Trulicity and Benzodiazepines Interaction: What Patients and Clinicians Need to Know

What the Trulicity label says about interactions

The Drug Interactions section of the current Trulicity label covers two things: oral medications whose absorption may be slowed by delayed gastric emptying, and concomitant use with insulin or an insulin secretagogue such as a sulfonylurea [1]. Benzodiazepines are not mentioned. They are also absent from the Contraindications section, which covers only a personal or family history of medullary thyroid carcinoma or MEN 2, and serious hypersensitivity to dulaglutide or a product component [1]. The label therefore gives no benzodiazepine-specific dose change, warning or contraindication.

Different clearance pathways

Dulaglutide is a GLP-1 receptor agonist with about 90% amino acid sequence homology to endogenous GLP-1 and a half-life of roughly 5 days [1]. The label states it is presumed to be degraded into amino acids by general protein catabolism, and that age, sex, race, body weight, and renal or hepatic impairment have no clinically relevant effect on its pharmacokinetics [1].

Benzodiazepines are cleared differently. Alprazolam and diazepam are CYP3A substrates (diazepam also CYP2C19), clonazepam is partly CYP3A metabolized, and lorazepam and temazepam are cleared mainly by glucuronidation [2][4][5][3][6]. The alprazolam label shows how much CYP inhibitors can matter for that drug: ketoconazole raised alprazolam plasma levels 3.98-fold and itraconazole 2.70-fold, and strong CYP3A inhibitors other than ritonavir are contraindicated with Xanax [2]. Dulaglutide is not among the drugs the Xanax label lists for these interactions [2].

Gastric emptying: the one pathway the label flags

Dulaglutide slows gastric emptying, and the label says this has the potential to reduce the rate of absorption of oral medicines taken at the same time [1]. The delay is dose-dependent, is largest after the first dose, diminishes with subsequent doses, and is attenuated by the recommended stepwise dose increase [1]. At 1.5 mg, dulaglutide did not affect absorption of the oral medications tested to a clinically relevant degree, and the label notes limited experience with the 3 mg and 4.5 mg doses [1]. The label does not mention benzodiazepines in this context [1].

The Trulicity label says it is not recommended in patients with severe gastroparesis. In the label's placebo-controlled pool, 0.2% of placebo patients, 1.3% on 0.75 mg and 3.5% on 1.5 mg stopped treatment for GI reasons [1].

Hypoglycemia risk sits with insulin and sulfonylureas

The Trulicity label attaches hypoglycemia to two co-medications, not to sedatives. It says patients receiving Trulicity with an insulin secretagogue such as a sulfonylurea, or with insulin, may have an increased risk of hypoglycemia including severe hypoglycemia, and that reducing the sulfonylurea or insulin dose may be necessary [1]. The label's trial figures show the size of that effect: glucose below 54 mg/dL occurred in 14.7% of patients on Trulicity 1.5 mg with insulin glargine versus 9.3% on placebo, and in 3.3% with glimepiride versus 0% [1].

What the benzodiazepine labels warn about

The alprazolam, lorazepam, diazepam, clonazepam and temazepam labels carry the same three-part boxed warning: profound sedation, respiratory depression, coma and death when combined with opioids; abuse, misuse and addiction; and physical dependence with the risk of life-threatening withdrawal after abrupt discontinuation or rapid dose reduction [2][3][4][5][6]. The Xanax label lists additive CNS depression with other CNS depressants, including ethanol, and cautions against driving or operating machinery and against alcohol and other CNS depressants during treatment; the Valium label says concomitant alcohol is not recommended [2][4]. These warnings concern opioids, alcohol and other CNS depressants, and Trulicity is not named in them [2][4].

On side effects, fatigue is a listed Trulicity adverse reaction: 2.6% on placebo versus 4.2% at 0.75 mg and 5.6% at 1.5 mg [1]. Nausea is more common still, 5.3% on placebo versus 12.4% and 21.1% [1]. For comparison, drowsiness was reported by 41% of patients taking alprazolam in 4-week generalized anxiety trials versus 22% on placebo [2]. These figures describe each drug separately, not the combination.

Procedures and deep sedation

The Trulicity label reports pulmonary aspiration during general anesthesia or deep sedation in patients receiving GLP-1 receptor agonists who underwent elective surgeries or procedures [1]. It does not identify a benzodiazepine-specific interaction or dose change [1].

Putting it together

The label-based picture is narrow. Absorption of an oral benzodiazepine may be slower, most noticeably after the first Trulicity dose, and at 1.5 mg the tested oral drugs showed no clinically relevant change [1]. The benzodiazepine labels warn about additive CNS depression with opioids, alcohol and other CNS depressants [2]. Hypoglycemia becomes a practical concern when insulin or a sulfonylurea is in the regimen, and the Trulicity label ties that risk to those drugs rather than to sedatives [1].