Tirzepatide (sold as Zepbound) is currently the most effective prescription medication for weight loss, producing an average of 20.2% body weight reduction in clinical trials. That means a person weighing 250 pounds could expect to lose roughly 50 pounds. Its closest competitor, semaglutide (Wegovy), averaged 13.7% in a head-to-head comparison. Both are weekly injections, and both require a prescription.
But “best” depends on more than raw numbers. Cost, insurance coverage, how you feel on the medication, and whether you prefer a pill or an injection all matter. Here’s what you need to know about every FDA-approved option.
The Two Most Effective Options
Tirzepatide and semaglutide belong to a class of drugs that mimic hormones your gut naturally releases after eating. These hormones signal your brain to feel full, slow the rate your stomach empties, and boost insulin release. The net effect is that your appetite drops significantly, and you eat less without the constant feeling of fighting hunger.
Semaglutide (Wegovy) targets one of these hormone pathways. Tirzepatide (Zepbound) targets two, which likely explains its edge in weight loss. In the SURMOUNT-5 trial, which directly compared the two drugs, tirzepatide produced 20.2% body weight loss versus 13.7% for semaglutide. Both are given as a weekly self-injection using a small pen device, and both are gradually increased in dose over several months to reduce side effects.
Oral Medications: Pills That Work
Not everyone wants or can afford an injectable. The FDA has approved several oral medications for long-term weight management, and two stand out.
Phentermine-topiramate (Qsymia) is a once-daily pill and was the most effective oral option in a large systematic review. For every three people who took it, one achieved at least 10% body weight loss who wouldn’t have on placebo alone. It works by suppressing appetite through two different mechanisms. The weight loss is less dramatic than the injectables, but it’s meaningful, and the pill format is simpler for many people.
Naltrexone-bupropion (Contrave) is taken once or twice daily and showed similar numbers: for every three people treated, one hit the 5% weight loss threshold. It works partly by reducing food cravings, particularly for people who eat in response to stress or emotion. Both oral medications have higher rates of side effects that lead people to stop taking them compared to placebo, so finding the right fit sometimes takes trial and error.
Orlistat (Xenical or Alli) takes a completely different approach. Instead of suppressing appetite, it blocks your body from absorbing about a third of the fat you eat. It produces more modest weight loss and can cause uncomfortable digestive side effects when you eat high-fat meals. A lower-dose version (Alli) is available over the counter, making it the only weight loss medication you can get without a prescription.
How These Drugs Actually Feel
The most common side effects across the injectable medications are gastrointestinal. In clinical studies, about 21% of people on GLP-1 drugs experienced nausea, 11% had diarrhea, and 9% had vomiting. These symptoms are usually worst during the first few weeks and during dose increases, then tend to fade. Eating smaller meals and avoiding fatty or greasy foods helps most people manage them.
Constipation and indigestion each affect roughly 8% of users. Rare but serious complications like bowel obstruction have been reported, primarily in people who already had gut motility problems. The gradual dose-escalation schedule that most prescribers follow exists specifically to minimize these effects.
One concern that gets less attention is muscle loss. When you lose a large amount of weight quickly, some of that loss comes from lean muscle, not just fat. This is true regardless of how the weight is lost, but it’s especially relevant with the newer, more powerful drugs that produce rapid loss. Resistance training and adequate protein intake are consistently recommended alongside any weight loss medication to preserve muscle.
Who Qualifies for a Prescription
Weight loss medications are generally prescribed for adults with a BMI of 30 or higher (which qualifies as obesity) or a BMI of 27 or higher with at least one weight-related health condition like high blood pressure, type 2 diabetes, or high cholesterol. Your doctor will assess whether medication makes sense based on your full health picture, not just the number on the scale.
Phentermine, a short-term appetite suppressant, is FDA-approved for only a few weeks of use. The six medications approved for long-term use are orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide (Saxenda, a daily injection), semaglutide, and tirzepatide.
Cost Is a Major Factor
The injectable weight loss drugs can cost $1,300 or more per month without insurance. That’s a significant barrier, and insurance coverage is inconsistent. Some employers specifically exclude these drugs from their health plans. Many insurers require prior authorization and may deny coverage unless you have an obesity-related medical condition beyond a high BMI alone. Medicare currently cannot cover weight loss medications at all.
The oral options tend to be cheaper, especially generic phentermine (for short-term use) and orlistat. If cost is a deciding factor, Qsymia and Contrave offer real results at a lower price point than the injectables, though they still require a prescription and may not be covered by every plan.
What Happens When You Stop
This is the part most people don’t hear about upfront. A 2025 systematic review in The BMJ found that people regain weight at a rate of about 0.8 kg (roughly 1.75 pounds) per month after stopping the newer injectable medications. On average, people are projected to return to their original weight within about 1.5 years of stopping treatment.
That doesn’t mean the medication “didn’t work.” It means obesity is a chronic condition, and these drugs manage it rather than cure it, similar to how blood pressure medication controls hypertension but doesn’t eliminate it. Many people need to stay on medication long-term to maintain their results, which makes cost and tolerability even more important considerations. Others use the initial weight loss period to build exercise and eating habits that help them keep off at least a portion of the weight after stopping.
Choosing the Right Medication
If maximum weight loss is your priority and cost isn’t a barrier, tirzepatide (Zepbound) has the strongest clinical evidence. Semaglutide (Wegovy) is a close second and may be easier to access depending on your insurance. If you prefer a pill, phentermine-topiramate (Qsymia) offers the best results among oral options. And if you want something available without a prescription, low-dose orlistat (Alli) is your only choice, though the results will be more modest.
The “best” medicine is ultimately the one that produces meaningful weight loss you can sustain, with side effects you can tolerate, at a price you can afford. A conversation with your prescriber about your health history, your goals, and your budget will narrow the list quickly.