Diabetes drug may reduce coronary artery disease in those with 'Asian glow'

About a third of people of East Asian descent have a genetic variant that leads to “Asian glow,” a distinctive red flushing that appears after drinking alcohol. It’s due to the body’s inability to rid itself of acetaldehyde, a toxic byproduct of metabolizing alcohol.

The variant causes more harm than embarrassment at a cocktail party. Deficiency in aldehyde dehydrogenase, an enzyme that converts acetaldehyde into acetate (which the body harmlessly excretes) significantly increases the risk of coronary artery disease for the world’s estimated 540 million people who carry the variant, especially for those who drink.

A study led by Stanford Medicine, published Jan. 25 in Science Translational Medicine, demonstrates that ALDH2 deficiency can damage the cells that line the inside of blood vessels. This damage goes a long way toward explaining the association between the condition and high rates of coronary artery disease, said Joseph Wu, MD, PhD, professor of cardiovascular medicine and of radiology, director of the Stanford Cardiovascular Institute, and senior author of the study. 

The researchers also identified a widely available antidiabetic drug that may protect against damage to the endothelial cells of those with ALDH2 deficiency who consume alcohol.

A less effective enzyme

Those with the genetic mutation causing ALDH2 deficiency produce a slightly different enzyme, ALDH2*2. The variant is much less effective at getting rid of acetaldehyde, which can accumulate and cause harm including genetic mutations; liver damage; increased cancer risk; and, according to the study, damage to endothelial cells that line blood vessels, leading to vascular dysfunction.

“We suspected that the harm to endothelial cells was causing the coronary artery disease, but the mechanism was still unknown,” said Wu, the Simon H. Stertzer, MD, Professor. He set out with his colleagues to discover how ALDH2 deficiency harms these cells and if it’s possible to interrupt that process.

In search of links between heart disease and genetic markers, the researchers first conducted a genome-wide search of data from BioBank Japan. They discovered that the gene variant causing ALDH2 deficiency had a strong association with coronary artery disease.

The team then tested the capacity of blood vessels to dilate, and thus the performance of endothelial cells, by tracking blood flow. Using a device that fits on the finger, they tested study participants immediately before and after the subjects drank alcohol. “The study showed that having even one drink significantly impaired vasodilation for those with the variant, but not for those without it,” said Hongchao Guo, PhD, an instructor at the cardiovascular institute and the paper’s lead author.

The group then used genetically modified human induced pluripotent stem cells to make ALDH2-deficient endothelial cells in a petri dish; these revealed an increase in cell damage from oxidative stress and inflammation, and a decrease in production of blood-vessel-relaxing nitric oxide compared with cells without the deficiency. All three of these changes represent ways that the ALDH2 variant harms or disables endothelial cells, Guo said. Moreover, all these harmful effects were amplified when alcohol was added to the mix.

Search for a drug

Finally, the team conducted a computer-based molecular search for compounds that might compensate for the absence of ALDH2. They discovered that the medication empagliflozin, already commonly used to treat diabetes, was a good fit. They tested it in mouse models of alcohol exposure and diabetes with ALDH2 deficiency. Mice medicated with empagliflozin showed improved vascular response, healthier endothelial cells and improved circulation overall.

To identify the mechanism behind the diabetes drug’s benefit, the team went back to the lab. They added a dose of empagliflozin to ALDH2-deficient human endothelial cells and saw that the drug reduced the amount of oxidative damage and inflammation in the cells. It also increased nitric oxide production, roughly compensating for the ALDH2 deficiency in all the right places.

“Empagliflozin targets the downstream pathways of ALDH2*2 rather than directly stimulating ALDH2 activity, so it won’t reduce alcohol flush. However, it may be used as a preventive measure against vascular diseases, especially in high-risk patients such as ALDH2*2 carriers who drink excessively,” Wu said.

Wu would like to see clinical trials that examine whether ALDH2 deficiency and alcohol consumption together exacerbate endothelial dysfunction in diabetics or those with existing coronary artery disease. “If confirmed, this should better inform patients on cutting down alcohol consumption in general, and especially for ALDH2 carriers (those who show the alcoholic flush) to avoid drinking alcohol if possible,” Wu said.

“In addition, the ALDH2 variant is linked to an increased risk of atrial fibrillation in habitual drinkers, which is one of the most common types of cardiac arrhythmias,” Wu said. “We are looking into the role of alcohol-induced arrhythmias in ALDH2 carriers using patient-specific induced pluripotent stem cell models.”

Wu said his overall message is simple: “If you’re drinking, drink less. If you’re not drinking, don’t start.”

Researchers from Greenstone Biosciences contributed to the study.

The work was supported by the National Institutes of Health (grants K99 HL150319, K99 HL150216, R01 AA11147, R35 GM119522, R01 HL130020, R01 HL126527, R01 HL113006, R01 HL146690 and P01 HL141084), the American Heart Association and the Tobacco-Related Disease Research Program.