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Abstract

The article provides an overview of sulfonylureas and meglitinides as second-line agents for treating type 2 diabetes mellitus (T2DM). Implications for occupational health clinicians who work with these individuals when they take either of these medications to achieve target glycemic indices are emphasized.

Keywords

metformin sulfonylureas meglitinides type 2 diabetes mellitus

Over 29 million Americans have diabetes, with the majority of them 45 years of age or older (Centers for Disease Control and Prevention [CDC], 2014). Most of these individuals have type 2 diabetes mellitus (T2DM; American Diabetes Association [ADA], 2014a) and take glucose-lowering agents to achieve target glycemic indices. When monotherapy with metformin fails to achieve target glycemic indices in these individuals, a second glucose-lowering agent, such as sulfonylureas or meglitinides, with different actions often is required because of a decline in beta cell function over time (Mearns et al., 2015). Occupational health nurses commonly assist workers who use these agents. Hence, this article provides an overview of glucose-lowering agents, sulfonylureas and meglitinides, and implications for occupational clinicians.

Standards of Practice

The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) and the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) recommend a variety of agents be used in conjunction with metformin when prescribing dual drug therapy. The AACE/ACE recommend considering dual therapy when HbA1cs are 7.6% to 9%; the ADA/EASD recommend dual therapy for HbA1cs of 9% or greater (Bailey, 2013). The AACE/ACE protocol includes sulfonylureas for dual therapy; non-sulfonylurea secretagogues (meglitinides or glitinides) are also recommended by the AACE/ACE (Garber et al., 2013). Both sulfonylureas and meglitinides are two of many agents suggested for dual therapy by the ADA/EASD (Inzucchi et al., 2012). These agents are prescribed for about 20% of individuals new to oral glucose-lowering agents (Desai et al., 2012). Furthermore, in reviewing over 900 common clinical scenarios, sulfonylureas are recommended as a suitable second-line agent by experts for about 25% of individuals with diabetes mellitus (Ampudia-Blasco et al., 2015).

Evidence of Effectiveness

Glucose-lowering agents are effective in lowering HbA1cs by 0.8% (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee et al., 2013) to 1.5% (Hirst, Farmer, Dyar, Lung, & Stevens, 2013) in clients who use sulfonylureas alone. Meglitinides generally reduce levels by 0.7% (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee et al., 2013). Only two randomized trials comparing repaglinide and nateglinide, either as monotherapy or in conjunction with metformin, have been published. In one randomized trial, 192 individuals with T2DM were given one of two drug combinations (i.e., repaglinide/metformin or nateglinide/metformin) for 16 weeks. In comparing repaglinide/metformin and nateglinide/metformin, HbA1Cs (7.5% vs. 7.1%; p < 0.001) and fasting plasma glucoses (−39 vs. −21 mg/dl; p = 0.002) were significantly lower for repaglinide/metformin than for nateglinide/metformin (Raski et al., 2003). In another 16-week randomized trial of 150 individuals with T2DM that compared repaglinide and nateglinide, HbA1cs (7.3% vs. 7.9%) and fasting plasma glucoses (−57 vs. −18 mg/dl; p < .001) were significantly lower for repaglinide monotherapy than for nateglinide monotherapy (Rosenstock et al., 2004). Although few, these two studies suggest that repagline used alone reduces HbA1cs more than nateglinide, and the reduction is even greater when used with other drugs, such as metformin (Marino, 2014).

Sulfonylureas

Sulfonylureas stimulate the release of insulin from pancreatic beta cells by inhibiting adenosine triphosphate channels [ATP]-dependent potassium channels, both soon after a meal and over several hours (Pfizer, 2013a, 2013b, 2015; Sanofi-Aventis, 2009, 2013). Second-generation agents include glimepiride (Amaryl®; Sanofi-Aventis, 2009), glipizide (Glucotrol®; Pfizer, 2013a), glipizide extended release (Glucotrol XL®; Pfizer, 2013b), and glyburide (DiaBeta®; Sanofi-Aventis, 2013). Micronized glyburide (i.e., Glynase®PresTab®) is composed of very small particles that are potentially absorbed more effectively (Pfizer, 2015).

Advantages

Sulfonylureas rapidly (12 weeks) lower glucoses (Mishriky, Cummings, & Tanenberg, 2015) and are relatively inexpensive. Benefits are realized when glucose levels must be lowered quickly or for workers for whom finances are a significant issue. Although costs vary regionally, the average costs of sulfonylureas are approximately US$55 per month (Tucker & Vega, 2014), with many of these agents available for less than US$15 for a 90-day supply (CVS/Caremark, 2016; Walmart, 2015). Sulfonylureas also are alternatives if metformin is contraindicated or poorly tolerated (Pfeiffer & Klein, 2014).

Disadvantages

Sulfonylureas have short-term durability and are usually prescribed with another agent for optimal glucose control (Mishriky et al., 2015). Hypoglycemia and weight gain are the most common side effects associated with sulfonylureas (Mearns et al., 2015). Other common side effects include nausea, diarrhea, headache, dizziness, and malaise (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDKD], 2014). Although empirical data about whether these agents are associated with cardiovascular disease risk are conflicting (Ferrannini & DeFronzo, 2015), sulfonylureas must not be used in workers with acute coronary syndrome (Kalra, Madhu, & Bajaj, 2015). Health care providers also should avoid prescribing two sulfonylureas because of similar action (Kalra & Gupta, 2015); however, sulfonylureas can be used with other medications such as metformin, alpha glucosidase inhibitors, incretin-based agents, and insulin (NIDDKD, 2015).

Certain drugs (e.g., non-steroidal anti-inflammatory agents, ACE inhibitors, clarithromycin), when given with sulfonylureas, can cause hypoglycemia, and individuals receiving these agents in conjunction with sulfonylureas should be monitored by occupational health nurses for hypoglycemia. A potential interaction has been reported between oral miconazole and sulfonylureas, resulting in severe hypoglycemia (Pfizer, 2013a, 2013b, 2015; Sanofi-Aventis, 2009, 2013). Sulfonylureas also should be used with caution in those at risk for hypoglycemia, such as individuals who eat irregular meals (Tran et al., 2015). In contrast, other drugs are associated with hyperglycemia when given with sulfonylureas (e.g., thiazides and other diuretics, corticosteroids, thyroid agents, estrogens, nicotinic acid), and individuals receiving these agents in conjunction with sulfonylureas should be monitored by occupational health nurses for hyperglycemia (Pfizer, 2013a, 2013b, 2015; Sanofi-Aventis, 2009, 2013).

Contraindications and Cautions

Individuals who have glucose 6-phosphate dehydrogenase (G6PD) deficiency can develop hemolytic anemia when given a sulfonylurea and, therefore, should be prescribed other glucose-lowering agents (Pfizer, 2013a, 2013b, 2015; Sanofi-Aventis, 2009, 2013). Glyburide cannot be given with bosentan, a medication used for pulmonary artery hypertension, because of resulting elevation in liver enzymes (Pfizer, 2015; Sanofi-Aventis, 2013). Concurrent administration of sulfonylureas with colesevelam can reduce absorption, and therefore, sulfonylureas should be administered at least 4 hours before colesevelam. Drugs that interact with specific sulfonylurea agents may vary and health care providers should refer to specific instructions from manufacturers of these agents (Pfizer, 2013a, 2013b, 2015; Sanofi-Aventis, 2009, 2013).

First-generation sulfonylureas should be avoided in workers with chronic renal diseases because both the parent drug and its metabolites are eliminated by the kidneys, which could increase their half-life and the risk of hypoglycemia. Glyburide should be avoided in chronic renal diseases; glimepiride dosage should be reduced to 1 mg daily. Although any condition that alters renal clearance of a sulfonylurea medication will prolong glucose-lowering effects, glipizide is often the preferred sulfonylurea, primarily because no active metabolites further increase the risk of hypoglycemia and no dose adjustment is necessary in chronic kidney disease (National Kidney Foundation [NKF], 2012). Pharmacokinetic data are very limited regarding sulfonylureas and chronic liver dysfunction. Therefore, this classification of oral glucose-lowering agents should be used with caution in workers with liver impairment (Scheen, 2014).

Findings regarding the safety of sulfonylureas from a systematic review of 140 trials and 26 observational studies indicated that all-cause mortality was slightly lower with metformin than with sulfonylureas in observational studies but the risk for bias in these studies was moderate. Cardiovascular mortality was slightly lower with metformin than with a sulfonylurea, but results were imprecise and had a moderate risk for bias. Although sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia compared with either metformin monotherapy or combination therapy, severe hypoglycemia did not occur more often with any particular monotherapy or combination therapy (Bennett et al., 2011).

Use in Older Adults

Although sulfonylureas are appropriate second-line agents for older adults, they are not recommended for those at high risk for hypoglycemia (International Diabetes Federation [IDF], 2012). Of course, glucoses should be assessed by individuals when suspecting and after treating low glucoses until their glucoses are normal (ADA, 2015). The AACE and ACE recommend self-monitoring of glucoses after meals or in the middle of the night for those with hypoglycemic symptoms (Handelsman et al., 2015). Empirical evidence also suggests avoiding the use of glyburide in older adults because of the high risk of hypoglycemia (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee et al., 2013; IDF, 2012).

Meglitinides

Meglitinides (glitinides) are insulin secretagogues that stimulate insulin release from the pancreas (i.e., interacts with the ATP-sensitive potassium channel on pancreatic beta cells; Novartis, 2013; Novo Nordisk, 2011). However, meglitinides attach to a different part of the sulfonylurea receptor in beta cells than sulfonylurea drugs; the interaction of meglitinides with the receptor is not as “tight” as that of sulfonylureas agents, meaning that a shorter duration of action and a higher blood glucose level is required before meglitinides secrete insulin from the pancreas (Marino, 2014). Examples of these agents are nateglinide (i.e., Starlix; Novartis, 2013) and repaglinide (i.e., Prandin; Novo Nordisk, 2011). Although meglitinides can be used alone or together with other agents (e.g., metformin; Bailey, 2013), they should not be used with sulfonylureas because of their similar action (Kalra & Gupta, 2015; NIDDKD, 2015). Meglitinides primarily are used to lower post-prandial glucoses (Guardado-Mendoza, Prioletta, Jiménez-Ceja, Sosale, & Folli, 2013).

Advantages

Because of their short-action, meglitinides are useful for individuals with T2DM who have irregular mealtime schedules and develop hypoglycemia while taking sulfonylureas. Meglitinides also may be used in individuals allergic to sulfonylureas and in older adults unable to take insulin when the goal is to avoid hypoglycemia (McCulloch, 2015). Another advantage of meglitinides is their flexibility compared with sulfonylureas because of their faster onset and shorter duration of action (Pfeiffer & Klein, 2014). Meglitinides also do not appear to be associated with an increase in cardiovascular mortality or negative events (e.g., stroke, myocardial infarction, heart failure; Huang, Abdelmoneim, Light, Qiu, & Simpson, 2015).

Although weight gain is similar to that of sulfonylureas, hypoglycemia may be less frequent with meglitinides (Bailey, 2013), because meglitinides are not associated with chronic hyperinsulemia, unlike sulfonylurea agents (Guardado-Mendoza et al., 2013). Repaglinide is more often associated with hypoglycemia than nateglinide, and repaglinide also causes more weight gain than nateglinide (Marino, 2014). However, findings from a recent meta-analysis of clinical trials cited an increased risk of hypoglycemia when nateglinide and metformin were compared with placebo (Mearns et al., 2015).

Disadvantages

The cost of meglitinides is relatively high. Similar to sulfonylureas, meglitinides lose their effectiveness as beta cell function declines over time (Marino, 2014). These agents are metabolized by the liver and, therefore, should be avoided in workers with liver dysfunction and used cautiously if renal dysfunction is present (Novartis, 2013; Novo Nordisk, 2011) although repaglinide has little renal clearance (McCulloch, 2015). Dose adjustments of repaglinide are necessary in workers with a glomerular filtration rate (GFR) of less than 30 mL/min/1.73m², starting with a dosage of 0.5 mg with meals. Similarly, for the same GFR, start with a meglitinide dosage of 60 mg with meals (NKF, 2012).

The most common side effect of repaglinide is hypoglycemia (Novo Nordisk, 2011). Uncommon side effects of repaglinide (i.e., <1% of adults) include increased liver enzymes, thrombocytopenia, leukopenia, and anaphylactic reactions. Other rare adverse events of repaglinide include alopecia, hemolytic anemia, Stevens–Johnson syndrome, and severe liver dysfunction (Novo Nordisk, 2011). For nateglinide, hypoglycemia is less common; upper respiratory infections are the most common adverse events. Rare cases of hypersensitivity reactions (e.g., rash) have been reported, along with jaundice, cholestatic hepatitis, and increased liver enzymes. Although clinical significance is unknown, elevated levels of uric acid have been described in individuals with T2DM treated with nateglinide (Novartis, 2013).

Contraindications and Cautions

Repaglinide interacts with other drugs. When given with gemfibrozil (Lopid), to lower cholesterol, repaglinide blood levels may increase approximately 28.6-fold. Similarly, when repaglinide is given with both gemfibrozil and itraconazole (i.e., the antifungal Sporanox), repaglinide blood levels can increase 70.4-fold, 7 hours after administration. Thus, repaglinide should not be taken with gemfibrozil. The dosage of repaglinide may need to be adjusted when given with other drugs (e.g., ketoconazole, itraconazole, rifampin, carbamazepine, montelukast, or deferasirox). Clarithromycin also has the potential to increase plasma levels of repaglinide. Extreme caution is advised in using this agent in women who are either pregnant or breastfeeding (Novo Nordisk, 2011). In contrast, drug interactions are less likely with nateglinide (Marino, 2014). Breastfeeding is contraindicated in individuals who have a known hypersensitivity to nateglinide, are pregnant, have a history of type 1 diabetes mellitus, or have diabetic ketoacidosis (Novartis, 2013).

Use in Older Adults

In comparing individuals with T2DM who were greater than 65 years old with those under 65 years of age, no differences were found in either frequency or severity of hypoglycemia with the use of repaglinide, but occupational health nurses should use caution with oral agents that have the potential to cause hypoglycemia in older adults (Novo Nordisk, 2011). Similarly, age does not appear to affect pharmacokinetic characteristics, so no adjustments in dosage are recommended for individuals taking nateglinide (Novartis, 2013).

Implications for Occupational Health Nurses

Research suggests that available support can improve self-efficacy and motivation in workers with T2DM (Mladenovic, Wozniak, Plotnikoff, Johnson, & Johnson, 2014). Thus, the role of occupational health nurses in assisting individuals to promote healthy lifestyles and manage T2DM is crucial. Development of diabetes management programs at work that include education and monitoring by occupational health nurses and sharing responsibilities with primary care providers are integral components. For example, research supports the effectiveness of nutritious meal plans in improving glucose control in T2DM (Lim et al., 2011). Hence, individuals with T2DM should be educated about how to develop healthy meal plans, including eating carbohydrates from various sources (e.g., fruits, vegetables, whole grains); low fat (e.g., lean meats, egg whites, low-fat milk), low cholesterol foods (less than 300 mg cholesterol per day); and foods low in sodium (e.g., less than 2,300 mg per day) and high in fiber (e.g., whole grains). For those taking sulfonylureas, meals should be consumed about the same time every day, because these individuals are at risk for low blood glucoses (Delahanty & McCulloch, 2015). With longer acting sulfonylureas, a three-meal pattern, in conjunction with three snacks during the day, is preferred (Kalra & Gupta, 2015), and work schedules should accommodate this meal and snack plan. Although meglitinides are more accommodating of irregular meal schedules (McCulloch, 2015), these individuals should be allowed to eat after taking their medication, rather than delaying their meals.

The weight of individuals taking sulfonylureas (or meglitinides) should be assessed at each contact and individuals taking these glucose-lowering agents should be instructed to report any sudden weight gain (Kalra & Gupta, 2015). In addition, many individuals with T2DM should be encouraged to lose excessive weight by decreasing their caloric intakes (Delahanty & McCulloch, 2015). Individuals attempting to either lose or maintain weight should exercise about 30 minutes per day, 5 or more days per week (Peterson, 2015). Individuals with T2DM should avoid any physical activity between when they take sulfonylureas and eat a meal, and any strenuous exercise in the first few hours after taking this glucose-lowering agent (Kalra & Gupta, 2015).

Assistance and support at the workplace may prevent potential complications of T2DM (e.g., cardiovascular disease) and enhance health and well-being in this population. Cardiovascular health and a history of coronary syndromes should be assessed prior to prescribing sulfonylureas. Individuals with T2DM and their families should be educated about symptoms of angina (Kalra & Gupta, 2015).

Occupational health nurses can also assist individuals with T2DM in managing their treatment regimen and monitoring potential side effects. For instance, when individuals with T2DM discontinue a sulfonylurea with a longer half-life (e.g., glyburide) and begin repaglinide, the occupational health nurses should closely monitor for side effects (e.g., hypoglycemia) for 1 week or more (Novo Nordisk, 2011). Individuals taking sulfonylureas and meglitinides and their family members should be educated about symptoms of both hypoglycemia and hyperglycemia. Individuals with T2DM also must be assessed for factors that contribute to hypo- and hyperglycemia and referred to their primary health care providers as needed. Individuals with T2DM who work and take sulfonylureas and meglitinides must be allowed reasonable accommodations (e.g., time and place to monitor glucose, access to a source of carbohydrate, and a schedule that follows their prescribed meal plan (U.S. Equal Employment Opportunity Commission, 2015). Although individuals with T2DM who perform activities which require adequate blood glucose levels to function both cognitively and physically (i.e., commercial or recreational drivers, pilots) can take these medications, consideration of alternate glucose-lowering medications with less risk for hypoglycemia should be made. Therefore, the use of sulfonylureas by individuals who are employed in hazardous work is a concern because of the increased risk for mild to moderate hypoglycemia; these workers should be evaluated by their health care providers (ADA, 2014b; Federal Aviation Administration, 2014; Handelsman et al., 2015).

Although the ADA (2015) and AACE/ACE (Handelsman et al., 2015) provide recommendations for the glucose self-monitoring of individuals who either take multi-dose insulin or are on insulin pump therapy, a more individualized approach (without specifying how often individuals with T2DM should monitor their glucose) based on individual needs and goals is suggested for those on oral therapy. In a review of 15 systematic reviews and 21 randomized controlled trials, Aakre, Watine, Bunting, Sandberg, and Oosterhuis (2012) concluded that clinical practice guidelines favored self-monitoring (and was, potentially biased because of industry funding) compared with actual results from systematic reviews. As such, individuals with T2DM who are not using insulin may benefit from glucose self-monitoring to provide feedback regarding their lifestyle and efficacy of medications (Handelsman et al., 2015).

Contraindications and Cautions

Contraindications or cautions related to sulfonylureas should be monitored routinely by occupational health nurses in collaboration with primary health care providers to avoid untoward side effects (e.g., a history of G6PD or chronic liver dysfunction, bosentan and glyburide, concurrent administration with colesevelam, first-generation sulfonylureas and glyburide prescribed for workers with chronic kidney disease, or glyburide prescribed for older adults). Occupational health nurses can monitor routine serum laboratory values (e.g., serum HbA1cs, lipids, GFR, creatinine values, and liver enzymes) to prevent or identify potential complications associated with sulfonylureas and meglitinides.

Among individuals taking repaglinide, those who either miss or add meals should learn about either skipping or adding a dose of repaglinide. Although rare, individuals taking repaglinide should also learn about uncommon side effects or complications (e.g., alopecia, Stevens–Johnson syndrome) and their responsibility to report associated symptoms (e.g., hair loss, flu-like symptoms followed by a spreading painful red or purplish rash with blisters) promptly. Complete blood counts with differential and related tests (e.g., G6PD) should be monitored routinely to detect other complications (e.g., thrombocytopenia, leuokopenia, hemolytic anemia). Emergency events (i.e., anaphylactic reactions) may occur suddenly when starting repaglinide (Novo Nordisk, 2011). In contrast, workers taking nateglinide should be monitored for the onset of upper respiratory infections, a common side effect, and rashes, an indicator of hypersensitivity reactions.

Therefore, occupational health nurses have many responsibilities when caring for individuals with T2DM who take sulfonylureas or meglitinides. These responsibilities include promoting a nutritious meal plan and education regarding the timing of meals, assessing cardiovascular health and providing interventions to promote health and well-being (e.g., exercise, weight loss), education about hypo- and hyperglycemia, monitoring appropriate laboratory values, and assessing for medication contraindications and either untoward side effects or emergent events associated with these medications. Therefore, diabetes management programs at work that include education and monitoring by occupational health nurses in collaboration with primary care providers can improve the health of workers with T2DM.

Recommended and Maximum Dosages: Sulfonylureas

Sulfonylureas work more efficiently when taken with meals (i.e., glimepiride, glipizide XL, micronized glyburide, glyburide) and some of these medications (i.e., glipizide) need to be taken 30 minutes prior to a meal (Pfizer, 2013a, 2013b; Sanofi-Aventis, 2009, 2013). Dosing recommendations for glipizide, glipizide XL, and glyburide, respectively, are 2.5 to 10 mg daily, 5.0 to 10 mg daily, and 2.5 to 10 mg daily (McCulloch, 2015). Higher dosages should be given in divided doses, up to a maximum dosage of 40 mg daily for glipizide and 20 mg daily for glipizide XL and glyburide, although higher dosages do not appear to improve glycemic control (Pfizer, 2013a, 2013b; Sanofi-Aventis, 2013). The starting dose for micronized glyburide is 1.5 to 3 mg daily, with a maximum total daily dosage of 12 mg (Pfizer, 2015). For glimepiride, the recommended dosage is 2 to 4 mg daily, with a maximum total daily dosage of 8 mg (Sanofi-Aventis, 2009). Older adults and those who are either malnourished/underweight or debilitated should be started at more conservative dosages (Pfizer, 2013a, 2013b; Sanofi-Aventis, 2013).

Recommended and Maximum Dosages: Meglitinides

Nateglinide: Recommended starting dose is 120 mg, 3 times a day prior to meals, unless individuals with T2DM are near their glycemic target, and then 60 mg, 3 times a day prior to meals is appropriate. There is no maximum daily dosage specified by the manufacturer (Novartis, 2013).

Repaglinide: Recommended starting dose is 0.5 mg, prior to meals, for workers who either have not taken glucose-lowering medicines previously or have HbA1C levels <8.0%. For other individuals who have either been treated with other glucose-lowering agents or who have HbA1C levels ≥8.0%, the recommended starting dose is 1 to 2 mg, typically taken before each meal (2, 3, or 4 times a day). The maximum recommended daily dose is 16 mg/day (Novo Nordisk, 2011).

In Summary

The role of the occupational health nurse in assisting individuals to promote healthy lifestyles and manage type 2 diabetes mellitus (T2DM) is crucial.

Nutritious meal plans, exercise, and education are components of workplace T2DM treatment programs.

Individuals with T2DM who work and take sulfonylureas or meglitinides must be allowed to monitor their glucoses, have access to a source of carbohydrates, and follow their prescribed meal plan.

Footnotes

Conflict of Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author Biographies

Dr. Grant has expertise in adult health nursing. She examines co-morbidities such as diabetes mellitus in adult patients and their families.

Dr. Graven has expertise in heart failure research. She examines factors related to self-care in heart failure patients, including the influence of co-morbidities, such as diabetes mellitus.

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Progressing From Metformin to Sulfonylureas or Meglitinides

Abstract

Keywords

Standards of Practice

Evidence of Effectiveness

Sulfonylureas

Advantages

Disadvantages

Contraindications and Cautions

Use in Older Adults

Meglitinides

Advantages

Disadvantages

Contraindications and Cautions

Use in Older Adults

Implications for Occupational Health Nurses

Contraindications and Cautions

Recommended and Maximum Dosages: Sulfonylureas

Recommended and Maximum Dosages: Meglitinides

In Summary

Footnotes

Conflict of Interests

Funding

Author Biographies

References