Triple Agonists (GLP-1/GIP/Glucagon) Special-Populations Summary

What the retatrutide trials measured

338 adults received weekly retatrutide or placebo for 48 weeks. Mean weight change at 48 weeks was -8.7% with 1 mg, -17.1% with 4 mg, -22.8% with 8 mg and -24.2% with 12 mg, versus -2.1% with placebo. Gastrointestinal events were the most common adverse events and were mostly mild to moderate [2].

In a substudy of 98 adults with steatotic liver disease and at least 10% liver fat, mean relative liver fat at 24 weeks changed by -42.9% with 1 mg, -57.0% with 4 mg, -81.4% with 8 mg and -82.4% with 12 mg, versus +0.3% with placebo [3].

Kidney and liver impairment

Approved GLP-1 labels warn of acute kidney injury from volume depletion and say to monitor renal function in patients reporting reactions that could lead to volume depletion [4][5]. The Foundayo (orforglipron) label covers a different, single oral GLP-1 agonist and says that drug is not recommended in severe hepatic impairment [5].

Pregnancy, breastfeeding and contraception

The Wegovy label says weight loss offers no benefit in pregnancy and may cause fetal harm, that for weight reduction or cardiovascular risk reduction Wegovy should be discontinued when pregnancy is recognized and at least 2 months before a planned pregnancy because of the long half-life of semaglutide, and that breastfeeding is not recommended during treatment with Wegovy tablets [4]. The Foundayo label says to discontinue Foundayo when pregnancy is recognized [5].

GLP-1 drugs delay gastric emptying, which can change absorption of oral medicines [4]. The tirzepatide label advises a non-oral contraceptive method or an added barrier method for 4 weeks after starting and after each dose increase; the Foundayo label advises the same for 30 days after starting and after each dose escalation [7][5].

Children and adolescents

Wegovy injection is approved for weight reduction in children aged 12 and older with obesity, and Saxenda for children aged 12 and older weighing over 60 kg with obesity [4][8].

Insulin and sulfonylureas

The Wegovy label states that use in patients with type 1 diabetes, or in combination with insulin, has not been evaluated [4]. GLP-1 drugs raise hypoglycemia risk when combined with insulin or a sulfonylurea, and labels advise considering a lower dose of the insulin or sulfonylurea when starting [4][5]. In the Foundayo type 2 diabetes trial, glucose below 54 mg/dL occurred in 7% of patients taking a sulfonylurea versus 0.5% of those not taking one [5].