Metformin is a popular prescription drug that is used as a first-line treatment for type 2 diabetes. 

For the majority of users, metformin is effective and well-tolerated. But if you are experiencing severe or persistent side effects when taking this medicine, or if it simply isn’t working, you may wonder if there are any other options.

The answer is yes. This article will investigate the best alternatives to metformin for people with type 2 diabetes. 

Key Points:

  • While an effective treatment for many, metformin can cause significant side effects such as gastrointestinal issues, and it may have negative interactions with other common medicines. 
  • In some cases, metformin is not effective in managing blood glucose levels or is not advised because of health conditions or insurance coverage limitations.
  • Several classes of diabetes medicines offer different mechanisms of action and benefits for managing type 2 diabetes. These alternatives may be more suitable for people who cannot tolerate metformin or find it ineffective.
  • Each alternative class of medication comes with its own set of potential side effects, ranging from gastrointestinal issues to risks of hypoglycemia and weight gain. Understanding these effects is vital for selecting the most appropriate treatment option.
  • Along with medication, lifestyle modifications such as increased physical activity and dietary changes can be effective in managing type 2 diabetes. Although difficult to maintain, these measures can significantly improve blood sugar management and overall health. 

Table of Contents

Why would you not take metformin?

Metformin helps better manage blood sugar levels, fight insulin resistance (a condition in which the body does not use insulin efficiently), and can even help with weight loss. Most guidelines recommend it as the first-line treatment for type 2 diabetes. 

It is also very affordable and generally effective, but that effectiveness can come with a cost: side effects. 

Side effects

Metformin can cause a variety of potentially detrimental side effects, including:

For some people who have strict work or school schedules, enduring some of these side effects may not be possible. 

Additionally, experiencing these side effects can also impact other areas of your life. Dealing with chronic gastrointestinal issues, for example, can become an obstacle to eating well or prevent you from maintaining a regular exercise habit. 

Contraindications

In other cases, people may avoid taking metformin because it is contraindicated (not advised) to take with many other common prescription drugs. (Here is an overview of the drugs that may interact with metformin.) 

Sometimes it’s impossible to stop taking another medicine that negatively interacts with metformin, and therefore, a substitute is necessary. 

Ineffectiveness

And for some people, metformin simply is not effective. It does not help everyone better manage their blood sugars, lower their HbA1c levels (a measure of glucose control over the previous 2 to 3 months), or lose weight. In fact, some people even gain weight when taking metformin.

Insurance or lifestyle considerations

Finally, some people may opt to not take metformin because their health insurance doesn’t cover it, or they wish to manage their diabetes without the use of pharmaceuticals. 

What are alternatives to metformin? 

The following are some alternatives that you can discuss with your doctor.

(Remember to always work with your healthcare provider before making any changes to your diabetes management.) 

Sulfonylureas 

Sulfonylureas are oral diabetes medications that are generally taken with or before a meal. They work to lower blood sugar by increasing the production of insulin from the beta cells in the pancreas. These pills are usually either taken once a day before breakfast or twice daily, before both breakfast and dinner. 

Sulfonylureas include:

  • Glipizide (brand name Glucotrol)
  • Glimepiride (Amaryl)
  • Glyburide (Diabeta, Glynase)

Sulfonylurea side effects

Some possible side effects include: 

Thiazolidinediones (TZDs)

TZDs are an oral class of type 2 diabetes medication that increases insulin sensitivity and helps decrease glucose production by the liver.

They are easily accessible and affordable and do not have a high risk of causing hypoglycemia.

Thiazolidinediones include:

  • Pioglitazone (Actos)
  • Rosiglitazone (Avandia)

Thiazolidinedione side effects

Some possible side effects include:

  • Weight gain
  • Increased risk for heart disease
  • Edema (swelling) of feet, legs, arms, and hands 
  • Increased risk for bone fracture 

DPP-4 inhibitors 

DPP-4 inhibitors lower blood sugar and HbA1c levels without causing low blood glucose (unless taken with other medicines that can cause hypoglycemia, such as insulin or sulfonylureas).

They function by interfering with the breakdown of two hormones in the body, GLP-1 and GIP, that reduce blood glucose levels. 

These hormones are typically broken down very quickly. By helping slow this process, DPP-4 inhibitors allow the hormones to function for longer, lowering blood sugar levels only when they are elevated.

These drugs are taken orally, often in combination with metformin, but they can be taken without metformin as well. 

DPP-4 inhibitors include:

  • Sitagliptin (Januvia)
  • Saxagliptin (Onglyza)
  • Linagliptin (Tradjenta)
  • Alogliptin (Nesina)

DPP-4 inhibitor side effects

Possible side effects include:

  • Low blood sugar, if taken along with insulin or sulfonylureas
  • Gastrointestinal issues like upset stomach 
  • Increased risk for pancreatitis (inflammation of the pancreas)
  • Fever, body aches, and other flu-like symptoms 

GLP-1 receptor agonists 

GLP-1 receptor agonists can either be taken orally or through an injection (either once a day or once weekly), depending on the specific medicine used. They function similarly to the GLP-1 and GIP hormones in the body that lower insulin levels but are more resistant to being broken down. 

In addition to lowering blood sugar and HbA1c levels, some of these medicines also protect against heart disease. 

Notably, although they are not weight-loss drugs, GLP-1 receptor agonists can aid with weight loss. According to the Mayo Clinic, studies indicate that all GLP-1 drugs can lead to a total weight loss of between 10.5 and 15.8 pounds. 

GLP-1 receptor agonists include:

GLP-1 receptor agonist side effects

Possible side effects include:

  • Nausea 
  • Vomiting
  • Low blood sugar levels (if taken in combination with insulin)
  • Decreased need for insulin, if on insulin therapy 
  • Diarrhea 
  • Weight loss 

SGLT-2 inhibitors 

SGLT-2 inhibitors are a class of oral medication, generally taken daily, used to lower blood sugar levels and HbA1c levels by causing the release of excess glucose in the urine. They rarely cause low blood sugar.

These medications can protect against heart failure and improve outcomes in people who have heart disease, kidney disease, or heart failure.

SGLT-2 inhibitors include:

SGLT-2 inhibitor side effects

Possible side effects include:

  • Frequent urination
  • Increased frequency of urinary tract infections (UTIs) 
  • Increased risk for kidney damage
  • Increased risk for diabetic ketoacidosis (DKA)
  • Dehydration
  • Thirst
  • Low blood pressure 
  • For Invokana, specifically, increased risk of amputations 

GIP/GLP-1 receptor agonists

The first medicine in this class was approved in 2022. It is an injectable drug taken once weekly, and it functions by mimicking the actions of both GLP-1 and GIP to help lower blood sugar levels. 

Research indicates that this medication leads to an average weight loss of about 15 percent to 20 percent.

GIP/GLP-1 receptor agonists include:

GIP/GLP-1 receptor agonist side effects

Possible side effects include:

  • Gastrointestinal issues
  • Hypoglycemia, particularly when used with another medicine that can cause low blood sugar such as a sulfonylurea or insulin
  • Weight loss
  • Pancreatitis
  • Changes in cholesterol and triglyceride levels
  • Kidney issues
  • Fatigue and dizziness

Insulin

Insulin has been a cornerstone in diabetes therapy since its discovery in 1921. In type 2 diabetes, it is often used when other medicines do not provide adequate blood sugar control. 

The goal of insulin treatment is to mimic the body’s natural insulin production. It is administered via injection, infusion (from an insulin pump), or inhalation. The different types of insulin vary in onset, peak times, and duration of action. 

Some of the more common insulins used in the United States include:

Rapid-acting insulin

  • Insulin lispro (Humalog, Admelog)
  • Insulin aspart (NovoLog, Fiasp)
  • Insulin glulisine (Apidra)

Short-acting insulin

  • Regular human insulin (Humulin R, Novolin R)

Intermediate-acting insulin

  • NPH (isophane) insulin (Humulin N, Novolin N)

Long-acting insulin

  • Insulin glargine (Lantus, Basaglar, Toujeo)
  • Insulin detemir (Levemir)
  • Insulin degludec (Tresiba)

Possible side effects 

  • Hypoglycemia, particularly if the insulin dose is not balanced with food intake and physical activity
  • Weight gain
  • Changes in fat tissue at injection sites
  • Allergic reactions, ranging from local injection site reactions to systemic ones
  • Swelling of arms and legs
  • Insulin resistance, especially with higher doses over time

Less-commonly used alternatives

Alpha-glucosidase inhibitors

The starches you eat are broken down into sugars by your body. Alpha-glucosidase inhibitors help lower blood sugar levels by blocking the digestion of starches. They are taken with the first bite of each meal.

Alpha-glucosidase inhibitors include:

  • Precose (generic only)
  • Miglitol (Glyset)

Alpha-glucosidase inhibitor side effects

Common side effects include: 

  • Gastrointestinal issues such as gas and diarrhea

Meglitinides

Meglitinides are a type of oral medication that stimulates the insulin-producing beta cells of the pancreas to release insulin. They are taken before each meal to help lower after-meal blood glucose levels.

Meglitinides include:

  • Repaglinide (Prandin)
  • Nateglinide (Starlix)

Meglitinide side effects

Common side effects include: 

  • Hypoglycemia
  • Weight gain

Lifestyle changes 

Finally, adopting healthy lifestyle changes is always a good approach, whether or not you are taking medication. Engaging in regular physical activity and eating a balanced, nutritious diet can help manage blood sugar levels, lower your HbA1c, and potentially lead to weight loss as well. 

This may be the cheapest option, but it can be hard to maintain. And it’s also not guaranteed that lifestyle changes will allow you to stop taking medications. 

Other factors, such as a genetic predisposition for diabetes, can make medication necessary, even if you are in great physical condition and otherwise healthy. 

Talk with your doctor and meet with a registered dietitian (RD) to develop an exercise and eating plan that will work for your lifestyle and health goals. 

Final thoughts

While metformin is an extremely popular, affordable, and accessible drug for type 2 diabetes management, it is not for everyone. 

Some people experience debilitating side effects that make taking this drug over the long term impossible. Others may not have insurance coverage for metformin or may not wish to take additional medicines, or metformin may simply not be working for them. 

Fortunately, other options are available. Drug classes including sulfonylureas, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors, GIP/GLP-1 receptor agonists, and less common alternatives like alpha-glucosidase inhibitors and meglitinides can be used to treat type 2 diabetes.

Adopting healthy lifestyle approaches such as increased physical activity and a nutritious diet can also help, whether or not you’re taking medicine.

Do some research to see what your health insurance will cover to make sure that any changes in your diabetes medications are financially sustainable over the long term. 

If metformin is not working well and you want to make a switch, speak with your doctor about possible alternatives, and discuss what will work best for you, your lifestyle, and your health goals.