Type 2 Diabetes Medications: Metformin, SGLT2 Inhibitors, and GLP-1 Drugs

You have type 2 diabetes, and your clinician wants to start or change a medicine. Names like metformin, empagliflozin, and semaglutide can blur together. Some drugs do more than lower sugar: they also protect the heart and kidneys. This guide compares three main groups.

Why medicine choice has changed

For many years, diabetes drugs were chosen mainly by how much they lowered A1C. A1C is a blood test that shows your average blood sugar over about 3 months.

Since 2015, large trials showed that some newer drugs also reduce heart attacks, strokes, heart failure, and kidney decline [3] [4]. Guidelines now ask two questions [1] [2]:

• What is your blood sugar goal?
• Do you have, or are you at high risk of, heart disease, heart failure, or kidney disease?

Metformin

How it works

Metformin lowers the amount of sugar the liver releases. It also helps the body respond better to insulin.

Benefits

• Lowers A1C well
• Low cost and decades of use
• Does not cause low blood sugar on its own
• Does not cause weight gain

Side effects

• Stomach upset, bloating, or diarrhea, especially at the start. Extended-release forms and taking it with food can help.
• Lower vitamin B12 over time. Your clinician may check your B12 level.
• A very rare but serious problem called lactic acidosis. This is why it is not used when kidney function is very low.

SGLT2 inhibitors

How they work

SGLT2 inhibitors make the kidneys pass extra sugar into the urine. Examples are empagliflozin, dapagliflozin, and canagliflozin.

Benefits

• Moderate A1C lowering and some weight loss
• Lower the risk of heart failure hospital stays
• Slow kidney disease
• In EMPA-REG OUTCOME, people with type 2 diabetes and heart disease took empagliflozin or placebo. Heart attacks, strokes, and heart deaths together fell from 12.1% to 10.5% over about 3 years. Deaths from heart causes fell by 38% [3].

Side effects

• Genital yeast infections
• Peeing more often and dehydration
• A rare, serious acid buildup called ketoacidosis, which can occur even when blood sugar is not very high. Your clinician may ask you to pause the drug when you are sick, cannot eat or drink, or before surgery.

GLP-1 drugs

How they work

GLP-1 receptor agonists act like a natural gut hormone. They help the pancreas release insulin when sugar is high, slow stomach emptying, and reduce appetite. Examples are semaglutide, dulaglutide, and liraglutide. Most are weekly or daily injections, and one form of semaglutide is a pill. Tirzepatide acts on both GLP-1 and a second hormone receptor, called GIP.

Benefits

• Strong A1C lowering
• Weight loss, often more than with other diabetes drugs
• Fewer heart attacks and strokes in people with heart disease. In LEADER, liraglutide lowered heart attacks, strokes, and heart deaths together from 14.9% to 13.0% over about 4 years [4].

Side effects

• Nausea, vomiting, diarrhea, or constipation, mostly when starting or raising the dose
• Gallbladder problems
• Pancreatitis, which is rare
• The US label has a boxed warning about thyroid C-cell tumours seen in rodents. These drugs are not used in people with a personal or family history of medullary thyroid cancer or a condition called MEN 2.

What your doctor looks at

US guidance

The ADA Standards of Care 2026 advise choosing medicine based on your other health conditions, not only on A1C [1]:

• For people with heart or blood vessel disease, an SGLT2 inhibitor or GLP-1 drug with proven heart benefit.
• For people with heart failure, an SGLT2 inhibitor.
• For people with chronic kidney disease, an SGLT2 inhibitor, and a GLP-1 drug as another option.
• For people with weight goals, a GLP-1 drug or tirzepatide.
• These choices apply whatever your A1C is and whether or not you take metformin.

Canadian guidance

The Diabetes Canada 2024 update also recommends an SGLT2 inhibitor or a GLP-1 drug with proven benefit for adults with heart disease, heart failure, or chronic kidney disease, to lower the risk of heart and kidney events, regardless of A1C [2]. For most other adults, it keeps metformin as a first medicine and adds others to reach the glucose target [2].

Other drugs

Other groups include DPP-4 inhibitors, sulfonylureas, pioglitazone, and insulin [5]. Insulin and sulfonylureas can cause low blood sugar. Insulin is still the most powerful glucose-lowering treatment and is needed by many people over time.

Cost and coverage

Newer drugs can be costly. Coverage differs by province, state, and insurance plan. Ask your pharmacist about coverage and lower-cost options.

Questions to ask your clinician

• What A1C goal is right for me?
• Do I have heart disease, heart failure, or kidney disease that changes my medicine choice?
• Would an SGLT2 inhibitor or a GLP-1 drug protect my heart or kidneys?
• Which side effects should I watch for with this medicine?
• What should I do with my diabetes medicines on sick days?
• Can this medicine cause low blood sugar?
• Is this medicine covered by my plan?

When to get care quickly

Go to the emergency department for:

• Nausea, vomiting, belly pain, fast breathing, or unusual tiredness while on an SGLT2 inhibitor, which can be signs of ketoacidosis
• Severe belly pain that spreads to the back, which can be a sign of pancreatitis
• Signs of severe low blood sugar, such as confusion, seizures, or passing out

Bottom line

Metformin, SGLT2 inhibitors, and GLP-1 drugs all lower blood sugar, but they do different things beyond that. For people with heart disease, heart failure, or kidney disease, Canadian and US guidelines advise drugs with proven heart and kidney benefits. Talk to your clinician or pharmacist before you start, stop, or change any diabetes medicine.

Primary AI can show you the guideline and study sources behind this topic in plain language, so you can bring better questions to your appointment.