Patients with type 2 diabetes can have a two to three times higher risk of developing coronary artery disease (CAD). If they also have genetic variants linked to an increased risk of developing CAD—the leading cause of death and disability worldwide—the health implications become more dire.

The good news is diseases such as type 2 diabetes and CAD are not influenced solely by genetics, but by a complex interplay of genetic and environmental factors.

Diabetes interventions such as implementing lifestyle changes (increasing exercise, improving diet, etc.) or taking medication can help reduce this risk. But do those strategies work the same for patients who are at a high genetic risk for CAD as well?

Researchers from the Center for Genomic Medicine and the Diabetes Unit at Massachusetts General Hospital recently took a closer look at this question with the help of data provided by participants in the Diabetes Prevention Program (DPP).

The team, which was led by Jordi Merino, PhD, and Jose Florez, MD, PhD, recently published their findings in the journal Diabetes. Dr. Florez is chief of the Diabetes Unit and an MGH Research Scholar 2013-2018.

Details of the Study

The study team started by building a polygenic risk score for coronary artery disease based on 201 known gene variants that have associated with an increased risk of CAD.

In a study of more than 2,650 DPP participants with dysglycemia, the team measured the effects of the polygenic risk score on cardiometabolic risk factors, and the extent to which diabetes prevention strategies, including lifestyle interventions or regularly taking the diabetes drug metformin, interacted with genetic liability over the course of a year.

The cardiometabolic risk factors assessed in the study included:

• Body mass index (BMI)
• Waist circumference
• Fasting glucose
• Blood pressure
• Lipid levels including total cholesterol, LDLc, HDLc, and triglycerides
• Inflammatory and thrombolytic markers including c-reactive protein, fibrinogen, and tissue plasminogen activator

What They Found

The team found that the genetic risk score is associated with several cardiometabolic risk factors at baseline.

Participants in both intervention groups demonstrated greater risk reduction compared to those in the placebo group—and these improvements occurred irrespective of an individual’s genetic risk for coronary artery disease.

Participants in the lifestyle intervention group improved the most across all risk factors in comparison to the placebo group. Not surprisingly, they also had the greatest changes in physical activity, diet and body shape.

Individuals in the metformin group showed significant improvement in BMI, waist circumference and levels of cholesterol, tissue plasminogen activator and c-reactive protein.

Those in the metformin group who also incorporated healthy lifestyle behaviors received additional benefits in terms of reduced risk, which suggests a combined approach could be even more effective.

Limitations of the Study

The team cautions that their findings are based on a unique randomized clinical trial that made replication of reported findings challenging.

They also assigned risk factors to participants based on a composite genetic risk score, and there may be other undiscovered genetic variants related to CAD that could show different results.

Next Steps

The team will next try to find a way to replicate these findings, which will be challenging considering the unique study set.

They will also take a closer look at individual lifestyle interventions to see which ones are most effective when combined with metformin treatment.

About the Mass General Research Institute
Research at Massachusetts General Hospital is interwoven through more than 30 different departments, centers and institutes. Our research includes fundamental, lab-based science; clinical trials to test new drugs, devices and diagnostic tools; and community and population-based research to improve health outcomes across populations and eliminate disparities in care.
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