[ESC 2025 Spotlight] Is the era of "increasing statins" coming to an end? A new LDL-C management strategy demonstrated by Inclisiran

Introduction

"It is better to lower LDL cholesterol."

This is now common knowledge in the field of cardiology.

However, in reality,

• muscle pain occurs when increasing the statin dose

• cannot continue high-dose statins

• cannot easily reach the LDL-C target value

There are not a few patients like this.

The VICTORION-Difference trial introduced here is

an RCT that answered this very practical question.

It is a study that attracted significant attention at ESC 2025 and has the potential to greatly change future lipid management.

LDL-C management is in the era of "how much to lower"

In recent guidelines,

is not the only thing.

Currently, it is

in other words,

• earlier

• Significantly

• Long-term

It is considered important to keep lowering LDL-C.

Especially

• history of myocardial infarction

• post-PCI

• multivessel disease

• comorbid diabetes

For such patients, an LDL-C level of less than 55 mg/dL is recommended.

However, in clinical practice,

the goal achievement rate is by no means high.

The biggest reason for this is

the limitations of increasing statin doses

.

What is Inclisiran?

Inclisiran is

a drug that prevents the production of PCSK9

.

Conventional PCSK9 inhibitors (Evolocumab, Alirocumab) work by

neutralizing the PCSK9 protein

was doing so.

On the other hand, Inclisiran

degrades PCSK9 mRNA

by

preventing the liver from producing PCSK9 itself.

In other words,

it is a completely new approach that

does not "stop it after it is made"

but rather "prevents it from being made"

.

Moreover, administration is only

• Day 1

• Day 90

• and every 6 months thereafter

.

The excellent adherence of twice-yearly administration is also a major attraction.

Now for the main topic

VICTORION-Difference trial

design

Phase 4

Double-blind

Placebo-controlled RCT

Number of patients

1,770 cases

Mean age

63.7 years old

Comparison

Inclisiran group

• Inclisiran add-on

• minimally required lipid therapy

VS

ioLLT group

Individual optimized lipid-lowering therapy

In other words

"increase statins as much as possible"

is the conventional strategy.

Rosuvastatin was increased as much as possible.

In short, this trial is

a direct head-to-head comparison.

Result 1

LDL-C goal attainment rate

After 90 days

Inclisiran

84.9%

ioLLT

31.0%

It is a staggering

approx. 3-fold

difference.

Odds Ratio

12.09

P<0.001

This is an extremely significant difference.

Result 2

LDL-C reduction rate

After 360 days

Inclisiran

-59.5%

ioLLT

-24.3%

Between-group difference

-35.1%

P<0.001

The fact that such a large difference was maintained for one year is extremely important.

Result 3

Muscle symptoms

This may be the most significant point of this trial.

Muscle-related adverse events

Inclisiran

11.9%

ioLLT

19.2%

OR

0.57

In other words,

a reduction of approximately 40%

.

This could be considered expected.

Because there is no need to force an increase in statins

Muscular symptoms were reduced.

QOL also improved

Pain score

Pain severity

Pain interference

Both improved significantly in the Inclisiran group.

For patients,

"no pain"

"easier to continue"

This means that,

it is extremely important for long-term treatment.

The impact of this trial on clinical practice

Lipid management until now has been

First,

maximum dose of statins

↓

add ezetimibe

↓

PCSK9 inhibitors

which is

Stepwise therapy

was the standard.

However, this trial

"Is it really necessary to insist on increasing statin doses?"

raises this question.

In the future,

could become the mainstream strategy.

If there are fewer muscle symptoms

and LDL-C is significantly reduced,

the benefits for patients would be substantial.

On the other hand, there are points to note.

This trial

LDL-C achievement rate

was the primary evaluation metric.

In other words,

myocardial infarction,

cerebral infarction,

mortality,

and other such

This was not a trial that evaluated hard endpoints.

Of course,

there is abundant evidence that

LDL-C reduction equals event reduction,

but regarding whether Inclisiran itself reduces events,

we must wait for the results of

ORION-4

and other ongoing trials.

Points I focused on

What impressed me most about this trial was

the perspective of "whether the patient can continue treatment" rather than "how much LDL-C was lowered".

High-dose statins are certainly effective, but there are not a few patients who cannot continue them due to muscle symptoms. If sufficient LDL-C reduction is not achieved, the event suppression effect that could originally be expected will not be obtained.

Since Inclisiran only requires administration twice a year, it has the potential to solve the major challenge of medication adherence.

As a treatment strategy that balances "efficacy" and "ease of continuation," its presence will likely continue to grow in the future.

Summary

The message obtained from the VICTORION-Difference trial is simple.

✅ LDL-C goal achievement rate is 84.9%

✅ LDL-C reduced by approximately 60%

✅ Muscle-related side effects reduced by approximately 40%

✅ QOL also improved

In other words,

a shift from the era of "forcing statin dose escalation" to an era of "introducing powerful combination therapy early"is what this trial suggests.

If the cardiovascular event reduction effect is proven in future studies such as ORION-4, lipid management algorithms may change even more significantly.

This is the latest evidence that not only cardiologists, but also general practitioners and diabetologists should definitely keep in mind.