Does Glucophage (metformin) cause side effects?

Glucophage (metformin) is an oral antihyperglycemic drug that lowers blood glucose (sugar) by influencing the body's sensitivity to insulin and is used to treat type 2 diabetes in adults and children. 

It may be used alone or in combination with other diabetic medications. Glucophage also has been used to prevent the development of diabetes in people who are at risk. It is also used to treat polycystic ovarian syndrome (PCOS) and for weight gain due to medications used for treating psychoses. 

Insulin is a hormone produced by the pancreas that controls glucose levels in blood by reducing the amount of glucose made by the liver and by increasing the removal of glucose from the blood by muscle and fat tissues. As a result, insulin causes blood glucose levels fall. 

Glucophage acts by increasing the sensitivity of liver, muscle, fat, and other tissues to the uptake and effects of insulin. These actions lower the level of sugar in the blood. Unlike glucose-lowering drugs of the sulfonylurea class, Glucophage does not increase the concentration of insulin in the blood and, therefore, does not cause excessively low blood glucose levels (hypoglycemia) when used alone. 

Common side effects of Glucophage include

Serious side effects of Glucophage include lactic acidosis. Symptoms of lactic acidosis include

Drug interactions of Glucophage include cimetidine, because it decreases the elimination of Glucophage from the body, which can increase the amount of Glucophage in the blood by 40%, which may increase the frequency of side effects from Glucophage. 

Ioversol and other iodinated contrast media may reduce kidney function, which reduces elimination of Glucophage, leading to increased concentrations of Glucophage in the blood. 

Thiazide diuretics, steroids, estrogens, and oral contraceptives may increase blood glucose and reduce the effect of Glucophage.

Alcohol consumption increases the effect of Glucophage on lactate production, increasing the risk of lactic acidosis. 

There are no adequate studies of Glucophage in pregnant women. Most experts agree insulin is the best treatment for pregnant women with diabetes

Glucophage is excreted into breast milk and can therefore be transferred to the nursing infant. Breastfeeding mothers should not use Glucophage.

What are the important side effects of Glucophage (metformin)?

The most common side effects with metformin are

These symptoms occur in one out of every three patients. These side effects may be severe enough to cause therapy to be discontinued in one out of every 20 patients. These side effects are related to the dose of the medication and may decrease if the dose is reduced.

Metformin may also cause:

A serious but rare side effect of metformin is lactic acidosis. Lactic acidosis occurs in one out of every 30,000 patients and is fatal in 50% of cases. The symptoms of lactic acidosis are

  • weakness,
  • trouble breathing,
  • abnormal heartbeats,
  • unusual muscle pain,
  • stomach discomfort,
  • light-headedness, and
  • feeling cold.

Patients at risk for lactic acidosis include those with reduced function of the

Glucophage (metformin) side effects list for healthcare professionals

The following adverse reactions are also discussed elsewhere in the labeling:

  • Lactic Acidosis
  • Vitamin B12 Deficiency
  • Hypoglycemia

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Glucophage

In a U.S. clinical trial of Glucophage in patients with type 2 diabetes mellitus, a total of 141 patients received Glucophage up to 2550 mg per day. Adverse reactions reported in greater than 5% of Glucophage treated patients and that were more common than in placebo-treated patients, are listed in Table 1.

Table 1: Adverse Reactions from a Clinical Trial of Glucophage Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus

  Glucophage
(n=141)
Placebo
(n=145)
Diarrhea 53% 12%
Nausea/Vomiting 26% 8%
Flatulence 12% 6%
Asthenia 9% 6%
Indigestion 7% 4%
Abdominal Discomfort 6% 5%
Headache 6% 5%

Diarrhea led to discontinuation of Glucophage in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of Glucophage treated patients and were more commonly reported with Glucophage than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

In Glucophage clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.

Pediatric Patients

In clinical trials with Glucophage in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.

Glucopage XR

In placebo-controlled trials, 781 patients were administered Glucophage XR. Adverse reactions reported in greater than 5% of the Glucophage XR patients, and that were more common in Glucophage XR-than placebo-treated patients, are listed in Table 2.

Table 2: Adverse Reactions from Clinical Trials of Glucophage XR Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus

  Glucophage XR
(n=781)
Placebo
(n=195)
Diarrhea 10% 3%
Nausea/Vomiting 7% 2%

Diarrhea led to discontinuation of Glucophage XR in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of Glucophage XR patients and were more commonly reported with Glucophage XR than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

What drugs interact with Glucophage (metformin)?

Table 3 presents clinically significant drug interactions with Glucophage/Glucophage XR.

Table 3: Clinically Significant Drug Interactions with Glucophage/Glucophage XR

Carbonic Anhydrase Inhibitors
Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Glucophage/Glucophage XR may increase the risk for lactic acidosis.
Intervention: Consider more frequent monitoring of these patients.
Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.
Drugs that Reduce Glucophage/Glucophage XR Clearance
Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.
Intervention: Consider the benefits and risks of concomitant use with Glucophage/Glucophage XR.
Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine.
Alcohol
Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention: Warn patients against excessive alcohol intake while receiving Glucophage/Glucophage XR.
Insulin Secretagogues or Insulin
Clinical Impact: Coadministration of Glucophage/Glucophage XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
Drugs Affecting Glycemic Control
Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
Intervention: When such drugs are administered to a patient receiving Glucophage/Glucophage XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glucophage/Glucophage XR, observe the patient closely for hypoglycemia.
Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

Summary

Glucophage (metformin) is an oral antihyperglycemic drug that lowers blood glucose (sugar) by influencing the body's sensitivity to insulin and is used to treat type 2 diabetes in adults and children. Common side effects of Glucophage include nausea, vomiting, gas, bloating, diarrhea, loss of appetite, weakness or lack of energy, respiratory tract infections, low levels of vitamin B-12, low blood glucose (hypoglycemia), constipation, indigestion, muscle pain, heartburn, and chills. There are no adequate studies of Glucophage in pregnant women. Breastfeeding mothers should not use Glucophage.

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Medically Reviewed on 9/17/2020
References
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Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.
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