Let's talk about metformin. Some take it for diabetes and polycystic ovary syndrome, and some even use it for weight loss, longevity, or anti-aging. Even though metformin is one of the safer diabetes medications available, it still poses real risks and side effects you should be aware of, and metformin can also lead to important vitamin deficiencies that most people don't know about.
In this article, I'll go over who should, and more importantly, who should not take this medication. I'll also cover the best way to take metformin to avoid side effects or vitamin deficiencies, and at the end, discuss the best alternatives if it turns out metformin isn't right for you. As always, this article is educational only, so please talk to your doctor before making any changes to your health regimen.
I'm Dr. Leonid Kim. I'm board-certified in Obesity and Internal Medicine, and I discuss the most up-to-date, evidence-based information on weight loss, metabolic health, and longevity. Let's get into it.
What Is Metformin and How Does It Work?
So what's so special about metformin? Metformin, also known as Glucophage, traces its roots to a plant first used in medieval Europe to treat symptoms we now associate with diabetes, including frequent urination and thirst.
Metformin acts primarily on the liver, where it blocks gluconeogenesis, the process by which the liver makes glucose from fats and protein. More specifically, it disrupts mitochondrial function in liver cells, interfering with the energy processes that produce natural sugars in the body.
Common Side Effects and How to Minimize Them
When it comes to side effects, the most common is diarrhea, which affects up to a third of people taking this medication. Some people may also experience nausea, vomiting, indigestion, or bad gas. The good news about these GI side effects is that they typically subside on their own over time.
A few things can help minimize these effects:
- Ask your doctor about the extended-release formulation, which is about 50% less likely to cause side effects compared to the immediate-release form.
- Stay on a lower dose longer, since these GI side effects are dose-dependent, meaning the higher the dose, the more intense the side effects. It's okay to stay on a lower dose for months to let your body adjust.
- Take metformin with food. If you're on the extended-release form, the best time to take it is right after dinner.
Metformin and Vitamin B12 Deficiency
One of the most important things to know about metformin is that it can cause malabsorption, or reduced absorption, of important vitamins, particularly vitamin B12 and folate. In fact, just 4 months of taking metformin can put you at risk for vitamin B12 deficiency, and meta-analyses have shown that vitamin B12 levels are reduced by metformin in a dose-dependent manner.
If you've been taking metformin and are experiencing symptoms such as fatigue, neuropathy, trouble concentrating, or anemia, you should definitely have your vitamin B12 levels checked. I've written a separate, dedicated article on the warning signs of B12 deficiency that's worth reading if you want to learn more.
If you start metformin and plan to continue it for more than 4 months, I'd recommend checking your B12 levels regularly. For those at higher risk of developing B12 deficiency, I would actually recommend supplementing with B12 for as long as you're taking metformin, though again, discuss this with your doctor, since everyone's situation is different.
When it comes to folate, the data aren't as clear as for vitamin B12. Still, some studies show that adding both B12 and folate to metformin therapy was associated with beneficial effects on HDL cholesterol and renal function in patients with diabetes.
Lactic Acidosis: The Most Serious Risk
When it comes to more serious side effects or precautions, the most life-threatening safety concern is lactic acidosis, a condition involving a dangerous buildup of lactic acid in the body. This is extremely rare, but it carries a black box warning from the FDA.
The way metformin works is that it causes a subclinical, or barely observable, buildup of lactic acid, which, in and of itself, doesn't pose any problems. In fact, the body naturally produces small amounts of lactic acid through strenuous exercise. It only becomes dangerous in extreme overdoses or if you have a condition that slows the clearance or removal of lactic acid from the body.
Who Should Not Take Metformin
This brings us to important precautions regarding who should and shouldn't be on metformin:
- Advanced kidney disease. You should not take metformin if you have advanced kidney disease. If you have chronic kidney disease, your kidney function needs to be closely monitored while on metformin.
- Acutely worsening heart failure. You should stop taking metformin if you experience sudden worsening or deteriorating heart failure. As with kidney disease, it's not chronic, stable heart failure that's typically a concern, but the acute, sudden worsening, usually accompanied by leg swelling and shortness of breath.
- Advanced or worsening liver disease. Metformin should also be discontinued in cases of advanced or worsening liver disease, as the liver is responsible for clearing excess lactate, which can lead to lactic acidosis.
- Heavy alcohol use. Metformin should not be taken by people who are heavy drinkers or who have alcoholism.
I want to emphasize that we are generally not worried about metformin use in people with stable chronic liver disease, chronic kidney disease, or stable chronic heart failure. In fact, recent systematic reviews looking at data from the 1990s through 2016 found that metformin use in patients with moderate chronic kidney disease, chronic heart failure, or chronic liver disease was safe and actually improved clinical outcomes. It's the acute worsening of these conditions that calls for stopping metformin.
Metformin and CT Scans with Contrast
Another important precaution involves imaging: if you ever need a CT scan requiring iodine-based contrast (a chemical injected into your veins to help visualize structures on the scan), you may need to stop metformin temporarily beforehand.
Historically, there was concern that some people might experience kidney damage from the contrast medium, which is why there used to be blanket recommendations to stop metformin before receiving iodine-based contrast, in case impaired kidney function prevented the body from clearing metformin or its metabolites, or led to a buildup of lactic acid. However, with today's improved techniques and contrast agents, the risk of worsening kidney function is now considered extremely low.
Current guidelines generally only recommend stopping metformin before a contrast CT if you have kidney disease, liver disease, heart failure, or a history of alcoholism. That said, each clinic and imaging center may have its own protocol, so double-check with your healthcare provider and let them know you're taking metformin before getting a contrast CT scan.
Alternatives to Metformin: Berberine
Let's say you've been prescribed metformin but couldn't tolerate the side effects, or you want to try something else. In that case, an alternative worth discussing with your doctor is a supplement called berberine.
Berberine works similarly to metformin, acting on the same AMPK pathway in the mitochondria. The data on berberine isn't as robust as what we have for metformin, but it's still quite impressive. A meta-analysis of 27 randomized controlled trials, including over 2,500 patients, showed that berberine's effect on type 2 diabetes is comparable to that of other oral therapeutic regimens, with no statistically significant difference between berberine and oral hypoglycemic medications. More specifically, one small study showed that over 3 months, the glucose-lowering effects of berberine were similar to those of metformin.
In addition to helping with diabetes and insulin resistance, berberine also has therapeutic effects on cholesterol, with limited but promising data. I've written a separate article covering berberine in more detail, for anyone who wants to learn more.
Conclusion
Metformin remains one of the safest and most well-studied medications for diabetes and insulin resistance, but "safe" doesn't mean "without risk." Being aware of common GI side effects, the potential for vitamin B12 and folate deficiency, the rare but serious risk of lactic acidosis, and the specific situations where metformin should be paused or avoided, like advanced kidney, liver, or heart disease, or before certain contrast imaging, can help you use it more safely and effectively. For those who can't tolerate metformin or are looking for alternatives, berberine offers a reasonably well-supported option. However, it should still be discussed with your doctor, given differences in the strength of the evidence and the need for individualized care.
FAQ
What are the most common side effects of metformin?
The most common side effect is diarrhea, affecting up to a third of users, along with nausea, vomiting, indigestion, and gas. These typically improve over time, especially with the extended-release formulation, lower starting doses, and taking it with food.
Does metformin cause vitamin deficiencies?
Yes. Metformin can reduce the absorption of vitamin B12 and folate. Just 4 months of metformin use can increase the risk of B12 deficiency, so regular monitoring is recommended for those on metformin long-term.
What is the most serious risk associated with metformin?
Lactic acidosis is the most serious, though extremely rare, risk, carrying an FDA black box warning. It's more likely in people with significant kidney, liver, or heart failure that impairs the body's ability to clear lactic acid.
Who should not take metformin?
People with advanced kidney disease, acutely worsening heart failure, advanced or worsening liver disease, or heavy alcohol use should generally avoid metformin. Stable chronic conditions are generally not a concern, and metformin may still be safely used.
Do I need to stop metformin before a CT scan with contrast?
Current guidelines generally only recommend stopping metformin before contrast imaging if you have kidney disease, liver disease, heart failure, or a history of alcoholism, since modern contrast agents carry a much lower risk than in the past. Always confirm with your specific clinic or imaging center.
Is berberine a good alternative to metformin?
Berberine acts through a similar mechanism (the AMPK pathway) and has shown glucose-lowering effects comparable to metformin in some studies, along with cholesterol-lowering benefits. However, the overall evidence base is smaller than that for metformin, so it's best to discuss it with a doctor before switching.