Actos Discussions Part 2: Dangers of the Drug

By Independent Staff Writer

Could Your Heart Failure Be Linked to Actos?
Links to higher heart disease rates have been associated with the use of Actos, and, in fact, Actos may cause as many heart problems as GlaxoSmithKline’s drug, Avandia. The American Heart Association reported that studies showed patients taking either diabetes drug were at least four times as likely to experience heart attacks, heart failure or even death. When a 2007 study on Avandia showed a 43 percent higher chance of heart attack, Actos quickly became the market leader. A subsequent study on both drugs showed that 602 Avandia users and 599 Actos users in the study suffered either a heart attack, heart failure or both, with 217 deaths in each group.  The latest study regarding Actos in the journal Lancet found the risk for heart failure greatest among those patients with a prior history of heart disease and heart failure, however overall the relative risk when taking Actos was as much as 72 percent higher than those not taking the drug. Both Glaxo and Takeda dispute the results of these negative studies, citing a study published in the Journal of the American Medical Association which suggests Actos might actually cut the risk of heart attack, stroke and death.

Link between Actos and Heart Failure
Actos is in a class of drugs known as thiazolidinediones, whose use has long been attributed to certain liver and cardiovascular health issues. A listed side effect of Actos includes the threat of congestive heart failure with the link between Actos and congestive heart failure being so undeniable that in 2007 the FDA escalated warnings regarding heart disease when taking the drug. Actos causes the body to retain excess fluid, leading to swelling and weight gain. This extra body fluid can worsen some heart problems, leading to heart failure or can actually cause heart problems.

When Actos causes swelling in the body, this swelling also occurs around the heart, rendering it unable to effectively pump blood throughout the body. As fluid builds up around the heart and lungs, it becomes more difficult for the heart to pump, causing it to become less and less efficient. This can lead to shortness of breath, trouble breathing when lying down, a feeling of excessive tiredness or an unusually rapid increase in weight. After an intense debate over the cardiovascular risks of Actos, the FDA agreed to surround the heart risk warnings on Actos with an emphatic black outline commonly known as a black box warning. This black box warning is the strongest FDA label change which can be added to any drug on the market.

Link Between Actos and Bladder Cancer
The FDA issued its safety announcement regarding the connection between using Actos for more than one year and the risk of bladder cancer on June 15, 2011. The bladder lies in the center of the lower part of the abdomen, and its primary purpose is to store urine prior to excreting it from the body. When cells in the bladder become cancerous, a tumor can form. Actos helps diabetics use their own insulin better by hitting at least two of the three main PPAR receptors known as the Gamma and Alpha receptors. The Gamma receptor works on glucose while the Alpha receptor affects cholesterol. Actos appears to have a higher affinity with the Alpha receptor which is why it does a good job on raising good cholesterol and lowering triglycerides.

It has been hypothesized that the way in which Actos reacts with these receptors may also be the reason it contributes to the risk of bladder cancer. Potential symptoms of bladder cancer include bloody urine, chronic and persistent infections of the bladder, a strong urge to urinate or pain and burning during urination. X-rays may reveal an abnormality in the bladder walls, or red blood cells found in the urine during lab tests. If the bladder is swelling, a biopsy may be done or a growth in the bladder could be discovered through a CT or MRI scan. Bladder cancer is typically treated with removal of the tumor, surgical removal of all or part of the bladder or with drugs which help the immune system fight the cancer.

Could Actos Damage Your Liver or Kidneys?
In addition to potentially damaging the heart and bladder, Actos may also be linked to rhabdomyolysis which occurs when muscle fibers rapidly bread down releasing proteins and myoglobin into the blood stream. Myoglobin can be toxic to the kidneys, leading to the development of rhabdomyolysis. Symptoms of this serious kidney disease include muscle pain or tenderness, stiffness or weakness in the joints and dark-colored urine. Actos has also been documented to cause elevated liver enzymes, a precursor to liver damage. Anyone who is considering taking Actos should have their liver enzymes tested before they start taking the drug, and should periodically monitor the liver enzymes while on Actos.

Actos® Adverse Effects

Actos® Adverse Effects

Many of us would be very surprised to find that a drug can be approved by the FDA yet still have serious—and undisclosed—side effects. The drug Actos, used in the treatment of Type 2 diabetes, is one such drug. Actos works by decreasing the body’s resistance to insulin as a way of controlling blood sugar levels. Actos is currently being used by millions of people across the globe, with sales jumping from around $2.9 billion in 2006 to over $4.3 billion in 2010. Actos has often been prescribed in place of the drug Avandia, which was found to carry significant risks of heart disease and possibly even death in 2007. Actos, which is manufactured by the Japanese pharmaceutical giant Takeda Pharmaceuticals, has recently fallen under scrutiny as well as studies have linked it to an increased risk of bladder cancer as well as correlating it to other serious diseases such as heart attack, stroke and liver failure.

“Minor” Side Effects of Actos
The truth is, all prescription medicines as well as most over-the-counter medications, carry some risk of adverse effects. Fortunately the incidence of serious side effects is rare and for the most part the majority of people have either no side effects or relatively minor ones. Minor side effects associated with Actos include flu-like symptoms, headaches, toothache, sore throat or sinus pain and weight gain. More serious side effects which should prompt the user to seek medical attention include an allergic reaction which includes difficulty breathing or chest tightness, blurry vision, symptoms of heart or liver failure including breathing difficulties, a sudden gain in weight, stomach pains, dark urine, jaundice or vomiting, low blood sugar symptoms such as tremors, anxiety or chills, severe and unusual bone pain and total exhaustion along with feeling weak and shaky.

Actos® and Cardiovascular Dangers

Actos® and Cardiovascular Dangers

The drug Actos, marketed by Takeda Pharmaceutical Corporation, is used in the treatment of Type 2 diabetes. Actos largely replaced its predecessor, Avandia, after Avandia was found to have serious risks of heart attack and heart failure. At the time, it was believed that Actos offered much less risk of cardiovascular damage than Avandia. Actos is used to lessen blood glucose labels and improves how the body handles insulin. Type 2 diabetes, which affects between eighteen and twenty million Americans, can cause loss of sight, kidney trouble and cardiovascular illness if left untreated, however it appears that the treatment may also come with its fair share of serious dangers. Just like Avandia, Actos may carry significant levels of cardiovascular risks, however it has not been associated with heart attack deaths in the same way Avandia has.

Although Takeda is in the middle of a ten-year study regarding the safety of Actos, other studies have been conducted as well. One well-known cardiologist, Dr. Steven Nissen of the Clevenland clinic focused his review of Actos dangers, finding that it significantly increases the likelihood of a heart attack by as much as forty-two percent. The FDA issued a black box warning label for Actos in June of 2007 during a House of Representatives hearing. During this hearing the fact that the FDA was aware of the potential cardiovascular risks associated with Actos yet failed to adequately respond was discussed, and since that time both lawmakers and health experts have criticized the FDA for failing to properly safeguard public health.

Actos® Damages and Typical Settlements

Actos® Damages and Typical Settlements

The Type 2 diabetes drug Actos is one of a class of drugs known as thiazolidinediones and has recently been linked to an increased risk of bladder cancer, liver disease and cardiovascular issues. The FDA felt that the link between heart failure and Actos was serious enough to require increased warnings on the drug packaging concerning congestive heart failure. According to the Washington Post on 8/05/11, the first of what is expected to be literally thousands of lawsuits was filed alleging the use of Actos resulted in bladder cancer. Takeda Pharmaceuticals, a Japanese corporation is the manufacturer of Actos although it was jointly launched with the American company, Eli Lilly. Actos quickly became a top-seller of the giant pharmaceutical corporations, becoming the tenth best-selling drug in the United States in 2008 with sales over 2.5 billion dollars increasing to a staggering 4.3 billion in 2010.

In June of 2011, Takeda halted its sales of Actos in both France and Germany after receiving considerable pressure from health regulators in both those countries. New Zealand is currently in the process of pulling the drug as well. Since June, both the FDA and the European Medicines Agency have prudently issued warnings regarding the potential risk of bladder cancer for those taking the drug, but are allowing the continuation of sales pending further studies. The FDA has, however, warned doctors not to prescribe the drug for those who have a history of bladder cancer or who currently have bladder cancer.

Actos® Side Effects other than Heart Disease and Bladder Cancer

Actos® Side Effects other than Heart Disease and Bladder Cancer

Osteoporosis and Bone Fractures
While many people are now aware of the association between the Type 2 diabetes drug, Actos, and both bladder cancer and heart disease, there are several other quite serious side effects also associated with the drug. For instance, there is strong evidence to suggest that Actos, like its sister-drug, Avandai, may cause osteoporosis and bone fractures among those taking it, most especially in female patients. In one particular randomized trial which studied patients with Type 2 diabetes who were currently taking Actos, an increased occurrence of bone fractures was observed in the female patients and in a follow-up study at nearly three years, almost 5.1% of the females taking Actos had suffered a bone fracture.

Most of the bone fractures were seen in arms and legs, and there was no apparent escalation of fracture occurences among male patients. Because this drug study lasted less than five years, it is strongly believed that a much greater frequency of fractures and osteoporosis would be seen in women taking Actos for longer periods of time. Since men typically have much stronger bones than women, fractures and osteoporosis would probably not have been seen in men who were studied for only a few years. Since broken hipbones happen to be a primary killer of the elderly, seniors should not take Avandia or Actos as their benefits do not appear to outweigh the serious side effects.

Macular Edema
A study presented at the yearly meeting of the American Diabetes Association this past June found that those taking Actos have a three to six times increased risk of developing macular edema. Macular edema causes an eye disease in which the retina swells and thickens and can lead to permanent blindness. Diabetic eye disease is now the most common cause of blindness in those younger than age 65, and although the best way to avoid this particular side-effect of diabetes is by keeping your blood sugar under control, Actos appears to increase the risk of macular edema even though it does control the blood sugar.

Weight Gain
Weight gain also appears to be a side effect of Actos, however it must be noted that there is significant difference between a slow weight gain as the result of the drug and a rapid weight gain which could signal congestive heart failure. Rapid weight gain is any more than five pounds in a week, and should be a reason to consult your physicians immediately. On average, those taking Actos gained from two to six pounds over a period of four months to six months, while those patients not taking Actos lost about three pounds during the same time period.

In patients who were taking both Actos and insulin or other oral diabetes medications, the weight gain increased to between nine and ten pounds on average. Patients taking higher dosages of Actos gained larger amounts of weight than those taking lower doses, however those whose weight gain was related to fluid retention likely suffered more serious cardiovascular problems. Actos has been shown to worsen congestive heart failure or in some cases cause it. A primary initial symptom of congestive heart failure is an unexplained, quick weight gain, so it is important for those taking Actos to monitor their weight regularly.

Liver Disease
Patients who have shown signs of prior liver disease should not take Actos or any other drug in the thiazolidinedione class. These drugs have been definitively associated with significant elevations in liver enzymes, jaundice, liver failure and death due to liver failure. These liver problems have been seen both in long-term and short-term patient use of Actos. Any patients taking Actos should be aware of the potential liver problems, and should report any unexplained nausea, vomiting, fatigue, dark urine or abdominal pain to their physician immediately. If jaundice develops the medication should be immediately discontinued. Those taking Actos who show even a moderate increase in liver enzymes should continue the drug only with their physician’s approval, and with great caution. If Actos use has led to a seriously impaired liver, a liver transplant may be necessary. Conversely, while Actos has been shown to potentially cause liver enzymes to increase to serious levels, there is medical evidence which shows Actos may actually provide beneficial effects in treating fatty liver disease. Several studies have shown that Actos can reduce the liver fats by half in less than half a year.

Other Serious Side Effects
Actos has also been known to cause allergic reactions, blurry vision, easy bruising or bleeding, flu-like symptoms, muscle pain and serious tooth pain and problems. Actos is contraindicated in those who are scheduled for an upcoming surgery or have any type of known allergy to foods, dyes or preservatives. Women who are pregnant or thinking of becoming pregnant, or those who are breastfeeding should not take Actos as it is considered a Pregnancy Category C drug meaning it is not considered safe to take when pregnancy is a possibility. Actos can also pass into breast milk, so should definitely not be taken by women who are currently breastfeeding. Actos can also potentially interact with other prescription drugs as well as non-prescription medications, vitamins and herbal supplements, so it is important that your doctor be aware of everything you take regularly. While bladder cancer and cardiovascular problems are the most serious of the known side effects of Actos, the side effects listed above can also have potentially serious consequences.

Pioglitazone Receives New Warnings Due to Slight Increase in Bladder Cancer Risk

Pioglitazone Receives New Warnings Due to Slight Increase in Bladder Cancer Risk

The health review of the Type 2 diabetic drug, pioglitazone, performed by the European Medicines Agency, confirmed the drug remains a valid treatment option for certain patients while acknowledging a minimal increase in bladder cancer risk. The caveat in the conclusions of the health review centered upon advising physicians to use care and caution when prescribing the drug. The results further stated that those who are prescribed pioglitazone—especially those who take relatively high doses or have taken the drug for longer than a year—must have their overall health monitored closely.  Exclusion of certain higher risk groups, such as the elderly is also recommended.

Assessing Risk Factors in Potential Patients
Physicians are warned to screen patients carefully, and avoid prescribing pioglitazone to those who have a history of bladder cancer or who currently have bladder cancer. Patients with uninvestigated macroscopic haematuria are also advised against taking pioglitazone.  As stated, age carries a specific risk, as the elderly are already more likely to develop bladder cancer based solely on age. Because of this an alternative diabetes medication with less risk in this area should be prescribed. Patients taking Actos should undergo regular 3-6 month reviews to assess and monitor benefit vs. risk.

Sources of Information
In making its safety recommendations, the Committee for Medicinal Products for Human Use considered results of pre-clinical and clinical studies as well as spontaneous reports and epidemiological studies. The Scientific Advisory Group on Diabetes also weighed in with advice regarding pioglitazone. The CHMP concluded from this array of evidence that while there is a slight increase in bladder cancer among those taking pioglitazone, this risk exists primarily in those who take the drug for long periods of time or in relatively high doses. That being said, those who take the drug for a short amount of time cannot be excluded from the risks.

No Recall Yet for Type 2 Diabetes Drug, Actos

The FDA has joined forces with France and Germany regarding a warning about the Type 2 diabetes drug, pioglitazone, however no recall is expected at this time. Pioglitazone, also known as Actos, is manufactured by Takeda Pharmaceuticals, a Japanese drug company. The drug currently accounts for some 27% of Takeda’s annual revenues. 2008 saw this powerhouse diabetes medication become the tenth best-selling prescription medication in the United States. Over the past year, Takeda has accrued nearly $4.8 billion dollars in revenues through worldwide sales of Actos.

Clinical Studies of Pioglitazone
Pre-clinical studies—in which male rats were given body-weight equivalent doses of Actos—showed an increase in the incidence of bladder cancer while two subsequent clinical studies using human subjects also revealed an elevated risk of bladder cancer. Due to these findings, the FDA mandated that the potential risks be revealed on the label of the drug, ordering a safety review in September, 2010.  Takeda additionally agreed to carry out a ten-year observational study in those diabetic patients currently taking Actos, to be conducted on patients from Kaiser Permanente Northern California Health Plan.

Benefit-Risk Balance Deemed Positive for Type 2 Diabetics Taking Pioglitazone

Benefit-Risk Balance Deemed Positive for Type 2 Diabetics Taking Pioglitazone

Following safety reviews of the drug pioglitazone—a medicine used in the treatment of Type 2 diabetes—the European Medicines Agency delivered their decision that while there is a marginally increased risk of bladder cancer in those taking the drug, it remains a viable treatment option for some patients. Pioglitazone, also sold under the brand name Actos, is used along with a sensible diet and exercise program to increase the body’s sensitivity to insulin, thereby controlling blood sugar levels.

Reducing Potential Risks
The EMA’s conclusions following extensive study of the drug was that the slight increased risk of bladder cancer could be alleviated through implementation of a more stringent screening of potential patients. Medical professionals are warned against prescribing pioglitazone in any patients with a history of bladder cancer, and to exercise caution when prescribing the drug to the elderly as well. Those patients deemed good candidates for pioglitazone should nonetheless be monitored closely every three to six months to ensure the benefits continue to outweigh the risks.

High Doses, Significant Duration Linked
The results of the controlled epidemiological studies determined that the small risk associated with pioglitazone was seen primarily in those patients who took the drug for significant lengths of time and in the highest doses. Even though the studies showed only a 0.15% increase in risk of bladder cancer this does not mean that those who are prescribed the drug for short term use have no risk at all of contracting bladder cancer.