An Overview of Metformin and Implications in the Workplace

Abstract

Diabetes mellitus is expensive; one of the top 10 most costly health concerns for employers. Individuals with type 2 diabetes mellitus (T2DM) who achieve glycemic targets through healthy lifestyles and appropriate glucose-lowering agents lessen diabetes-related complications. The purpose of this article is to provide a brief review of a first-line agent used in treating T2DM, the biguanide metformin hydrochloride. Implications for health providers who assist employees who use metformin also are addressed.

Type 2 diabetes mellitus (T2DM) has escalated at alarming rates around the world. For example, in the United States, approximately 29 million Americans have diabetes mellitus, and 95% of Americans have T2DM. Diabetes mellitus also is expensive to the working population and one of the top 10 most costly health concerns for employers. Expenditures include direct health care expenses, absenteeism from work, and short-term disability (Centers for Disease Control and Prevention [CDC], 2014). Individuals with T2DM who achieve glycemic targets through healthy lifestyles and appropriate glucose-lowering agents lessen diabetes-related complications (Garber et al., 2013). Diabetes-associated complications such as cardiovascular diseases and retino-, neuro-, and nephropathy also affect quality daily activities such as optimal work productivity (CDC 2014). As such, there is a crucial need for individuals with T2DM to maintain healthy lifestyles (e.g., heart-healthy diet, consistent exercise, weight reduction) and use appropriate medications to achieve glycemic targets and lessen these complications.

The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE; Garber et al., 2013) and American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD; Inzucchi et al., 2012) included the biguanide metformin hydrochloride, diet, and exercise as first-line therapy in treating T2DM. Metformin hydrochloride also is currently the most commonly prescribed oral anti-diabetes agent worldwide (He et al., 2015). Hence, this agent is commonly used by individuals with T2DM in the workplace. Therefore, the purpose of this article is to provide a brief overview of metformin hydrochloride. Implications for health providers who assist employees who have T2DM and take metformin also are addressed.

Classification

Metformin hydrochloride belongs to the classification of biguanides, which reduces blood glucose synthesis by activating AMP-kinase (Bridges, Jones, Pollak, & Hirst, 2014; R. A. Miller & Birnbaum, 2011). Although biguanides do not cause hyperinsulinemia, they improve insulin sensitivity by increasing peripheral insulin uptake and utilization (U.S. Food and Drug Administration [FDA], 2008). These oral agents also decrease intestinal absorption of glucose (U.S. FDA, 2008) and hepatic glucose production, its primary role (Inzucchi et al., 2012). Common brand names of metformin hydrochloride (commonly called metformin) tablets include Glucophage and Glucophage extended release (XR; U.S. FDA, 2008).

Metformin lowers both basal and postprandial plasma glucoses (U.S. FDA, 2008). Glycosylated hemoglobin (HbA1c) levels typically are safely lowered by 0.5% to 1.5% with monotherapy, either at maximum or near maximum doses of metformin (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, 2013). However, although both the ADA/EASD (Inzucchi et al., 2012) and AACE/EASD (Garber et al., 2013) recognize the value of metformin, limitations are also recognized. For example, AACE/ACE experts recommend metformin monotherapy for those individuals who have HbA1c levels less than 7.5% and dual therapy for HbA1c levels 7.5% or greater up to 9.0% (Garber et al., 2013). Similarly, the AED/EASD indicate individuals with high baseline HbA1cs (e.g., ≥9.0%) are very unlikely to achieve target glucoses using metformin alone (Inzucchi et al., 2012).

Advantages to metformin include no weight gain with chronic use; limited, if any, hypoglycemia (Inzucchi et al., 2012); and low costs (Bailey, 2013; Rotenstein et al., 2012). Although uncommon, hypoglycemia potentially can occur with a significant caloric deficit, especially during strenuous exercise and using the drug concurrently with other glucose-lowering agents, such as sulfonylureas and ethanol (U.S. FDA, 2008). In relation to cardiovascular effects, metformin also reduces plasma lipids, such as triglycerides and low density lipoprotein (LDL) cholesterol levels (Nakhjavani et al., 2011), but consistent cardiovascular benefits (e.g., myocardial infarction, stroke, etc.) from clinical trials have not been robust (Asche, Hippler, & Eurich, 2014). Furthermore, metformin may have a protective effect against cancer mortality (Landman et al., 2010).

Disadvantages of metformin include negative initial gastrointestinal effects and a decreased absorption of vitamin B12 (Inzucchi et al., 2012; Nathan et al., 2009). Common gastrointestinal side effects include nausea, vomiting, diarrhea, a metallic taste, and abdominal discomfort in the first few days of therapy (Inzucchi et al., 2012; Lorenzati, Zucco, Miglietta, Lamberti, & Bruno, 2010). For this reason, metformin should be started at a low dose, with gradual titration to higher doses (Inzucchi et al., 2012). Subnormal levels of Vitamin B12 may be due to this agent interfering with absorption from the B12-intrinisic factor complex, occurring in only about 7% of individuals with T2DM. This B12 deficiency rarely causes anemia and reverses rapidly when metformin is discontinued (U.S. FDA, 2008).

The use of this drug is contraindicated in those who are at higher risk for lactic acidosis (a rare complication), such as in advanced renal insufficiency, alcoholism (Inzucchi et al., 2012; Nathan et al., 2009), and clinical or laboratory evidence of hepatic dysfunction (U.S. FDA, 2008). Providers should avoid metformin for individuals with a glomerular filtration rate (GFR) less than 45 mL/min/1.73 m² or a serum creatinine equal to or greater than 1.5 mg/dL in men and 1.4 mg/dL in women. This drug also should be avoided in those who are greater than 80 years of age or have chronic heart failure (Kidney Disease: Improving Global Outcomes [KDIGO] CKD Work Group, 2013; National Kidney Foundation [NKF], 2012).

Implications

Opportunities for encouraging certain lifestyle changes are a priority in the workplace (C. Miller, 2011). Information should include topics such as reducing excess weight, performing consistent exercise, eating a heart-healthy diet (e.g., buying lower fat foods available in grocery stores and restaurants, portion control and sizes), and stopping or reducing smoking (ADA, 2014). Contacts also should emphasize the importance of limiting alcohol intake; checking glucoses routinely, especially during and after exercise; and linking serum laboratory values (e.g., serum HbA1Cs, lipid, GFR, and creatinine values) to prevent or identify potential complications associated with metformin and T2DM (U.S. FDA, 2008).

Glycosylated hemoglobin levels should be assessed in relation to glycemic targets to evaluate the effectiveness of metformin and the need to adjust dosages or to add additional glucose-lowering agents. To reduce gastrointestinal effects, taking 500 mg once daily with the evening meal and, if tolerated, adding a second dose with breakfast is recommended (Lorenzati et al., 2010). The majority of individuals having mild hyperglycemia (i.e., HbA1C < 7.5%) will achieve glycemic targets at doses of 1,500 mg to 2,000 mg/day of metformin (Garber et al., 2013). Only marginal reductions in HbA1C are realized when increasing to the maximum dosage of either 2,000 mg/day for extended release or 2,550 mg/day (850 mg, three times a day) for non-extended formulations (Lorenzati et al., 2010).

Although rare, individuals should be assessed for vitamin B12 deficiency if megaloblastic anemia is suspected. Hence, both baseline and annual hematologic (e.g., serum hematocrit, hemoglobin, red blood cells) and other indices should be evaluated to assess for anemia and renal and hepatic functioning (U.S. FDA, 2008). Metformin also should be temporarily discontinued for 48 hours in individuals who have intravascular iodinated contrast materials administered (e.g., angiography, computed tomography) due to the threat of altering renal function.

Individuals on metformin should be taught to promptly report malaise, muscle aches, significant respiratory difficulty, increased somnolence, and later gastrointestinal distress (not initial gastrointestinal manifestations, which are common), because these clinical manifestations may indicate lactic acidosis. If present, metformin should be promptly discontinued and serum electrolytes, ketones, and blood glucoses obtained. Blood pH, lactate levels, and metformin levels also may be useful in assessing individuals with these clinical manifestations (U.S. FDA, 2008).

In Summary

• Metformin is an oral glucose-lowering agent that is a common first-line agent for treating individuals with T2DM.

• Health providers use a variety of strategies to assist these individuals to reduce excess weight, exercise, and eat a heart-healthy diet to achieve glycemic targets and lessen diabetes-related complications.

• For individuals with T2DM who take metformin, assessing routine laboratory values and clinical manifestations associated with complications also are important.