By: Beverly Thomassian
In the ever-evolving world of diabetes care, medications come in and out of favor based on new research, shifting safety data, and individual needs. Pioglitazone (Actos), once a go-to medication for improving insulin sensitivity, fell out of favor in the early 2010s due to concerns about bladder potential side effects and newer medications.
Now, pioglitazone is gaining renewed interest, especially for individuals with increased cardiovascular risk and steatosis, who may benefit from its unique profile. Even though pioglitazone only lowers A1C by 0.5 – 1.0%, this medication’s properties compel us to consider reintroducing it into the medical management of diabetes, especially in the presence of liver and heart disease. Plus, as a generic medication, its price tag of less than $5.00 a month makes it affordable for most people.
Potent Insulin Sensitizer
Pioglitazone is one of the thiazolidinedione (TZD) class of medications that work by enhancing insulin sensitivity, primarily through activation of PPAR-γ receptors in adipose and muscle tissue.
In a recent podcast, Banting Award Recipient, Dr. Ralph DeFronzo, provides an Insulin Resistance Master Class. He notes that pioglitazone, an insulin-sensitizing medication, improves cardiometabolic health, in part, by shifting fat distribution from visceral to subcutaneous areas. This redistribution of fat, may be associated with some weight gain. But, Dr. DeFronzo explains that this weight gain is actually a sign that the pioglitazone is working to improve insulin sensitivity. Compared to other oral agents, pioglitazone remains one of the most effective insulin sensitizers, especially useful in those with significant insulin resistance.
Why the Renewed Interest?
1. Cardiovascular Benefits – Decrease stroke and MI
The IRIS trial demonstrated that pioglitazone reduced the risk of stroke and myocardial infarction in insulin-resistant patients with a history of cerebrovascular events (Kernan et al., 2016). This benefit is being re-evaluated in the context of cardiometabolic risk, especially in people with atherosclerotic disease or metabolic syndrome.
The ADA Standard #3 states, “In people with a history of stroke and evidence of insulin resistance and prediabetes, pioglitazone may be considered to lower the risk of stroke or myocardial infarction. However, this benefit needs to be balanced with the increased risk of weight gain, edema, and fractures. Lower doses may mitigate the risk of adverse effects but may be less effective.”
2. Role in MASLD and MASH
Pioglitazone has shown promise in improving liver histology in people with metabolic-associated steatohepatitis (MASH), making it one of the few medications with such benefits (Cusi et al., 2017). Studies demonstrate it improves hepatic insulin sensitivity, reduces liver fat, and may slow fibrosis progression.
The ADA Standards of Care #4, include recommendations to start pioglitazone and GLP-1’s for individuals with diabetes and steatosis to prevent progression and slow fibrosis. “In phase 2 clinical trials, pioglitazone and some GLP-1 RAs have been shown to be potentially effective to treat steatohepatitis and to slow fibrosis progression. They may also decrease CVD, which is the number one cause of death in people with type 2 diabetes and MASLD.
3. Re-Evaluating Safety Concerns
Initial concerns about the risk of bladder cancer stemmed from observational studies; however, more recent analyses suggest that the risk is low or not statistically significant (Lewis et al., 2015). Furthermore, thoughtful prescribing—avoiding use in individuals with heart failure or active bladder cancer risk—helps mitigate potential harm. In addition, this medication is not recommended for those at risk of falls and fractures.
Comparative Benefits of Diabetes Medications
Here is a visual summary comparing the relative effects of pioglitazone versus other common medications:
Clinical Considerations
When considering pioglitazone (Actos), carefully assess:
- Cardiovascular history
- benefit for those with insulin resistance
- caution in heart failure
- Liver function and history of MASLD/MASH – recommended
- Bladder cancer history – avoid
- Fracture Risk – avoid
Pioglitazone may also be especially helpful in combination with agents like metformin or GLP-1 receptor agonists, balancing out each other’s side effects and mechanisms of action.
Conclusion
Pioglitazone (Actos) may never regain its former status as a front-line diabetes treatment, but it has a clear and valuable role in today’s therapeutic landscape. For select individuals—especially those with insulin resistance, cardiovascular risk, or liver disease—pioglitazone offers an underutilized tool backed by strong evidence and decades of experience.
In diabetes care, what’s old can be new again—especially when paired with clinical wisdom and person-centered decision-making.
📚 References
Want to learn more about ADA Standards?
Enroll in our upcoming webinar
Join us live on April 8, 2025, at 11:30 am PST
This course provides the need-to-know information regarding the microvascular complications of diabetes. It includes a brief overview of pathophysiology & clinical manifestations along with prevention strategies & screening guidelines. This straightforward program will provide participants with the information they can use in a clinical setting & also provides critical content for certification exams.
![](/wp-content/uploads/2023/01/insta-png-v5.png")
