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Metformin: First-Choice Drug for Type 2 Diabetes

Worst Pills, Best Pills Newsletter article August, 2018
Important Warning About Metformin

Food and Drug Administration-Required Black-Box Warning: Lactic Acidosis*[1]

Well before metformin was approved, it was found to be associated with a rare but serious condition called lactic acidosis (a buildup of lactic acid in the blood), which can cause hypothermia (low body temperature), hypotension (low blood pressure), an abnormally slow heart rate and death. The onset of metformin-associated lactic acidosis often is subtle,...

Important Warning About Metformin

Food and Drug Administration-Required Black-Box Warning: Lactic Acidosis*[1]

Well before metformin was approved, it was found to be associated with a rare but serious condition called lactic acidosis (a buildup of lactic acid in the blood), which can cause hypothermia (low body temperature), hypotension (low blood pressure), an abnormally slow heart rate and death. The onset of metformin-associated lactic acidosis often is subtle, with nonspeci?c symptoms such as malaise (a general feeling of discomfort or illness), muscle pain, trouble breathing, sleepiness and abdominal pain. The condition is diagnosed by blood test results, including a high blood lactate level.

Risk factors for metformin-associated lactic acidosis include impaired kidney function, concomitant use of certain other drugs (for example, topiramate [TOPAMAX, TROKENDI XR]), age of 65 or older, undergoing a radiographic study with injected contrast, undergoing surgery and other procedures, conditions that cause low blood oxygen levels (for example, acute heart failure), excessive alcohol intake and impaired liver function.

In patients who may have metformin-associated lactic acidosis, the drug should be discontinued immediately and general supportive measures should be instituted in a hospital setting. Prompt hemodialysis treatment also is recommended.

Additional Important Safety Warnings

  • Before starting metformin, a blood test to measure kidney function must be done. Metformin should never be used by patients with severe kidney impairment and starting the drug is not recommended in patients with advanced moderate kidney impairment that is approaching the severe level.
  • Metformin should not be used by patients with other types of metabolic acidosis, including diabetic ketoacidosis, which should be treated with insulin.
  • Metformin should be avoided in patients with evidence of liver disease.
  • Metformin should be used with caution in patients with any of the other risk factors for metformin-associated lactic acidosis mentioned in the black-box warning above.
  • Metformin may cause vitamin B12 deficiency by interfering with absorption of this vitamin.

* These warnings are paraphrased from the FDA-approved drug labeling.

 

Metformin (FORTAMET, GLUCOPHAGE, GLUMETZA, RIOMET) was approved by the Food and Drug Administration (FDA) in 1995 for use in combination with diet and exercise to control blood sugar in patients with type 2 diabetes.

It is the drug of choice for initial treatment of patients with type 2 diabetes who are not able to control their blood sugar through diet and exercise alone and who do not have severe kidney impairment.[2] One of the most effective drugs for lowering blood sugar, metformin does not cause weight gain, rarely causes hypoglycemia, has few side effects and is available in generic versions at low cost.[3]

It is the only FDA-approved drug that belongs to the biguanide family of drugs — a group of oral type 2 diabetes drugs that work by preventing the production of glucose by the liver, improving the body’s sensitivity towards insulin and reducing the amount of sugar absorbed by the intestines.[4]

Based on an overall evaluation of benefits and risks, the American Diabetes Association treatment guidelines and multiple other experts all recommend metformin as initial monotherapy in patients with type 2 diabetes.[5],[6],[7] For patients who fail to achieve adequate lowering of their blood hemoglobin A1c level (a measure of blood sugar control over the preceding two to three months) with metformin alone, adding a second- or third-generation sulfonylurea, such as glyburide (DIABETA, GLYNASE) or glipizide (GLUCOTROL), may be appropriate.[8]

Public Citizen’s Health Research Group has designated metformin as Limited Use because it can cause a serious condition called lactic acidosis and should not be used in patients with severe kidney impairment because they are at greatest risk for this rare but potentially fatal adverse reaction (see text box above).

Over the past two decades, many fixed-dose combination medications containing metformin and another oral diabetes drug (see table below) have been marketed in the U.S. We have designated all of these combinations as Do Not Use. Nine of these products contain another diabetes drug that does not offer any proven clinical benefits over metformin alone but has additional serious, unique risks. The tenth combination product, METAGLIP, contains glipizide, which could be used in combination with metformin, but it is best to adjust the doses of these two drugs individually.

Fixed-Dose Combination Medications Containing Metformin Available In the U.S.*

Brand Name Second Active Ingredient
ACTOPLUS MET pioglitazone
INVOKAMET canagliflozin
JANUMET sitagliptin
JENTADUETO linagliptin
KAZANO alogliptin
KOMBIGLYZE saxagliptin
METAGLIP glipizide
SEGLUROMET ertugliflozin
SYNJARDY empagliflozin
XIGDUO dapagliflozin

* Public Citizen’s Health Research Group designates all of these combination products as Do Not Use.

The United Kingdom Prospective Diabetes Study (UKPDS), which was published in The Lancet in 1998, included a randomized clinical trial that compared use of metformin with conventional treatment (primarily diet alone) in more than 750 overweight subjects with newly diagnosed type 2 diabetes.[9] The UKPDS researchers found that metformin treatment resulted in improved survival and a reduction in cardiovascular complications.

Specifically, after an average follow-up of more than 10 years, subjects in the metformin group had a 36 percent lower risk of death from any cause than did subjects in the diet group. Subjects receiving metformin also had a 30 percent lower risk of adverse cardiovascular events (heart attack, sudden death, chest pain from coronary artery disease, stroke and peripheral vascular disease) than did those in the diet group.

Adverse effects

Although recommended as the first-choice drug among all oral diabetes drugs, metformin is associated with an increased risk of lactic acidosis. Lactic acidosis (a buildup of lactic acid in the blood) is an extremely rare[10] but serious condition that is estimated to be fatal in about 50 percent of cases. The increased risk of lactic acidosis is the reason that the FDA required a black-box warning in the drug’s product labeling (see box, right). A black-box warning is the strongest type of warning that the FDA can require.

Metformin should never be taken by patients with severe kidney impairment because they are at greatest risk of this adverse effect. The drug also should be avoided in patients with liver disease and used with caution in patients with any other risk factors for metformin-associated lactic acidosis, including heart failure.

The FDA initially required that the product labeling warn against the use of metformin in patients with any degree of kidney impairment.[11]

However, in 2016, the agency announced that it had concluded that metformin can be used safely in patients with mild kidney impairment and in some patients with moderate kidney impairment. Therefore, the agency required changes to the product labeling for metformin to reflect this conclusion.

Metformin also can reduce the intestinal absorption of vitamin B12 from ingested food. Long-term use of metformin may result in vitamin B12 deficiency.[12]

What You Can Do

Before starting metformin, make sure your doctor does a blood test to measure your kidney function. If you have advanced moderate or severe kidney impairment, you should not start taking metformin.

When using metformin, your doctor should check your kidney function periodically. If you develop severe kidney impairment while taking the drug, you should be switched to another diabetes drug, such as a second- or third-generation sulfonylurea or insulin.


References

[1]Bristol-Myers Squibb. Label: metformin (GLUCOPHAGE). April 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf. Accessed May 2, 2018.

[2]American Diabetes Association. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S73-S85.

[3]Drugs for type 2 diabetes. Med Lett Drugs Ther. 2017 Jan 16;59(1512):9-18.

[4]Bristol-Myers Squibb. Label: metformin (GLUCOPHAGE). April 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf. Accessed May 2, 2018.

[5]American Diabetes Association. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S73-S85.

[6]Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: A meta-analysis. JAMA. 2016;316(3):313-24.

[7]Drugs for type 2 diabetes. Med Lett Drugs Ther. 2017 Jan 16;59(1512):9-18.

[8]American Diabetes Association. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S73-S85.

[9]UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-865.

[10]Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care. 1999;22(6):925-927.

[11]Food and Drug Administration. FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. https://www.fda.gov/Drugs/DrugSafety/ucm493244.htm. Accessed May 2, 2018.

[12]De Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181