Alternatives to Metformin

by Jessica Pyhtila, PharmD, BCPS, BCGP

If you have type 2 diabetes, chances are that your doctor has prescribed metformin to you at some point. Metformin works by reducing how much sugar the liver makes, improving insulin’s efficiency in the body, and slowing down the conversion of carbohydrates into sugar. Metformin has long been considered first-line therapy for type 2 diabetes by the American Diabetes Association. Data shows that metformin may reduce the risk of cardiovascular events and death, benefits not known to be shared by most other oral alternatives. Further, metformin is generally inexpensive and is on the formulary of many insurance plans. However, not everyone can take metformin: some people cannot tolerate diarrhea, one of metformin’s most common side effects. Further, metformin should be avoided in those with severe kidney disease. Luckily, many other oral alternatives to metformin are available to help control your blood sugar if you cannot take the drug.


Sulfonylureas include drugs like glipizide (Glucotrol), glimepiride (Amaryl), and glyburide (Glynase). Like metformin, they can lower A1c by up to 1.5% and work best at lowering fasting blood sugar. They were one of the first oral medications developed for diabetes and have been a mainstay of diabetes treatment for decades. Generally, they are taken by mouth once or twice a day before meals.

Although frequently prescribed due to their low cost, sulfonylureas have fallen out of favor in recent years among diabetes specialists. Sulfonylureas work by forcing the pancreas to produce more insulin. However, doing so can overwork the pancreas and may cause the insulin-producing cells in the pancreas to burn out faster than they otherwise would. For this reason, sulfonylureas tend to start to lose their effectiveness after 1 to 2 years.

Because sulfonylureas cause more insulin production whether your body needs it or not, side effects like low blood sugar are also a concern. This is especially true of long-acting sulfonylureas like glyburide. Weight gain is also common on sulfonylureas. Further, if you have a serious sulfa drug allergy, you may need to avoid this class of medication.

Dipeptidyl Peptidase-4 Inhibitors, or DPP4 inhibitors

DPP4 inhibitors are common oral diabetes medications that can reduce A1c by up to 1% and help lower fasting blood sugar. They work by stopping the action of the DPP4 enzyme in the body. This enzyme breaks down the hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). As such, stopping the DPP4 enzyme allows these hormones to do their work in the body. The effect of these hormones is increased insulin production after meals and stopping the liver from producing too much sugar. DPP4 inhibitors include sitagliptin (Januvia), alogliptin (Nesina), saxagliptin (Onglyza) and linagliptin (Tradjenta).

Common DPP4 side effects include upper respiratory infection, headache, nausea, diarrhea, urinary tract infections and swelling. However, low blood sugar is uncommon unless the DPP4 inhibitor is taken with another diabetes medication. Further, unlike sulfonylureas, they do not tend to cause weight gain. DPP4 inhibitors can be used alongside many other diabetes medications but should not be used with GLP-1 agonists.

Glucagon-like Peptide-1 (GLP-1) Agonists

Although most GLP-1 agonists are injectable medications, an oral formulation of one of the most common GLP-1 agonists is available. Oral semaglutide (Rybelsus) was approved by the FDA in 2019 and is taken on a daily basis. This class of medication can lower A1c by up to 1.5% and help lower after-meal blood sugars. GLP-1 agonists work by stimulating insulin secretion after a meal in a targeted manner, minimizing the risk of low blood sugar. They also stop the liver from making excessive amounts of sugar. Further, they can help to protect the cells in the pancreas that produce insulin. Recent data has also shown that this class of medications can have a significant cardiovascular benefit, improving heart function, blood flow and cardiac output while reducing the risk of a cardiovascular event.

The major side effects of GLP-1 agonists are gastrointestinal in nature, with nausea, vomiting and diarrhea being most common. When used on their own, GLP-1 agonists typically do not cause low blood sugar. In addition, they often have a beneficial side effect of weight loss. In fact, one of the injectable GLP-1 agonists, liraglutide (Victoza, Saxenda) has FDA approval for weight loss. However, GLP-1 agonists should not be used alongside DPP4 inhibitors. Further, they should not be used if you have a history of severe gastrointestinal disease or pancreatitis, or a family history of certain types of thyroid cancers.

Sodium-glucose Cotransporter-2 Inhibitors, or SGLT2 inhibitors

SGLT2 inhibitors have received a lot of attention over the past several years not only as a treatment for diabetes, but also for their cardiovascular benefit, especially in heart failure. They can lower A1c by up to 1% and help lower after-meal blood sugar by making your body pass excess sugar in your urine. SGLT2 inhibitors include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). The medications are taken once daily.

Common side effects of SGLT2 inhibitors include genital and urinary tract infections as microbes take advantage of the extra sugar in your urine. However, low blood sugar is uncommon unless the medication is paired with another diabetes medication. You may need to avoid SGLT2 inhibitors if you have poor kidney function.

Thiazolidinediones, or TZDs

TZDs work by helping your body use insulin more effectively. Medications in this class include pioglitazone (Actos) and rosiglitazone (Avandia), which are taken once daily. They can reduce A1c by up to 1.5% and help lower fasting sugars. However, TZDs have largely fallen out of favor due to their significant serious side effect burden which includes fluid retention and congestive heart failure, weight gain, increased fracture risk, and bladder cancer. As such, they should not be used if you have a history of heart failure, liver problems, bladder cancer, high fracture risk, or if you have a chance of becoming pregnant.

Alpha-glucosidase Inhibitors

Alpha-glucosidase inhibitors work by slowing the digestion of carbohydrates, which break down into sugars. As such, this class of medications helps to lower after-meal sugars and can lower A1c by up to 1%. This class of medications includes acarbose (Precose) and miglitol. Acarbose, in particular, has been linked to increased life expectancy and can reduce the risk of cardiovascular events. This class of medications needs to be administered three times daily with the first bite of each meal. Because they work by slowing the digestion of carbohydrates, bacteria in the colon then digest the carbohydrates. This causes the major side of this drug class, which is gas, occurring in 78% of people who take the drug, especially if they eat a high-carbohydrate diet. You should avoid alpha-glucosidase inhibitors if you have intestinal conditions that can worsen from extra gas, or if you have other intestinal medical conditions like inflammation, ulceration, or obstruction.


Meglitinides such as repaglinide (Prandin) and nateglinide (Starlix) help to reduce after-meal sugars and can lower A1c by up to 1%. They work by increasing insulin production from the pancreas. Similar to alpha-glucosidase inhibitors, meglitinides need to be taken before each meal. Common meglitinide side effects include low blood sugar, weight gain, and upper respiratory infections. Although they can be used with most other diabetes medications, repaglinide should not be used with the cholesterol medication gemfibrozil (Lopid).

Other oral agents

Other drugs that can be used to help control your blood sugar include the bile acid sequestrant colesevelam (Welchol), which is commonly used for triglyceride-lowering, and bromocriptine (Cycloset, Parlodel), which is used for movement disorders like parkinsonism. However, due to both a high side effect burden and lower effectiveness compared with the other diabetes drugs on the market, they are rarely used.


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