Key takeaways
Metformin is commonly prescribed for Type 2 diabetes, prediabetes, PCOS, and off-label for weight loss, working by increasing insulin sensitivity and lowering glucose production in the liver.
Unexplained increases in blood sugar levels may indicate metformin’s ineffectiveness, necessitating consultation with a healthcare provider for possible dosage adjustments or alternative treatments.
Common side effects of metformin include gastrointestinal issues such as diarrhea and nausea, while serious side effects like lactic acidosis are rare but require immediate medical attention.
If metformin is ineffective, alternatives include SGLT2 inhibitors, sulfonylureas, thiazolidinediones, and DPP-4 inhibitors, often combined with lifestyle changes like diet and exercise to manage blood sugar levels.
Metformin uses | Signs metformin is working | Metformin side effects | Serious side effects |Signs metformin is not working | What to do if metformin is not working? | Metformin alternatives |Maximizing metformin benefits
Metformin is a generic diabetes medication that is frequently prescribed as a first-line drug (along with diet and exercise) to help control blood sugar in patients with Type 2 diabetes.
Type 2 diabetes occurs when the body is unable to produce or use insulin properly, which results in high glucose (sugar) levels. Metformin is generally effective as a diabetes medication in controlling blood glucose levels. However, not everyone’s body responds the same to drug treatments.
Unexplained increases in blood sugar may be the first indication that metformin is not working. Knowing what additional symptoms may point to metformin’s potential ineffectiveness is crucial for seeking out alternate therapies.
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Metformin uses
Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, and polycystic ovary syndrome (PCOS). It is also commonly prescribed as an off-label treatment for weight loss. An off-label treatment is a use that is not specifically approved by the FDA. Metformin is commonly known by the brand name, Glucophage; however, Glucophage is no longer available in the United States as a brand-name drug.
Type 2 diabetes
Type 2 diabetes is a chronic metabolic disease that occurs when the body does not use insulin (a hormone produced by the pancreas) properly, resulting in high levels of glucose (sugar) in the blood. Insulin helps glucose from the foods we eat get into cells in the body to produce energy or to be stored for later use. If glucose cannot enter cells, it remains in the blood and causes high blood sugar (hyperglycemia). Left untreated, Type 2 diabetes has the potential to lead to various complications, including heart disease, kidney disease, and loss of vision.
Due to its success in decreasing blood glucose in the body, the Food and Drug Administration (FDA) has approved metformin for use in patients (adults and children 10 years and older) with Type 2 diabetes mellitus. In patients with Type 2 diabetes, metformin works by aiding the body in its response to natural insulin production by decreasing the amount of glucose from the effects of food consumption and decreasing glucose production in the liver. Taken regularly, metformin reduces the levels of glucose the liver makes so that the body’s blood sugar levels are decreased. Because of its effectiveness in controlling blood sugar, metformin is often the first line of treatment and the most frequently prescribed diabetes drug used in the treatment of Type 2 diabetes.
Prediabetes
Based on information from the Centers for Disease Control and Prevention (CDC), prediabetes is a serious health condition where a person’s blood sugar levels are higher than normal but not high enough for a diabetes diagnosis. High blood sugar can lead to Type 2 diabetes, heart disease, and stroke, so it’s important to take this condition seriously. Metformin has been proven successful as an off-label use to prevent the progression of pre-diabetes to Type 2 diabetes.
Polycystic ovary syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is a hormonal disorder that affects an estimated 5%-10% of women of reproductive age. PCOS disrupts period cycles, produces heightened androgen levels, and causes failure of the ovaries to regularly release eggs, which greatly impacts fertility.
Insulin resistance is a main marker of women with PCOS. As such, the American Diabetes Association identifies PCOS as a risk factor for Type 2 diabetes. For this reason, metformin has been effective for off-label usage in the treatment of polycystic ovary syndrome. Metformin also improves the metabolic and reproductive abnormalities associated with PCOS and helps increase the chances of conception.
Note: Metformin may stimulate ovulation in women of childbearing age (who do not have PCOS), which may result in unintended pregnancy. Women of childbearing age should discuss this with their healthcare provider.
Weight loss
In the Diabetes Prevention Program (DPP) study, metformin was shown to help with weight loss, and it also helped to delay or prevent diabetes. Throughout this study and the follow-up study, the DPP Outcomes Study, or DPPOS, after a 10-year period, participants in the study who took metformin maintained a 2.5 kg (about 5.5 pound) weight loss. Patients who took the medication every day as prescribed (compared to those who skipped doses) were more likely to lose weight. The weight loss also helped to prevent or delay diabetes.
“Research shows that metformin does help with weight loss in people who are overweight or obese with Type 2 diabetes, those at high risk for diabetes, and PCOS,” says Sapna Shah, MD, a board certified endocrinologist. According to Dr. Shah, metformin may help with weight loss “because the body is more likely to use stored energy sources when blood glucose levels are not as high. Thus, it may increase your ability to burn fat for energy.”
Another possibility, according to Dr. Shah, is that “one of the more troublesome side effects of metformin is stomach upset, including diarrhea, reduced appetite, and nausea—all symptoms that may decrease your desire to eat.”
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Signs metformin is working
Wondering if a new prescription medication is working can be troublesome. Luckily, there are telltale signs that can reveal if metformin is performing as it should. These signifiers vary for usage in the treatment of Type 2 diabetes, prediabetes, and PCOS.
Type 2 diabetes
Metformin does not immediately lower blood sugar levels. Improvement in blood sugar levels may take place within one to two weeks, but it may take two to three months for significant changes to take place. Typically, the starting dose of metformin is prescribed at 500 mg twice daily with meals. Over the course of one to two months, this dose may be gradually increased if necessary. This gradual increase is to help lessen bothersome gastrointestinal side effects. A daily dose of 1500 mg or more is usually needed to achieve positive outcomes.
After this introductory course of treatment, an increase in energy may be noticed. This is because the body is now able to use insulin more efficiently. Other symptoms related to Type 2 diabetes, such as blurred vision, headaches, dry mouth, increased thirst, and frequent urination may noticeably decrease or disappear. These are all signs that metformin is doing its job.
Prediabetes
Because there aren’t many known symptoms of prediabetes, it may be difficult to know if metformin is working. After four to six weeks of taking metformin as prescribed, the patient will usually follow up with their healthcare provider. The healthcare provider may order a fasting glucose test to be done in the lab and/or check blood glucose in the office. At the three-month mark, an A1C test will let the doctor know if metformin is working in lowering blood glucose levels. A hemoglobin A1C test is a measure of blood glucose control over a period of about three months.
A fasting glucose test with results of 100 to 125 mg/dL would indicate prediabetes. A1C results of 5.7% to 6.4% would be a signifier of prediabetes. When taking metformin for prediabetes, these numbers should start to decrease.
PCOS
Improvements in ovulation, menstrual regulation, and blood glucose levels are all signs that point in the direction that metformin is working if taken for PCOS. As with the use of metformin for other conditions, it may take a few months for positive results to be noticed. Since there is no specific test to diagnose PCOS, a doctor may administer blood tests to measure hormone levels, blood sugar, and cholesterol, all of which should measure within normal ranges if metformin is working.
Weight loss
In addition to taking metformin off-label for weight loss, your healthcare provider may suggest a diet and exercise plan to follow. He or she will likely want to follow up in several months to check your weight loss progress. The weight loss may be very modest—or can be more dramatic based on other diet and exercise changes—and may also help to prevent or delay diabetes.
Metformin side effects to expect
When first taken, metformin may cause some common side effects. Usually, these adverse effects subside as the body gets used to the medication. This medication is typically prescribed because the benefits of metformin are proven to outweigh the possibility of side effects. However, consult a healthcare professional right away if symptoms become severe, persistent, or worsening.
Gastrointestinal
Approximately 30% of patients treated with metformin experience gastrointestinal side effects. Gastrointestinal (GI) adverse events (AEs) are the most common side effects associated with metformin. Common GI reactions to metformin include:
- Diarrhea
- Nausea
- Flatulence (gas)
- Heartburn
- Vomiting
- Stomach pain
Diarrhea is the most common side effect reported by patients taking metformin. This is believed to occur because metformin works in the gut by increasing the bile acid pool within the intestine. Many patients find this to be the most troubling side effect to tolerate and can occur at the onset of the first dose. Many GI side effects will typically go away within a few weeks, as your body gets used to the medication. Taking metformin with meals may help prevent or decrease the severity of these side effects. If GI side effects persist or are bothersome, consult your healthcare provider.
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Serious side effects of metformin
Rarely, more serious side effects may occur. If any of the following symptoms occur, contact a healthcare professional immediately or get emergency medical help:
- Lactic acidosis
- Liver toxicity
- Megaloblastic anemia
- Severe allergic reactions
Lactic acidosis
Lactic acidosis is the buildup of lactic acid in the bloodstream. Lactic acid is produced when oxygen levels become low in cells within the areas of the body where metabolism takes place. While considered to be a rare side effect, in some cases metformin can cause lactic acidosis, especially in patients with certain conditions like heart failure, kidney disease, or those who consume excess alcohol. As a result of this increased risk, the Food and Drug Administration (FDA) has placed a black box warning on metformin. Symptoms of lactic acidosis include:
- Abdominal pain and vomiting
- Fast, shallow breathing
- Unusual sleepiness or weakness
- Muscle pain/cramping
The symptoms of lactic acidosis are severe and quick to appear and require emergency medical attention.
Severe allergic reactions
Allergic reactions to metformin are rare. Patients taking metformin should be alert to the signs of an allergic reaction—hives, difficulty breathing, and swelling of the face, lips, tongue, or throat. These symptoms require emergency medical attention.
Signs metformin is not working
The full effects of blood glucose control may not be seen for up to two to three months but improvements in blood glucose control may be detectable in one to two weeks. However, over time, the effectiveness of metformin may decrease and no longer work for the purposes of its prescribed usage. The following signs can be indications that metformin is no longer working.
Type 2 diabetes and prediabetes
A rise in blood sugar levels (hyperglycemia) is typically the first sign that metformin is no longer working for those with Type 2 diabetes or its precursor, prediabetes. Symptoms of hyperglycemia include:
- High blood sugar
- Increased thirst and/or hunger
- Blurred vision
- Frequent urination
- Headache
- Fatigue (feeling weak, tired)
- Weight loss
- vagin*l and skin infections
- Slow-healing cuts and sores
If any of these signs are present, an A1C (glycated hemoglobin) blood test requested by a healthcare professional can determine if there has been a rise in previous blood sugar levels over the last few months. If metformin is not working as it should to lower a person’s blood glucose, a dosage adjustment, an alternative or additional medication, or an insulin regimen may be recommended.
PCOS
For usage to treat PCOS in order to improve menstruation function and increase fertility, it may take at least four to six months for results from metformin to take place. However, some women may notice ovulation resuming within just a few months of metformin treatment. If a decrease in excessive hair growth, acne, and weight gain as well as improved ovulation and menstrual regulation is not noticed in this time frame, it may be beneficial to contact your healthcare provider to discuss whether or not a metformin prescription is providing the benefits to aid in managing PCOS.
Weight loss
If you are adhering to your medication regimen, and you do not see a slight weight loss after a few months, contact your healthcare provider. He or she may make some changes to your regimen—or, if you have elevated blood sugar, there is a possibility that he or she may recommend that you keep taking metformin even if you do not lose weight, for its benefits on blood sugar control.
What to do if metformin is not working
If a person suspects that metformin is not working, contacting a healthcare provider or a healthcare team for medical advice should be the first step taken. It is important to understand that metformin begins to work once it builds up in the body, and desired results may not be noticeable right away. Some adverse effects such as chest pain or rash may be severe. Call a doctor right away or seek emergency care if any of these signs are encountered. If a doctor determines that metformin is not working, a new medication regimen may be initiated. There are many prescription medications that can replace or work alongside metformin.
Alternatives to metformin
Metformin is in a drug class called biguanides. Biguanides help reduce the amount of sugar the liver makes while improving insulin sensitivity, which helps reduce high blood sugar. Synjardy, Invokamet, and Trijardy XR (empagliflozin-linagliptin-metformin), are common combination drugs in this class that contain metformin as an ingredient and are also used for the treatment of Type 2 diabetes. Medication for Type 2 diabetes is usually accompanied by dietary and lifestyle/exercise changes, which you can discuss with your healthcare provider. Other drug classes have proven beneficial including:
1. SGLT2 inhibitors
SGLT2 inhibitors help block glucose (sugar) from being reabsorbed by helping the kidneys to eliminate sugar in the urine, which aids in the lowering of glucose levels. Drugs in the SGLT2 inhibitor class include:
- Invokana (canagliflozin)
- Farxiga (dapagliflozin)
- Jardiance (empagliflozin)
- Steglatro (ertugliflozin)
2. Sulfonylureas
Sulfonylureas aid in the reduction of glucose levels by stimulating the release of insulin from pancreatic beta cells. Commonly used sulfonylurea drugs include:
- Glucotrol/Glucotrol XL (glipizide/glipizide ER)
- Glyburide
- Amaryl (glimepiride)
3. Thiazolidinediones
Also known as glitazones, thiazolidinediones are oral insulin-sensitizing drugs used to treat Type 2 diabetes mellitus. They lower blood sugar with little chance of hypoglycemia (low blood sugar) and may have advantages against atherosclerosis. Thiazolidinediones may also be used to treat polycystic ovarian syndrome due to their potential to enhance ovulation, lower insulin resistance, and enhance endothelial function. Commonly prescribed thiazolidinediones include:
- Actos (pioglitazone)
- Actoplus Met (pioglitazoneand metformin)
- Duetact (glimepiride/pioglitazone)
- Oseni (pioglitazone/alogliptin)
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4. Dipeptidyl peptidase-4 (DPP-4) inhibitors
Used with diet and exercize, DPP-4 inhibitors reduce blood sugar by assisting the body in raising its post-meal insulin levels. Also known as gliptins, DPP-4 inhibitors are typically prescribed to patients with Type 2 diabetes who do not respond favorably to conventional diabetes medications such as metformin. The most common DPP-4 inhibitors include:
- Januvia (sitagliptin)
- Onglyza (saxagliptin)
- Tradjenta (linagliptin)
- Nesina (alogliptin)
What’s next when metformin isn’t enough for Type 2 diabetes?
Because it is both extremely effective and reasonably priced, metformin is used as first-line therapy. If you are not seeing desired results, talk to your healthcare provider. Sometimes, an additional drug may be needed, which can be effective when used in combination with metformin. This can be done with single-ingredient drugs or combination drugs.
Using a SingleCare discount card can help with additional savings at local pharmacies if cost is a concern. Stop taking metformin only after consulting a healthcare professional for medical advice. Hyperglycemia may result if metformin is abruptly stopped. Metformin should only be stopped abruptly in the case of a severe allergic reaction or other emergency situations.
When to switch from metformin to insulin?
Many Type 2 diabetes patients require treatment with insulin, either as a stand-alone medication or as an addition to an oral regimen, because they are unable to achieve adequate glycemic control with oral medications. The start of insulin may be recommended if there is evidence of long-term and chronic hyperglycemia, given how quickly and effectively insulin lowers blood sugar levels. A medical team may recommend using insulin if glucose targets are unable to be made after being diagnosed (whether this is due to a condition that has worsened over time, the ineffectiveness of present treatments to lower your glucose, or the development of problems occurring).
What are the steps you should take if metformin stops working?
Your diabetes care team needs to reevaluate your plan (including lifestyle changes and medications) if metformin is no longer keeping blood sugar levels within the desired range. Talking to a healthcare provider about concerns should always be the first step in seeking alternative treatments.
How to take metformin to maximize benefits
Lifestyle changes, such as exercise and a healthy diet, are the most effective treatments for improving diabetes management and cardiovascular health while taking metformin. Both of these lifestyle modifications can help to maximize the benefits of metformin.
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The DASH (Dietary Approaches to Stop Hypertension) plan is a wholesome, well-balanced, and long-lasting eating regimen that can help with a variety of health issues, such as hypertension, insulin resistance, and obesity. Some of the most beneficial foods to eat (along with taking metformin) to help blood sugar control include non-starchy vegetables such as asparagus, broccoli, cauliflower, leafy greens, salad greens, squash, and green beans, to name a few. Avoiding saturated fats and consuming lean meats and plant-based proteins are also beneficial. It is suggested to avoid drinking sugary drinks and avoiding food high in carbohydrates (such as cookies and chips) to help prevent excessive blood sugar spikes after meals.
Metformin may contribute to a vitamin B12 deficiency. A doctor may recommend B12 testing be done while taking metformin.
Exercise encourages muscle cells to take in and use more sugar, which lowers blood sugar levels. Exercise can both lower the chance of developing diabetes and make it simpler to manage a current diagnosis. Make it a point to get some exercise for at least 30 minutes a day, 5 days a week (or as directed by your doctor). A simple 10-minute walk three times a day is an effective way to accomplish this goal.
