Two shots cut a blood fat tied to heart disease by nine tenths, trial finds

Most blood fats rise and fall with what people eat. One kind is different, because how much of it a person has is mostly set at birth. It is called lipoprotein(a), or Lp(a). Studies of hundreds of thousands of people link high Lp(a) to heart disease and to a stiff, narrow heart valve [3].

A new trial tested a shot built to lower it. In the groups given the most medicine, Lp(a) fell by more than nine tenths compared with a fake shot, and it stayed down for close to a year [1].

The main caveat is just as important. The trial measured a blood test, not heart attacks or strokes. A lower number on a test is a sign, not proof that people will be healthier [1][3].

The shot is called lepodisiran. The trial, named ALPACA, was led by Steven Nissen of the Cleveland Clinic and published in the New England Journal of Medicine in 2025. The drug company Eli Lilly, which makes the shot, paid for it, and several authors work there. The lead author's hospital has been paid by the company to run trials [1].

What does the shot do?

Lp(a) is a tiny ball made in the liver that carries fat and cholesterol in the blood. It looks a lot like LDL, the so called bad cholesterol, but with one extra protein stuck to it [3][4]. Its level is mostly set by the genes a person is born with [5]. It reaches adult levels by about age 5, and changes in food move it only a little [3].

The shot is a small interfering RNA, a short piece of genetic code made in a lab. RNA is the copy of a gene that a cell reads like a recipe to build a protein. This piece finds one recipe in liver cells and gets it torn up, so the cells make much less of the extra protein that Lp(a) needs. Without it, the liver cannot build as many Lp(a) balls [1][4].

The trial took in 320 adults with high Lp(a). Chance, like a coin flip, split them into five groups. Three got a low, middle or high amount at the start and again about six months later. A fourth got the high amount and then a fake shot, and a fifth got two fake shots [1].

Lp(a) fell more with each step up in amount. Between day 60 and day 180, compared with the fake shot, it was 40.8 points lower in the low group. It was 75.2 points lower in the middle group and 93.9 points lower in the high groups. Those points are percentage points, the gap between two percents. Across nearly a year, the group that got the high amount twice stayed 94.8 points lower [1]. The researchers summed it up:

Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration.

In plain words, the shot lowered the blood level of Lp(a) for months after it was given. An earlier, smaller trial of 48 adults found something similar. Almost a year after one shot of the highest amount, Lp(a) was still about 94 percent lower than at the start [4].

In the larger trial, 35 people had a serious health problem, and the doctors running it judged that none were caused by the shot or the fake shot. Reactions where the shot went in were mostly mild and grew with the amount. In the highest group, 8 of 69 people had one. A trial of 320 people over about a year cannot find rare problems or show what happens over many years [1].

Will it protect the heart?

Nobody knows yet. European experts wrote in 2022 that only new trials can show whether lowering Lp(a) helps the heart [3]. A later look at blood from this same trial said the same thing in its own words:

These findings provide additional biological rationale for the ongoing lepodisiran phase 3 cardiovascular outcomes trial, but do not establish clinical benefit.

In plain words, the results give scientists more reason to run the big heart trial, but they do not prove that anyone is better off [5].

That big trial is called ACCLAIM Lp(a), listed in the public trial registry as NCT06292013. It plans to include about 17,300 adults with high Lp(a), some who have had heart disease and some at risk of a first heart problem. It will count heart deaths, heart attacks, strokes from a blocked vessel and urgent heart procedures. The registry lists March 2029 as the estimated date for its main results, and the maker of the shot is its sponsor [2].

This trial does not show whether the shot prevents heart attacks or strokes. Nor does it show how it works in other groups, or how it compares with other ways of lowering Lp(a). What it does show is narrower but clear. Two shots of a small piece of lab made genetic code cut an inherited blood fat by more than nine tenths, for close to a year [1][2].