Incretin Drugs | Mimetics and DPP-4 Inhibitors (Enzyme Blockers)

Incretins are are gut hormones that contribute to the secretion of insulin secretion when glucose is ingested. It does not have an effect on IV glucose infusions. A incretin hormone like glucagon-like peptide (GLP-1) is stimulated in varying quantities depending on the amount of glucose ingested (glucose-dependent). It also suppresses glucagon secretion and delays gastric emptying. GLP-1 may also reduce appetite and promote weight loss. The enzyme dipeptidyl peptidase-4 or DPP-4 degrades GLP-1 so that it does not have a prolonged effect.

Incretin-based therapies for diabetes mellitus (sugar diabetes) involves using drugs that :

  1. stimulate insulin secretion in response to glucose intake in a similar manner to incretin incretin mimetics or glucagon-like peptide (GLP-1)
  2. inhibit the enzymes (dipeptidyl peptidase-4 / DPP-4) that break down incretin and related molecules – DPP-4 inhibitors

Incretin-based therapies are most useful in obese patients. It can be used in combination with other oral anti-diabetic agents like metformin and sulfonylurea.

Incretin Mimetics

What is an incretin mimetic?

Also known as glucagon-like-polypeptide 1 (GLP-1) analogues, the first GLP-1 analogue was originally identified in the saliva of the lizard Gila monster.

Incretins like GLP-1 are responsible for stimulation of insulin secretion in response to the glucose intake. Exenatide (synthetic) and liraglutide (recombinant) are analogues of GLP-1 which is approved as an adjunctive therapy with metformin or sulfonylureas for type 2 diabetes. Exenatide is given subcutaneously twice daily within 1 hour before a meal while liraglutide is given once daily independent of the meals.

Actions of Incretin Mimemtics

GLP-1 analogues enhance the glucose-mediated insulin secretion and suppress the post-meal glucagon release. Like the naturally occurring incretin hormones, it can also cause appetite loss and slow gastric emptying.

Side Effects of Incretin Mimetics

The prominent side effects of incretin mimetics are nausea, vomiting and diarrhea. Other side effects include hypoglycemia (more when combined with sulfonylureas), dizziness, headache, abdominal pain and dyspepsia. Nausea usually decreases with continued treatment.

Serious side effects include acute pancreatitis. Any indication of pancreatitis during the treatment should warrant discontinuation of the treatment with GLP-1 analogues. Urticaria and anti-liraglutide antibody formation is also seen with liraglutide.

Contraindications of Incretin Mimetics

A known allergy to this family of drugs and a history of pancreatitis are contraindications for the use of incretin mimetics. In addition, liraglutide is contraindicated in patients with family history of thyroid cancer (medullary carcinoma).

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

What are DPP-4 inhibitors?

DPP-4 inhibitors are drugs that inhibit the enzyme that breaks down incretin and other related molecules. Sitagliptin and saxagliptin are the currently approved DPP-4 inhibitors. The drugs are taken once daily.

Actions of DPP-4 Inhibitors

By inhibiting the DPP-4 enzyme, there is an increase in the circulating levels of incretins (GLP-1 and GIP). This also leads to an increase in the responsiveness of insulin release to glucose, and a decrease in glucagon concentrations. The drugs lead to lower fasting glucose levels and reduction a in the post-meal rise in blood glucose.

Side Effects of DPP-4 Inhibitors

Hypersensitivity reactions like anaphylaxis, angioedema, rash, and even Stevens-Johnson syndrome have been reported with DPP-4 inhibitor use, more commonly with sitagliptin. Liver enzyme elevation, acute pancreatitis, constipation, vomiting, and headache have been seen with sitagliptin. Hypoglycemic episodes were rare with DPP-4 inhibitors, but in combination with insulin secretagogues, like sulfonylureas, it is more likely to occur. The drugs also facilitated weight loss. Saxagliptin treatment was associated with increased upper respiratory tract infection, urinary tract infection, and headache.

Contraindications of DPP-4 Inhibitors

DPP-4 inhibitors are contraindicated in patients with a known allergy to the drug, in type 1 diabetes and diabetic complications like diabetic ketoacidosis.

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