Several types of medicine lower blood sugar, and the right one depends on how your body handles insulin, what other health conditions you have, and how much your blood sugar needs to come down. Metformin is the most widely prescribed starting medication for type 2 diabetes, typically lowering A1c by 0.7% to 1.0%. But newer drug classes, particularly GLP-1 receptor agonists and dual agonists, can reduce A1c by 2% or more while also promoting significant weight loss.
Here’s how each major class works, what to expect from it, and what sets them apart.
Metformin: The Standard Starting Point
Metformin has been the go-to first medication for type 2 diabetes for decades. It works in three ways: it reduces the amount of sugar your liver releases into your bloodstream, slows how much sugar your gut absorbs from food, and helps your muscles use insulin more effectively. In clinical trials, it lowered A1c by about 0.7% to 1.1% depending on the dose, and when added to insulin therapy, patients saw A1c reductions of around 2.1% compared to 1.6% with insulin alone.
Metformin is inexpensive, well-studied, and doesn’t cause weight gain. It also carries a very low risk of hypoglycemia (dangerously low blood sugar) when used on its own. The most common side effects are gastrointestinal: nausea, diarrhea, and stomach discomfort, which often improve after a few weeks or with an extended-release version.
GLP-1 Receptor Agonists
GLP-1 receptor agonists are injectable or oral medications that mimic a gut hormone your body naturally produces after eating. They prompt your pancreas to release more insulin when blood sugar is high, suppress a hormone called glucagon that raises blood sugar, and slow digestion so sugar enters your bloodstream more gradually. They also reduce appetite, which leads to meaningful weight loss for many people.
The most commonly prescribed GLP-1 drugs include semaglutide, liraglutide, dulaglutide, and exenatide. Semaglutide is available as both a weekly injection and a daily pill. These medications are increasingly used early in treatment, not just as a last resort, especially for people who also need to lose weight or have heart disease risk factors.
The tradeoff is a higher rate of digestive side effects. Nausea, vomiting, and diarrhea are common, particularly in the first few weeks as your body adjusts. Some people discontinue treatment because of these effects. In a large comparative review published in The BMJ, semaglutide, liraglutide, dulaglutide, and exenatide all showed significantly higher rates of diarrhea compared to placebo.
Tirzepatide: The Dual Agonist
Tirzepatide works on two gut hormone receptors instead of one, targeting both GLP-1 and GIP pathways. This dual action makes it the most potent blood-sugar-lowering medication currently available. In the SURPASS-2 trial, tirzepatide reduced A1c by 2.01% to 2.30%, compared to 1.86% for semaglutide. The difference was statistically significant.
Weight loss results are also notably larger. In that same trial, participants on tirzepatide lost 7.6 to 11.2 kg compared to 5.7 kg with semaglutide. A later obesity-focused trial found tirzepatide produced 20.2% body weight loss versus 13.7% for semaglutide, with half of tirzepatide users losing 20% or more of their body weight. Side effects are similar to other GLP-1 drugs, with nausea and diarrhea being the most frequent complaints.
SGLT2 Inhibitors
SGLT2 inhibitors take a completely different approach. Instead of acting on insulin or gut hormones, they work through the kidneys. These drugs block a protein that normally reabsorbs sugar back into your bloodstream, causing excess glucose to leave your body through urine. This also produces a mild diuretic effect, which lowers blood pressure.
What makes SGLT2 inhibitors stand out is their protective effect on the heart and kidneys. They reduce cardiac workload, lower blood pressure, decrease inflammation, and improve how the heart and kidneys use energy. These benefits exist even in people who don’t have diabetes, which is why some SGLT2 inhibitors are now approved specifically for heart failure and chronic kidney disease. Common side effects include urinary tract infections and genital yeast infections, both related to the increased sugar in urine.
DPP-4 Inhibitors
DPP-4 inhibitors work on the same incretin system as GLP-1 drugs but from a different angle. Instead of mimicking gut hormones directly, they block the enzyme (DPP-4) that normally breaks those hormones down. This lets your body’s own GLP-1 and GIP hormones stick around longer, boosting insulin release after meals. Common options include sitagliptin, linagliptin, saxagliptin, and alogliptin.
These medications are milder than GLP-1 agonists. They produce more modest A1c reductions, don’t cause significant weight loss, and rarely cause digestive side effects. They’re taken as a daily pill, which some people prefer over injections. One important note: DPP-4 inhibitors should not be combined with GLP-1 receptor agonists. The two classes work on overlapping pathways, and current guidelines confirm that adding a DPP-4 inhibitor to a GLP-1 drug provides no additional blood sugar benefit.
Sulfonylureas
Sulfonylureas are an older class of diabetes medication that stimulates the pancreas to produce more insulin regardless of your blood sugar level. They’re effective and inexpensive, but this constant insulin push creates a significant downside: they carry the highest risk of hypoglycemia among oral diabetes drugs. They also tend to cause weight gain. For these reasons, they’re used less often today as newer options have become available, though they remain a reasonable choice when cost is a major barrier to treatment.
Thiazolidinediones
Thiazolidinediones, with pioglitazone being the most common, improve blood sugar by making your fat, muscle, and liver cells more sensitive to insulin. They activate a receptor that regulates how your body processes glucose, fats, and proteins. The result is better insulin efficiency without directly increasing insulin production.
These drugs fell out of favor due to safety concerns. They cause fluid retention, which increases the risk of new or worsening heart failure. They’re also linked to weight gain, bone fractures (especially in women), and a possible connection to bladder cancer. Current guidelines still include pioglitazone as an option, particularly for people with fatty liver disease, but it’s used cautiously and avoided in anyone with heart failure risk.
Insulin
Insulin is necessary for all people with type 1 diabetes and for many with type 2 diabetes whose blood sugar can’t be controlled with other medications alone. It comes in several forms designed for different situations:
- Rapid-acting insulin starts working in about 15 minutes, peaks at 1 hour, and lasts 2 to 4 hours. It’s taken right before meals.
- Short-acting (regular) insulin begins in 30 minutes, peaks at 2 to 3 hours, and lasts 3 to 6 hours.
- Intermediate-acting insulin takes 2 to 4 hours to begin, peaks between 4 and 12 hours, and covers 12 to 18 hours.
- Long-acting insulin starts in about 2 hours, has no peak, and provides steady coverage for up to 24 hours.
- Ultra-long-acting insulin begins at 6 hours and lasts 36 hours or longer, also without a peak.
Many people use a combination: a long-acting insulin for baseline coverage throughout the day, plus rapid-acting doses before meals. Inhaled rapid-acting insulin is also available, starting in 10 to 15 minutes and lasting about 3 hours. The primary risk with insulin is hypoglycemia, particularly with premixed formulations and intensive dosing schedules that combine rapid and long-acting types.
How Doctors Choose Between Them
The choice of medication depends on more than just blood sugar numbers. If you have established heart disease or are at high cardiovascular risk, GLP-1 agonists and SGLT2 inhibitors offer protective benefits beyond glucose control. If kidney disease is present, SGLT2 inhibitors can slow its progression. If weight loss is a priority, GLP-1 agonists and tirzepatide deliver the most substantial results. If cost is the main concern, metformin and sulfonylureas are available as low-cost generics.
Many people end up on a combination of two or three medications that work through different mechanisms. For example, metformin paired with a GLP-1 agonist addresses insulin resistance and appetite while lowering blood sugar from multiple angles. Treatment often evolves over time as your body’s needs change, with insulin added later if other medications can no longer keep blood sugar in range.