Prescription Weight-Loss Drugs Compared (2026): All 6 FDA-Approved Options

The short version

Six drugs hold full FDA approval for long-term weight management in the US, and they are not interchangeable. Two injectable incretin drugs lead on results: semaglutide (Wegovy) produced about 15% mean body-weight loss over 68 weeks, and tirzepatide (Zepbound) reached about 21% at its 15 mg dose over 72 weeks [1][2]. Three oral options deliver less but cost far less and suit people who will not inject: phentermine-topiramate (Qsymia, roughly 10%) [3], naltrexone-bupropion (Contrave, roughly 6%) [4], and orlistat (Xenical/Alli, about 3% above placebo) [5]. Phentermine on its own is FDA-approved only for a few weeks of short-term use [6]. The right pick depends on your weight-loss target, other health conditions, side-effect tolerance, and budget, not on which drug is simply the most potent.

The two heavyweights: semaglutide and tirzepatide

Both are once-weekly injections that work on gut hormone pathways to blunt appetite and slow stomach emptying. Semaglutide is a GLP-1 receptor agonist; in the STEP-1 trial the 2.4 mg dose produced a mean 14.9% weight loss versus 2.4% on placebo at 68 weeks [1]. Tirzepatide activates two receptors, GIP and GLP-1, and in SURMOUNT-1 the 15 mg dose produced a mean 20.9% loss at 72 weeks [2]. A head-to-head trial, SURMOUNT-5, found tirzepatide beat semaglutide directly, with a larger average reduction over 72 weeks [7].

The trade-offs are shared. Nausea, vomiting, diarrhea, and constipation are the common side effects, usually worst during dose escalation. Both carry a boxed warning against use in people with a personal or family history of medullary thyroid carcinoma or MEN2. Weight tends to return after stopping, so these are chronic treatments, not a short course. They are also the most expensive options by a wide margin.

Phentermine-topiramate (Qsymia): the strongest pill

Qsymia is a once-daily capsule combining low-dose phentermine, an appetite-suppressing stimulant, with extended-release topiramate, an anti-seizure drug that also curbs appetite. In the CONQUER trial the top 15/92 mg dose produced a 9.8% mean weight loss and the 7.5/46 mg dose 7.8%, versus 1.2% on placebo, over 56 weeks [3]. That makes it the most effective oral option approved for chronic use.

The cautions are specific. Topiramate can cause birth defects including cleft lip and palate, so Qsymia is dispensed through a risk program with pregnancy testing and requires reliable contraception. It can also cause tingling in the hands and feet, trouble with concentration and word-finding, mood changes, and a rare form of acute glaucoma. The phentermine component raises heart rate and blood pressure, so it is avoided in people with uncontrolled hypertension or recent cardiovascular events.

Naltrexone-bupropion (Contrave): for cravings and reward eating

Contrave pairs naltrexone, an opioid-receptor blocker, with bupropion, an antidepressant that raises dopamine and norepinephrine. The combination targets the brain's appetite and reward circuits rather than gut hormones. In the COR-I trial the 32/360 mg dose produced a 6.1% mean weight loss versus 1.3% on placebo at 56 weeks, with 48% of treated patients losing at least 5% of body weight [4].

It can be a sensible match for people whose eating is driven by cravings, or who also have depression or want to stop smoking, since bupropion treats both. Nausea is the most common side effect. Bupropion carries a boxed warning about suicidal thinking and neuropsychiatric effects, and Contrave is contraindicated in people with a seizure disorder, uncontrolled hypertension, eating disorders, or chronic opioid use.

Orlistat (Xenical/Alli): the non-systemic choice

Orlistat works entirely in the gut, blocking the lipase enzymes that digest dietary fat so about a quarter of the fat you eat passes through unabsorbed. Because it is not absorbed into the bloodstream, it avoids the cardiovascular and central-nervous-system effects of the other drugs. It is also the weakest: in the 4-year XENDOS trial, orlistat produced 5.8 kg of weight loss versus 3.0 kg on placebo, roughly a 3% edge over placebo [5].

Side effects are the point of friction. Oily stools, gas with discharge, and fecal urgency scale directly with how much fat you eat, which some people use as built-in feedback. It is sold over the counter as Alli (60 mg) and by prescription as Xenical (120 mg). A daily multivitamin with fat-soluble vitamins A, D, E, and K is recommended, taken at a different time than the pill.

Phentermine alone: short-term only

Plain phentermine is the oldest and cheapest option, a generic sympathomimetic stimulant that suppresses appetite. Its FDA label is narrow: it is approved only as short-term monotherapy, described as a few weeks, for managing obesity, and it is a Schedule IV controlled substance because it is chemically related to amphetamines [6]. It is widely prescribed off-label for longer than the label allows, but that use is not FDA-endorsed.

Because it raises heart rate and blood pressure and can cause insomnia and jitteriness, it is avoided in people with heart disease, uncontrolled hypertension, hyperthyroidism, a history of substance misuse, or who take MAO inhibitors, and it is not for use in pregnancy. It can work as a short jump-start but is not built for the years-long treatment that obesity, as a chronic condition, usually needs.

How to match a drug to the person

Start with your target. If you need double-digit weight loss and can inject and afford it, tirzepatide or semaglutide are the clear front-runners, and both also improve blood sugar, which matters if you have type 2 diabetes or prediabetes. If you need or prefer a pill, Qsymia is the strongest oral choice for chronic use. If cravings, reward eating, depression, or smoking are in the picture, Contrave's mechanism fits. If you want to avoid any drug that acts on the brain or heart, orlistat is the only non-systemic option, accepting a smaller result. Phentermine alone fits a short, budget-limited jump-start.

Layer your other conditions on top. Uncontrolled high blood pressure or recent heart events steer you away from the stimulant-containing options. A seizure history or chronic opioid use rules out Contrave. Plans for pregnancy rule out Qsymia and the GLP-based drugs. None of these is a decision to make from a comparison table alone: a clinician weighs your full history, and coverage often decides the practical answer.

Cost and access in 2026

Price is frequently the deciding factor because many insurance plans still exclude obesity drugs. As of 2026 the injectables carry list prices near $1,000 to $1,350 a month, though manufacturer self-pay programs cut cash prices substantially; Eli Lilly's direct vials for Zepbound, for example, are offered well below list to people paying out of pocket [8]. The oral drugs are far cheaper: Qsymia and Contrave commonly run around $100 a month with manufacturer coupons, over-the-counter Alli is roughly $50 to $60 a month, and generic phentermine can be $10 to $30 a month.

Prices, coupons, and coverage change often, so confirm the current number with the manufacturer, your pharmacy, and your plan before deciding. A drug you can actually stay on for years usually beats a stronger one you cannot afford to continue, since weight tends to return once any of these treatments stops.