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The Metformin Update

August 29, 2016

More than 29 million people in the United States were living with diabetes and 86 million were living with prediabetes in 2012. Currently, there are 12 classes of diabetes medications approved by the US Food and Drug Administration (FDA). In this Q&A, Dr. Susan Cornell, PharmD, CDE, FAPhA, FAADE, of Midwestern University Chicago College of Pharmacy in Downers Grove, Illinois, offers insight about metformin use in diabetes care. Dr. Cornell is also a diabetes care and medication management provider with the Access Community Health Network-Chicago and Bolingbrook Christian Health Clinic.




PLN: What are the current FDA-approved indications for metformin in the United States?

Dr. Cornell: Metformin is FDA-approved to treat type 2 diabetes mellitus. It is the current recommendation from the American Diabetes Association for first-line therapy in conjunction with healthy lifestyle modifications (ie, diet, exercise).

However, metformin is also acknowledged for off-label use in patients with prediabetes, gestational diabetes mellitus, and various forms of polycystic ovary syndrome. 


PLN: What is the role of metformin in the care of patients with type 1 diabetes? Can you briefly discuss any noteworthy recent or upcoming studies on metformin use for type 1 diabetes?

Dr. Cornell: Historically, patients with type 1 diabetes were rarely overweight. Unfortunately, as obesity rates increase in the United States, more people with type 1 diabetes are included in this epidemic. Therefore, it is becoming more common to see patients with type 1 diabetes present with insulin resistance. Obviously, increasing the dose of exogenous insulin will not fix the resistance problem. Weight loss through exercise and healthy eating can improve insulin sensitivity, but in many cases drugs commonly used for type 2 diabetes are being used off-label in type 1 patients in an effort to directly or indirectly combat insulin resistance.

Of the 12 classes of medications available to treat type 2 diabetes, TZDs [thiazolidinediones] are the only agents that directly target insulin resistance. The adverse effects of TZDs, especially with insulin use, make them not an ideal option for use in patients with type 1 diabetes.

Due to its efficacy and weight loss potential, metformin is probably one of the more common type 2 diabetes medications being used off-label in patients with type 1 diabetes. Several clinical trials are underway to study the effectiveness of metformin added to basal-bolus insulin regimens in this population.


PLN: How does metformin work in the care of patients with diabetes?

Dr. Cornell: Metformin targets the liver and decreases blood glucose levels through the inhibition of hepatic gluconeogenesis, resulting in lower fasting glucose levels. When used as monotherapy, metformin is associated with a low risk of hypoglycemia or weight gain. However, the understanding of metformin’s mechanism of action is beginning to expand. Recent studies suggest that the gut may play a role in the glucose-lowering effects of metformin. This includes secretion of enteroendocrine L-cell products, such as glucagon-like peptide-1 and peptide YY, as well as bile acid metabolism, and a role in the gut microbiome. More exploration of metformin in the gut is underway.

Nevertheless, since metformin only targets one of the eight dysfunctional organs in type 2 diabetes, monotherapy has a short sustainability in maintaining A1C goals. Combination therapy is very commonly warranted to address the other pathologic processes.

PLN: What are the potential contraindications and adverse effects of metformin in patients with diabetes?

Dr. Cornell: In general, metformin is well tolerated, and the more common adverse effects, such as gastrointestinal disturbances (eg, nausea, vomiting, diarrhea, abdominal bloating, flatulence), usually subside within the first few weeks of therapy, especially when dose titration is gradual.

The more serious concerns revolve around renal function. Contraindications to metformin include renal disease or renal dysfunction (serum creatinine ≥1.5 mg/dL in men or ≥1.4 mg/dL in women), an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2, or abnormal creatinine clearance from any cause.

In addition, metformin has a black box warning label for lactic acidosis, which is a rare but potentially severe side effect that requires urgent care. Lactic acidosis risk is increased in patients with heart failure, dehydration, excessive alcohol intake, and hepatic or renal impairment, and metformin should not be prescribed for these individuals.

Another adverse effect of metformin that has gained notable attention is vitamin B12 deficiency. Metformin may impair vitamin B12 absorption, which can lead to some microvascular complications, such as hearing disturbances. Rapid reversal of vitamin B12 deficiency is usually observed with discontinuation of metformin therapy.


PLN: What are the potential side benefits of the drug?

Dr. Cornell: In general, metformin is associated with a slight weight loss, usually 2 kg to 5 kg. In addition, metformin has a favorable effect on lipids. It may decrease triglycerides by approximately 16%, low-density lipoprotein cholesterol by approximately 8%, and total cholesterol by approximately 5%; it may and raise high-density lipoprotein cholesterol by approximately 2%.  


PLN: Can you explain the recent FDA safety announcement regarding metformin and any other recent FDA label changes?

Dr. Cornell: Over the past few decades, questions have been raised about metformin use in older patients and in those with renal impairment. The FDA recently made labeling changes regarding this issue for all medications that contain metformin. The FDA did review numerous clinical studies to assess the safety of metformin use in people with mild to moderate kidney impairment. A major concern from clinicians was how renal function was determined in the decision to use metformin. Historically, serum creatinine was the measure to determine whether a patient could be prescribed metformin. More recent studies support the use of the eGFR equation. The rationale behind this is that eGFR accounts for more than just a single laboratory parameter; it also takes into account the patient’s age, gender, race, and weight.

New recommendations for metformin-containing products include obtaining eGFR prior to initiating metformin therapy and then at least annually once metformin is started. However, an eGFR measure should be assessed more frequently in patients at increased risk for renal impairment. Metformin is contraindicated in those with an eGFR below 30 mL/min/1.73 m2 and is not recommended in patients with an eGFR between 30 mL/min/1.73 m2 and 45 mL/min/1.73 m2. If a patient is already on metformin and his or her eGFR falls below 45 mL/min/1.73 m2, the benefits of continuing metformin should be weighed against discontinuation. If the patient’s eGFR falls below 30 mL/min/1.73 m2, treatment should be discontinued. In terms of iodinated contrast imaging procedures, the new recommendations suggest discontinuing metformin at the time of or before procedures in patients with an eGFR between 30 mL/min/1.73 m2 and 60 mL/min/1.73 m2, in patients with a history of hepatic disease, alcoholism, or heart failure, and/or in patients who will receive intra-arterial iodinated contrast. The patient’s eGFR can be reevaluated 48 hours after the procedure; metformin can be restarted if his or her renal function is stable.  


-Meredith Edwards White



Topics like this will be addressed during the “Examining the Necessity of Newer Insulins for In-Hospital Diabetes Management” session at the regional Pharmacy Learning Network meetings. PLN meetings offers health-system pharmacists a full day (6.5 contact hours) of critical education presented by today’s leading experts in the field. Join us in Aurora, Colorado, on September 23. Point of Care Training is also available the following day, September 24.

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