Tirzepatide - the new antidiabetic drug

[Bikas Aryan]

How does the new antidiabetic drug Tirzepatide work ? what are the contraindications and side effects?

[Sanjeev Tiwari]

@bikas-aryan harmacology
Mechanism of Action
Dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist

GIP is an incretin hormone that induces insulin secretion in response to a meal (primarily by hyperosmolarity of glucose in the duodenum) to facilitate the metabolism of carbohydrates, fats, and proteins

GLP-1 receptor agonists increase insulin secretion in the presence of elevated blood glucose, suppress glucagon postprandially, delay gastric emptying to decrease postprandial glucose, and decrease glucagon secretion

Pharmacodynamic effects observed include lower fasting and postprandial glucose concentration, decreased food intake, and reduced body weight

Absorption
Bioavailability: 80%

Peak plasma concentration: 8-72 hr

Steady-state achieved: 4 weeks

Distribution
Protein bound: 99% (primarily to albumin)

Vd: 10.3 L

Metabolism
Metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis

Elimination
Half-life: ~5 days

Clearance: 0.061 L/hr

Excretion: Metabolites via urine and feces

Contraindications
Personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2

Known hypersensitivity to tirzepatide or to any of the product components

Cautions
On the basis of findings in rats and mice, may cause thyroid C-cell tumors, including MTC, in humans; human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, observed in patients treated with GLP-1 receptor agonists; after initiating, monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain, which sometimes radiates to the back and may or may not be accompanied by vomiting); if pancreatitis suspected, discontinue and do not restart if confirmed

Rapid improvement in glucose control associated with temporary worsening of diabetic retinopathy; tirzepatide has not been studied in patients with nonproliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema; monitor patients with a history of diabetic retinopathy

Gastrointestinal (GI) adverse reactions, sometimes severe, reported; has not been studied in patients with severe GI disease, including severe gastroparesis, and is not recommended in these patients

Acute gallbladder disease (eg, cholelithiasis, cholecystitis) reported in GLP-1 receptor agonist trials and postmarketing surveillance; if suspected, gallbladder studies and appropriate clinical follow-up are indicated

Kidney injury
Acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis in patients treated with GLP-1 receptor agonists, has been described
Most reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration
Events also reported in patients without known underlying renal disease
Monitor renal function when initiating or escalating doses in patients reporting severe adverse GI reactions
Hypersensitivity
Serious hypersensitivity reactions reported with GLP-1 receptor agonists; caution in patients with history of angioedema or anaphylaxis with a GLP-1 receptor agonist
Unknown whether such patients will be predisposed to these reactions with tirzepatide
If hypersensitivity reactions occur, discontinue treatment, treat promptly, and monitor until signs and symptoms resolve
Drug interaction overview
Insulin secretagogues or insulin
May require dosage modification
Coadministration with insulin secretagogues (eg, sulfonylureas) or insulin may increase risk of hypoglycemia
Consider lower dose of secretagogue or insulin to reduce risk of hypoglycemia
Inform patients using concomitant medications of risk of hypoglycemia and educate them on signs and symptoms of hypoglycemia
Oral drugs with narrow therapeutic index
Caution/dosage modification
Tirzepatide may delay gastric emptying, thereby potentially impacting oral absorption
Caution with drugs having a narrow therapeutic index (eg, warfarin)
Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or to add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each tirzepatide dose escalation