Oral Diabetes Medications Compared: Metformin, Sulfonylureas, and GLP-1 Agonists

When you're managing type 2 diabetes, choosing the right medication isn't just about lowering blood sugar-it’s about finding something that fits your life, your body, and your long-term health goals. Three main oral medications dominate the conversation: metformin, sulfonylureas, and GLP-1 receptor agonists. Each works differently, has different side effects, and affects more than just your A1C. Here’s what actually matters when deciding between them.

Metformin: The Longtime Standard

Metformin has been the go-to first-line drug for type 2 diabetes for over 25 years. It doesn’t make your pancreas pump out more insulin. Instead, it tells your liver to stop making so much glucose and helps your muscles use insulin better. That’s why it rarely causes low blood sugar-unlike other options.

Most people see their A1C drop by 1% to 2% on metformin, especially at the full dose of 2,000 mg per day. It’s also weight neutral or can even help you lose 2-3 kg over time. For someone trying to avoid weight gain, that’s a big deal.

But here’s the catch: up to 30% of people can’t tolerate it. Diarrhea, nausea, bloating-these side effects are real. Many quit after the first week. Extended-release versions help, but not everyone. One patient in Austin told me, “I tried every brand, every dose, every schedule. My stomach just won’t adjust.”

Metformin is cheap-often under $10 a month with insurance, sometimes even less without. It’s also been studied more than any other diabetes drug. Long-term data shows it reduces heart attack risk and may even lower cancer rates in diabetics. But a 2024 study of 2.5 million patients found a 2.2x higher risk of Alzheimer’s diagnosis in metformin users compared to those on GLP-1 agonists. That doesn’t mean metformin causes Alzheimer’s-it’s a correlation still being studied-but it’s something to discuss with your doctor if you have family history.

Sulfonylureas: Old School, High Risk

Sulfonylureas like glipizide and glimepiride were the first oral diabetes pills ever made, back in the 1950s. They work by forcing your pancreas to release more insulin, no matter what your blood sugar is. That’s powerful-but dangerous.

They lower A1C about 1% to 1.5%, similar to metformin. But they come with a heavy price: hypoglycemia. About 1 in 3 people on sulfonylureas have at least one mild low-blood-sugar episode per year. Severe lows-ones that require help from someone else-happen in 2% to 4% of users annually. That’s not just dizziness or shakiness. That’s passing out, seizures, or needing emergency glucagon.

And then there’s weight gain. Most people gain 2-4 kg on sulfonylureas. For someone already struggling with insulin resistance, that makes diabetes harder to control. One patient on Reddit shared: “I was on glipizide for three years. Had four ER visits for low blood sugar. My doctor said ‘just eat more carbs.’ But I was already overweight.”

Doctors still prescribe them because they’re cheap-$10 to $30 a month-and effective in the short term. But the American College of Physicians says they’re riskier than other options for hypoglycemia and don’t protect your heart. In fact, newer studies suggest they might even raise heart disease risk compared to metformin.

They’re fading fast. In 2023, only 8.2 million sulfonylurea prescriptions were filled in the U.S.-down from over 15 million a decade ago. GLP-1 agonists now outsell them.

GLP-1 Agonists: The New Powerhouse

GLP-1 receptor agonists are not traditional pills. Most are injections-once daily or once weekly. But there’s one exception: oral semaglutide (Rybelsus), approved in 2019. It’s the only oral GLP-1 on the market, and it’s changing the game.

These drugs mimic a natural hormone that tells your body to release insulin only when blood sugar is high. They also slow digestion, reduce appetite, and help your pancreas make more insulin over time. The result? A1C drops of 0.8% to 1.5%, weight loss of 3-6 kg, and fewer lows.

The biggest win? Heart protection. In the LEADER trial, liraglutide cut major heart events by 13%. Semaglutide did even better in the SELECT trial, reducing heart attacks and strokes by 20% in high-risk patients. That’s why the American Diabetes Association now recommends GLP-1 agonists for anyone with heart disease-even before switching from metformin.

Side effects? Nausea and vomiting affect 20% to 40% of users, especially at first. But most people adapt. Slow dose increases help. One patient on the ADA forum wrote: “First month on Ozempic? I couldn’t eat anything. Month three? My A1C dropped from 7.8 to 6.2. I lost 18 pounds. No diet changes. Worth it.”

Cost is the biggest barrier. Without insurance, GLP-1 agonists cost $700-$900 a month. Metformin? $4. But manufacturer programs like Novo Nordisk’s Care Connections can bring copays down to $0 for eligible patients. And with biosimilars coming, prices are expected to drop significantly by 2027.

How They Stack Up

Who Gets Which Drug?

There’s no one-size-fits-all. But here’s how most doctors decide:

• Start with metformin if you’re newly diagnosed, have no heart disease, and can tolerate the side effects. It’s safe, cheap, and proven.
• Avoid sulfonylureas if you’re older, live alone, drive for a living, or have had low blood sugar before. The risk isn’t worth the modest benefit.
• Choose GLP-1 agonists if you have heart disease, kidney disease, or need to lose weight. Even if you’re on metformin already, adding a GLP-1 agonist is often better than switching to a sulfonylurea.

Some patients need more than one. The GRADE trial showed that adding a GLP-1 agonist to metformin lowered A1C by 1.5%-compared to 1.0% with sulfonylureas. That difference matters over 10 years.

What’s Next?

The future of diabetes meds is moving fast. New triple agonists like retatrutide are showing A1C drops of over 3% and weight loss of nearly 25% in trials. Oral GLP-1s are getting better-more convenient, more effective. And as biosimilars hit the market, prices should drop.

But for now, the choice is still between three well-known drugs. Metformin is the foundation. Sulfonylureas are fading. GLP-1 agonists are rising-not just because they work better, but because they protect your heart, help you lose weight, and don’t make you pass out.

If you’re on sulfonylureas and have had a low blood sugar episode, ask your doctor about switching. If you’re on metformin and can’t handle the stomach issues, ask about switching to a GLP-1 agonist. And if you’re newly diagnosed, don’t assume metformin is your only option. The landscape has changed.

Final Thoughts

Diabetes isn’t just about numbers on a glucose meter. It’s about how you feel, how you live, and what you’re willing to tolerate to stay healthy. Metformin is the classic starter. Sulfonylureas are fading because they’re risky. GLP-1 agonists are the future-not because they’re trendy, but because they change outcomes. They don’t just lower A1C. They save hearts. They help you lose weight. They reduce hospital visits.

Cost and access are still huge barriers. But if you’re eligible for assistance programs, the switch could be life-changing. Talk to your doctor. Ask about alternatives. Don’t settle for a drug that makes you feel worse just because it’s cheap. Your long-term health is worth more than a $10 pill.