Diabetes Treatment Options When Metformin Stops Working
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Medically reviewed by Erika Prouty, PharmD
Along with lifestyle changes, Glucophage (metformin) can help you get your blood sugar, also called blood glucose, under control. If your blood sugar is not controlled, metformin may not be working for you, and you may need to replace it.
Here’s what to expect when metformin needs to be replaced.
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How Metformin Works
Metformin is an oral medication used to treat type 2 diabetes. It belongs to a class of drugs called biguanides.
Diabetes occurs when your blood sugar reaches higher than normal levels due to an insufficient amount of insulin in your body or an improper reaction of your cells to insulin.
Metformin is used to control your blood sugar when diet and exercise changes are not sufficient to manage it. It is often the first medication used when drug therapy is needed to control type 2 diabetes.
The primary mechanisms of metformin lower blood glucose levels in the following ways:
It reduces the amount of glucose your intestines absorb from your food.
It reduces the amount of glucose produced by the liver during digestion and released into your bloodstream.
It increases your body's sensitivity to insulin by reducing the insulin resistance that causes type 2 diabetes.
Metformin differs from other diabetes medicines because it doesn't increase insulin production. Diabetes medications that increase insulin production put you at risk of developing drug-induced hypoglycemia, or low blood sugar. Metformin can also help with weight loss, while most other diabetes medications cause weight gain.
Metformin is prescribed as an immediate-release tablet, oral solution, or extended-release drug. Common brand names for metformin include:
Fortamet
Glumetza
Riomet
Popularity of Metformin
Metformin has a long history as a well-regarded diabetes medication. It has been in use for since the 1940s as a first-line treatment for type 2 diabetes and ranks as the most commonly used oral drug to treat this disease. It is recommended as a first-line treatment for type 2 diabetes by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE).
Discussing Options With Your Healthcare Provider
After your initial diagnosis of type 2 diabetes, your healthcare provider will discuss your treatment options for managing your blood sugar levels and preventing disease complications. They will establish a treatment regimen based on the severity of your condition and many other factors. These considerations include:
Age
Length of diagnosis
Severity of disease
Efficacy
Adherence and treatment burden
Cost
Medical history
Other health conditions (comorbidities)
Known side effects are a major consideration in choosing a treatment for type 2 diabetes. Taking metformin can increase your risk of developing the following side effects:
Stomach pain
Bloating or gas
An unpleasant metallic taste in the mouth
Nail changes
Muscle pain
Chest pain
Serious Side Effect of Metformin
Metformin can occasionally cause lactic acidosis, a serious, life-threatening condition that involves the buildup of lactic acid in your bloodstream. It develops as a result of an imbalance between the use and production of lactic acid. The condition can be fatal if left untreated.
Contact your healthcare provider as soon as possible if you experience any of the following symptoms while taking metformin.
Symptoms of lactic acidosis include:
Persistent vomiting, nausea, or abdominal pain
Unexplained tiredness
Shortness of breath
Rapid breathing
Enlarged or tender liver
Cold or blue hands and feet
Abnormal heartbeat
Weight loss
Testing
Regular testing can help your healthcare provider monitor your type 2 diabetes and look for signs that metformin is working as expected. While testing may seem inconvenient at times, it can help identify potential complications before they become difficult to treat and create other health conditions.
Blood Sugar
Taking any oral diabetic medication usually includes having the following laboratory tests every three to six months, though the timing between these tests may be shorter or longer based on your condition:
Fasting blood glucose to measure your blood sugar after an overnight fast
Postprandial blood glucose to measure your blood sugar after a meal
Hemoglobin A1C (HbA1c) to measure your average level of blood sugar over the past three months
A urine glucose test to measure the amount of glucose in your urine and identify signs of elevated blood sugar
You can also monitor your blood sugar levels at home. If you are controlling your blood sugar with metformin, you may not have to measure your blood sugar levels every day. Your healthcare provider will help you establish a schedule for home testing based on your condition and the types of medication you take.
You'll require special equipment to measure your blood sugar levels at home. These options include:
A blood glucose monitor delivers an immediate reading of blood sugar from a drop of blood that you extract from your finger.
A continuous glucose monitor is a wearable device that provides a real-time blood sugar reading on demand.
Vitamin B12
Research indicates that taking metformin to treat type 2 diabetes may increase your risk of developing a vitamin B12 deficiency. Vitamin B12 is a water-soluble vitamin that is consumed by eating some foods or taking a dietary supplement or prescription medication.
Studies indicate that vitamin B12 deficiency may be present in up to 30% of diabetes patients who take metformin. There is evidence that vitamin B12 levels decrease as the length of time and dose of metformin increase.
Without treatment, a vitamin B12 deficiency can lead to the following conditions:
Low white blood cells and red blood cells and/or platelets
Glossitis of the tongue
Weight loss
Neurological changes such as numbness and tingling in the hands and feet
Recommendations from the American Diabetes Association and the American Association of Clinical Endocrinologists suggest monitoring vitamin B12 levels in diabetes patients taking metformin. Testing is advised every two to three years for all diabetic patients taking metformin. It is especially important for those who develop peripheral neuropathy and/or anemia while taking metformin.
A vitamin B12 deficiency can be measured in one of the following blood tests:
Methylmalonic acid (MMA) test
If you're diagnosed with a vitamin B12 deficiency, your healthcare provider will prescribe therapy based on the cause and severity of the problem. Oral vitamin B12 supplements can increase levels for those with a moderate deficiency. You may need vitamin B12 injections or a blood transfusion to treat a serious vitamin B12 deficiency.
Learn More: Best At-Home Diabetes Tests
Lifestyle Changes
Whether you are taking metformin or another diabetes medication, lifestyle changes are essential for managing blood sugar levels in diabetes. When supported with appropriate diabetes self-management education from a licensed professional, you can optimize your lifestyle choices from diagnosis through the changes that occur with disease progression.
Together, exercise and diet modifications can help you control blood sugar and lower your risk of complications.
Exercise
You can help lower blood sugar levels and reduce your risk of diabetes complications by maintaining an active lifestyle. Exercise can provide the following benefits for people with diabetes:
Lowering blood glucose concentrations
Improving insulin sensitivity
Reducing the risk of comorbidities, including hypertension, hyperlipidemia, and ischemic heart disease
Improving metabolism to burn calories more efficiently
According to the American College of Sports Medicine (ACSM) and American Diabetes Association (ADA), you can achieve these benefits by adhering to the following exercise criteria:
Exercise for 150 total minutes of moderate-intensity aerobic activity per week, with no more than two consecutive days without physical activity
Reduce total sedentary time by moving every 90 minutes
Perform resistance exercise that uses all eight muscle groups two or more times weekly
Working with an exercise professional can help you plan a program to help you achieve these goals safely and consistently. If you are becoming more active after living a sedentary lifestyle, check with your healthcare provider before you begin any exercise program more intense than brisk walking.
Diet
Establishing a diet that supports normal blood glucose levels can help you manage type 2 diabetes. A registered dietitian or diabetes educator can help you make choices that align with your preferences, lifestyle, goals, and health condition. Eating the right foods can help you avoid serious health problems like vision loss and health issues that can occur with uncontrolled diabetes.
You can achieve results by including a variety of healthy foods from the following categories:
Dark leafy vegetables
Fresh fruit that includes citrus and berries
Whole grains like whole wheat, brown rice, barley, oats, and quinoa
Proteins, like lean meats, chicken, turkey, fish, eggs, nuts, seeds, beans, lentils, and tofu
Low-fat or nonfat dairy products like milk, cheese, and yogurt
You should also limit foods that are high in carbohydrates and sugars, including foods from the following categories:
Sugary foods like candy, cookies, ice cream, cake, and sweetened cereals
Drinks with added sugars like regular soda, juice, and regular sports drinks
White rice and bread, pasta, and tortillas made with white flour
Starchy vegetables like white potatoes, corn, and peas
Learn More: Lifestyle Changes for People Diagnosed With Type 2 Diabetes
Alternative Medications
When metformin is not enough, you may be advised to add a new medication to your existing regimen. Or, you may be advised to take a different medication in place of metformin. It is not uncommon to take two or three different diabetes medications at the same time. The specific medication you're prescribed depends on your condition.
Several classes of drugs are used as alternatives to metformin. There is no standard recommended course of treatment. When metformin fails, you may be prescribed one of the following types of medications:
Alpha-glucosidase inhibitors: Alpha-glucosidase inhibitors help your body break down carbohydrates like bread and potatoes and slow down the breakdown of some sugars. These drugs include Precose (acarbose) and Glyset (miglitol).
Bile acid sequestrants (BASs) help lower and remove low-density lipoprotein (LDL) cholesterol from your body by binding with the bile acids in your intestines. Your body uses cholesterol to replace the lost bile acids, which lowers cholesterol levels. Welchol (colesevelam) is a commonly used BAS.
Dopamine-2 agonists stimulate parts of the brain influenced by dopamine to regulate glucose levels and reduce high cholesterol. These drugs include Parlodel (bromocriptine) and Cycloset (bromocriptine).
DPP-4 Inhibitors: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the action of DPP-4, an enzyme that interferes with the normal production of insulin and control of glucose output from the liver. These drugs include Januvia (sitagliptin), Nesina (alogliptin), Onglyza (saxagliptin), and Tradjenta (linagliptin).
GLP-1 agonists mimic the effects of GLP-1, a hormone known as incretin that is lower than normal in people with type 2 diabetes. GLP-1 helps control appetite, blood sugar levels, and the release of optimal amounts of insulin. These drugs include Adlyxin (lixisenatide), Bydureon (exenatide), Byetta (exenatide), Mounjaro (tirzepatide), Saxenda (liraglutide), and Victoza (liraglutide).
Meglitinides work to increase insulin output by stimulating the beta cells of the pancreas. These drugs include Starlix (nateglinide), and Prandin (repaglinide).
SGLT-2 Inhibitors: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors lower your blood sugar level by preventing your kidneys from reabsorbing sugar that is created by your body. These drugs include Farxiga (dapagliflozin), Invokana (canagliflozin), Jardiance (empagliflozin), and Steglatro (ertugliflozin).
Sulfonylureas are similar to meglitinides in that they stimulate the secretion of insulin from beta cells of the pancreas, though sulfonylureas are longer acting. These drugs include Diabinese (chlorpropamide), Amaryl (glimepiride), Diabeta (glyburide), Glynase (glyburide), and Glucotrol (glipizide).
Thiazolidinediones (TZDs), also called glitazones, lower your body's resistance to insulin and reduce the amount of sugar released by your liver. These drugs include Actos (pioglitazone) and Avandia (rosiglitazone).
Supplemental insulin replaces or supplements the insulin your body is lacking to maintain healthy blood sugar levels. Insulin can be used alone or with other diabetes medications.
Learn More: Type 2 Diabetes Treatment
Summary
Metformin is an oral diabetes drug that can help control blood sugar, also called blood glucose. It is viewed as the gold standard for non-insulin treatment of type 2 diabetes.
In some cases, the drug may stop working due to disease progression or changes to diet and workout programs. The effect can result in blood sugar levels that are too high. It is key to correct treatment failure to avoid disease complications.
When metformin is no longer useful, your healthcare provider may choose to replace it or combine it with a new drug. Adding insulin treatment may be a choice.
You can also help control blood sugar levels by making lifestyle changes to your diet and workout programs. Working with trained experts can ensure that you achieve your goals and control your disease.
A Word From Verywell
Metformin is well regarded as a first-level drug for controlling blood sugar levels in type 2 diabetes. To get optimal benefits, take the drug as prescribed and follow up with recommended office visits and tests.
You can also support the impact of metformin with a healthy lifestyle that includes consuming a well-balanced diet and participating in the recommended amount of physical activity. Following these guidelines can help you remain on this first-level drug and possibly avoid taking other medications and/or insulin.
Dealing with diabetes can be overwhelming. Don't be afraid to reach out for help. Consulting with a registered dietician and personal trainer can help you establish healthy habits to control your disease and avoid serious complications.
Consider joining an online or in-person diabetes support group to help you deal with the practical and emotional aspects of this lifelong disease and the challenges involved in maintaining good health.
Frequently Asked Questions
Can you build up a tolerance to metformin?
Most people can take long-term metformin therapy without the drug losing its effectiveness. When results change with metformin, it is more often due to the changes that occur with the natural progression of diabetes. Other factors, like drug interactions, improper dosage, or changes in lifestyle, can also affect how the drug works.
Do other medications interact with metformin?
While there are several medications that interact with metformin, it is not common. Taking Tagamet (cimetidine), furosemide, or Adalat (nifedipine) with metformin can increase the concentrations of metformin in your body. Rayos (prednisone), estrogen, progesterone, testosterone, contraceptive pills, and other diabetes medicines can also affect the results of metformin. Morphine, Qualaquin (quinine), Lanoxin (digoxin), quinidine, Midamor (amiloride), Dyrenium (triamterene), Vancocin (vancomycin), and Primsol (trimethoprim) may also cause interactions.
How long does it take metformin to lower blood sugar?
Metformin may lower blood sugar within one to two weeks of starting to take this drug. However, it may take up to two to three months to see the full impact of this drug on your blood glucose control. Monitoring your blood glucose levels can help you and your healthcare provider track the effectiveness of metformin.
