Diabetes Drugs: Thiazolidinediones

Editor’s Note: This is the fourth post in our miniseries about diabetes drugs. Tune in on September 4 for the next installment.


thiazolidinedionesThis class of drugs was introduced into practice over a decade ago, but the first thiazolidinedione turned out to be associated with severe side effects. The drug, named troglitazone (brand name Rezulin), was introduced into the United States in 1997 and removed from clinical use 3 years later due to concerns about liver damage. (Troglitazone was removed from use in England two years prior to its removal in the U.S.)

In 1999, two more drugs in this class, pioglitazone (Actos) and rosiglitazone (Avandia), were approved by the U.S. Food and Drug Administration (FDA). Liver toxicity does not appear to be associated with these drugs to the same extent as it was with troglitazone.

Thiazolidinediones do not act by increasing insulin secretion, but rather by increasing insulin sensitivity in the body: Normally, the DNA in cells receives instructions via chemical signals. The signaling chemicals interact with a class of molecules in the cells called nuclear transcription factors (NTFs). The NTFs are transported to the nucleus of the cell, where the DNA resides, and either promote or inhibit the DNA from making copies of genes. Ultimately, this process affects how the cell functions.

Thiazolidinediones interact with an NTF called PPAR {gamma}. PPAR {gamma} is present in fat tissue, the pancreas, vascular endothelial cells (the cells that line the inside surface of blood vessels), and muscle. The combination of a thiazolidinedione, a PPAR, and another NTF called RXR interacts with specific areas of DNA, which increases the production of proteins that regulate lipid (blood fat) metabolism, control energy, regulate a hormone called adiponectin (which improves insulin sensitivity), and decrease the production of a protein called TNF-alpha. All of these effects result in improved insulin sensitivity, increased glucose use by muscle, increased HDL (“good”) cholesterol levels, and reduced insulin secretion.

Pioglitazone and rosiglitazone are approved for use alone or in combination with metformin, sulfonylureas, or insulin. The joint guidelines issued by the American Diabetes Association and the European Association for the Study of Diabetes include thiazolidinedione therapy in their second tier of recommendations.

In placebo-controlled studies (in which people taking an active treatment are compared to people taking an inactive treatment), the reductions in HbA1c (an indicator of blood glucose control over the previous 2–3 months) for the maximum doses of both drugs was approximately 1.5%.

The blood glucose effects of these drugs become apparent in approximately four weeks, with the maximum effects starting to occur about eight to 16 weeks later. Changes in HbA1c can be seen after roughly eight weeks, with maximal effects occurring between 18 to 26 weeks. While these effects are slightly less than those seen with the use of metformin or sulfonylureas, one four-year study has shown the effects of thiazolidinediones to be longer lasting.

In addition to lowering blood glucose levels, thiazolidinediones increase HDL cholesterol; however, this does come at the cost of a small increase in LDL (“bad”) cholesterol. Small studies have shown that rosiglitazone is beneficial in preventing restenosis (blood vessel narrowing) after coronary angioplasty, but larger studies are needed before to confirm this benefit.

Side effects of drugs in this class include weight gain and anemia. There has been some controversy surrounding the long-term safety of these medicines, which are known to cause edema (swelling) and, to a lesser extent, heart failure. The American Heart association has made recommendations for people who are candidates for thiazolidinediones and for those who are on these drugs, indicating that people with mild heart failure should use these medicines with caution and those with more severe heart failure should not use them at all. A meta-analysis (a type of research in which statistics from several studies are combined and examined) of 42 studies linked rosiglitazone with an increased risk of heart attack and death. This has prompted the FDA to ask for stringent heart safety evaluations for all new drugs for diabetes.

Subsequent to the release of the meta-analysis results, two large studies, one with pioglitazone called the PROactive study, and one with rosiglitazone called the RECORD trial, have been completed. While the PROactive study confirmed an increased risk for heart failure with pioglitazone, a decrease in the risk for heart attacks was seen among study participants. The data published for the RECORD trial also demonstrated an increase in heart failure, as well as bone fractures (particularly in women), but it did not show a statistically significant increase in heart attacks. (A result is statistically significant if it is unlikely to have occurred by chance.) It should be noted that the RECORD study has been criticized on several fronts, and the cardiac safety of rosiglitazone still remains an open question.

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  • CalgaryDiabetic

    I used avandia up t0 10 mg per day for a year and it had no effect on either the average BG nor on the standard deviation. The only effect was damage to the pocket book.

  • ken

    I used Avandia for several years and it seemed to help, but when the bad news hit the media my insurance said they wouldn’t pay for it anymore. Doc switched me to Actos which as as side effect caused an rash (watery blister like) on one shin. When we stopped taking it the rash and itch went away, but damaged skin remained. Upon starting it again the rash and itching returned. So we have since switched to Amaryl which has so far not produced any side effects for me, and has been much more effective in reducing my glucose levels.

  • Beverly S.

    I’ve been taking Actos and metformin for several years now with a good result — an A1C that is close to normal. However, this only works when I watch my diet and get some exercise. Actos may be expensive, but metformin alone did not help much. I can only say that this regime works for me.

  • Ronata Lewis

    I take Avandia with metformin. My A1C has steadily decreased. I have been on this for almost 3 years and highly recommend it. I have no side effects and truthfully I am horrible at watching what I eat. When diagnosed my A1C was almost 8 now it is 5.3. Really the only difference in my diet is adding these medications.

  • Lori

    I have been taking Actos plus met (15/850) twice a day for about 6 months now. Before taking this medication my A1C were very high (only taking metformin 1000 x2 a day) since changing to the Actos plu Met my A1C have lower significatly it has gone from 9 to 5.5… The only thing is that I have the side effects.. I have gained 20 pounds which I don’t need as I am very obese and I now have sweeling in my ankles and knees which I never had before… I am hoping that it does not upset my gout.. I am wondering if there is anything that I can do or take to relieve the swelling..

  • Paul Wirth

    I am insulin dependent(on pump). Took Actos when it first came out but discontinued on advice of endoctrinologist on basis of:weight gain,and fear of liver risk. New endoctrinologist restarted about6 months ago. Basal and bolus rates decreasd significantly.Total daily insulin requirement reduced nearly 50%.HA1c reduced from range 6.0-6.9 to 5.5-5.9.
    I am experiencing slight anemia which my Primary Care and Endoctrinologist have not thought that it might be caused by the Actos.
    It just confirms that diabetics must do the research that their doctors don’t have the time or inclination to persue.
    Thank you for your great work.
    Col Paul.R. Wirth U.S.A.,Ret.

  • Mark Marino

    I am attaching the link to the American Heart Association Consensus statement on thaizolidinediones. It has information about anemia as well as edema and its suggested evaluation and treatment: http://circ.ahajournals.org/cgi/reprint/108/23/2941