Despite recent strides in elucidating the pathophysiology of pulmonary arterial hypertension (PAH), there have been few advances in the development of novel therapies to treat the disease. The medications currently approved for PAH treatment are most beneficial in the 5% to 10% of patients with PAH who are vasoresponders, although these therapies have been shown to improve exercise capacity, quality of life, and morbidity in other patients as well.1
In a review published in the Journal of the American Heart Association, Kurt W. Prins, MD, PhD, assistant professor of medicine in the cardiovascular division at the Lillehei Heart Institute at the University of Minnesota in Minneapolis, and colleagues, emphasized the pressing need for therapies that can modulate other molecular pathways in PAH, in addition to the endothelin, nitric oxide, and prostacyclin pathways modulated by vasodilators.1 To that end, they proposed investigating medications that have already been approved to treat other conditions with the aim of repurposing them as PAH therapies.
The potential advantages of this approach include accelerated development and reduced cost — an important consideration because many patients with PAH worldwide “do not even have access to currently approved therapies, so discovery of an inexpensive treatment option would very likely have a significant global impact,” according to Prins, et al. In addition, drugs that are already approved “have established safety profiles, so the considerable time and money required to exclude common toxicities and to demonstrate tolerability and safety can be reduced.”
Of the 22 medications reviewed, the 3 deemed to have the most rigorous preclinical data supporting their use in PAH are highlighted below.
Dichloroacetate
Currently used in the treatment of cancer and congenital mitochondrial diseases,2 this pyruvate dehydrogenase kinase inhibitor “consistently reduces [right ventricular hypertrophy] and increases cardiac output and exercise capacity in multiple preclinical models of PAH,” stated the review.1 Dichloroacetate has also been found to increase pyruvate dehydrogenase activity and oxygen consumption in ex vivo human lungs, and it reduced pulmonary vascular resistance and increased 6-minute walk test distance (6MWD) in a 4-month open-label trial (n=20).2
However, the “beneficial effects of dichloroacetate depend on the absence of polymorphisms in SIRT3 (sirtuin 3) or UCP2 (uncoupling protein 2), 2 proteins that regulate mitochondrial function in a [pyruvate dehydrogenase kinase]-independent manner.”1 Peripheral neuropathy is the most common adverse effect of dichloroacetate, which typically resolves when the drug is discontinued.
Metformin
Preclinical models have demonstrated that this antidiabetic drug can “promote pulmonary vasodilation by increasing endothelial nitric oxide synthase, to mitigate [pulmonary artery smooth muscle cell] proliferation by inhibiting the pro-proliferative MAPK (mitogen-activated protein kinase),3 to negate the estrogen pathway via inhibition of aromatase transcription,4 and to combat pathological lipid deposition5 in the right ventricle,” wrote Prins, et al.1 Gastrointestinal discomfort is the most common adverse event and rare cases of lactic acidosis have occurred.
A phase 2 clinical trial investigating metformin use in patients with PAH is currently underway, with primary end points of insulin resistance, oxidative stress, right ventricular lipid content and oxidative metabolism, and drug safety.6
Rosiglitazone and Pioglitazone
Two thiazolidinediones used as antidiabetic therapies, and these peroxisome proliferator-activator-γ agonists have demonstrated numerous favorable effects on PAH in preclinical studies. For example, rosiglitazone reversed pulmonary vascular remodeling, reduced right ventricular systolic pressure and right ventricular hypertrophy, increased peroxisome proliferator-activator-γ levels, and decreased levels of endothelin 1 and vascular endothelial growth factor, which “slows pathologic pulmonary vascular remodeling and lowers PA pressures.”7,8
Pioglitazone improved right ventricular function and right ventricular glucose uptake while reducing right ventricular fibrosis in Sugen-5416 (SU-5416) hypoxia rats.9 Despite high scientific rigor of this preclinical data, the researchers cautioned that both agents increase the risk for heart failure in patients with diabetes. At present, no trials are underway to further explore these findings in human patients.
“Perhaps precision medicine will help us identify PAH patients who will benefit from the 22 medications we have discussed,” the investigators concluded. For example, dichloroacetate would be indicated in patients with specific genetic profiles. “The use of genotyping and biomarker profiles are examples of a personalized approach that may enhance the success of translation from preclinical studies to human clinical trials.”