Steven Nissen, M.D., talks about the importance of lowering Lp(a)

High levels of lipoprotein(a) are a risk factor for cardiovascular disease and can lead to plaque buildup and narrowing of the arteries, inflammation and blood clots. This fat — which is similar in structure to low-density lipoprotein (LDL), the “bad cholesterol” — can cause plaque buildup and narrowing of the arteries, inflammation and blood clots.

Currently there are no drugs specifically approved to lower Lp(a) levels, but there are five drugs in development that have shown in phase 2 trials to have a significant impact on Lp(a) levels. Cardiologist Steven Nissen, M.D., is involved as an investigator in four of these drugs. He is chief academic officer, Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic.

Below, Nissen discusses the importance of lowering Lp(a) levels and the mechanism of how new therapies are in development for lowering Lp(a).

Q: Why is lowering Lp(a) important for prevention of heart disease?

A: A high Lp(a) is a risk factor that is almost exclusively genetic. There are some changes that take place during a person’s lifetime. For example, levels will go up a little bit in women at the time of menopause, but these changes are very small.

The traditional drugs that are used, such as statins or PCSK9 inhibitors, have a very small effect. It's been conventionally very difficult to treat because it isn’t altered by diet, lifestyle, or medications. It’s associated with a very substantial increase in the risk of atherosclerotic cardiovascular disease and aortic stenosis.

About 20% of the world population has elevated levels of Lp(a). That represents more than a billion people on our planet that have this disorder, and many of them will have premature events. It affects both men and women, sometimes in their 40s or even in their 30s. The higher the level, the higher the risk.

Related: New therapies on the way to lower Lp(a), a cardiovascular risk factor

Q: How many drugs are in development to lower Lp(a)?

A: There are five drugs in development for lipoprotein(a); my team and I are running the clinical trials for four of the five.

Q: How do the therapies in development work to lower Lp(a)?

A: It’s done primarily based on interfering with the production of a protein that’s part of lipoprotein A, and that’s called apolipoprotein A. We do that by blocking messenger RNA that codes for that protein. That can be done in two ways. One is the way that pelacarsen does. Pelacarsen is an antisense oligonucleotide. It’s a double-stranded snippet of DNA connected to a sugar that transports it into the liver, where it gets into the liver cells, the hepatocytes, and it blocks messenger RNA and reduces apolipoprotein A production. A phase 2 trial published in 2019 showed that pelacarsen lowered Lp(a) levels by 80%.

Another approach is small interfering RNAs, which are double-stranded small pieces of RNA. It also connects to the sugar known as galNAc that gets taken up into the liver, which leads apolipoprotein A to degrade. One drug with this approach is the Amgen drug olpasiran, and it has been shown to lower levels well over 90% in phase 2. This is a long-lasting drug and can be given every three months.