In emerging area of ‘diabetic lung disease,’ pioglitazone may play preventive role

Robert J. Chilton

PHILADELPHIA — Pulmonary arterial hypertension is a growing problem in the setting of insulin resistance and type 2 diabetes, and pioglitazone may serve as a tool to prevent or delay the disease course, according to a speaker here.

Right ventricular heart failure is the leading cause of death in pulmonary arterial hypertension, and insulin resistance — with or without type 2 diabetes — worsens endothelial function and, as a result, pulmonary vascular resistance, according to Robert J. Chilton, DO, professor of medicine and director of Cardiac Catheterization Labs and clinical proteomics at the University of Texas Health Science Center. Pioglitazone at a low dose, when paired with a therapy such as an SGLT2 inhibitor, is well tolerated and a “great choice” for many patients with type 2 diabetes, Chilton said.

“These new cardiovascular drugs are really important to cardiologists,” Chilton said during a presentation at the second annual Heart in Diabetes Clinical Education Conference. “I know they lower glucose, which most of you like, but, for me, I’m going for the hard endpoint of less heart attacks, strokes and peripheral vascular disease problems. This [pioglitazone] has the advantage of reducing those.”

“Pioglitazone is a drug that I think many of you were scared to use, but now has become important,” Chilton said.

Fueled in part by the growing obesity epidemic, Chilton said, clinicians are seeing more cases of what he called “diabetic lung disease” — insulin resistance playing a role in a growing problem of increased pulmonary vascular resistance.

“We’re starting to see, now, three or four people a week who come into the cath lab and we spend at least an extra hour, hour and a half with staff, training them to actually look inside the lungs ... because they have pulmonary hypertension,” Chilton said. “The potential problem in the lungs that you now are starting to see for the first time is the hint of maybe insulin resistance in diabetes as one of the causes of pulmonary hypertension, which then leads into right heart failure, which has a mortality worse than routine systolic dysfunction and diastolic dysfunction.”

One drug, m ultiple mechanisms

In the Insulin Resistance Intervention after Stroke (IRIS) trial, insulin-resistant patients with a recent ischemic stroke or transient ischemic attack assigned pioglitazone therapy experienced a reduced risk for developing type 2 diabetes and major cardiovascular events, Chilton said, and researchers observed significant reductions in acute coronary syndrome in patients assigned to pioglitazone. New analyses show that can potentially prevent diabetes, and inflammation is markedly reduced, he said.

Pioglitazone likely has multiple mechanisms that mediated its observed benefit in IRIS, Chilton said. Use of the drug was associated with a reduction in high-sensitivity C reactive protein, sharp improvements in HDL cholesterol, and reductions in triglyceride levels and blood pressure, leading to a reduction in acute coronary syndrome events, Chilton said.

In a 5-year follow-up of the IRIS trial, pioglitazone also had a beneficial effect on the overall pre-specified outcome of fatal and non-fatal stroke and MI and hospitalization for heart failure, Chilton said, with no direct cardiotoxic effects. He noted that in the IRIS study specifically, dose could be reduced for symptoms of edema or excessive weight gain.

“So, it is well tolerated if you use common sense,” Chilton said. “You use the low dose and you find it is a great choice for many patients with diabetes.”

A noninterventional diagnosis

Pulmonary arterial hypertension is not something an endocrinologist would typically see in their diabetic patient, Chilton said, in part because it would not be something an endocrinologist would look for.

“These are things that we hadn’t thought about before, because the only people who would be seeing this are pulmonary doctors sending patients to the cath lab,” Chilton said. “This is not something that you would see. But, now that you know about it, can you get it with noninvasive tests? You can.”

Chilton said outside of a cardiac catheterization lab, a clinician can measure the pressure in the lung with a noninvasive echocardiogram.

“So, it is possible that you can track this non-invasively,” Chilton said.

In the “diabetic lung,” the right ventricle of the heart becomes enlarged due to increased pressure, whereas the left ventricle is relatively normal, Chilton said. The pulmonary vascular resistance is now much higher as the right ventricle works to pump blood through the obstructed pulmonary vessel, Chilton said.

“What happens is the pressure rises [ on the right side], but the left side’s pressure is normal,” Chilton said. “Guess who has most of this? People with diabetes and insulin resistance.”

The damage to the heart and lungs via insulin resistance, Chilton said, is different: killing the very fine hairline vessels on the endothelial cells that are antioxidant and produce nitric oxide, damaging the vessel bed down to the fine level.

“When you have a patient with diabetes who is short of breath, and they come to [cath] lab and they have pulmonary hypertension, there should be some bells that come on in your head to say, ‘You know, you might want to consider drugs that lower glucose,’ i.e., pioglitazone, because it works in these areas,” Chilton said.

“Most of the time, when you think of pulmonary hypertension, you think of clots down the artery or a connective tissue problem,” Chilton said. “There is a new consideration now. Insulin resistance in diabetes has moved into the area of pulmonary hypertension, and, maybe, you have the wrong treatment, since none of them seem to work, except in half the patients. Maybe, it’s because they are insulin resistant, and you really need diabetes therapies that actually target this area.” – by Regina Schaffer

Reference:

Chilton RJ. Role of pioglitazone in the prevention and management of DM and CVD. Presented at: Presented at: Heart in Diabetes Clinical Education Conference; July 13-15, 2018; Philadelphia.

Disclosure: Endocrine Today was unable to determine relevant financial disclosures at the time of publication.