GLP-1 vs Phentermine: Semaglutide, Tirzepatide, and How They Compare to an Older Stimulant

How much weight loss do the GLP-1 drugs produce?

In STEP 1, 1,961 adults without diabetes received semaglutide 2.4 mg weekly or placebo for 68 weeks [1]. Mean weight change was -14.9% versus -2.4%, and 86.4% of the semaglutide group lost at least 5% of body weight versus 31.5% on placebo [1].

In SURMOUNT-1, 2,539 adults were randomized to tirzepatide 5, 10 or 15 mg or placebo for 72 weeks. Mean weight change was -15.0%, -19.5% and -20.9% against -3.1% on placebo [2]. Tirzepatide is labeled a dual GIP and GLP-1 receptor agonist rather than a pure GLP-1 agonist [6].

SURMOUNT-5 compared the two directly in 751 adults with obesity and no diabetes: the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) for 72 weeks produced -20.2% versus -13.7%, with waist circumference down 18.4 cm versus 13.0 cm [3].

Wegovy is also indicated to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight [4].

Where does phentermine fit?

Phentermine is an older oral appetite suppressant that does not act on the GLP-1 receptor. GLP-1 receptor agonists bind and activate the receptor for glucagon-like peptide-1, a natural hormone that helps regulate appetite and calorie intake, and the labels describe GLP-1 receptors in brain regions that regulate appetite [4][7].

The percentages in the trials above describe each GLP-1 drug against placebo, or tirzepatide against semaglutide, not against phentermine, so they cannot establish how much more or less weight either drug would produce than phentermine [1][2][3].

What do the GLP-1 labels say to watch for?

Among 2,116 adults on Wegovy 2.4 mg in weight-management trials, nausea occurred in 44% versus 16% on placebo, diarrhea in 30% versus 16%, vomiting in 24% versus 6% and constipation in 24% versus 11% [4]. Rates from different trials are not directly comparable [4].

In the same trials, 6.8% of adults on Wegovy 2.4 mg discontinued for adverse reactions versus 3.2% on placebo, and cholelithiasis was reported by 1.6% versus 0.7% [4]. The Wegovy label reports mean resting heart rate increases of 1 to 4 beats per minute [4].

Wegovy and Zepbound carry boxed warnings about thyroid C-cell tumors seen in rodents, with human relevance unknown, and both are contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN 2 [4][6]. The Foundayo boxed warning is worded differently: orforglipron did not produce tumors in rodents, the human relevance of GLP-1 receptor-dependent rodent tumors is undetermined, and it carries the same MTC and MEN 2 contraindication [7]. Byetta carries no boxed warning [8]. Labels also list acute pancreatitis, severe gastrointestinal reactions (not recommended in severe gastroparesis), acute kidney injury from dehydration, gallbladder disease, hypoglycemia when combined with insulin or a sulfonylurea, and pulmonary aspiration during anesthesia or deep sedation [4].

Does the weight come back when a GLP-1 drug stops?

In STEP 4, 803 adults who had reached semaglutide 2.4 mg were randomized to continue it or switch to placebo for 48 weeks [9]. Weight fell another 7.9% on continued semaglutide and rose 6.9% on placebo [9].