Trulicity and SNRIs (Venlafaxine, Duloxetine) Interaction: What Clinicians and Patients Need to Know

Is there a direct interaction between Trulicity and venlafaxine or duloxetine?

Dulaglutide is a once-weekly injectable GLP-1 receptor agonist. It is presumed to be degraded into amino acids by general protein catabolism, and the label reports no clinically relevant pharmacokinetic effect from renal or hepatic impairment [1].

The two SNRIs are handled differently. Venlafaxine is converted to its active metabolite O-desmethylvenlafaxine by CYP2D6, so poor metabolizers carry more parent drug and less metabolite [2]. Duloxetine is cleared by CYP1A2 and CYP2D6 and is itself a moderate CYP2D6 inhibitor [3]. The Trulicity label reports no testing of either medicine's levels with dulaglutide.

The Trulicity Drug Interactions section covers two areas: oral medicines whose absorption may slow, and insulin secretagogues or insulin [1]. Venlafaxine and duloxetine are not named in it.

Gastric emptying: what the label says

Dulaglutide delays gastric emptying, which gives it the potential to reduce the rate of absorption of oral medicines. The label describes that delay as dose dependent, largest after the first dose, diminishing with later doses, and attenuated by the recommended step-up in dose [1]. In clinical pharmacology studies, dulaglutide 1.5 mg did not affect absorption of the oral medicines tested to a clinically relevant degree, and experience with 3 mg and 4.5 mg is limited [1]. The label advises monitoring levels of narrow-therapeutic-index oral drugs such as warfarin [1].

Blood pressure: what each label actually says

Venlafaxine has the clearest signal. Its label reports dose-related increases in systolic and diastolic pressure. It directs that pre-existing hypertension be controlled before treatment starts, that blood pressure be measured regularly during treatment, and that dose reduction or discontinuation be considered if pressure stays up [2]. Sustained hypertension (supine diastolic at least 90 mm Hg and at least 10 mm Hg above baseline on three visits) occurred in 19 of 705 patients with major depression (75 to 375 mg/day), 3%, versus lower rates in other indications: 0.5% in generalized anxiety, 0.6% in social anxiety, 0.9% in panic disorder [2]. A rise of at least 15 mm Hg in supine diastolic pressure to 105 mm Hg or higher occurred in 1.4% versus 0.9% on placebo, and a rise of at least 20 mm Hg in supine systolic pressure to 180 mm Hg or higher in 1% versus 0.3% [2].

A meta-analysis of 3,744 depressed patients treated with venlafaxine, imipramine, and/or placebo found the effect highly dose dependent and clinically significant only above 300 mg/day on immediate-release data, and it did not worsen blood pressure control in patients with pre-existing hypertension [4]. The labeled maximum Effexor XR dose is 225 mg/day [2].

Duloxetine's pressor effect is smaller. In adult placebo-controlled trials the mean change was a rise of 0.5 mm Hg systolic and 0.8 mm Hg diastolic, against falls of 0.6 and 0.3 mm Hg on placebo, with no significant difference in sustained elevated blood pressure. At 200 mg twice daily, about 3.3 times the maximum recommended dose, supine pressure rose 4.7 to 6.8 mm Hg systolic and 4.5 to 7 mm Hg diastolic, and pulse 5 to 6.8 beats per minute [3]. The duloxetine label still directs blood pressure checks before and periodically during treatment, and it carries warnings for orthostatic hypotension, falls, and syncope [3].

Trulicity's Warnings and Precautions cover pancreatitis, hypoglycemia with insulin or secretagogues, hypersensitivity, kidney injury from volume depletion, severe gastrointestinal reactions, retinopathy complications, gallbladder disease, and aspiration during anesthesia; blood pressure is not among them [1].

Serotonin syndrome

The serotonin warning sits on the SNRI side. The venlafaxine label states that SNRIs can precipitate serotonin syndrome and that risk rises with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's wort, and with MAOIs; it can also occur when these drugs are used alone [2]. Listed signs include mental status changes, autonomic instability such as tachycardia and labile blood pressure, neuromuscular findings such as tremor and hyperreflexia, seizures, and gastrointestinal symptoms [2].

Dulaglutide works at GLP-1 receptors, and serotonin syndrome is not among the Trulicity Warnings and Precautions [1]. Dulaglutide is not on the venlafaxine label's list of serotonergic drugs [2].

Hypoglycemia: what the label names

The Trulicity label puts hypoglycemia risk with insulin secretagogues and insulin, and advises considering a reduction in those doses when starting dulaglutide [1]. In the label's trials, hypoglycemia below 54 mg/dL occurred in 14.7% of patients on dulaglutide 1.5 mg with insulin glargine versus 9.3% on placebo, and in 3.3% with glimepiride versus 0% on placebo. When added to metformin the rates were 0.7% on 1.5 mg versus 0% on placebo [1].

Other effects the labels describe

The venlafaxine label recommends reducing the dose gradually when treatment is discontinued and monitoring for discontinuation symptoms [2]. The Trulicity label highlights gastrointestinal reactions such as nausea, vomiting, and diarrhea, and kidney injury from the dehydration they can cause. It also states that Trulicity is not recommended in patients with severe gastroparesis [1].