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New drug could reduce risk of heart disease and diabetes

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New drugs that lower levels of triglycerides (a type of fat) in blood could
further reduce the risk of heart attack when added to statins. These new
drugs, which are in various stages of development, could also reduce blood
glucose levels and the risk of diabetes, according to a new genetic study
from the Medical Research Council Epidemiology Unit at the University of
Cambridge.

MRC scientists behind the research, published today in JAMA Cardiology,
suggest these new drugs – lipoprotein lipase enhancers – could be paired
with statins, the current gold standard for high cholesterol treatment, or
other cholesterol lowering agents. Their findings, which stem from a type of
genetic study which aims to simulate a clinical trial, hold promise for
clinicians and pharmaceutical companies that are considering testing the
efficacy of these novel drugs.

Dr Luca A. Lotta, Senior Clinical Investigator at the MRC Epidemiology Unit,
said: “Our study suggests that these new triglyceride-lowering agents could
give additional benefits to patients with heart disease when added to
statins. This combination could prevent more heart attacks as well as reduce
the risk of developing type 2 diabetes.”

Heart disease is a significant problem in the UK, tied to more than a
quarter of all deaths in the country, according to 2018 estimates. One of
the major factors leading to heart disease is high levels of low-density
lipoprotein or LDL cholesterol, often referred to as “bad cholesterol”.

Statins are widely prescribed to lower LDL levels and are effective at
preventing heart disease. Some people who are treated with statins will
still encounter heart attacks, which has been partly linked to raised levels
of triglycerides in their blood.

Normally, our bodies can break down triglycerides with a protein called
lipoprotein lipase or LPL. In recent years, scientists and drug developers
have tapped into this, developing several new agents that enhance the
activity of this enzyme. However, these drugs are still in pre-clinical or
early clinical stages of development.

In theory, these new heart drugs could be used in combination with statins
and other cholesterol-lowering agents, but there hasn’t been a large-scale
trial to show their efficacy. MRC scientists used genetic data to gain
insights into their likely efficacy and safety in advance of a large-scale
trial.

The new research studied the genetics of some 400,000 people from the UK
Biobank, EPIC-InterAct, and EPIC-Norfolk studies. Scientists used an
approach called Mendelian randomisation, which uses naturally occurring
genetic differences to simulate the effects of a clinical trial, to study
the likely effects of statins and these novel LPL-enhancing drugs.

Some people have variation in their DNA that naturally increases the
effectiveness of LPL, mimicking the effect that would be observed if the
LPL-enhancing drugs were used.

In this study, people who carried both triglyceride-lowering DNA variants in
the LPL gene and cholesterol-lowering variants in several other genes
(simulating the protective effect of statins) had a lower risk of heart
disease compared with people with only one of either of these sets of DNA
variants.

The researchers believe these drugs could mitigate some of the potential
side effects of statins, too. For some people, statins can increase the risk
of developing type 2 diabetes – 50 to 100 new cases for every 10,000
patients treated. The scientists found that those with LPL gene variants had
a lower risk of type 2 diabetes in all study groups, suggesting that these
new drugs may improve blood glucose control when paired with statins.

Dr Lotta said: “We’re using genetics to gain insight and help to predict the
likely result of future trials. Studies that simulate clinical trials are
invaluable because large-scale trials are expensive, take years to conduct
and considerable resources – scientists need strong evidence of a drug’s
likelihood of success before it gets to the trial stage.”

Clinical trials are costly endeavours but emerging findings indicate the
odds of successful drug development are increased when knowledge about these
novel agents is bolstered by genetic studies. To empower these studies, the
MRC, pharmaceutical companies, and other funders have invested in large
genetic resources including the recent announcement of a consortium of
companies to sequence the DNA of all participants of the UK Biobank, a study
of 500,000 people from the general UK population.

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