Incretin therapy

Incretin-based therapies address the beta cell dysfunction and abnormal glucagon secretion found in type 2 diabetes.

Mostly used in combination therapy, to control hyperglycemia while avoiding the adverse effects common to conventional antidiabetic agents.

Incretin-based therapies linked to precancerous cellular changes of the pancreas, and acute pancreatitis.

A large population study of incretin-based drugs was not associated with an increased risk of pancreatitis compared with other oral antidiabetic drugs (Azoulay L ).

Incretins are peptide hormones, which include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

Incretins are released from the small intestine after a meal.

GIP promotes insulin secretion.

GLP-1 stimulates insulin release from pancreatic beta cells, inhibits glucagon release, delays gastric emptying, and inhibits appetite, decreasing food intake and promotes weight loss.

GLP-1 agonists activate GLP-1 receptors, which enhances the effects of GLP-1 in the body.

GLP-1 agonists are available as injection only.

GLP-1 agonists are: Exenatide: Twice-daily or once-weekly formulations and Liraglutide: Once-daily formulation.

The enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades GLP-1 in the gut.

The use of glucagon like peptide 1 analogues is associated with an increased risk of bile duct and gallbladder adverse events in patients with type two diabetes.

DPP-4 inhibitors competitively inhibit the enzyme, preventing degradation and enhancing the effects of GLP-1.

The DPP-4 inhibitors are available as once-daily, oral formulations.

DPP-4 inhibitors are: Sitagliptin




The GLP-1 agonists and DPP-4 inhibitors offer several advantages over conventional therapy.

GIP & GLP-1 directly activate, the GLP-one receptor and produce improvements in glucose tolerance, as well as modest weight loss.

GLP-1 agonists associated with weight loss: Generally about 2 to 4 kg in most patients.

GLP-1 agonists associated with HbA1C decreases: Exenatide usually lowers A1C by by 0.5% to 1.0% from baseline; liraglutide lowers A1C up to 1.6%.

Postprandial glucose lowering is similar to insulin treatment.

Blood pressure reduction associated with approximately 2 to 5 mm Hg reduction.

DPP-4 inhibitors:

Are weight neutral.

Decreases HbA1C decrease by 0.5% to 0.8%.

Postprandial glucose is lowered.

Blood pressure reduction occurs only in patients with established arterial hypertension.

GLP-1 agonists may have the potential to increase risk because GLP-1 receptors are found in meninges, thyroid, pancreas, renal tubules, and bone.

Acute pancreatitis may be associated with GLP-1 agonists, especially exenatide.

GLP-1 agonists are contraindicated in patients with multiple endocrine neoplasia type 2

GLP-1agonists should be avoided in patients with genetic predisposition to thyroid cancer, or personal or family history of medullary thyroid carcinoma.

Liraglutide is linked to increased risk of thyroid tumors

GLP-1agonists are not indicated for those with stage 4 or 5 chronic kidney disease.

GLP-1agonists associated with nausea and GI distress which tends to decrease over time.

Less GI distress with liraglutide.

Long-acting GLP-1agonists associated with mildly increased heart rate by 2 to 5 beats per minute.

DPP-4 inhibitors

The DPP-4 enzyme is found in the cell membranes of numerous tissues throughout the body, including immune cells, which has raised some concerns about their long-term safety.

DPP-4 inhibitors carry potential increased risk for: Serious allergic and hypersensitivity reactions have been linked to sitagliptin, and acute pancreatitis, especially for sitagliptin.

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