Low-dose metformin reformulation shows promise in PAH rats
Therapy is first-line treatment for type 2 diabetes
Low-dose metformin, a medication for type 2 diabetes, delivered to the pulmonary arteries using lipid-based nanocapsules, safely eased signs of pulmonary arterial hypertension (PAH) in rats, a study reports.
“Administration of [metformin] nanocapsules is a safe and innovative therapeutic approach for PAH,” the researchers wrote. “This method could improve PAH treatment outcomes while minimizing adverse effects, with potential applications in other types of pulmonary hypertension.” The findings were published in Frontiers in Pharmacology in the study, “Pulmonary artery-targeted low-dose metformin-loaded nanocapsules safely improve pulmonary arterial hypertension in rats.”
In PAH, narrowing of the the pulmonary arteries, the small blood vessels that pass through the lungs, elevates resistance to blood flow and drives up blood pressure. Symptoms, such as shortness of breath, fatigue, weakness, chest pain, and dizziness, are associated with low blood oxygen due to a lack of blood flow.
Several therapies are approved for PAH, with most designed to relax and widen the arteries to improve blood flow and lower blood pressure. Still, the five-year survival rate is around 60%, most commonly due to right heart failure, as the elevated blood pressure in the lungs means the right side of the heart must work harder to pump blood.
Metformin is a first-line treatment for type 2 diabetes, particularly for people who are overweight. It’s also been shown to reduce the incidence of cancer in type 2 diabetes patients, suggesting a potential anti-cancer role. Animal studies and a Phase 2 clinical trial suggest metformin may benefit PAH patients.
In its available oral forms, however, metformin has been tied to serious side effects, including low blood sugar, liver dysfunction, gastrointestinal problems, and lactic acidosis, a life-threatening condition where blood becomes too acidic.
Improving PAH outcomes with metformin
Researchers in Japan used lipid-based nanocapsules to deliver low-dose metformin to the pulmonary arteries, the goal being to improve outcomes while minimizing the medicine’s side effects. The scientists first tested the formulation in pulmonary arterial smooth muscle cells (PASMCs), which line the pulmonary arteries and whose uncontrollable growth drives blood vessel narrowing in PAH.
Encapsulated metformin, but not free metformin, significantly inhibited the growth of PASMCs derived from either unaffected people or a woman with heritable PAHÂ in a dose-dependent manner.
The treatment was assessed in a rat model of PAH, induced by a combination of SU5416, a blood vessel growth blocker, and low oxygen levels (hypoxia), for three weeks. The rats then received two weeks of daily treatment under normal oxygen conditions via administration into their tail vein.
Treatment with encapsulated metformin significantly reduced a measure indicative of blood pressure in the pulmonary arteries and lowered right ventricular hypertrophy, when the muscle of the right heart thickens and enlarges in response to high pulmonary blood pressure.
A microscopic analysis of samples from the pulmonary arteries of metformin nanocapsule-treated rats showed reduced signs of PAH, including fewer actively growing cells, and less arterial narrowing, and muscularization, which is when smooth muscle accumulates excessively.
Examination found the nanocapsules significantly accumulated in the lungs of PAH rats over those of healthy control rats. There was no difference in nanocapsule distribution in the heart, kidneys, liver, and spleen between the PAH and healthy rats.
“The inflammation present in the small pulmonary arteries in PAH likely facilitated nanocapsule accumulation,” the researchers wrote.
No significant acute adverse effects were seen when empty or metformin nanoparticles were administered. Blood tests also showed no signs of adverse events related to the liver, kidneys, ketosis, or lactic acid levels.
“Low-dose metformin-loaded pulmonary artery-targeted nanocapsule administration suppressed PASMC proliferation in a rat model of SU5416 [plus] hypoxia-induced PAH, leading to improvements in [blood flow] and right ventricular hypertrophy, thereby slowing the progression of PAH,” the researchers wrote.
About the Author
