Weight Loss Medications: GLP-1 Agonists vs. Older Drugs - What Works Better and Why

When it comes to losing weight, pills and injections aren’t magic. But some are far more effective than others-and the gap between old-school weight loss drugs and the newer GLP-1 agonists is wider than most people realize.

GLP-1 Agonists: The New Standard

GLP-1 agonists like Wegovy, Zepbound, and Saxenda aren’t just another weight loss option. They’re changing how doctors treat obesity. These drugs mimic a natural hormone your body makes after eating-glucagon-like peptide-1-that tells your brain you’re full and slows down digestion. The result? Less hunger, fewer cravings, and more weight lost.

In clinical trials, people using Wegovy (semaglutide) lost around 15% of their body weight on average. Zepbound (tirzepatide), which also targets a second hormone called GIP, pushed that number even higher-up to 21% in some studies. That’s not a few pounds. For someone weighing 200 pounds, that’s 30 to 40 pounds gone. And it’s not just about appearance. Losing that much weight lowers blood pressure, improves blood sugar, and reduces risk of heart disease.

These drugs are injected once a week (except for Rybelsus, the oral version of semaglutide). They were originally designed for type 2 diabetes, but their weight loss effects were so strong that the FDA approved them specifically for obesity. Now, they’re the most prescribed weight loss medications in the U.S., making up nearly 80% of all new prescriptions for weight loss.

Older Drugs: The Tried-and-True, But Less Powerful

Before GLP-1 agonists, the main options were drugs like orlistat (Xenical, Alli), phentermine-topiramate (Qsymia), and naltrexone-bupropion (Contrave). These have been around for 10 to 20 years. They work differently: orlistat blocks fat absorption in your gut, Qsymia suppresses appetite through brain chemicals, and Contrave targets reward pathways to reduce food cravings.

But their results? Much slower and smaller. Most people on these older drugs lose 5% to 10% of their body weight. That’s about 10 to 20 pounds for someone weighing 200. Orlistat often causes oily stools and frequent bathroom trips because undigested fat leaves your body. Qsymia can cause tingling, dry mouth, or mood changes. Contrave might lead to headaches or increased blood pressure.

And here’s the kicker: even the best of these older drugs can’t match GLP-1s. One direct comparison showed Wegovy users lost 16% of their weight, while Saxenda users-another GLP-1-only lost 6%. That’s not a small difference. That’s a whole new level of effectiveness.

Cost: The Big Hurdle

There’s a reason you see so many ads for Wegovy and Zepbound-but also so many people complaining about them. The price tag is brutal. Without insurance, a monthly supply costs between $1,000 and $1,400. That’s more than most people spend on rent or car payments in a month.

Older drugs? A month of phentermine might cost $10 to $50. Qsymia and Contrave run $100 to $150. Orlistat is even cheaper, especially the over-the-counter version, Alli.

Insurance coverage is a mess. Most plans won’t cover GLP-1s for weight loss unless you have diabetes or a BMI over 40 (or 35 with other health issues like high blood pressure). Even then, prior authorizations get denied 45% of the time, according to patient surveys. Many people end up paying out of pocket-or giving up after a few months.

Manufacturer coupons help, but they cap savings at $500 to $1,000 per year. That’s not enough when you’re paying $1,300 a month.

Side Effects: Not Just Nausea

GLP-1 agonists aren’t side effect-free. Up to half of users experience nausea, vomiting, diarrhea, or constipation-especially when starting or increasing the dose. These usually get better over time, but for some, they’re severe enough to quit.

Reddit communities like r/Wegovy and r/Ozempic are full of stories: people who couldn’t eat without feeling sick, others who developed gastroparesis-like symptoms where food sits in the stomach for hours. One user on Drugs.com lost 78 pounds on Wegovy-but also spent three weeks in the ER with dehydration from vomiting.

Older drugs have their own issues. Orlistat causes embarrassing digestive accidents. Qsymia can cause birth defects, so women must use strict birth control. Contrave carries a black box warning for suicidal thoughts in rare cases.

The bottom line? GLP-1s are more effective, but harder to tolerate. Older drugs are gentler on the stomach but don’t deliver the same results.

Real-World Results vs. Clinical Trials

Here’s where things get messy. Clinical trials show GLP-1s work wonders. But real life? It’s different.

A 2024 study from NYU Langone Health followed over 50,000 people. Those on GLP-1s lost only 4.7% of their weight after six months-and 7% after a full year. That’s less than half the results seen in controlled trials. Why? People stop taking them. About 70% quit within a year, mostly because of cost, side effects, or not seeing fast enough results.

Compare that to bariatric surgery: the same study showed surgery patients lost 24% of their body weight in two years. And the weight stayed off longer. Surgery isn’t perfect-it’s invasive, risky, and requires lifelong dietary changes-but it’s more durable.

Even worse: once you stop a GLP-1 agonist, most people regain the weight. Studies show 50% to 100% of lost weight comes back within a year of quitting. These drugs don’t fix your habits-they just help you stick to them. If you go back to old eating patterns, the scale climbs again.

Who Should Use What?

There’s no one-size-fits-all. But here’s a rough guide:

• If you want the biggest possible weight loss and can handle injections and high costs, GLP-1 agonists like Wegovy or Zepbound are your best bet.
• If you’re on a tight budget or hate needles, older drugs like Qsymia or Contrave might be worth trying-just know you’ll likely lose less.
• If you have type 2 diabetes, GLP-1s are a no-brainer. They help your blood sugar AND your weight.
• If you’ve tried everything and still can’t lose weight, surgery may be more effective than any pill.

And remember: no medication works without lifestyle changes. You can’t out-inject a bad diet. These drugs help you eat less, but you still have to choose healthier foods and move more.

The Future: What’s Coming Next

GLP-1s aren’t the end. New drugs are already in the pipeline. Retatrutide, a triple agonist targeting GLP-1, GIP, and glucagon, showed 24.2% weight loss in early trials. MariTide, a new antibody from Amgen, is now in Phase 3 testing and looks promising.

By 2027, analysts predict GLP-1 drugs will make up 85% of the weight loss market. But if prices don’t drop, many people won’t be able to afford them. Generic versions might arrive after 2030, when semaglutide’s patents expire. That could change everything.

For now, the choice is clear: GLP-1 agonists are the most powerful weight loss tools we have. But they’re not easy, cheap, or permanent. They’re a tool-like a gym membership or a personal trainer. Use them right, and they can transform your health. Stop using them, and the results fade.