The pills and injectables that produce the most weight loss are tirzepatide (sold as Zepbound) and semaglutide (sold as Wegovy), both prescription medications. In a head-to-head clinical trial, tirzepatide led to an average weight loss of 20.2% of body weight, while semaglutide produced 13.7%. For a 250-pound person, that translates to roughly 50 pounds lost with tirzepatide versus 33 pounds with semaglutide.
These are the standout performers, but they aren’t the only options. Seven FDA-approved weight loss medications are currently on the market, ranging from daily pills to weekly injections, and they vary significantly in how much weight they help people lose.
How the Top Medications Compare
Most FDA-approved weight loss medications help adults lose between 3% and 12% of their starting body weight within a year. The two newest options blow past that range. In the SURMOUNT-1 trial, tirzepatide averaged 17.8% body weight loss, and in the STEP-1 trial, semaglutide averaged 12.4%. A later head-to-head study (SURMOUNT-5) pushed those numbers even higher when doses were optimized, with tirzepatide reaching 20.2% and semaglutide 13.7%. That makes tirzepatide roughly 47% more effective than semaglutide for pure weight loss.
Both of these medications are injectables given once a week, not daily pills. They work by mimicking gut hormones that regulate hunger. Tirzepatide activates two hormone receptors (GLP-1 and GIP), while semaglutide activates one (GLP-1). That dual action is likely why tirzepatide has the edge.
The Best Pill-Only Options
If you specifically want something you swallow rather than inject, the most effective prescription pill is phentermine/topiramate (Qsymia). In a 56-week clinical trial, people taking the highest dose lost an average of 32 pounds and about 5 inches off their waist. It works through two mechanisms: phentermine suppresses appetite by stimulating the central nervous system, while topiramate increases feelings of fullness and can even change how certain foods taste, making overeating less appealing. You take it once daily in the morning, and your doctor will gradually increase the dose over the first month.
Other prescription pill options include bupropion/naltrexone (Contrave), which targets brain pathways involved in cravings and reward, and phentermine on its own (Adipex-P), which is typically prescribed for shorter periods. An oral form of semaglutide also exists, though injectable versions generally produce stronger results because it’s easier to deliver a higher, more consistent dose through injection than through the stomach lining.
The only over-the-counter weight loss pill with FDA approval is orlistat, sold as Alli. It works differently from everything else on this list: instead of suppressing appetite, it blocks your body from absorbing about 25% of the fat you eat. The results are modest. In studies, people who combined Alli with diet and exercise lost an average of 5.7 extra pounds over a year compared to diet and exercise alone. About 40% of users lost at least 5% of their body weight. It’s the least powerful option, but it’s the only one you can buy without a prescription.
How These Medications Work in Your Body
The GLP-1 medications (semaglutide and tirzepatide) mimic a hormone your gut naturally releases after eating. This hormone tells your brain you’re full, slows down how quickly food leaves your stomach, and helps regulate blood sugar by prompting your pancreas to release insulin at the right time. When you take a GLP-1 medication, you’re amplifying that signal so your appetite drops and you feel satisfied with smaller portions. The slowed digestion also means fewer blood sugar spikes after meals, which reduces the cycle of hunger and craving that drives overeating.
Tirzepatide adds a second hormone signal (GIP) on top of GLP-1, which appears to enhance the appetite-suppressing and metabolic effects. This is why it consistently outperforms semaglutide in trials.
Qsymia takes a completely different approach. The phentermine component acts as a stimulant that directly dulls your appetite, while topiramate boosts activity of a brain chemical that promotes satiety. Together, they attack overeating from two angles. Because phentermine is a stimulant, you take the pill in the morning to avoid sleep disruption.
Side Effects to Expect
Nausea, vomiting, diarrhea, and constipation are by far the most common side effects of GLP-1 medications. For most people, these are worst in the first few weeks as the dose ramps up, then fade. Less common but more serious risks include inflammation of the pancreas, gallstone attacks, and gastroparesis (where food movement out of the stomach slows significantly or stops). Bowel obstruction, while rare, has also been reported.
Rapid weight loss from these medications can also change your appearance in unexpected ways. “Ozempic face” refers to the hollowed, aged look that can develop when fat is lost quickly from the face, leading to sunken cheeks, more visible wrinkles, and sagging skin around the jaw. This is more common with larger amounts of weight loss.
If you’re scheduled for surgery involving general anesthesia, your doctor will likely ask you to stop GLP-1 medications a few days beforehand. Because these drugs slow digestion, your stomach may not be empty when it needs to be for safe sedation.
Orlistat (Alli) has its own distinctive side effect profile. Because it blocks fat absorption, undigested fat passes through your system, which can cause oily stools, gas, and urgent bowel movements, especially after high-fat meals.
How Long Treatment Lasts
Weight loss medications are not short-term fixes. Your doctor will typically evaluate progress after 12 to 24 weeks. If the medication is working, you’ll likely stay on it long term to maintain results. One study followed patients for a median of nearly five years and found they maintained an average weight loss of 10.6% when combining medication with lifestyle changes over three to five years. Stopping medication often leads to regaining much of the lost weight, which is why most treatment plans are open-ended.
What They Cost Without Insurance
Cost is a real barrier. Both Wegovy and Zepbound are available directly from their manufacturers at $499 per month without insurance, with Zepbound’s lowest starter dose priced at $349 per month. These prices reflect recent reductions aimed at people paying out of pocket, but they’re still significant. Older medications like Qsymia and generic orlistat are considerably cheaper. Insurance coverage varies widely, and many plans still do not cover weight loss medications, though this has been changing as more employers and insurers recognize obesity as a chronic condition.
Ranking by Weight Loss Power
- Tirzepatide (Zepbound): ~20% body weight loss, injectable, most effective overall
- Semaglutide (Wegovy): ~14% body weight loss, injectable, strong second option
- Phentermine/topiramate (Qsymia): ~32 lbs average loss in trials, best pill-only option
- Bupropion/naltrexone (Contrave): moderate weight loss, oral pill targeting cravings
- Phentermine (Adipex-P): short-term appetite suppressant, oral pill
- Orlistat (Alli/Xenical): ~5.7 extra pounds lost per year, only OTC option
All of these medications work best alongside changes in diet and physical activity. The pill or injection handles the hunger and biological drive to overeat, but lasting results depend on building habits that support the weight loss once medication does its part.