Surrogate endpoint

A clinical outcome is something a person feels or experiences: a heart attack, a fracture, death, being able to climb stairs. A surrogate endpoint is a marker expected to predict one of those. US law, quoted on the FDA's surrogate endpoint table, describes it as "a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure" that is "not itself a direct measurement of clinical benefit".

Surrogates make trials possible. Waiting for heart attacks takes thousands of people and years; a change in LDL cholesterol shows within weeks.

Surrogates that support approval

The FDA lists the surrogates it has accepted. Some are rated as known to predict clinical benefit, which supports traditional approval. Others are only "reasonably likely" to, which supports accelerated approval with a requirement to confirm later.

Weight loss drugs are approved on weight change, which is not on that table. Whether a given amount of weight loss reduces heart attacks was an open question until outcome trials answered it.

When surrogates misled

CAST, 1989. Irregular heartbeats after a heart attack predict sudden death, so drugs that suppressed them looked promising. In the Cardiac Arrhythmia Suppression Trial, encainide and flecainide suppressed the arrhythmia, but total deaths were 56 of 730 (7.7 percent) on the drugs against 22 of 725 (3.0 percent) on placebo. That arm was stopped.

Torcetrapib, 2007. Higher HDL cholesterol is associated with lower heart risk. Torcetrapib raised HDL by 72.1 percent and lowered LDL by 24.9 percent at 12 months, and increased cardiovascular events (HR 1.25) and death from any cause (HR 1.58) in the ILLUMINATE trial of 15,067 people.

In both cases the marker moved in the right direction and the outcome moved in the wrong one. A drug can change a marker through a route that does not lead where the marker usually leads.

Where GLP-1 drugs stand

The GLP-1 drugs were approved for diabetes on HbA1c and for weight on weight change. Outcome trials have since tested the clinical events directly. SELECT found semaglutide 2.4 mg reduced major cardiovascular events (HR 0.80) in people with heart disease and obesity, and FLOW found semaglutide 1 mg reduced major kidney events (HR 0.76) in type 2 diabetes with kidney disease. That is the surrogate being checked against the outcome, which is how it should work.

For most research peptides, the evidence is a surrogate at best, often in animals. A change in a marker such as IGF-1 or hs-CRP is a reason to ask about outcomes, not an answer. The longevity markers page covers what common markers do and do not predict.

Your own labs are surrogates too, and they are still worth tracking. The bloodwork tracking feature reads markers such as HbA1c, LDL, triglycerides and hs-CRP from a lab PDF and plots them against your dose timeline.

Related terms: hazard ratio, clinical trial phases, insulin resistance, placebo-controlled trial. Back to the glossary.