Metformin: how it works and how to handle its side effects correctly

What is metformin and why is it the first choice?

Metformin belongs to the biguanide class of drugs and is the most widely prescribed medicine for type 2 diabetes in the world. Clinical use began in Europe in the 1950s and it remains the first recommendation of major international diabetes guidelines, including those of the American Diabetes Association and the European Association for the Study of Diabetes.

The reasons for its first-line position are multiple and well-founded. It has an excellent safety record spanning decades, and long-term studies have shown that it reduces the risk of cardiovascular complications from diabetes. It does not cause weight gain, unlike many other diabetes drugs, and it does not cause hypoglycaemia on its own. It is also available at reasonable cost across most of the region.

Metformin is sometimes also prescribed for prediabetes to delay the progression to full diabetes in high-risk individuals, and for polycystic ovary syndrome (PCOS) to improve insulin resistance. Each of these uses requires a specific decision by your doctor.

How does metformin lower blood sugar?

Metformin works through several mechanisms in the body. The most important is its effect on the liver: in type 2 diabetes the liver produces more glucose than it should even in the fasting state, and this contributes significantly to elevated fasting blood sugar readings. Metformin suppresses this excess hepatic glucose production and brings it back toward a normal level. Many patients notice that their morning fasting readings improve noticeably after a few weeks on the drug, and this is exactly why.

The second mechanism is improving insulin sensitivity, meaning the body's cells become more responsive to the insulin that is already present. In type 2 diabetes the muscle and fat cells resist insulin and do not absorb glucose as they should, as if the locks on those cells have become stiff. Metformin makes these cells more responsive to the insulin the body is already making, without forcing the pancreas to produce additional insulin. This fundamental difference is why metformin alone does not cause low blood sugar: it does not raise insulin levels independently.

Metformin also slows the absorption of glucose from the intestines after meals, softening the sharp blood sugar spike that follows eating. More recent research also points to effects on the gut's bacterial balance and on gut hormones, though these are still being studied. The combined effect of all these mechanisms means the drug works across multiple pathways throughout the day, which is part of why it remains so consistently effective after six decades of use.

Gastrointestinal side effects: why they happen and what to do

Nausea, diarrhoea, bloating, cramps, and other digestive symptoms are the most common side effects of metformin, occurring especially at the start of treatment or when the dose is increased. Studies suggest that between 10 and 30 percent of patients experience these symptoms to a degree that makes them consider stopping the drug.

The precise mechanism behind these effects is not fully understood, but research points to the drug affecting the gut's bacterial balance and the secretion of certain gut hormones. What is clear is that most people tolerate the drug much better after a few weeks as the body adjusts.

The key strategy for managing these symptoms is to take the drug with food or immediately after a meal, never on an empty stomach. Starting at a low dose and increasing gradually over several weeks cuts the symptoms substantially. If they persist despite this, your doctor can switch you to a slow-release formulation such as metformin XR or SR, which causes fewer digestive problems for many people.

Vitamin B12 deficiency: the effect that is rarely mentioned

One side effect that does not receive enough attention in routine diabetes follow-up is that long-term metformin use reduces the absorption of vitamin B12 from the intestines. A study published in 2022 in the journal Nutrients focused specifically on diabetic patients in Arab countries and found that a meaningful proportion of them have metformin-related B12 deficiency, and that this deficiency often produces no obvious symptoms in its early stages. The risk increases with longer duration of use and higher daily doses.

Vitamin B12 is essential for nerve health and the production of healthy red blood cells. Severe deficiency causes peripheral neuropathy, the sensation of numbness, tingling, and sometimes weakness in the feet and hands. The clinical complication is that people with diabetes are already at risk of diabetic peripheral neuropathy caused by high blood sugar itself, so distinguishing between two different causes of the same symptoms becomes very difficult unless B12 is checked routinely.

The practical recommendation is to check B12 levels after one or two years on metformin and then every two to three years, or as your doctor advises. If a deficiency is found, the doctor prescribes an oral supplement or in severe cases an injection. Do not stop taking metformin over this concern: the benefit of controlling diabetes far outweighs the risk of a correctable B12 deficiency, and the two issues can be managed in parallel without any conflict.

Managing metformin doses in Ramadan

Fasting in Ramadan changes the entire pattern of eating and drinking, and this affects the timing and effectiveness of the drug. Metformin alone does not cause low blood sugar during fasting because it does not stimulate the pancreas to release extra insulin. However, if it is combined with other drugs that raise insulin levels, such as sulphonylureas or fixed insulin doses, the risk of hypoglycaemia increases significantly during long fasting hours.

Guidelines for managing diabetes during Ramadan, updated in 2015 and based on studies of patients across the region, recommend discussing dose timing with your doctor before Ramadan begins rather than improvising once it starts. The doctor may redistribute the dose between iftar and suhoor rather than keeping meal-time dosing from the non-fasting schedule.

Fasting with a chronic disease like diabetes is not a straightforward medical decision. Many religious scholars permit breaking the fast for someone whose health would be genuinely at risk. Your doctor is your partner in assessing that risk honestly. The goal is to observe the fast safely if your health allows, not to push through at the expense of your wellbeing.

When is metformin not suitable?

Metformin is very safe for most people with type 2 diabetes, but there are situations where it is not appropriate or requires close monitoring. The most important is kidney function: metformin is cleared by the kidneys, and when they are significantly impaired the drug accumulates in the body and may in rare cases cause a condition called lactic acidosis. For this reason the dose is reduced or the drug stopped when the estimated glomerular filtration rate falls below a certain level.

Before any procedure using contrast dye, such as cardiac catheterisation or contrast-enhanced scanning, tell your doctor or the hospital team that you are taking metformin. Contrast can temporarily affect kidney function, which may change the decision about pausing the drug before and after the procedure.

Severe heart failure, severe liver disease, acute illness with dehydration, and certain other specific conditions all require a conversation with your doctor about whether to continue. The principle to follow is that you should not stop the drug on your own initiative: contact your doctor whenever your health situation changes significantly.

How do you know metformin is working?

Metformin does not produce any noticeable sensation when it is working correctly, and this can lead some patients to doubt its effectiveness. The only way to assess its effect is through regular blood sugar measurements and the HbA1c test (glycated haemoglobin). HbA1c gives you a picture of your average blood sugar over the past three months and is the most important measure for monitoring diabetes control.

The target your doctor aims for is a level agreed between you based on your age, your overall health, and whether you already have complications. For many people with type 2 diabetes the target is an HbA1c below 7 percent, but this varies from person to person and should be individualised.

Do not expect immediate results. Metformin takes several weeks for its full effect to be measurable. In some cases a doctor adds a second drug to metformin when the target is not reached, and this does not mean the metformin has failed. Diabetes is a progressive condition and sometimes needs treatment to be stepped up over time, which is a normal part of managing the disease well.

Practical tips for daily use

Taking metformin at the same times each day helps maintain consistent blood levels. If you miss a dose and remember close to your next one, skip the missed dose and do not double the next. A double dose does not mean double benefit: it increases the risk of digestive side effects and does not improve control.

Store the drug somewhere below 25 degrees Celsius with moderate humidity and away from direct sunlight. In the hot climate of the region, do not leave it in a car in summer. Intense heat degrades the drug faster and reduces its effectiveness, which is a genuine concern in the Gulf and parts of the Levant.

Metformin does not replace a healthy diet and regular physical activity. These are the essential partners of any diabetes drug, and neglecting them measurably weakens the drug's effect. Tracking your home blood sugar readings and bringing a log to your doctor appointments is one of the most practical things you can do to make your treatment work over the long term.

Sources

• Sanchez-Rangel E, Inzucchi SE: Metformin: clinical use in type 2 diabetes, Diabetologia, 2017
• McCreight LJ, Bailey CJ, Pearson ER et al: Metformin and the gastrointestinal tract, Diabetologia, 2016
• Alhaji JH: Vitamin B12 Deficiency in Patients with Diabetes on Metformin: Arab Countries, Nutrients, 2022
• Sayedali E, Yalin AE, Yalin S et al: Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes, World journal of diabetes, 2023
• Ibrahim M, Abu Al Magd M, Annabi FA et al: Recommendations for management of diabetes during Ramadan: update 2015, BMJ open diabetes research and care, 2015
• LaMoia TE, Shulman GI: Cellular and Molecular Mechanisms of Metformin Action, Endocrine reviews, 2021