Metformin was found to be well-tolerated and safe for the treatment of pulmonary atrial hypertension (PAH), according to study results published in the Journal of the American Heart Association.
In this single-center, open-label, mechanistic phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT01884051), 20 patients (mean age, 42±10 years; 85% women; mean body mass index, 30±6 kg/m2) with heritable idiopathic PAH were recruited from Vanderbilt University Medical Center and given 2 g/day of metformin. Patients were assessed at baseline and 8 weeks using laboratory and 6-minute walk distance tests, transthoracic echocardiograph, and magnetic resonance spectroscopy. Participants were receiving intravenous prostacyclin therapy, and had mean 6-minute walk distances of 434±75 m.
At study conclusion, fractional area change increased by 3% with metformin therapy compared with baseline (23±8% vs 26±6%, respectively; P =.02), and myocardial triglyceride decreased (3.2±1.8% vs 1.6±1.4%, respectively; P =.015). Plasma isoprostane (0.035±0.019 vs 0.041±0.017 ng/mL, respectively; P =.18) and glycosylated hemoglobin (5.21±0.27% vs 5.33±0.42%, respectively; P =.07) were reduced at 8 weeks compared with baseline.
Metformin therapy did not have a significant effect on 6-minute walk distance (P =.26), brain natriuretic peptide level (P =.60), isoprostan to isofurans ratio (P =.98), or fasting insulin (P =.57).
In a pathway analysis, the levels of143 biochemicals were found to differ from baseline levels. In total, concentrations of 84 biochemicals were increased and those of 58 were decreased after 8 weeks of metformin treatment. Markers of lipid b-oxidation were significantly different (P <.05). Lactate and pyruvate levels were increased by 1.20- and 1.28-fold, respectively (P <.05 for both) and levels of glucose- and urea cycle-related metabolism markers were decreased (P <.05 for all).
The pathway analysis identified Central nodes of the sex steroid pathway, dhydroepiandrosterone and androstenediol monosulfate were found to be upregulated by 1.32- and 1.24-fold, respectively and in a pathway analysis after metformin therapy (P <.05 for both).
All but 1 patient tolerated the 2 g metformin dosage. The other patient tolerated a 1500 mg metformin dose per day. The most common adverse event was diarrhea (45%) followed by heart burn (20%) and abdominal pain (15%). No serious adverse events were observed during the 8-week study period. An average reduction of 1.9 kg in body weight was observed.
This study was limited by its sample size and open-label, single center design. It also lacked sufficient power to evaluate clinical efficacy.
These data indicated metformin was safe and well-tolerated for the treatment of heritable idiopathic PAH. After 8 weeks of daily therapy of metformin, some patients had altered lipid and glucose metabolism markers, indicating a beneficial effect of the therapy. Future studies among a larger sample size are needed to evaluate its efficacy.
Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.
Brittain E L, Niswender K, Agrawal V, et al. Mechanistic phase II clinical trial of metformin in pulmonary arterial hypertension. J Am Heart Assoc. 2020;9(22):e018349. doi:10.1161/JAHA.120.018349