ORFORGLIPRON TAB

Clinical Criteria Summary

Known pregnancy
Lactating
Type 1 diabetes (exception: may be considered under careful supervision if followed by a diabetes/weight management specialist)
Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2
Severe gastrointestinal dysmotility, including gastroparesis
History of pancreatitis (except when the cause is known and no longer presents a risk)
Known proliferative diabetic retinopathy (PDR), severe non-proliferative diabetic retinopathy (NPDR), clinically significant macular edema (ME), or diabetic macular edema (DME) unless risks/benefits are discussed with the patient, documented in the EHR with monitoring plans/follow-up, and an eye specialist is informed at initiation
Severe hepatic impairment (Child-Pugh Class C)
Concurrent therapy with a strong CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin)
Concurrent therapy with a strong CYP3A4 inhibitor that also inhibits OATP1B (e.g., ritonavir, clarithromycin)

Documented participation in a comprehensive lifestyle intervention (CLI) targeting diet, physical activity, and behavioral changes within the past year on at least one occasion/visit
BMI ≥ 27 kg/m² with at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, prediabetes, dyslipidemia, metabolic syndrome, obstructive sleep apnea, osteoarthritis, metabolic dysfunction-associated steatotic liver disease, heart failure with preserved ejection fraction, previous myocardial infarction, previous stroke, or symptomatic peripheral arterial disease)
Discontinuation of medications that may precipitate weight gain if clinically appropriate

Pregnancy must be excluded prior to receiving orforglipron
Contraceptive counseling regarding potential risks vs. benefits of taking orforglipron if pregnancy occurs is required
Females of childbearing potential using oral contraceptives must be counseled to switch to a non-oral contraceptive method or add a barrier method for 30 days after initiation and for 30 days after each dose escalation

Known pregnancy
Lactating status
Type 1 diabetes (exception: may be considered under careful supervision if followed by a diabetes/weight management specialist)
Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2
Severe gastrointestinal dysmotility, including gastroparesis
History of pancreatitis (except when the cause is known and no longer presents a risk)
Known proliferative diabetic retinopathy (PDR), severe non-proliferative diabetic retinopathy (NPDR), clinically significant macular edema (ME), or diabetic macular edema (DME) unless risks/benefits are discussed with the patient, documented in the EHR with monitoring plans/follow-up, and an eye specialist is informed at initiation
Severe hepatic impairment (Child-Pugh Class C)
Concurrent therapy with a strong CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin)
Concurrent therapy with a strong CYP3A4 inhibitor that also inhibits OATP1B (e.g., ritonavir, clarithromycin)

Documented participation in a comprehensive lifestyle intervention (CLI) targeting diet, physical activity, and behavioral changes within the past year on at least one occasion/visit
BMI ≥ 27 kg/m² with at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, prediabetes, dyslipidemia, metabolic syndrome, obstructive sleep apnea, osteoarthritis, metabolic dysfunction-associated steatotic liver disease, heart failure with preserved ejection fraction, previous myocardial infarction, previous stroke, or symptomatic peripheral arterial disease)
Consideration of discontinuing medications that may precipitate weight gain if clinically appropriate

Pregnancy must be excluded prior to receiving orforglipron for females who can become pregnant
Contraceptive counseling regarding potential risks vs. benefits is required
Females of childbearing potential using oral contraceptives must be counseled to switch to a non-oral contraceptive method or add a barrier method for 30 days after initiation and 30 days after each dose escalation

Adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition
Indicated for use in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term

Initial dose: 0.8 mg orally daily for at least 30 days
Titration every 30 days to 2.5 mg, then 5.5 mg, then 9 mg, then 14.5 mg, then 17.2 mg once daily
Maintenance doses: 5.5 mg – 17.2 mg daily
Tablets should be swallowed whole and can be taken with or without food

Personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
Known serious hypersensitivity to orforglipron or its excipients
Risk of thyroid C-cell tumors (based on rodent data; human relevance undetermined)
Acute pancreatitis
Severe gastrointestinal reactions
Acute kidney injury due to volume depletion
Hypoglycemia when used with insulin or secretagogues
Serious hypersensitivity reactions
Complications of diabetic retinopathy
Acute gallbladder disease
Risk of pulmonary aspiration during general anesthesia

Clinical trials included adults without diabetes mellitus (BMI ≥30, or BMI 27–30 with at least one obesity-related complication such as hypertension or dyslipidemia)
Clinical trials for type 2 diabetes (T2D) included adults with T2D and BMI ≥27, baseline A1C 7–10%, with other T2D therapies stable for at least 90 days prior to trial initiation
Average weight loss is lower in people with T2D; clinically meaningful weight loss over diet and exercise alone may not be shown unless titrated to the highest maintenance dose (17.2 mg daily)
Treatment should be in conjunction with comprehensive lifestyle intervention

Maximum dosage is 9 mg when co-administered with a strong CYP3A4 inhibitor
Avoid strong CYP3A4 inhibitors that also inhibit OATP1B (e.g., ritonavir, clarithromycin)
Avoid strong CYP3A4 inducers
Simvastatin dosage should not exceed 20 mg once daily due to orforglipron’s effect on simvastatin’s active metabolite
Delayed gastric emptying may impact absorption of other oral medications, including oral contraceptives