Genetic studies: a powerful tool for testing combination therapies

Some people suffer heart attacks despite taking cholesterol lowering agents, often as a result of high levels of triglycerides in the blood. Triglycerides are normally broken down naturally by lipoprotein lipase (LPL), which has led scientists to the hypothesis that the breakdown of triglycerides could be helped by enhancing LPL.

A genetic study carried out by the University of Cambridge’s Medical Research Council (MRC) Epidemiology Unit has tested this hypothesis, and found that combining LPL enhancers with cholesterol lowering agents such as statins could further reduce the risk of heart attack and of diabetes.

So far, the new LPL enhancer drugs remain in the pre-clinical and early clinical stages of development, and no large clinical trials have been carried out to demonstrate LPL enhancers’ efficacy in combination with cholesterol-lowering agents, but this study is a vital step in exploring the potential of combination therapies for coronary and other conditions.

MRC’s findings came from a genetic study that aims to simulate a clinical trial that would test the efficacy of the LPL enhancers.

Dr Luca Lotta, senior clinical investigator at the MRC Epidemiology Unit, explains the premises behind a genetic study: “A recent concept that has been emerging is that some naturally occurring genetic variants that are present in the general population can simulate and can mimic the effect of drugs. So they can be used to study whether the drug is likely to prevent a certain outcome.

“Basically because genetic variants are randomly assigned at conception this is similar to what happens in a randomised control trial, where you may randomise people to receive nothing…or to receive a drug that enhances [in this case] LPL. So this similarity has been used as a rationale for this type of investigation.”

In this study, the researchers studied people in the general population that have low cholesterol due to their genetic make-up and people with low level of triglycerides, due to genetic variants in the LPL gene (which are fairly common). This simulates a trial of cholesterol lowering drugs and LPL enhancing drugs.

The data came from 400,000 samples from the UK Biobank, EPIC-InterAct and EPIC Norfolk studies and relied upon the Mendellian randomisation technique.

The MRC research team chose to undertake a genetic study on this particular subject to help drug developers in the design of clinical trials, which can take years and cost millions of pounds.

“Our hope is that these studies will inform the design and conduction of some of the trials that are upcoming. That this would be used as supportive evidence for these studies,” Lotta says. “The genetic evidence supporting pharmacological indication in previous drugs that have gone through the pipeline show that drugs that have this type of genetic evidence are more likely to succeed.”

The genetic study established that people with triglyceride-lowering alleles in the LPL gene were better protected from coronary disease and type 2 diabetes than those lacking that genetic variation, which led the researchers to the following conclusion: “Triglyceride-lowering alleles in the LPL pathway are associated with protection against coronary disease and type 2 diabetes independently of LDL-C lowering genetic mechanisms. These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C-lowering therapy.”

Dr Lotta adds: “Our study suggests that these new triglyceride-lowering agents could give additional benefits to patients with heart disease when added to statins.”

The success of combination therapy was of interest to the researchers because statins are already effective at reducing stroke, so the main prescription for LPL enhancers would be adding more drugs to improve the mechanism of action and also mitigate the potential side effects of statins, which include type 2 diabetes.

Since Lotta’s team is primarily focused on investigating the use of genetics for the identification and validation of new therapies in the context of diabetes and its complications, he believes the main implication of the genetic study’s finding is that combination therapy could be more effective in regard to diabetes risk.

“The association with diabetes may make some of the drug developers think whether these drugs could also be used in general in the context of diabetes to reduce glycaemic levels,” Lotta adds.

The next step for the MRC epidemiology team is to explore other ways in which to use genetics to inform on the future therapies for very prevalent conditions.