Metformin May Benefit Pulmonary Hypertension Associated With HFpEF, But Not PAH

Although the use of metformin may be preferentially beneficial for the treatment of pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF), the agent demonstrates limited efficacy for the treatment of pulmonary arterial hypertension (PAH), according to the results of a recent study of skeletal muscle sirtuin-3 levels in metformin-treated SU5416/hypoxia (SuHx) mice that was published in the American Journal of Respiratory and Critical Care Medicine.¹

Currently, there are no approved treatments available for PH-HFpEF. It has been recently reported that metformin, the first-line antidiabetic agent and the canonical AMP-activated protein kinase (AMPK) activator, demonstrates therapeutic efficacy in the early treatment of PH-HFpEF in preclinical rat models.² The investigators evaluated metformin therapy for the treatment of group 1 PH, with the knowledge that PH-HFpEF and PAH share many of the same pathophysiologic characteristics, as well as that many patients with PAH exhibit signs of insulin resistance and glucose intolerance in the absence of diabetes and obesity.^3,4

The study results showed that although metformin prevents the development of PAH in hypoxia and monocrotaline rat models,⁵ reverses PAH in SuHx rats,⁶ and is currently in phase 2 clinical trials for the treatment of PAH, metformin failed to reverse pulmonary pressures and vascular remodeling in mice with SuHx-induced PAH.

In the current analysis, the researchers evaluated the preventive effect of metformin in the conventional SuHx rat model of PAH, using a higher dose of metformin (300 mg/kg) than was used in a prior experimental model (100 mg/kg). Comparable with observations in mice with SuHx-induced PAH, there was no significant difference in right ventricular systolic pressure reported in metformin-treated SuHx rats compared with untreated animals.

The investigators concluded that these data taken collectively show a lack of efficacy of metformin for the prevention or reversal of PAH induced by SuHx, which is in sharp contrast to the clear beneficial effects demonstrated in PH-HFpEF rat models with metabolic syndrome. Study findings do imply that the reduction of skeletal muscle sirtuin-3 levels may be, in part, a unifying mechanism in the regulation of both PAH and PH-HFpEF.

References

1. Goncharov DA, Goncharova EA, Tofovic SP, et al. Metformin therapy for pulmonary hypertension associated with HFpEF versus PAH [published online May 4, 2018]. Am J Respir Crit Care Med. doi:10.1164/rccm.201801-0022LE
2. Lai YC, Tabima DM, Dube JJ, et al. SIRT3–AMPK activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF). Circulation. 2016;133(8):717-731.
3. Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation. 2007;115(10):1275-1284.
4. Paulin R, Dromparis P, Sutendra G, et al. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab. 2014;20(5):827-839.
5. Agard C, Rolli-Derkinderen M, Dumas-de-La-Roque E, et al. Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension. Br J Pharmacol. 2009;158(5):1285-1294.
6. Dean A, Nilsen M, Loughlin L, Salt IP, MacLean MR. Metformin reverses development of pulmonary hypertension via aromatase inhibition. Hypertension. 2016;68(2):446-454.