Tirzepatide's stomach-slowing effect fades with repeat dosing, study finds

Tirzepatide slowed the rate at which the stomach empties about as much as semaglutide did, but that effect disappeared after two weeks of repeated dosing, according to a brief report published June 10, 2020, in the journal Diabetes, Obesity and Metabolism ^[1]. The work was led by researchers at Eli Lilly and Company, which funded the study ^[1].

Gastric emptying is how quickly the stomach passes food into the small intestine. Slower emptying is one of the ways GLP-1 drugs such as semaglutide are thought to affect blood sugar and appetite ^[1]. In mice, tirzepatide delayed gastric emptying to a similar degree as semaglutide, but those acute effects were "abolished" after two weeks of treatment ^[1]. A long-acting GIP analog given alone had no effect on gastric emptying, and adding it to a GLP-1 drug did not slow emptying any more than the GLP-1 drug alone ^[1].

The human portion came from a phase 1, four-week multiple-dose study. Tirzepatide was given once a week to participants with and without type 2 diabetes, and gastric emptying was measured using acetaminophen absorption ^[1]. In people with type 2 diabetes, single doses of tirzepatide at 5 mg or higher delayed gastric emptying; in people without type 2 diabetes, doses of 4.5 mg or higher did the same ^[1]. After multiple doses in healthy participants, that effect diminished for both tirzepatide and the comparison drug dulaglutide ^[1]. In participants with type 2 diabetes who followed an escalating schedule of 5/5/10/10 mg or 5/5/10/15 mg, a leftover delay in gastric emptying was still seen after several doses ^[1].

An earlier conference abstract describing the same program, presented at the American Diabetes Association's 2019 Scientific Sessions, gives more detail ^[2]. That study enrolled 35 healthy participants in the multiple ascending dose portion and 53 people with type 2 diabetes in the proof-of-concept portion ^[2]. After the first tirzepatide dose above 1.5 mg, peak acetaminophen levels fell by about 50% and the time to peak was delayed by an hour, while total drug exposure was not notably changed ^[2]. With fixed doses, the effect was largest after the first dose and showed "complete tachyphylaxis" — a full loss of the effect — after repeated dosing by day 23 ^[2]. In the step-up dosing groups, the loss of effect was incomplete ^[2].

Tirzepatide has a half-life of about five days, which supports once-weekly dosing ^[1]. In an earlier phase 2b study cited in the report, tirzepatide produced greater reductions in HbA1c and body weight than dulaglutide, with HbA1c falling up to 25.4 mmol/mol compared with 13.7 mmol/mol, and weight falling 11.3 kg compared with 2.7 kg ^[1]. Because tirzepatide's effect on gastric emptying did not last, the report's authors suggest the drug's blood sugar benefit is probably not mainly explained by slowed stomach emptying ^[1].

Why it matters for patients

Feeling full quickly, nausea and stomach discomfort are common reasons people stop GLP-1 medications, and slowed stomach emptying is often assumed to be the cause. This study suggests that for tirzepatide, that slowing is strongest right after the first dose and largely goes away within a few weeks of continued treatment, at least in healthy volunteers ^[1][2]. Two things follow from that. First, stomach-related side effects early in treatment may ease on their own, though the study did not measure symptoms directly. Second, if slowed emptying fades while blood sugar and weight effects continue, those effects are likely coming from other actions of the drug ^[1].

Some limits are worth noting. Much of the evidence comes from mice, and animal results do not always carry over to people ^[1]. The human portion was a phase 1 study, not a large trial designed to compare clinical outcomes ^[1]. The report does not say whether the residual delay seen in people with type 2 diabetes on step-up dosing lasts beyond four weeks, whether it changes how patients feel, or how these findings apply to the higher doses used later in treatment. Those questions have not been reported. The authors of the study are employees of Eli Lilly, which makes tirzepatide and funded the work ^[1].