Using Dose Titration to Resolve Constipation on Zepbound (tirzepatide)

What the Label Says About Dose Titration

The Zepbound label starts everyone at 2.5 mg once weekly for 4 weeks. After that, the dose goes to 5 mg, and it can then be raised by 2.5 mg increments, but not sooner than 4 weeks on the current dose [1]. The 2.5 mg dose is for treatment initiation and is not approved as a maintenance dose [1]. Maintenance for weight reduction is 5 mg, 10 mg or 15 mg weekly; for obstructive sleep apnea it is 10 mg or 15 mg weekly; the maximum is 15 mg weekly [1].

The label says to consider treatment response and tolerability when choosing the maintenance dose, and if a maintenance dose is not tolerated, to consider a lower maintenance dose [1]. It also says the escalation schedule is followed to reduce the risk of gastrointestinal adverse reactions [1].

Does a Higher Dose Mean More Constipation?

In the pooled Zepbound weight-management trials (SURMOUNT-1 and SURMOUNT-2), constipation, including hard stools, was reported in 17% of patients on 5 mg, 14% on 10 mg and 11% on 15 mg, compared with 5% on placebo [1]. The rate was highest at 5 mg and lowest at 15 mg. Any gastrointestinal adverse reaction was reported by 56% of patients on each Zepbound dose versus 30% on placebo [1].

The label says most nausea, vomiting and diarrhea events occurred during dose escalation and decreased over time [1]. That statement covers nausea, vomiting and diarrhea; the label does not make the same statement for constipation [1].

Dose Reduction and Constipation

The label allows a lower maintenance dose when a maintenance dose is not tolerated [1]. The pooled rates above describe groups, not what will happen to one person after a reduction.

Delaying or Alternating Doses

The label sets a minimum interval of 4 weeks before an increase and then relies on response and tolerability for maintenance selection [1]. It gives once-weekly dosing and lists 5 mg, 10 mg and 15 mg as maintenance doses for weight reduction [1]. A 7.5 mg dose is an escalation step in a 2.5 mg increment schedule, not one of the listed maintenance doses [1]. An alternating 5 mg and 7.5 mg weekly schedule is not one of the label's listed maintenance schedules [1].

What About Laxatives?

The AGA/ACG guideline strongly recommends polyethylene glycol, sodium picosulfate, linaclotide, plecanatide and prucalopride for chronic idiopathic constipation in adults, and conditionally recommends fiber, lactulose, senna, magnesium oxide and lubiprostone [2]. Those recommendations are for chronic idiopathic constipation, not for constipation during Zepbound [2].

When Constipation Is More Than a Titration Question

The Zepbound label warns about severe gastrointestinal adverse reactions, which occurred in 1.7% on 5 mg, 2.5% on 10 mg and 3.1% on 15 mg versus 1% on placebo, and says Zepbound is not recommended in patients with severe gastroparesis [1]. The label also warns about acute kidney injury from volume depletion and says to monitor renal function in patients reporting adverse reactions that could lead to volume depletion, especially during dosage initiation and escalation [1].