Compound 15 Could Rival Ozempic for Type 2 Diabetes and Obesity

An oral medicine could eventually challenge drugs such as Ozempic in the treatment of type 2 diabetes and obesity, a new study suggests. Its effectiveness has not yet been assessed in humans, but the compound may avoid some of the damaging side effects linked with comparable treatments.

Rather than belonging to the well-known group of GLP-1 receptor agonist drugs, this potential treatment acts on the β2-adrenergic receptor (β2AR). Medicines that target this receptor already exist: salbutamol, marketed as Ventolin among other names, is commonly prescribed in short courses for asthma and chronic obstructive pulmonary disease.

Clenbuterol is prescribed for asthma in certain countries as well, although it is more widely recognised as a performance-enhancing substance. The World Anti-Doping Agency bans it because of its anabolic effects.

β2AR agonists for type 2 diabetes and obesity

Scientists have spent over a decade seeking to capture the benefits of β2AR agonists without provoking their harmful consequences. These drugs can increase glucose uptake in skeletal muscle and promote fat burning, recreating effects associated with exercise. However, their potential to severely disrupt heart function has made them too dangerous for diabetes or obesity treatment.

β2-adrenergic receptors in the body are linked to G proteins. When they remain activated for extended periods, including through β2AR medicines, those G proteins initiate a sequence of events that can result in cardiovascular complications.

"That would lead to heart rate increases, systolic blood pressure increases, and, eventually, that over-sustained exposure would lead to increases in heart weight and cardiac hypertrophy," molecular biologist Shane Wright, from Karolinska Institute in Sweden, told Mar de Miguel of Bioworld.

A research effort involving scientists at Karolinska Institute, Stockholm University and biotech firm Atrogi AB has now identified a group of β2AR agonist molecules able to avoid the harmful pathway set in motion by G proteins.

Compound 15 targets muscle pathways

By switching on only selected pathways, one candidate, called ‘compound 15’, appears less likely to produce those worrying side effects. Confirmation will require further clinical trials.

In contrast with GLP-1 receptor agonists such as Ozempic, compound 15 neither curbs appetite nor causes muscle loss, potentially making it safer in this respect. It may also be easier to use because it is swallowed rather than injected.

"The goal was to try to target this other action that this receptor has expressed in the skeletal muscle, not in the heart, where it is mediating glucose uptake as a very beneficial outlet for lowering blood glucose levels," Wright said.

To date, the newly developed medicine has been examined in laboratory-grown cells, male mice, rats and beagles, as well as in phase 1 clinical trials involving healthy men and men with type 2 diabetes. Phase 1 trials assess safety rather than efficacy.

"Lead candidates of the chemical series increased glucose tolerance in preclinical models of diabetes and obesity with little or no increase in contractile force, cardiac lesions, and cardiac hypertrophy," the authors report. The candidates also reversed muscle atrophy caused by GLP-1 drugs.

"Clinical evaluation demonstrated that our lead candidate was orally bioavailable and safe in both healthy volunteers and type 2 diabetics, underlining its therapeutic potential."

Further clinical trials of compound 15

Considerably more testing, along with a more memorable name, will be necessary before compound 15 or related medicines can be offered as alternatives to GLP-1 drugs. Phase 2 clinical trials are in progress to determine whether the increased muscle growth, stable glucose levels and insulin sensitivity observed in animal studies are replicated in people.

"A well-tolerated GRK2-biased agonist offers significant therapeutic potential beyond type 2 diabetes and obesity… like muscular dystrophy and sarcopenia," the authors add.

The study was published in Cell.