Phentermine vs. semaglutide: a short-term stimulant or a weekly GLP-1

The two work in unrelated ways. Phentermine is a sympathomimetic amine, chemically and pharmacologically related to the amphetamines, according to its label. It suppresses appetite through the nervous system, which is also why it can raise heart rate and blood pressure and disturb sleep. It is a Schedule IV controlled substance, taken by mouth once a day, usually 37.5 mg before breakfast or one to two hours after it, and approved as a short-term adjunct lasting a few weeks. Semaglutide mimics GLP-1, a gut hormone that slows stomach emptying and reduces appetite. As Wegovy it is injected once weekly, escalating over 16 weeks to a usual 2.4 mg maintenance dose, and is approved to reduce excess weight and keep it off long term. Wegovy's label also covers cardiovascular risk reduction in adults with established heart disease. Phentermine's label lists heart disease as a reason not to use it.

There is no randomized trial comparing phentermine with semaglutide, so any comparison sets separate studies side by side, with different populations, durations and designs. For semaglutide, the STEP 1 trial (NEJM, 2021) randomized 1,961 adults without diabetes to Wegovy 2.4 mg or placebo for 68 weeks. Mean body weight changed by −14.9% with semaglutide versus −2.4% with placebo, and 86.4% versus 31.5% lost at least 5%. For phentermine alone, the best randomized data come from the 28-week EQUATE trial (Aronne et al., Obesity, 2013), which tested it as a comparator for the phentermine–topiramate combination. There, 46.2% of people on phentermine 15 mg lost at least 5% of their weight, against 15.5% on placebo, where average loss was 1.7%. Longer use has only observational data: in a 13,972-person health-record cohort (Lewis et al., Obesity, 2019), people using phentermine continuously for more than 12 months lost 7.4 percentage points more at 24 months than those who stopped within 3 months. Being observational, it cannot rule out that longer users simply differed. The trials also measured different things over different spans: STEP 1 ran more than twice as long as EQUATE, and EQUATE's phentermine arm used 15 mg rather than the usual 37.5 mg. None of these figures predicts what any one person will lose.

The side-effect profiles barely overlap. Phentermine's label lists raised blood pressure, palpitations and a fast heart rate, insomnia, restlessness, dizziness, tremor, dry mouth, an unpleasant taste, and diarrhea or constipation. Rarer but serious are primary pulmonary hypertension and heart-valve disease. Tolerance to the appetite effect usually develops within a few weeks, and there is a risk of abuse and dependence. Semaglutide's problems are mostly digestive. In Wegovy's label, nausea affected 44% versus 16% on placebo, diarrhea 30% versus 16%, and vomiting and constipation 24% each against 6% and 11%. These are worst during dose increases. Wegovy carries a boxed warning about thyroid C-cell tumors seen in rodents, and warnings for pancreatitis and gallbladder disease. It raised average resting heart rate by 1 to 4 beats per minute in adult trials, which the label asks prescribers to monitor.

Phentermine can suit a healthy adult with no heart disease, normal or well-controlled blood pressure and no history of substance misuse, who wants a generic, short course alongside diet and exercise, and who accepts that its label frames it as a few weeks of treatment. It does not suit anyone with coronary disease, arrhythmia, heart failure, a past stroke, uncontrolled hypertension, hyperthyroidism, glaucoma, agitation, or recent MAO inhibitor use, and it is not for pregnancy or breastfeeding. Semaglutide suits people who want long-term weight management, and it is the only one of the two with a label indication to reduce cardiovascular events in adults with established heart disease. It does not suit anyone with a personal or family history of medullary thyroid carcinoma or MEN 2, a history of pancreatitis needs careful discussion, and it too is not for pregnancy. Access matters too: Temi cannot prescribe phentermine at all, so it has to come from a prescriber who writes controlled-substance prescriptions. Neither is right if you want a medicine to replace changes in diet and activity: both labels approve them only as additions to those.