Avandia and Actos

The thiazolidinediones are 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 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.

Rezulin, the first of these drugs, and the one that endocrinologists tell me was by far the most effective was withdrawn after it was found to cause fatal liver failure in a small, but significant number of patients.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 later discovered that this is not entirely true as there were reports of liver failure associated with these drugs.

But it took almost a decade for the real problems with these drugs to surface, partially, it is now clear, 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 work by decreasing insulin resistance. They do this by causing the formation of new fat cells primarily on the arms, thighs, and butt, which then are able to 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 manufacturer's own prescribing information makes it clear that they produce only a modest change in blood sugar and insulin levels, though possibly a bit more than Metformin.

Studies funded by the manufacturer 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.(2), (3),

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.(4) .

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

The hope that these drugs could rejuvenate beta cells--a premise which had been sold to doctors so effectively by drug company sales people that many patients now take these drugs under the belief that this is what they are doing, was dashed by a large-scale study in humans.

On May 2, 2007, Diabetes in Control reported that a follow up to the DREAM study, a study that initially appeared to show that taking Avandia could prevent the onset of diabetes, found that as soon as the drug was stopped, people developed diabetes at the same rate as if they hadn't taken the drug.

From the Diabetes in Control report: "As yet unpublished results from a follow-up study which were presented at a medical conference in December 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."

This makes it crystal clear that the claim that these drugs let the beta cells heal themselves is not true. Had beta cells been rejuvenated, blood sugar response would have been improved after the drug was discontinued.



http://www.diabetesincontrol.com/results.php?storyarticle=4766

Avandia Causes Heart Attacks

Even worse, the DREAM study which had been funded by the manufacturer, Glaxo-Smith-Wellcome, to prove that Avandia would prevent heart disease 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 5/21/07).

As the story cited above 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.

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

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

Only the abstract is available online, however, as reported by Bloomberg.com, "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,"
Diabetes drugs 'double risk of heart failure'

Comparing Actos with Metformin

A comparison of Metformin and Actos run by researchers from Lilly, the drug company that makes Actos which was conducted, for some strange reason, in medical centers in Hungary and Russia, found that the drugs had similar effects on fasting blood sugar and HbA1c but that Actos did a better job of lowering fasting insulin levels.

Again, this study showed that the changes in blood sugar levels were very similar for both Metformin and Actos and very modest no matter what drug the participants were taking. The average fasting plasma glucose levels were over 162 mg/dl (9 mmol/L) for both drug groups--more than high enough to speed them on their way to the development of diabetic complications. (5)

The Most Recent Research Suggests Actos is NOT Effective

A meta study published in October of 2006 which analyzed the results of 22 randomized clinical trials involving 6,200 patients with type II diabetes receiving Actos concluded that:

“Our results showed that published scientific studies of at least 24 weeks of pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects and health-related quality of life are positively influenced by this drug,” said lead author Bernd Richter, M.D.

“Until new evidence becomes available, the benefit-risk ratio of pioglitazone [Actos} therapy in type 2 diabetes mellitus remains unclear,” added Richter, assistant professor in the department of endocrinology, diabetes and rheumatology at Heinrich-Heine University in Düsseldorf, Germany.

According to Richter, not only did the review demonstrate no clear-cut benefit to using pioglitazone, but it also showed an increased occurrence of edema and heart failure — including heart failure requiring hospital admission — among patients taking the drug.

http://www.diabetesincontrol.com/modules.php?name=News&file=article&sid=4237

Since Actos and Avandia are so similar, this metastudy casts some doubt on the manufacturer's enthusiastic claims for both Actos and Avandia.

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 soley 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

http://care.diabetesjournals.org/cgi/reprint/26/11/3148

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 whatever gain the group 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

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. (8)

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, and experts suggest that monitoring liver enzymes may not be enough to prevent damage.(9) (10)

Bone loss with TZD?

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. (11)

This finding was reinforced by another study by Dr. Steven Kahn which was published in December in 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.

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.

ADOPT was yet another large study that documented a significantly higher number of fractures with Avandia when 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."



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.

.

CITATIONS

1 Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes, Sep 2002, 51(9) p2796-803

http://diabetes.diabetesjournals.org/cgi/content/full/51/9/2796

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

http://care.diabetesjournals.org/cgi/content/full/26/11/3184

3 J.E. Gerich; Redefining the clinical management of type 2 diabetes: matching therapy to pathophysiology. European Journal of Clinical Investigation(2002) 32(Suppl.3) 46-53)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12028374

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

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14532171

5 Imre Pavo, György Jermendy, Tamas T. Varkonyi, Zsuzsa Kerenyi, Andras Gyimesi, Sergej Shoustov, Marina Shestakova, Matthias Herz, Don Johns, Belinda J. Schluchter, Andreas Festa and Meng H. Tan. Effect of Pioglitazone Compared with Metformin on Glycemic Control and Indicators of Insulin Sensitivity in Recently Diagnosed Patients with Type 2 Diabetes. The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 4 1637-1645 2003.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12679450

6 Kermani A, Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema.Mayo Clin Proc. 2003 Sep;78(9):1088-91.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12962163

7 Hollenberg NK. Considerations for management of fluid dynamic issues associated with thiazolidinediones.Am J Med. 2003 Dec 8;115 Suppl 8A:111S-115S.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14678876

8 Karla Harby, Glitazone Use May Be Associated With Macular Edema in Diabetics

http://www.medscape.com/viewarticle/464732

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

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11960075

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

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12879989

11 TZD’s Can Increase Bone Loss in Type 2 Women - Diabetes in Control Newsletter

http://www.diabetesincontrol.com/modules.php?name=News&file=article&sid=4285

Diabetes, TZDs, and Bone: A Review of the Clinical Evidence.
Ann V. Schwartz. PPAR Res. 2006; 2006: 24502.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17259663