/jc.2009-1385

In this study, as summarized in the newsletter, Endocrine Today, which gives more information than the abstract, researchers,
... studied 19,070 patients at Henry Ford Hospital in Detroit between January 2000 and May 2007. The study group included 9,620 women and 9,450 men. During the study period, 4,511 patients had at least one prescription filled for a TZD. The investigators used electronically maintained medical claims data to identify nontraumatic bone fractures.

TZD use was associated with an increased risk for fracture in the overall cohort (adjusted HR=1.35; 95% CI, 1.05-1.71) and in women (HR=1.57; 95% CI, 1.16-2.14). Men, regardless of age, were not at an increased risk for fractures (HR=1.05; 95% CI, 0.70-1.58). Women aged 65 years and older appeared to be at the greatest risk for fracture (HR=1.72; 95% CI, 1.17-2.52). They found that the increased risk for fracture in women appeared after approximately one year of TZD use.

Database Analysis Confirms Actos/Avandia Fracture Link in ALL Women AND Men

A study done by Medco, analyzing it's health claims database was presented at the ADA 2009 Scientific Sessions. Here's what it did:
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.

A study published in August of 2008, "...studied 84 339 patients from British Columbia, Canada, who began treatment with a thiazolidinedione or a sulfonylurea." It found that "treatment with a thiazolidinedione was associated with a 28% increased risk of peripheral fractures compared with treatment with a sulfonylurea." In addition,
The use of pioglitazone hydrochloride was associated with an increased risk of peripheral fracture of 77% in women (HR, 1.76; 95% CI 1.32-2.38). Compared with exposure to sulfonylureas, exposure to pioglitazone was associated with more peripheral fractures in men (HR, 1.61; 95% CI 1.18-2.20)[i.e. 61% more risk of fractures in men]
Remind your doctor of this if he or she claims Actos (pioglitazone) is safer than Avandia.

Thiazolidinediones and fractures in men and women. Dormuth CR, et al. Arch Intern Med. 2009 Aug 10;169(15):1395-402.

Analysis of results in 19,070 patients in the huge TRIAD study confirm this finding.

Thiazolidinedione Use and the Longitudinal Risk of Fractures in Patients with Type 2 Diabetes Mellitus Zeina A. Habib et al. J. Clin Endo & Metab.Vol. 95, No. 2 592-600. doi:10.1210/jc.2009-1385

The real scandal here is the way that American Diabetes Association, as usual devoted to the interests of its sponsors, the drug companies, not those of the people in whose name it collects money continues to urge patients to ignore this data and continue on taking these damaging drugs. David Kendall, the ADA's Chief Medical and Scientific officer was quoted saying the following:
This is certainly not the first of these larger studies where I would say this unanticipated event was noted... Depending on the study, it appears that people who take TZDs for longer periods of time have about a one-and-a-half to twofold increase in their risk of fractures..

These are very effective medicines for some patients. We have to understand there are potential risks. Certainly anyone already considered to be at fracture risk -- a woman with osteoporosis -- or someone who suffers from instability or frequent falls, you should think carefully about the use of the medications. On the other hand, fractures in total [in Herman's study] were generally rare. Far more people didn't have fractures than did have.
By the same logic, we should be giving Thalidomide to pregnant women, because more of them did not have babies with flipper limbs than did. Or we should encourage smoking because not all smokers get lung cancer.

Given the weight of evidence against Actos and Avandia, and the poor evidence that they do much for patients beyond making them permanently fatter, the ADA's continued advice to patients "Those with diabetes on TZD drugs should not stop these medicines without talking to their doctor," is indefensible.

Remember, this is the same organization that continues to warn people that the long term effects of the low carb diet are "unknown" and hence it should be avoided, though every bit of evidence from all studies shows it to be safe and much more effective for people with Type diabetes than either Actos or Avandia.

Bottom line: Broken hips are one of the biggest killers of older people whose bones naturally thin with age. Hastening the degeneration of your bones is suicide. Don't take either Avandia or Actos. These drugs do not provide anywhere near enough benefit to outweigh their dangerous side effects.

Actos Is Proven to be Associated with A Higher Rate of Bladder Cancer

On Sept 17, 2010, the FDA announced that it was conducting a safety review of Actos, because prelimnary (5 year) results from a 10 year study found "...there was an increased risk of bladder cancer in patients with the longest exposure to Actos and in those with the highest cumulative dose of the drug.

In June of 2011 the FDA confirmed FDA confirmed that there was a heightened risk of bladder cancer with Actos.

Years later, in May of 2016 a study published in the high impact British Medical Journal, which studied the records of 145,806 patients again concluded that "Piaglitazone [Actos] is associted with an increased risk of bladder cancer." This association was only true for Actos, not Avandia, suggesting something about the drug itself, not the class of drugs, was at fault.

Pioglitazone use and risk of bladder cancer: population based cohort study. Marco Tuccori, et al.

BMJ 2016; 352 doi: However, doctors can still prescribe Actos.

Restrictions on the use of Avandia

In May of 2011 the FDA tightened the restrictions on prescribing Avandia but they did not take it off the market.The new restrictions state that patients who are now taking the drug will have to sign an informed consent statement acknowledging that they understand all the risks before they will be allowed to refill their prescriptions and that new patients will not be able to receive the drug unless their doctors certify that they are unable to control their blood sugar levels with other therapies and that medical problems preclude them from taking Avandia's primary competitor, Actos.

As you can see, this means nothing. Doctors who prescribe Avandia will keep on prescribing it. The FDA is not likely to take either of these dangerous drugs off the market until weeks before their patents expire. They are just too profitable.

Avandia (rosiglitazone): REMS - Risk of Cardiovascular Events includes Avandia, Avandamet, and Avandaryl

Beware the New Spin Studies Promoting Actos

In November of 2008, a much touted study was published which analyzed Medicare records and reported that while people taking Avandia had a 13% higher risk of congestive heart failure, no difference was seen in heart attack risk. This is being used to promote Actos as safe.

Comparison of Cardiovascular Outcomes in Elderly Patients With Diabetes Who Initiated Rosiglitazone vs Pioglitazone Therapy Wolfgang C. Winkelmayer, MD, ScD, et. at.Arch Intern Med. 2008;168(21):2368-2375.

In fact, the question you have to ask is this: Why didn't they compare the people taking both drugs with another group of matched controls not taking any drug? Also, why did they not look at the incidence of bone fractures and sight-threatening retinal edema? Both are found with Actos.

The "conflict of interest" section of this study is not available without a very expensive subscription to the journal. My guess is that the authors received their funding from the makers of Actos, hence this study is merely marketing material, not good science.

Bottom line: Neither of these drugs is safe. Don't let the spin doctors damage your health by prescribing Actos and telling you it is safe.
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