Pioglitazone is the forgotten diabetes drug. This pill, available as an inexpensive generic, has a powerful effect on insulin resistance, reliably reduces blood sugar levels, and improves cardiovascular outcomes. But fears over its side effects have largely sidelined pioglitazone as a type 2 diabetes treatment. It is rarely discussed and is only prescribed to a slim minority of eligible patients.
Those fears “are based entirely on misconceptions,” says Ralph DeFronzo, MD. “This is a very, very good drug.”
It would be difficult to find an expert on diabetes medication of greater stature than Dr. DeFronzo, the chief of diabetes at UT Health San Antonio. In his storied career, DeFronzo helped define our modern understanding of insulin resistance, spearheaded the development and approval of metformin in the United States, and established the scientific basis for the drug class of SGLT2 inhibitors.
DeFronzo believes that pioglitazone has been ignored by the medical community for all the wrong reasons, and he wants to set the record straight. In his telling, there are millions of patients that could benefit from pioglitazone, but clinicians are unfortunately hesitant to recommend the drug due to unfounded “negative bias.”
What Is Pioglitazone?
Pioglitazone is a member of the thiazolidinedione (TZD) family of medications that is approved for type 2 diabetes. It is sometimes sold under the brand name Actos, though it is also available as a generic. It is a once-daily pill.
The American Diabetes Association explains that pioglitazone can “help insulin work better in the muscle and fat and reduce glucose production in the liver.”
Why Pioglitazone Is Unique Among Diabetes Drugs
DeFronzo states that pioglitazone is “the only true drug which improves the insulin resistance in people with type 2 diabetes.”
No other drug treats insulin resistance in the same way. Despite popular understanding, DeFronzo explains, “metformin is not an insulin sensitizing drug. It can’t even get into the muscle, therefore it’s impossible to be an insulin-sensitizing drug.” And while newer drugs like GLP1 receptor agonists such as semaglutide (Ozempic) can improve insulin resistance, they do it by promoting weight loss, not by directly addressing its root cause.
There are two central causes of type 2 diabetes: insulin resistance, which makes the body less sensitive to the hormone insulin, and beta cell dysfunction, which causes the body to secrete less insulin. The collision of those two problems — needing more insulin and making less of it — defines the progression of diabetes.
“We have a number of drugs that improve beta cell function, particularly GLP1 receptor agonists, and those drugs keep getting better and better, but other than pioglitazone, there is no drug that corrects the underlying insulin resistance.”
DeFronzo believes that this makes pioglitazone a uniquely valuable drug for type 2 diabetes, especially when used in combination with other medications. He prescribes it to his patients as a matter of course, often along with GLP1 receptor agonists, SGLT2 inhibitors, and/or metformin.
The Benefits of Pioglitazone
Pioglitazone is first and foremost a glucose-lowering drug. A 2010 review in Diabetes Care found that pioglitazone, at a moderate dosage, “achieved an A1C reduction of ∼1 percent versus placebo,” a result on par with metformin. It also carries a low risk of hypoglycemia, unlike insulin or sulfonylureas.
This pill leads to many significant secondary benefits, as well. A 2001 review found that the drug reduces triglycerides and increases HDL cholesterol (“good cholesterol”); studies also show that it decreases blood pressure and may reduce the risk of kidney disease too.
Finally, pioglitazone also appears to offer strong cardiovascular protection. A 2007 meta-analysis of 19 major trials and over 16,000 patients found that pioglitazone reduced the risk of stroke, myocardial infarction, and death.
Pioglitazone’s Worrying Side Effects
If pioglitazone is so great, why did it ever fall out of favor with doctors? The answer is that “a gray cloud has hung over pioglitazone,” according to DeFronzo. The drug is commonly believed to be associated with a number of bad side effects. DeFronzo enumerated each of these effects, and explained why he thought they were misconceptions, one by one.
Pioglitazone causes weight gain. According to a 2019 review, the average TZD user could gain 2.30 to 4.25 kilograms (kg) (5 to 9.4 pounds [lb]).
Weight gain, generally speaking, is just about the last thing you want in the setting of type 2 diabetes. “We know that weight gain is bad,” says DeFronzo, “and of course it is what is driving the diabetes epidemic.”
But the weight gain that pioglitazone causes has a “unique and paradoxical” effect, according to DeFronzo:
“With pioglitazone, the more weight you gain, the greater the improvement in insulin sensitivity. The more weight that you gain, the greater the improvement in beta cell function. The more weight you gain, the greater the drop in blood pressure, the greater the drop in triglycerides, the greater the rise in HDL cholesterol. The more weight you gain, the less likely that you die!”
“It’s reality. This is seen in every study. We have weight gain, but everything single thing that’s good seems to be getting better.”
The weight gain associated with pioglitazone, therefore, is “a purely cosmetic issue,” according to DeFronzo. And today it can be easily counteracted with diabetes drugs that create weight loss, particularly GLP1 receptor agonists like semaglutide (Ozempic) or tirzepatide (Mounjaro).
Pioglitazone causes heart failure. This, understandably, worries clinicians.
And yet, DeFronzo believes that the evidence is absolutely clear that the drug creates only good cardiovascular outcomes, not bad ones: “It’s a very powerful drug for reducing cardiovascular events.”
A 2007 meta-analysis found that the risk of heart failure increased from 1.8 percent (in a control group) to 2.3 percent in those treated with pioglitazone, but “without an associated increase in mortality.”
In fact, the patients with heart failure actually had a surprising decrease in the risk of mortality. DeFronzo goes over the details in an article co-authored with Steven Nissen, MD, an eminent cardiologist with the Cleveland Clinic. And in smaller trials, pioglitazone has actually shown an ability to improve the function of the heart in a variety of ways.
Other experts agree. A 2021 review in Cardiovascular Diabetology concluded that this “overlooked drug” offers “cardiovascular protective potential, despite the risk of fluid imbalance in overt heart failure.”
Pioglitazone can cause edema, or fluid retention, in some 5 to 10 percent of users, leading to swelling in the feet, ankles, legs, or other parts of the body.
Edema can be uncomfortable; it’s also associated with a variety of negative health effects, including heart failure and diseases of the lungs, liver, thyroid or kidneys. Nevertheless, there is little or no evidence linking the fluid retention caused by pioglitazone with any significant negative health outcomes. When his own patients experience fluid retention, DeFronzo treats them with a diuretic.
Pioglitazone has been banned in Germany, France, and India due to an apparent risk of bladder cancer. In the United States, the government seems somewhat less certain, with the U.S. Food and Drug Administration (FDA) stating that it “may be linked to an increased risk of bladder cancer.”
DeFronzo insists that this is all a grave error, mostly based on sloppy recruitment for one of pioglitazone’s biggest tests, the PROActive trial. This trial, in short, enrolled a small number of volunteers with blood in their urine who “probably had bladder cancer before they began the study,” according to DeFronzo. Unluckily, most of them were randomly placed into the group of pioglitazone users (as opposed to the control group), creating an erroneous association between the medicine and the disease.
After the association was identified in the PROActive trial, the FDA required pioglitazone’s maker to follow up with a long-term test of pioglitazone and bladder cancer. That study, published in 2015, concluded that “pioglitazone use was not associated with a statistically significant increased risk of bladder cancer” but didn’t close the door on the topic, calling for “further investigation.”
A 2018 systematic review noted that the risk of bladder cancer was not significantly increased if one were to exclude the controversial PROActive participants who developed cancer within the first year of treatment, but ultimately concluded that there is a “slightly but significantly increased risk of bladder cancer.”
Takeda Pharmaceuticals, the maker of pioglitazone (Actos), has paid billions to settle lawsuits related to bladder cancer, a legal result that at least one diabetes expert decried as an injustice: “So much for evidence-based medicine.”
The reputation of pioglitazone also suffers due to association with a different TZD, rosiglitazone (Avandia), which may cause cardiovascular disease. Rosiglitazone was once the best-selling diabetes drug in the world, but it has been removed from the market in many nations, and for years was only sold with special restrictions in the United States. Though the drug remains available in the United States today, sales have cratered due to the fears.
“People have not been able to separate the potential negative effects of rosiglitazone from the very, very, very positive effects of pioglitazone,” DeFronzo says.
To underline his point, DeFronzo shares that his colleague Dr. Nissen, the single expert most responsible for drawing attention to rosiglitazone’s potential harms, “uses pioglitazone as first-line therapy in his patients.” And, indeed, Nissen is on the record attesting to pioglitazone’s cardioprotective benefits.
Pioglitazone is a forgotten option for type 2 diabetes management. It is the only drug that directly addresses insulin resistance, one of the root causes of diabetes, and it leads to lower A1C and improved cardiovascular and metabolic health. It is available as an inexpensive generic pill.
Pioglitazone, however, carries a risk of concerning side effects, including weight gain, fluid retention, and heart failure, especially at the highest approved doses. Paradoxically, these negative effects seem to be associated with better health outcomes.
DeFronzo explains that his peers — other experts at leading academic hospitals — understand the upsides of pioglitazone, but that few practicing clinicians do. And because the trademarks on pioglitazone have expired, there’s little financial incentive to rehabilitate its reputation.
DeFronzo argues that pioglitazone should be part of the standard of care for most people with type 2 diabetes, and that it can be used to great effect in combination with SGLT2s or GLP1 RAs, which will also help counteract weight gain: “I use it all the time, especially with newly diagnosed type 2 diabetes.”
Pioglitazone may be inappropriate for certain patients; it is critical to discuss your options with your healthcare provider.
DeFronzo encourages Diabetes Daily readers to ask their doctors about pioglitazone: “They should bring it up with their doctors.”
“But the doctors, in all likelihood, are going to say no.”
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