Why are NASH patients at increased CV risk & how can PPAR agonists potentially improve outcomes?

NASH patients are in excessively higher risk for developing cardiovascular complications because they are most frequently obese. Many of them suffer from type 2 diabetes and both obesity and diabetes already mean a higher risk for developing cardiovascular complications. On top of these, obesity and type 2 diabetes are associated with dyslipidemia with high cholesterol, high triglycerides and also with adipocyte dysfunction. That means the adipose tissue doesn’t function as it should. It is insulin resistant and as a consequence there is a release of free fatty acids from the adipose tissue, which ends in the liver and is the source for developing triglyceride position in the liver.

Relationship between adipose tissue dysfunction and development of fatty liver disease and other complications

There is a causal relationship between adipose tissue dysfunction and development of fatty liver disease and cardiovascular complications.The important role of PPAR is that agonism of PPAR gamma for example, particularly modulates and demodulates the function of the adipocytes. So adipose becomes more insulin sensitive and they take up fatty acids. They store the triglycerides and thereby prevent the overflow of fat from the adipose tissue to the liver. So by this, they already decrease the fat content in the liver and they also contribute to the reduction of increased lipids in the circulation and this could be the key mechanism by which PPARs could actually reduce the risk for cardiovascular or cerebrovascular complications. There are clinical studies that have shown that if you treat patients with obesity in type 2 diabetes with PPARs particularly with PPAR gamma pioglitazone. For example, can you reduce the so-called mace which is cardiovascular mortality, morbidity and stroke by something like 20%. A recent study and a recent meta analysis has confirmed this by pulling a number of clinical studies, making clear that PPAR can indeed have a positive effect on cardiovascular complications. 

Side effects and its implications 

However, side effects need to be taken into account, which is particularly the increase in edema fluid retention, which might occur in something like 5% of the patients. So that patients with cardiovascular problems particularly those with the myocardial insufficiency

heart failure should not take PPARs because they might actually develop progressive myocardial dysfunction. However, PPARs don’t have a negative effect on cardiovascular  function. They can actually that has been shown in a number of studies to improve that.