For several years, health experts have known that side effects of diabetes drugs like Avandia and Actos may increase the risk of heart problems, but new research may explain why, and offers a potential solution.
In a study published last month in the journal JCI Insight, researchers report that the diabetes drugs may have negative effects on mitochondria, which provide the body’s cells with energy.
Researchers from the Lewis Katz School of Medicine at Temple University studied the effects of dual PPARα/γ agonists, such as Avandia, Actos, and Galida. The drugs were developed as a two-part approach to target high cholesterol and high blood sugar in patients with type 2 diabetes.
The drugs focus on major complications of diabetes, such as excess of lipids and glucose in the blood. However, the drugs can also have dangerous and toxic side effects on the heart.
For several years, concerns about heart attacks with Avandia led to restrictions on the drug, and Actos bladder cancer side effects have largely led to disuse of the drug, although it is still on the market. The development of Galida, manufactured by AstraZeneca, was stopped midway through clinical trials because of the toxic effects on the heart.
In this new study, research showed for the first time PPARα/γ agonists like Avandia do cause heart dysfunction in patients with diabetes. The drugs affect on the generation and function of mitochondria, which are the powerhouse of the cells that provide energy by activating both PPARα and PPARγ receptors. This blocks the activity of SIRT1 proteins involved in mitochondrial generation and energy production. However, the researchers say they found a potential way to counteract the toxic effects.
Researchers conducted studies on diabetic mice treated with a dual agonist drug, like Avandia and Actos. The drugs reduced triglyceride and glucose levels, but the mice developed cardiac dysfunction.
The researchers then conducted the experiment again by giving the mice the drug in combination with resveratrol, an antioxidant commonly found in the skin of grapes and known to have health boosting effects. Resveratrol is also an activator of the SIRT1 protein, which was being blocked by the drugs.
The mice taking the combination of the drug and resveratrol had reduced heart toxicity. Furthermore, their heart cells also had normal mitochondrial function.
By reactivating the protein with resveratrol, heart toxicity was reduced and the benefits of the drug remained, the researchers determined. However, more research is needed to help focus on creating type 2 diabetes drugs that provide benefits without the unwanted toxic side effects, according to the authors of the study.
“Now we have much a clearer idea of how heart toxicity arises from treatment with dual PPARα/γ agonists,” Dr. Konstantinos Drosatos, lead author of the study, said in a September 25 press release. “This allows us to more effectively guide the development of future PPAR-targeting drugs. By targeting fewer proteins, there should be fewer toxic effects to worry about.”
Avandia (rosiglitazone) was a popular type 2 diabetes drug that was used by millions of people before it was linked to an increased risk of heart attacks and heart problems. Some reports have suggested that as many as 100,000 heart attacks may have been caused by Avandia. The FDA restricted Avandia for several years before loosening those restrictions in a controversial decision in 2015.
GlaxoSmithKline reportedly paid more than $1 billion to settle Avandia heart attack lawsuits brought by former users of the medication who allege that the drug maker provided inadequate warnings to consumers and the medical community.
As the medical community moved away from Avandia, Actos (pioglitazone) became of the more widely used diabetes drugs. However, after concerns emerged about the link between Actos and bladder cancer, the FDA required Takeda Pharmaceuticals to add new warning label information about the risk in June 2011, further strengthening that warning in 2016, leading most doctors to avoid use of the medication.
In 2015, the drug makers agreed to pay a massive Actos settlement, resolving thousands of claims brought by individuals diagnosed with bladder cancer following long term use of the drug. However, even years after the deal was reached, additional Actos lawsuits continue to be filed by individuals diagnosed with bladder cancer.