PCSK9 inhibitor Alirocumab cuts risk of subsequent heart attack in Diabetes patients

Taking twice-monthly injection of cholesterol-lowering drug alirocumab may cut the risk of a subsequent heart attack in patients with high blood sugar or diabetes, revealed a study published in Lancet Diabetes & Endocrinology.

Alirocumab is a human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), a circulating protein that modulates the activity of the LDL cholesterol receptor in the liver. It is part of a class of cholesterol-lowering drugs called the PCSK9 inhibitors. The monoclonal antibody lowers serum LDL cholesterol and is used to treat severe hypercholesterolemia.

Professor Kausik Ray, Chair in Public Health (clinical) at Imperial College London, and first author of the study explained "In this study, we found that alirocumab had a greater reduction in risk for patients with diabetes compared to those without. People with diabetes who have recently had a heart attack and who have high LDL cholesterol, despite statins, are an easily identifiable and cost-effective group to think about giving these treatments to."

The findings come from a trial of almost 19,000 patients with a recent heart attack or unstable angina and who were already taking the highest doses of cholesterol-lowering medication statins.

Researchers found that patients taking an additional twice-monthly injection of another type of cholesterol-lowering drug, called alirocumab, further cut their cholesterol levels significantly and reduced their risk of having another heart attack.

High levels of low-density lipoprotein (LDL) cholesterol (so-called 'bad' cholesterol) in the blood are a known risk factor for cardiovascular disease. But patients with diabetes are at twice the risk of cardiovascular events, such as a heart attack or stroke, due to damage to the heart and blood vessels. The researchers say that the injections reduce this risk by further lowering their levels of LDL cholesterol.

The scientists behind the latest analysis - led by researchers at Imperial College London - say that alirocumab could provide more benefit to patients with diabetes, compared to those without diabetes, following a recent heart attack.

Their findings, published in the journal Lancet Diabetes & Endocrinology, could inform current guidelines for use of cholesterol-lowering medications, potentially advocating more aggressive cholesterol reduction in those with diabetes after a heart attack.

As an estimated one-third of heart attack patients have diabetes, the researchers say these patients are a common and easily recognizable group who would benefit from achieving even lower cholesterol levels from this injectable treatment.

Alirocumab is a monoclonal antibody licensed for patients throughout the world. The drug is delivered by injection every two weeks and works by blocking the action of a key enzyme in the liver to reduce LDL cholesterol levels in the blood.

Previous research has shown that alirocumab is safe and effective at reducing LDL cholesterol levels, without increasing the risk of diabetes.

However, PCSK9 inhibitors are more expensive than other cholesterol-lowering drugs, such as statins, and cost an estimated £4000 per patient per year in the UK, so their use is restricted to patients with the highest levels of low-density lipoprotein(LDL) cholesterol. Doctors are therefore considering who would benefit most from this class of drugs.

Professor Kausik Ray said that "Cholesterol-lowering injections, such as alirocumab, are effective but they are expensive, so we need to consider targeting them to where they will have the most impact. Patients with high blood sugar make up about one-third of all heart attacks and these patients have roughly twice the risk as those with nor blood sugar.

In the latest study, 18,924 patients recruited in 57 countries were classified into three groups: having diabetes; having pre-diabetes (higher than normal blood sugar); or normoglycaemia (healthy blood sugar levels).

All patients had previously been hospitalized due to a 'cardiac event' (heart attack, unstable angina - chest pains caused by poor blood flow to the heart at rest) and all patients were randomized to receive either alirocumab or placebo every two weeks, on top of their existing high-intensity statins.

The distribution of patients in the trial was similar to earlier studies, with diabetes or prediabetes making up approximately 70 percent of the cohort. Whether a patient had diabetes or not did not influence their LDL cholesterol levels at the start of the trial, or during the treatment period (when they received either alirocumab or placebo).

Four months into the trial, LDL cholesterol levels in patients taking alirocumab were reduced to an average of 0.8 mmol/L (for diabetes, pre-diabetes and normoglycaemia) compared to those taking placebo - who had low-density lipoprotein (LDL) cholesterol levels of 2.25 mmol/L in patients with diabetes and prediabetes, and 2.28 mmol/L in the normoglycaemia group. By comparison, the NHS advises a healthy adult should have an LDL level of 3 mmol/L and 2 mmol/L or less for those at high risk such as those who have had a heart attack.

After an average follow up period of 2.8 years, the team found that alirocumab was equally effective in reducing risk across the three groups but because people with diabetes were at highest risk they gained bigger absolute benefits. Analysis revealed that for diabetes patients, in absolute terms, treatment with alirocumab reduced their risk of further cardiovascular events by an average of 2.3 per cent.

Following a heart attack, the number of diabetes patients that needed to be treated was 43 for 2.8 years to prevent one event, versus 82 for those without diabetes.

While reducing blood cholesterol has proven benefits for cardiovascular health, there has been some uncertainty regarding whether achieving very low levels of low-density lipoprotein (LDL) cholesterol increases the risk of diabetes. The researchers say the current study, amongst almost 19,000 patients including more than 5000 people with more than three years of follow up, shows there was no increased risk of diabetes with alirocumab.