Benefits of Tethered Combination Therapy for Type 2 Diabetes

Tethered combination therapy for type 2 diabetes could be more beneficial than two medications taken concurrently.

Biomedical engineers presented this new approach at Duke University. The drugs included in this experiment have a glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor 21 (FGF21). The glucagon-like peptide is a 30-amino acid peptide hormone that is produced in the intestinal epithelial endocrine L-cells. GLP-1 is generally released in response to meal intake. GLP-1 levels rise after food ingestion leading to glucose-dependent insulin secretion, suppressing glucagon, slower gastric emptying, and increased satiety. Decreased secretion of GLP-1 may contribute to the development of obesity and high blood glucose levels. GLP-1 agonists medications are Byetta, Victoza, Trulicity, Adlyxin, and Ozempic. The fibroblast growth factor 21 was initially identified in mouse embryos and subsequently in humans; its product is a secreted protein of 210 amino acids in mice and 209 amino acids in humans. FGF21 treatment reduces plasma glucose concentrations, but the mechanisms of this action are not well understood. Studies in rodents suggest that FGF21 decreases food, especially sugar, intake, and may be added to anorexigenic hormones. GLP-1 increases insulin secretion by the pancreas, while FGF21 enhances the body’s response to insulin. GLP-1 reduces food intake, while FGF21 helps burn more calories.

Glucagon-like peptide-1 and fibroblast growth factor 21 contribute to glycemic control and the potential weight reduction in diabetic mice. Rather than merely injecting diabetic mice with both drugs simultaneously, the researchers decided to link GLP-1 and FGF21 together into a single injection. There are many advantages to combining these two drugs. One advantage is the adherence to the medication regimen. Tethering these two drugs together was a complicated process due to both drugs being peptide-based. Peptide-based drugs have a short half-life. The short half-life is due to the rapid clearance of the drug from the body. To combine these two drugs into one, the researchers received help from The Chilkoti research group.

The Chilkoti research group provided the researchers with an elastin-like polypeptide (ELP) linker. Chilkoti’s research group currently has two Phase II clinical trials in process using the ELP as a slow delivery system. The ELP forms the combination molecule and makes a gel-like depot when injected under the skin. The substance slowly dissolves over at least a week and releases the active drug over time. In this current study, GLP-1 and FGF21 retain their respective functions and potencies when linked together by an ELP. Results verified that drug circulating in the system remained steady while blood sugar levels were brought to a healthy level. The blood glucose levels were also maintained for up to 10 days following single dosing. The combination of these two medications also worked better than when they were given individually. The researchers believed that giving the medication tethered together also allows the mechanism of action to work together simultaneously. A low dose was used in this study. Therefore, no side effects were reported. Additional research may be needed to check for potential side effects. However, the researchers believe that this study’s data is so compelling that there are hopes that this strategy will be used commercially.

Practice Pearls:

• Tethered combination therapy for type 2 diabetes could be more beneficial than two medications taken concurrently.
• The study found that the linked drugs’ effects last longer than one week with a single injection.
• Results from tethering these two drugs verified that drugs circulating in the system remained steady while blood sugar levels were brought down to a healthy level.

American Association of Clinical Endocrinologists and the American College of Endocrinology Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan. Endocr Pract.

Tethering together type 2 diabetes drugs increases the efficacy of combination therapy (Press /Release), Dushman, ScienceDaily,

Destiny Funchess, PharmD Candidate, Tougaloo College, South College School of Pharmacy