Drug Interaction Report

ADJUST DOSE: Coadministration of a glucagon-like peptide-1 (GLP-1) receptor agonist or dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist with insulin may potentiate the risk of hypoglycemia. GLP-1 receptor agonists and dual GLP-1 and GIP receptor agonists lower blood glucose by stimulating insulin secretion and lowering glucagon secretion. An increased incidence of hypoglycemia has been observed in patients treated with a combination of basal insulin and GLP-1 or dual GLP-1 and GIP receptor agonists. Additionally, patients with diabetic retinopathy who received treatment with basal insulin and subcutaneous semaglutide in one clinical trial had an increased risk of developing diabetic retinopathy complications. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy, but other mechanisms cannot be excluded. The safety and efficacy of GLP-1 or dual GLP-1 and GIP receptor agonists in combination with non-basal insulin have not been established.

MANAGEMENT: When a GLP-1 receptor agonist or dual GLP-1 and GIP receptor agonist is used as add-on therapy to basal insulin, a lower dosage of insulin may be required. Some clinical trials have reduced the basal insulin dose by 20% in patients with a baseline hemoglobin A1c <= 8% when a GLP-1 or dual GLP-1 and GIP receptor agonist was initiated. Because diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation or dose reduction of insulin, a stepwise approach to insulin dose reduction is recommended and blood glucose levels should be closely monitored. Patients should receive guidance on the recognition and management of hypoglycemia as well as precautions to take to avoid hypoglycemia, particularly while driving or operating hazardous machinery. Those with diabetic retinopathy should also be monitored for progression of the condition or complications. A rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.

Liraglutide delays gastric emptying, which may impact the absorption of concomitantly administered oral medications. In pharmacokinetic studies, liraglutide did not affect the absorption of several orally administered medications to any clinically significant extent (see below). For each interaction studied, administration of the interacting drug was timed so that its absorption peak would coincide with the peak plasma concentration of liraglutide (8 to 12 hours).

Acetaminophen: Administration of a single 1000 mg dose of acetaminophen eight hours after liraglutide dosing (1.8 mg/day) at steady state did not change acetaminophen systemic exposure (AUC). However, acetaminophen peak plasma concentration (Cmax) was decreased by 31% and median time to maximal concentration (Tmax) was delayed up to 15 minutes.

Atorvastatin: Administration of a single 40 mg dose of atorvastatin five hours after liraglutide dosing (1.8 mg/day) at steady state did not change atorvastatin systemic exposure (AUC). However, atorvastatin peak plasma concentration (Cmax) was decreased by 38% and median time to maximal concentration (Tmax) was delayed from 1 hour to 3 hours.

Digoxin: Administration of a single 1 mg dose of digoxin seven hours after liraglutide dosing (1.8 mg/day) at steady state resulted in a 31% and 16% reduction in digoxin peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, and a delay in digoxin median time to maximal concentration (Tmax) from 1 hour to 1.5 hours.

Griseofulvin: Coadministration of a single 500 mg dose of griseofulvin with liraglutide (1.8 mg/day) at steady state did not change griseofulvin systemic exposure (AUC) or median time to maximal concentration (Tmax). However, griseofulvin peak plasma concentration (Cmax) increased by 37%.

Lisinopril: Administration of a single 20 mg dose of lisinopril five minutes after liraglutide dosing (1.8 mg/day) at steady state resulted in a 27% and 15% reduction in lisinopril peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, and a delay in lisinopril median time to maximal concentration (Tmax) from 6 hours to 8 hours.

Oral Contraceptives: Administration of a single 0.03 mg-0.15 mg dose of ethinyl estradiol-levonorgestrel oral contraceptive under fed conditions seven hours after liraglutide dosing (1.8 mg/day) at steady state resulted in a 12% and 13% reduction in the peak plasma concentration (Cmax) of ethinyl estradiol and levonorgestrel, respectively, and a delay in median time to maximal concentration (Tmax) by 1.5 hours for both. Ethinyl estradiol systemic exposure (AUC) was not changed, while levonorgestrel AUC increased by 18%.

MONITOR: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists can delay gastric emptying, which may impact the absorption of concomitantly administered oral medications. Mild to moderate decreases in plasma concentrations of coadministered drugs have been demonstrated in pharmacokinetic studies for some GLP-1 receptor agonists (e.g., exenatide, lixisenatide), but not others. According to the prescribing information, liraglutide did not affect the absorption of several orally administered drugs to any clinically significant extent, including acetaminophen, atorvastatin, digoxin, griseofulvin, lisinopril, and an oral contraceptive containing ethinyl estradiol-levonorgestrel. Likewise, no clinically relevant effect on absorption was observed for concomitantly administered oral drugs studied with albiglutide (digoxin, ethinyl estradiol-norethindrone, simvastatin, warfarin), dulaglutide (acetaminophen, atorvastatin, digoxin, ethinyl estradiol-norelgestromin, lisinopril, metformin, metoprolol, sitagliptin, warfarin), or semaglutide (atorvastatin, digoxin, ethinyl estradiol-levonorgestrel, metformin, warfarin). The impact of dual GLP-1 and GIP receptor agonist tirzepatide on gastric emptying was reported to be dose- and time-dependent, with the greatest effect observed after a single 5 mg dose but diminished after subsequent doses. When acetaminophen was administered following a single 5 mg dose of tirzepatide, acetaminophen peak plasma concentration (Cmax) was decreased by 50% and its median time to peak plasma concentration (Tmax) delayed by 1 hour. However, no significant impact on acetaminophen Cmax and Tmax was observed after 4 consecutive weekly doses of tirzepatide (5 mg/5 mg/8 mg/10 mg), and the overall exposure (AUC) of acetaminophen was unaffected. Tirzepatide at lower doses of 0.5 mg and 1.5 mg also had minimal effects on acetaminophen exposure.

MANAGEMENT: Although no specific dosage adjustment of concomitant medications is generally recommended based on available data, potential clinical impact on some oral medications cannot be ruled out, particularly those with a narrow therapeutic index or low bioavailability, those that depend on threshold concentrations for efficacy (e.g., antibiotics), and those that require rapid gastrointestinal absorption (e.g., hypnotics, analgesics). Pharmacologic response to concomitantly administered oral medications should be monitored more closely following initiation, dose adjustment, or discontinuation of a GLP-1 receptor agonist or a dual GLP-1 and GIP receptor agonist.

GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.