Wednesday, October 23, 2013

PCOS Treatment: TZDs and Other Glucose-Lowering Medications

We've been discussing Polycystic Ovarian Syndrome (PCOS) and its impact on the health of women of size. It's time to discuss the use of non-metformin options in the treatment of PCOS.

If you've missed the last few posts, so far we've talked about the definition and symptoms of PCOS, how it presents, its testing and diagnosis, and its possible causes.

Currently, we are discussing common treatment protocols for PCOS, and the pros and cons of each. Unlike most resources, we are emphasizing a size-friendly, weight-neutral approach, rather than promoting weight loss for treatment.

We've already discussed metformin. Now, we discuss the TZDs, a.k.a. Actos, Avandia and related drugs, as other insulin-sensitizing agents often used in the treatment of PCOS.
Disclaimer: While the following information is based on my best understanding of the research, I am not a medical health-care professional and no medical advice should be inferred. Always do your own research and consult your healthcare provider.  
Trigger Warning: Passing mention of weight gain/weight loss side effects of some diabetes drugs.
Types of Insulin-Sensitizing Agents 

To summarize the information from previous posts, there are two main types of insulin-sensitizing agents ─ the group of drugs known as biguanides, and the group known as thiazolidinediones (which are also known as glitazones or TZDs). To repeat the summary from one website on insulin resistance:
  • Biguanides. Biguanides are drugs that improve the body's sensitivity to insulin by lowering the absorption of glucose in the small intestine, decreasing the liver's production of glucose, and increasing the uptake of glucose in muscle and fatty tissues...
  • Thiazolidinediones. These drugs stimulate glucose uptake in the muscles and fatty tissues by activating specific receptors in the cell nucleus. They also lower blood insulin levels in patients with hyperinsulinemia.
Of the biguanides, metformin hydrochloride (brand name: Glucophage) is the only drug still left in use. Metformin has been in use a long time, is very effective for many people, seems to prevent or reduce the risk of many poor outcomes, and has a longer safety profile than many other insulin-resistance (IR) drugs on the market. Because of this, it is the dominant insulin-sensitizing agent on the scene today, and deservedly so.

Thiazolidinediones (TZDs) were all the rage a few years ago because they seemed even more effective than metformin against IR and PCOS symptoms. However, safety concerns arose over the years and two TZDs (Rezulin and Avandia) were pulled from the market or limited in their use, while a third (Actos) remains under investigation.

In addition to metformin and TZDs, there are a few other insulin-sensitizing options for women with PCOS. Inositol (myo-inositol, d-chiro inositol, pinitol) is one option that received a lot of buzz at first and which is now experiencing a resurgence of interest. More on that in a separate post later on.

Limitations of the Data

A big limitation on our discussion here is that we do not have much information on the use of the TZDs for women with PCOS. Most of the information we have on insulin-sensitizing drugs has been done on the type 2 diabetes population only, so their effect on women with PCOS is somewhat speculative.

Furthermore, the studies we do have specifically on insulin-sensitizing drugs in a PCOS population are often short-term. And they place too much emphasis on surrogate outcomes like lower blood sugar or better insulin sensitivity, assuming that these will then translate to less morbidity and mortality down the line, but without actually examining whether or not they do.

As we shall see, drugs with short-term positive effects on risk factors don't always result in result in fewer heart attacks or deaths; sometimes they can actually worsen long-term outcomes. So it is key that we have long-term data on actual end-points, not just the effect on risk factors.

The bottom line is that data on the long-term efficacy and safety of these drugs in PCOS populations is urgently needed. Please keep that in mind as you read this post.

TZDs (glitazones)

The thiazolidinediones (known as glitazones or TZDs) include:
Basically, TZDs work mostly by improving sensitivity to insulin in muscle and fat tissue. As one resource explains:
The TZDs are a group of medicines that stimulate peroxisome proliferator-activated receptors (PPARs). There are many of these receptors, including PPAR-alpha, PPAR-gamma, and PPAR-delta...Once you stimulate the PPAR-gamma receptors, you improve insulin sensitivity not just in the liver, but everywhere in the body, especially in the adipose tissue and the skeletal muscles.
Like metformin, TZDs also inhibit hepatic (liver) glucose production. They are metabolized by the liver and excreted into the bile. They were introduced in the late 1990s.


TZDs have been shown to markedly improve blood sugar. Some research shows that TZDs may improve blood sugar in diabetics even better than metformin.

More importantly in PCOS, TZDs seem to improve insulin sensitivity. Many researchers feel that this is key in helping address the underlying metabolic disturbances of PCOS.

TZDs restores menstrual cycles and ovulation in many women with PCOS, both by itself and when used in combination with clomiphene. It also seems to improve ovulation and pregnancy rates in PCOS women who are clomiphene-resistant and those who don't respond to metformin.

TZDs may improve lipid and triglyceride levels as well. It also seems to lessen androgen levels, improve hormone balance, and improve hirsutism.

Recent research suggests that Actos may also be associated with an improvement in depressive severity in women with PCOS.

TZDs were thought to be the next class of wonder-drugs for insulin resistance. Many women with severe PCOS responded better to TZDs than to metformin, or responded well to a combination of both a TZD and metformin. Therefore, TZDs seemed to be a major step forward for women with PCOS.

But alas, as with many drugs, population-wide use soon found that TZDs came with drawbacks as well as benefits.

Safety Issues and Side Effects

Unfortunately, a number of safety issues have arisen with TZDs.
  • Troglitazone (Rezulin) was taken off the market in 2000 because it was associated with a increase in hepatotoxicity (liver problems)
  • Rosiglitazone (Avandia) was taken off the market in Europe in 2010 and subjected to restrictions in the US because of a purported increase in cardiovascular events (heart problems)
  • Pioglitazone (Actos) has a more favorable risk profile, but has recently been suspended in some European countries because some research suggested it might be associated with an increase in the risk for bladder cancer
At this time, TZDs are only approved for use with type 2 diabetics. Although commonly used for PCOS, this off-label use is still considered experimental.

As noted, most of the safety information we have is based on studies with diabetics and may not be the same for women with PCOS. In addition, it should be pointed out that many of the studies we do have on TZDs and PCOS are very small and short-term, and most do not meet the gold standard of randomized controlled trials.  

One of the risks of TZDs for diabetics is liver failure and/or hepatitis. Rezulin (troglitazone) was taken off the market because of its risk for liver toxicity, but all of the TZDs carry some degree of liver risk. Thus, many doctors recommend liver tests every few months when starting a TZD, and yearly thereafter. They should not be prescribed to anyone with existing liver disease.

A lesser-known risk associated with TZDs is a modestly increased risk of bone fractures and/or decreased bone density. This seems more associated with Actos than other TZDs, but data is still preliminary at this point and some research does not support an association. 

A common side effect of TZDs is edema (fluid retention). Although most who take a TZD don't experience it, edema from TZD use can lead to a significant worsening of undetected pre-existing heart failure. Therefore, weight gain and heart symptoms must be watched for closely in those on TZDs.

Although Avandia has been shown to lead to an increase in cardiovascular events and mortality in diabetic patients, there is still considerable debate over the validity of this finding. TZDs clearly increase the risk for congestive heart failure but the risk for myocardial infarction (heart attack) is less clear. Even if the risk is increased, the actual numerical risk is quite low, so many American doctors feel that the benefits of Avandia still outweigh the risks for some patients. European doctors, on the other hand, have basically discontinued its use.

Unlike Avandia, Actos has actually been shown to decrease some cardiovascular events, especially in those who have already had cardiac events. It can also decrease blood pressure and lipids. So the cardiovascular risk may depend on which TZD you take.

On the other hand, recent information also suggests that Actos could be associated with an increase in risk for bladder cancer in some users:
Although there was no increased risk of bladder cancer among Actos users overall, there was an increased risk of bladder cancer among those who had used the drug the longest. There was also a greater risk of bladder cancer among Actos users who had been exposed to the highest cumulative dose of the drug...FDA officials say in light of this new information, Actos should not be prescribed to people with bladder cancer or people with a history of bladder cancer.
Conversely, TZDs are associated with a lower risk for liver cancer and/or colorectal cancer in some studies. At this time, the relative benefit-risk ratio for each of these cancers is not available so it's difficult to weigh the pros and cons of their use.

Other side effects associated with TZDs may include upper respiratory tract infections, headaches, weight gain, anemia, muscle soreness, macular edema, and decreased effectiveness of oral contraceptives.

It should also be noted that TZDs are considered Pregnancy Class C drugs and, while effective for ovulation induction, should not be continued into pregnancy.

The bottom line is that the very significant benefits of TZDs may be balanced by significant risks.

Current Status and Future Use

While still used, TZDs have begun to fall from favor and many doctors do not consider them a first-line therapy for most people with diabetes. However, they are often still used to help lower blood sugar as diabetes progresses because they are very effective at lowering blood sugar, especially in combination with other drugs.

The use of TZDs as a mainstay treatment for PCOS is even less well-defined. Based on the evidence so far, most care providers feel that they are probably not the best first-line treatment for PCOS. However, they can be effective for those with more severe cases of PCOS, those with very high blood sugar, those with severe insulin resistance, or those who do not respond to/cannot tolerate metformin.

It should be pointed out that a recent review of the TZDs notes that the current TZD drugs comprise only the first generation of this drug class. Many times, the first generation of a drug class finds safety issues and results are improved upon in later generations of that drug class. Several recent reviews hint that the second generation of TZDs are on their way and may show significant improvements in both action and safety. However, only time will tell, since several other "next generation" TZD-related medications have been discontinued due to safety concerns.

For now, the benefits and risks of the current generation of TZDs (mostly Actos) must be weighed on an individual basis. For some, the possible risks may be offset by the considerable improvement in blood sugar and insulin sensitivity that may result. The trade-off would not be acceptable in someone with pre-existing heart disease or liver issues, however.

It is important to consult your healthcare provider carefully about the pros and cons of TZDs before incorporating them into your care, and to get frequent checks of your liver function if you decide to use them.

Combination Drugs

Metformin and a TZD are often used in conjunction for diabetes treatment. This combination seems particularly potent for lowering blood sugar in those with severe insulin resistance or those whose blood sugar does not normalize with metformin alone.

Rather than prescribing two different pills, the two medications are often combined into one pill. This makes it simpler and more convenient for the consumer, and the drug company is able to hold onto exclusive patent use longer for the drugs, thus prolonging the profit margins. As a result, these drug combinations are an increasingly popular way to prescribe diabetes medication.

Here are some common combination drugs:
  • Avandamet is a combination of metformin and Avandia (rosiglitazone). It was pulled from the market for a while because of manufacturing problems, but is available again. The controversy over Avandia's cardiovascular safety makes it less popular now, but there is a generic form coming soon
  • Actoplus Met is a combination of metformin with Actos (pioglitazone)
Again, the combination of metformin with either Avandia or Actos should probably be reserved for those with severe PCOS, or those whose diabetes does not respond adequately to metformin alone and who have contraindications to other diabetes medications.


Metformin is the first-line insulin-sensitizing treatment for diabetes
 because of its long history of usage and good safety profile, and deservedly so because it works well for many people with a relative minimum of side effects. It also seems quite effective for women with PCOS, although whether it should be used for normoglycemic women with PCOS is still debated.

However, metformin is not the only choice out there. In some people's opinion, TZDs also remain a viable choice for some women with PCOS. They are usually considered only when metformin fails to work well enough, has intolerable side effects, or when the patient has pre-existing kidney disease. They also are considered for women with severe hyperinsulinemia or hard-to-control diabetes.

There was much excitement when TZDs first came on the market, perhaps too much. Significant safety questions have arisen over the years, casting doubt on TZDs as a first-line treatment for either diabetes or PCOS. Because of restrictions, pioglitazone (Actos) remains the only real TZD available for most people these days, but it can be a powerful choice if monitored closely.

Newer-generation TZDs may be on their way, but users should remain vigilant about emerging safety research on these and other TZDs.

The potential for toxicity with these drugs is strong. Therefore, it is very important to have frequent blood monitoring before and during any trials of treatment with these drugs, including kidney tests, liver tests, blood sugar (fasting and HbA1c tests), and insulin levels.

The good news is that there are more choices than ever for dealing with the significant insulin resistance and blood sugar complications that seem to be an integral part of PCOS for most patients. The catch is that research into their safety is ongoing and the risks of newer drugs may not be fully known for some time.

Careful vigilance when using any of these drugs is obligatory.


General Information on Insulin-Sensitizing Agents
Overview of Various Diabetes Medications

Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Mar. Report No.: 11-EHC038-EF.
AHRQ Comparative Effectiveness Reviews.  PMID: 21735563
...The objective of this review was to summarize the benefits and harms of medications (metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. RESULTS: The review included 140 randomized controlled trials and 26 observational studies..Most medications lowered HbA1c on average by 1 absolute percentage point, but metformin was more efficacious than the DPP-4 inhibitors. Two-drug combinations had similar HbA1c reduction. Compared with metformin, thiazolidinediones and sulfonylureas had a more unfavorable effect on weight (mean difference of +2.6 kg). Metformin decreased low density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Diarrhea occurred more often for metformin compared with thiazolidinedione users...Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events.
Risks of TZDs
BMJ. 2011 Mar 17;342:d1309. doi: 10.1136/bmj.d1309. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. Loke YK, Kwok CS, Singh S. PMID: 21415101
...To determine the comparative effects of the thiazolidinediones (rosiglitazone and pioglitazone) on myocardial infarction, congestive heart failure, and mortality in patients with type 2 diabetes. DESIGN: Systematic review and meta-analysis of observational studies...RESULTS: Cardiovascular outcomes from 16 observational studies (4 case-control studies and 12 retrospective cohort studies), including 810,000 thiazolidinedione users, were evaluated after a detailed review of 189 citations...CONCLUSION: Among patients with type 2 diabetes, use of rosiglitazone is associated with significantly higher odds of congestive heart failure, myocardial infarction, and death relative to pioglitazone in real world settings.
JAMA. 2007 Sep 12;298(10):1189-95. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. Singh S, Loke YK, Furberg CD. PMID: 17848653 
...Recent reports of serious adverse events with rosiglitazone use have raised questions about whether the evidence of harm justifies its use for treatment of type 2 diabetes...Studies were selected for inclusion if they were randomized controlled trials of rosiglitazone for prevention or treatment of type 2 diabetes, had at least 12 months of follow-up, and monitored cardiovascular adverse events and provided numerical data on all adverse events. Four studies were included after detailed screening of 140 trials for cardiovascular events... CONCLUSION: Among patients with impaired glucose tolerance or type 2 diabetes, rosiglitazone use for at least 12 months is associated with a significantly increased risk of myocardial infarction and heart failure, without a significantly increased risk of cardiovascular mortality.
JAMA. 2007 Sep 12;298(10):1180-8. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Lincoff AM, et al. PMID: 17848652
...Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes....A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P = .005)...CONCLUSIONS: Pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortality.
BMJ. 2009 Dec 3;339:b4731. doi: 10.1136/bmj.b4731. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. Tzoulaki I, et al. PMID: 19959591
...To investigate the risk of incident myocardial infarction, congestive heart failure, and all cause mortality associated with prescription of oral antidiabetes drugs... CONCLUSIONS: Our findings suggest a relatively unfavourable risk profile of sulphonylureas compared with metformin for all outcomes examined. Pioglitazone was associated with reduced all cause mortality compared with metformin. Pioglitazone also had a favourable risk profile compared with rosiglitazone; although this requires replication in other studies, it may have implications for prescribing within this class of drugs.
BMJ. 2012 May 30;344:e3645. doi: 10.1136/bmj.e3645. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. Azoulay L, Yin H, Filion KB, Assayag J, Majdan A, Pollak MN, Suissa S. PMID: 22653981
OBJECTIVE: To determine if the use of pioglitazone is associated with an increased risk of incident bladder cancer in people with type 2 diabetes. DESIGN: Retrospective cohort study using a nested case-control analysis. SETTING: Over 600 general practices in the United Kingdom contributing to the general practice research database.PARTICIPANTS:
The cohort consisted of people with type 2 diabetes who were newly treated with oral hypoglycaemic agents between 1 January 1988 and 31 December 2009. All incident cases of bladder cancer occurring during follow-up were identified and matched to up to 20 controls on year of birth, year of cohort entry, sex, and duration of follow-up. Exposure was defined as ever use of pioglitazone, along with measures of duration and cumulative dosage...Overall, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio 1.83, 95% confidence interval 1.10 to 3.05). The rate increased as a function of duration of use, with the highest rate observed in patients exposed for more than 24 months (1.99, 1.14 to 3.45) and in those with a cumulative dosage greater than 28,000 mg (2.54, 1.05 to 6.14). CONCLUSION: The use of pioglitazone is associated with an increased risk of incident bladder cancer among people with type 2 diabetes.
Benefits of TZDs

*See the many links within the post for further studies

Hum Reprod. 2003 Aug;18(8):1618-25. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Glueck CJ, et al. PMID: 12871871
...In an observational study of 13 women with polycystic ovary syndrome (PCOS) not optimally responsive to metformin diet, we assessed the efficacy and safety of addition of pioglitazone. We also compared these 13 women to 26 women with PCOS, who were responsive to metformin diet, matched by age and by pre- treatment menstrual history and not different by obesity categories...In women with PCOS who failed to respond optimally to metformin, when pioglitazone was added, insulin, glucose, IR, insulin secretion, and DHEAS fell, HDL cholesterol and sex hormone-binding globulin rose, and menstrual regularity improved, without adverse side-effects.
J Affect Disord. 2011 Jul 20. Use of insulin sensitizers for the treatment of major depressive disorder: A pilot study of pioglitazone for major depression accompanied by abdominal obesity. Kemp DE, et al. PMID: 21782251
...This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. METHOD: In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference greater than 35 in. in women and greater than 40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months...During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. CONCLUSION: Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.
Other TZD Studies

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