Pioglitazone is the forgotten diabetes drug. This pill, available as a cheap generic, has a strong effect on insulin resistance, reliably reduces blood sugar levels, and improves cardiovascular outcomes. But fears over its unintended effects have largely sidelined pioglitazone as a sort 2 diabetes treatment. It is never discussed and is just prescribed to a slim minority of eligible patients.
Those fears “are based entirely on misconceptions,” says Ralph DeFronzo, MD. “It is a very, excellent drug.”
It might be difficult to seek out an authority on diabetes medication of greater stature than Dr. DeFronzo, the chief of diabetes at UT Health San Antonio. In his storied profession, DeFronzo helped define our modern understanding of insulin resistance, spearheaded the event and approval of metformin in america, 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 of the improper reasons, and he desires to set the record straight. In his telling, there are tens of millions of patients that may benefit from pioglitazone, but clinicians are unfortunately hesitant to recommend the drug on account of unfounded “negative bias.”
What Is Pioglitazone?
Pioglitazone is a member of the thiazolidinedione (TZD) family of medicines that’s approved for type 2 diabetes. It is usually sold under the brand name Actos, though additionally it is available as a generic. It’s a once-daily pill.
The American Diabetes Association explains that pioglitazone can “help insulin work higher within the muscle and fat and reduce glucose production within the liver.”
Why Pioglitazone Is Unique Amongst Diabetes Drugs
DeFronzo states that pioglitazone is “the one true drug which improves the insulin resistance in individuals with type 2 diabetes.”
No other drug treats insulin resistance in the identical way. Despite popular understanding, DeFronzo explains, “metformin will not be an insulin sensitizing drug. It will possibly’t even get into the muscle, due to this fact it’s unattainable to be an insulin-sensitizing drug.” And while newer drugs like GLP1 receptor agonists equivalent to semaglutide (Ozempic) can improve insulin resistance, they do it by promoting weight reduction, 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’ve various drugs that improve beta cell function, particularly GLP1 receptor agonists, and people drugs keep convalescing and higher, but apart from pioglitazone, there isn’t a drug that corrects the underlying insulin resistance.”
DeFronzo believes that this makes pioglitazone a uniquely invaluable drug for type 2 diabetes, especially when used together with other medications. He prescribes it to his patients as a matter in fact, often together with GLP1 receptor agonists, SGLT2 inhibitors, and/or metformin.
The Advantages of Pioglitazone
Pioglitazone is initially 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 results in many significant secondary advantages, 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 will reduce the danger of kidney disease too.
Finally, pioglitazone also appears to supply strong cardiovascular protection. A 2007 meta-analysis of 19 major trials and over 16,000 patients found that pioglitazone reduced the danger 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 reply is that “a gray cloud has hung over pioglitazone,” based on DeFronzo. The drug is often believed to be related to various bad unintended effects. DeFronzo enumerated each of those effects, and explained why he thought they were misconceptions, one after the other.
Weight Gain
Pioglitazone causes weight gain. Based on a 2019 review, the typical TZD user could gain 2.30 to 4.25 kilograms (kg) (5 to 9.4 kilos [lb]).
Weight gain, generally speaking, is just in regards to the last item you wish within the setting of type 2 diabetes. “We all know that weight gain is bad,” says DeFronzo, “and naturally it’s what’s driving the diabetes epidemic.”
But the burden gain that pioglitazone causes has a “unique and paradoxical” effect, based on DeFronzo:
“With pioglitazone, the more weight you gain, the greater the advance in insulin sensitivity. The more weight that you simply gain, the greater the advance 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 simply die!”
“It’s reality. That is seen in every study. We’ve weight gain, but every little thing single thing that’s good appears to be convalescing.”
The load gain related to pioglitazone, due to this fact, is “a purely cosmetic issue,” based on DeFronzo. And today it could be easily counteracted with diabetes drugs that create weight reduction, particularly GLP1 receptor agonists like semaglutide (Ozempic) or tirzepatide (Mounjaro).
Heart Failure
Pioglitazone causes heart failure. This, understandably, worries clinicians.
And yet, DeFronzo believes that the evidence is totally clear that the drug creates only good cardiovascular outcomes, not bad ones: “It’s a really powerful drug for reducing cardiovascular events.”
A 2007 meta-analysis found that the danger 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.”
Actually, the patients with heart failure actually had a surprising decrease in the danger of mortality. DeFronzo goes over the main points in an article co-authored with Steven Nissen, MD, an eminent cardiologist with the Cleveland Clinic. And in smaller trials, pioglitazone has actually shown a capability to enhance the function of the guts in quite a lot of ways.
Other experts agree. A 2021 review in Cardiovascular Diabetology concluded that this “missed drug” offers “cardiovascular protective potential, despite the danger of fluid imbalance in overt heart failure.”
Fluid Retention
Pioglitazone may cause edema, or fluid retention, in some 5 to 10 percent of users, resulting in swelling within the feet, ankles, legs, or other parts of the body.
Edema will be uncomfortable; it’s also related to quite a lot of negative health effects, including heart failure and diseases of the lungs, liver, thyroid or kidneys. Nevertheless, there’s little or no evidence linking the fluid retention brought on by pioglitazone with any significant negative health outcomes. When his own patients experience fluid retention, DeFronzo treats them with a diuretic.
Bladder Cancer
Pioglitazone has been banned in Germany, France, and India on account of an apparent risk of bladder cancer. In america, the federal government seems somewhat less certain, with the U.S. Food and Drug Administration (FDA) stating that it “could also be linked to an increased risk of bladder cancer.”
DeFronzo insists that that is all a grave error, mostly based on sloppy recruitment for one in every of pioglitazone’s biggest tests, the PROActive trial. This trial, in brief, enrolled a small variety of volunteers with blood of their urine who “probably had bladder cancer before they began the study,” based on DeFronzo. Unluckily, most of them were randomly placed into the group of pioglitazone users (versus the control group), creating an erroneous association between the drugs and the disease.
After the association was identified within 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 related to a statistically significant increased risk of bladder cancer” but didn’t close the door on the subject, calling for “further investigation.”
A 2018 systematic review noted that the danger of bladder cancer was not significantly increased if one were to exclude the controversial PROActive participants who developed cancer inside the first 12 months of treatment, but ultimately concluded that there’s a “barely 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 the least one diabetes expert decried as an injustice: “A lot for evidence-based medicine.”
Rosiglitazone
The popularity of pioglitazone also suffers on account of association with a special TZD, rosiglitazone (Avandia), which can cause heart problems. Rosiglitazone was once the best-selling diabetes drug on the earth, but it surely has been faraway from the market in many countries, and for years was only sold with special restrictions in america. Though the drug stays available in america today, sales have cratered on account of the fears.
“People haven’t been capable of 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 one expert most accountable 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 advantages.
Takeaways
Pioglitazone is a forgotten option for type 2 diabetes management. It’s the only drug that directly addresses insulin resistance, one in every of the foundation causes of diabetes, and it results in lower A1C and improved cardiovascular and metabolic health. It is on the market as a cheap generic pill.
Pioglitazone, nevertheless, carries a risk of concerning unintended effects, including weight gain, fluid retention, and heart failure, especially at the very best approved doses. Paradoxically, these negative effects appear to be related to higher 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 since the trademarks on pioglitazone have expired, there’s little financial incentive to rehabilitate its popularity.
DeFronzo argues that pioglitazone needs to be a part of the usual of look after most individuals with type 2 diabetes, and that it could be used to great effect together with SGLT2s or GLP1 RAs, which can even help counteract weight gain: “I exploit it on a regular basis, especially with newly diagnosed type 2 diabetes.”
Pioglitazone could also be inappropriate for certain patients; it’s critical to debate your options together with your healthcare provider.
DeFronzo encourages Diabetes Every day readers to ask their doctors about pioglitazone: “They need to bring it up with their doctors.”
“However the doctors, in all likelihood, are going to say no.”
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