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Many people swallow two to three drugs daily to lower their cholesterol and blood pressure to healthy levels. What if they could achieve the same results with medications that require just a few injections per year — no pills?

This isn't just a far-flung promise. Inclisiran (Leqvio), a long-lasting injectable drug that dramatically lowers LDL cholesterol, was approved in 2021. It's the first cholesterol-lowering medication that works through RNA interference, a technique that's the basis for an expanding class of novel therapies for treating a variety of diseases. Several additional RNA-targeted drugs for cardiovascular disease are currently in late-stage trials. How exactly do these drugs work, and who might benefit from them?

Harnessing the power of RNA

Found in all living cells, RNA is the molecule that copies and transfers genetic instructions from DNA (the cell's genetic blueprint) to create proteins. The human body contains tens of thousands of different proteins that provide countless functions, including supporting tissues and organs, carrying out biochemical reactions, and ferrying different molecules around the body. Many diseases, it turns out, result from problems with proteins.

For example, in people with very high cholesterol (hypercholesterolemia), the body produces too much low-density lipoprotein (LDL), one of the proteins that transports cholesterol. While cholesterol is vital for making cell membranes, many hormones, and vitamin D, excess cholesterol in the bloodstream contributes to artery-clogging plaque. Certain drugs for hypercholesterolemia use antibodies to block PCSK9, a protein made in the liver that regulates LDL. But inclisiran prevents PCSK9 from being made in the first place.

"Many of these therapies work by interfering with the strand of RNA before it has the opportunity to be translated into a protein," says cardiologist Dr. Michelle O'Donoghue, associate professor of medicine at Harvard Medical School. Some, known as small-interfering RNA (siRNA) drugs, have long-lasting effects. After being injected, the drug travels to the liver and, in the case of inclisiran, interferes with the creation of PCSK9. Among people with stubbornly high cholesterol who are already taking the maximum dose of a statin, the drug reduces blood levels of LDL by about half.

Silencing Lp(a)

Other RNA-interfering drugs in development target a different particle called lipoprotein(a), or Lp(a). These particles feature an extra lipoprotein molecule that makes them "stickier," which appears to accelerate fatty plaque buildup inside arteries even more than regular LDL. High levels of Lp(a) — which affect about one in five people in the general population — have been linked to a higher risk of heart attack, stroke, and narrowing of the aortic valve (aortic stenosis).

Because Lp(a) levels are largely based on genetic factors, eating and exercise habits don't seem to affect the levels in your bloodstream. As yet, there are no FDA-approved drugs shown to effectively lower Lp(a), which is frustrating for patients and doctors alike. However, there are many promising drugs in the pipeline. Pelacarsen, olpasiran, zerlasiran, and lepodisiran are given by injection every one to six months and have been shown to lower Lp(a) levels between 70% and 100%. Larger, longer trials looking at whether these drugs will help prevent heart-related problems are currently under way, with results expected within the next few years, says Dr. O'Donoghue, who is a lead investigator on the clinical trials of olpasiran.

Decreasing blood pressure

Another siRNA drug, zilebesiran, interferes with the liver's production of angiotensinogen, a protein that plays a key role in blood pressure regulation. Nearly half of all adults have high blood pressure, defined as a reading at or above 130/80 mm Hg. And fewer than half of people with the condition have it under control, despite the availability of more than 200 different blood pressure medications.

In an early study, zilebesiran led to meaningful drops in blood pressure that persisted for six months; ongoing studies are testing it in combination with different blood pressure drugs. One concern about this particular drug, however, is that its effects can't be quickly reversed, which could pose problems for people who receive it and then later develop a serious infection or another condition that causes dangerously low blood pressure.

To date, side effects from all these medications are uncommon and include mild redness or pain at the injection site. "None have been studied on a large enough scale that we can be completely confident about their efficacy and safety. That's what the ongoing trials will answer. But so far, the evidence is encouraging," says Dr. O'Donoghue.

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