Health Rounds: Genetic variations linked to weight loss, side effects from GLP-1 drugs

By Nancy Lapid

April 9 (Reuters) - Hello Health Rounds readers! Today we feature a pair of studies that took a deeper dive into the effects of GLP-1 drugs being widely used for weight loss and diabetes. We also report on a fascinating Israeli study in mice that found gender development can be affected and even reversed by a minuscule DNA variation.

Genetic variants ‌predict responses to GLP-1 drugs

Weight-loss responses to GLP-1 obesity drugs, and risks of side effects, may be linked to genetic variants, according to a study conducted by DNA-testing service 23AndMe.

The study of nearly ‌28,000 23AndMe users who reported taking the weight-loss drugs found that a mutation in GLP1R, the gene for the protein targeted by GLP-1 drugs, is modestly but significantly associated with increased efficacy of the medications, researchers reported in Nature.

People carrying one copy of that variant lost, ​on average, 1.7 pounds (0.76 kilograms) more over a median of eight months of treatment than people who had no copies. People carrying two copies of the variant lost some 3.3 pounds more.

Mutations in the GLP1R gene and in another gene – GIPR, which is related to insulin secretion and energy production – were associated with medication-related nausea or vomiting.

The GIPR side effect association was only seen in people using Eli Lilly's tirzepatide, however. People carrying that variant were 83% more likely than non-carriers to vomit after taking tirzepatide, sold as Mounjaro for diabetes and Zepbound for obesity.

The genetic effect on weight loss was relatively small, researchers acknowledged.

“These findings provide direct genetic evidence that variation in the drug-target genes contributes to ‌inter-person variability in response and lay the foundation for precision medicine approaches in ⁠the treatment of obesity,” they said.

GLP-1 heart benefits may be distinct from obesity effects

The cardiovascular benefits derived from GLP-1 drugs may be more directly tied to dosage than to degree of weight loss, according to a study that suggests the effects of the medicine on the heart may be separate from the impact on obesity.

If that proves ⁠to be the case, doctors might someday optimize patients’ GLP-1 regimens for long-term cardiovascular benefits, not just for diabetes management and weight loss, researchers said in a report published online ahead of peer review.

Researchers studied 47,199 patients with cardiovascular disease who received Novo Nordisk's GLP-1 drug semaglutide, sold as Ozempic for diabetes and Wegovy for obesity, for up to two years.

They found, as expected, that higher doses were associated with greater weight loss.

Two years after stopping treatment, those who had received higher doses ​had ​lower risks of death from any cause. They also had lower risk of heart attack, stroke or cardiovascular-related death, clogged blood ​vessels in the brain, heart failure, and heart valve problems.

But those risks were not ‌affected by how much weight people had lost, the researchers said.

When they analyzed tissues from the heart and other organs, they found the cell-surface proteins targeted by GLP-1 drugs were most numerous in the pancreas, which one would expect given the drugs’ benefit in diabetes.

The heart had the second-highest number, however.

“All the focus has been on the pancreas but... is it possible that this medicine is directly acting in the heart?” said study leader Venky Soundararajan of Cambridge, Massachusetts data analytics firm nference.

“It’s purely a hypothesis,” Soundararajan added. “But we can say at this point that heart benefits are not directly correlated to weight loss, and there is enough molecular data to warrant actual experiments in the heart to begin to understand what the drug does.”

Researchers trigger sex reversal with one DNA mutation

Insertion of one tiny mutation outside a gene caused mice to develop as males instead of females, researchers found.

Working ‌with so-called XX mice embryos – bred to develop into females - they introduced the mutation into a section of DNA known as ​Enh13, which controls the activity of Sox9. The Sox9 gene is essential for testis development. For ovaries to develop normally, Sox9 must ​be kept turned off.

When the researchers introduced the mutation using CRISPR genome editing, the needed female repression ​failed. As a result, Sox9 was activated and testes developed, leading to complete internal and external male development, they reported in Nature Communications.

The outcome is especially striking, they said, ‌because the mutation was not made in a gene itself, but in a part ​of DNA known as the non-coding genome - the 98% ​of DNA that does not make genes but helps regulate when and how they are turned on and off.

The fact that such a tiny change - just one DNA letter out of roughly 2.8 billion - was enough to produce a dramatic developmental outcome, "shows that non-coding DNA can have a profound effect on development and disease,” study leader Nitzan Gonen from Bar-Ilan University in Israel said in a statement.

The researchers ​say their study may have important implications for people with Differences of Sex ‌Development, a group of conditions affecting about 1 in 4,000 births worldwide.

More than half of cases lack a genetic diagnosis even after sequencing the protein-coding parts of the genome, the researchers said.

“Our ​findings show that it is not enough to look only at genes,” study co-author Elisheva Abberbock, also of Bar-Ilan University, said in a statement.

“Important disease-causing mutations may also lie in ​the non-coding genome, in DNA regions that control gene activity,” Abberbock said.

(Reporting by Nancy Lapid; Editing by Bill Berkrot)