Type. Diabetes Drugs. A Review

Type Diabetes is a common diagnosis for home care patients. Diabetes drugs are now available that target the multiple defects of metabolism that characterize Type 2 diabetes. Understanding the wide variety of medications available will assist clinicians in guiding their patients through the complexities of diabetes self-care to promote optimal glucose control. Introduction As the number of people with Type 2 diabetes mellitus has grown, so has the number of drugs to treat this chronic illness. T2DM is not a single defect of glucose metabolism rather it is a progressive metabolic disorder with defects in multiple systems (Unger et al., 2013). As more is learned about its complexity, drug therapies in development focus on a multitude of systems and mechanisms. Treatment options have become more complex, it is important for care providers to understand the differences in the various drug classes and insulin preparations. T2DM treatment must also address healthy lifestyle and cardiovascular health; however, this review will focus on hyperglycemia treatment. As with any review, specific drug details are not included. Professionals are encouraged to seek out complete references related to any particular medication. 2 Diabetes Drugs A Review Pharmacologic Therapies by Drug Class Although practitioners do not universally agree on drug therapy combinations of choice for T2DM, initial monotherapy with metformin is considered standard of care followed by additional oral agents (Table 1) or insulin (Table 2) (Garber et al., 2013; Inzucchi et al., 2012). As T2DM progresses and metformin fails to achieve the desired response, multiple treatment options are available and the approach to selection is not a one size fits all. Generally, decisions are made based on pharmacologic targets and specific patient factors including, but not limited to risk of hypoglycemia, likelihood of adherence, cost, side effects, and comorbidities. It is important to know that all oral hypoglycemic agents and insulin are considered high-alert medications (Institute for Safe Medication Practice [ISMP], 2014). Biguanide Metformin is currently the only drug available in the biguanide class. It is the most often prescribed and recommended as the first-line drug in the treatment of T2DM (Inzucchi et al., 2015). There is strong evidence of safety and efficacy, it is low in cost and is associated with evidence demonstrating lower cardiovascular events (American Diabetes Association [ADA], 2015). This medication works primarily by reducing hepatic glucose Barbara Freeland, DNP, RN, ACNS-BC, CDE and Margo S. Farber, PharmD 304 Volume 33 Number 6 www.homehealthcarenow.org

2.0 HOURS Continuing Education production and enhancing insulin sensitivity with the greatest effect on fasting glucose. Metformin does not stimulate insulin production (Bailey, 2014), thus, has a low risk for hypoglycemia. It may be used alone or in combination with nearly any other diabetes drug. Metformin is excreted almost entirely through the kidneys and must be used with caution in patients with poor renal function. It is contraindicated for those with an elevated serum creatinine ( 1.5 mg/dl in men and 1.4 mg/dl in women) (Deglin et al., 2011). Therefore, metformin should not be used when renal function may be compromised, such as diagnostic procedures requiring contrast dye or major surgery. Excessive use of alcohol can enhance lactate metabolism; thus, metformin should be avoided in patients who abuse alcohol. Although rare, lactic acidosis is a potential risk of metformin therapy; however, there is no risk when appropriately prescribed (Bailey, 2014). Patient education for metformin should include an understanding of how the drug works as well as discussion about alcohol use. Initially, patients may experience some bloating, diarrhea, nausea, anorexia, or a metallic taste. These effects resolve over time and are lessened by starting with lower initial doses (Bailey, 2014). Taking it with food is recommended. A major advantage of metformin is that it decreases glucose without the risk of hypoglycemia or weight gain. Some patients may in fact experience small weight loss. Chris Walker/MCT/Newscom Sulfonylureas and Glinides Sulfonylureas are the oldest class of oral agents used in the treatment of T2DM (the first-generation agents were available in the 1950s). Second-generation sulfonylureas such MediaforMedical/Jean-Paul Chassenet/Alamy June 2015 Home Healthcare Now 305

as glyburide, glimepiride, and glipizide are currently in use. These drugs work by stimulating insulin secretion and because of this, patients taking these drugs are at risk for weight gain and hypoglycemia. It is important that patients understand the behaviors that would put them at risk for low blood glucose, the symptoms of hypoglycemia and its treatment. Sulfonylureas should not be taken if the patient is to undergo any procedure that requires fasting. Declining renal function predisposes patients to drug accumulation and can increase the risk factor for hypoglycemia. As renal function naturally declines with age, the elderly are particularly prone to sulfonylurea-induced hypoglycemia (Romeo et al., 2014). Lower doses and/or an alternative drug class may be needed. Sulfonylureas are used extensively due to their low drug cost relative to many of the newer oral agents. This drug class may not have a sustained effect on glucose lowering due to the progressive decline of pancreatic insulin production (Inzucchi et al., 2012). Patients allergic to sulfonamides may experience sensitivity (Deglin et al., 2011). It is also important to alert patients taking beta-blockers that the symptoms of low blood glucose may be blunted and more frequent glucose monitoring may be needed. Sulfonylureas may appear in a combination tablet with metformin or other diabetes drugs. They are not approved for use in pregnancy (Deglin et al., 2011). Glinides (nateglinide, repaglinide) also stimulate insulin release from the pancreas; however, in a slightly different manner. Insulin secretion is stimulated when glucose levels are higher and the drug effects decrease as glucose lowers. However, this does not eliminate the risk of hypoglycemia. Thiazolidinediones (TZD) This drug class may be referred to as insulin sensitizers given their mechanism of action. TZDs (rosiglitazone and pioglitazone) increase glucose uptake by 30% to 50% in muscle and adipose tissue, reduce hepatic glucose production, and decrease insulin resistance (D Alessio & Hirsch, 2011). The onset of full effectiveness may take as long as 12 Table 1. Oral Agents for T2DM, Used as Monotherapy or in Combination Teaching Note: Topics to include are name of drug, purpose and action, accurate dose, timing of administration, and storage requirements. If hypoglycemia is a risk, include definition, risk factors, recognition/symptoms, glucose monitoring, and treatment options. Drug Class Generic Name Approximate % A1c Lowering Risk of Hypoglycemia Side Effects/Cautions Patient Teaching Biguanide Metformin Glucophage Immediate or extended release Sulfonylurea Glyburide Glipizide Glimepiride Metiglinide Nateglinide Repaglinide 1 2 Minimal to none GI side effects. Vitamin B12 deficiency. Best tolerated when taken with food. Caution with renal insufficiency, hepatic disease, or heart failure. Hold if NPO or renal compromise likely. 1 2 Yes Caution in sulfa allergy. Hold if NPO. May cause weight gain. Decreased efficacy over time. 0.75 1.5 Yes Hold if NPO or meal is skipped. May cause weight gain. Decreased efficacy over time. Thiazolidinedione Pioglitazone Rosiglitazone DPP-4 inhibitor Sitagliptin Saxagliptin SGLT-2 blocker Canagliflozin Dapagliflozin 0.75 1.5 Minimal to none Not for use in preexisting edema, heart failure, or hepatic failure. Weight gain is expected. Requires initial and periodic liver function tests. May increase risk of fracture. Not approved for use in pregnancy. 0.5 1 Minimal to none Daily at any time of day with or without food. No expected weight gain, may be slight weight loss. Dose adjusted in renal failure. 0.7 1 Minimal to none UTI and genital yeast infections more common. Polyuria. Not for use with severe renal impairment, egfr less than 30 ml/min/1.73 m 2, or ESRD. May LDL. NPO = nothing by mouth; egfr = estimated glomerular filtration rate; GI = gastrointestinal; UTI = urinary tract infections; ESRD = end-stage renal disease; LDL = low-density lipoprotein. Note. Table recreated with information from Riddle & Yuen (2014) and Inzucchi et al. (2015). 306 Volume 33 Number 6 www.homehealthcarenow.org

Table 2. Commonly Used Insulin Preparations Teaching Note: Topics to include are name of insulin, accurate dose measurement, timing of administration, onset, peak, and duration, injection sites, and storage requirements. Ask patient to demonstrate preparing and injecting insulin. Hypoglycemia is a risk for all patients taking insulin; include definition, risk factors, carrying medical ID, recognition/symptoms, glucose monitoring, and treatment options. Products Available Onset Peak Duration General Use Rapid-Acting Insulin Analogs Aspart (Novolog) Glulisine (Apidra) Lispro (Humalog) Available in vial and pen form Short-Acting Regular insulin (Humulin R, Novolin R) Available in vial Intermediate-Acting NPH insulin (Humulin N, Novolin N) Long-Acting Insulin Analogs 15 min 1 2 hours 4 6 hours Used as a bolus or mealtime dose, may be administered just prior, during, or immediately after a meal. Drugs of choice for prandial or mealtime insulin. 30 45 minutes 2 4 hours 6 8 hours Can be administered as bolus or mealtime insulin, but should be administered 30 to 45 minutes prior to the meal. 1 2 hours 6 12 hours 12 24 hours Requires twice-daily administration. Detemir (Levemir) Glargine (Lantus) Available in vial and pen form Premixed Insulin 70% insulin aspart protamine + 30% insulin aspart (NovoLog Mix 70/30); 75% insulin lispro protamine + 25% insulin lispro (Humalog Mix 75/25) Available in pen form 70% NPH + 30% regular (Humulin 70/30, Novolin 70/30) 50/50 preparations are also available Concentrated Insulin U500 Note. Table recreated with information from Olson et al. (2014) and Inzucchi et al. (2015). 1 2 hours No peak 12 24 hours Basal or background insulin of choice; peakless; generally given once daily, every 24 hours. 15 30 min 1 6 hours Up to 24 hours 30 45 minutes 2 12 hours Up to 24 hours Combining protamine with aspart or lispro, allows for slow, continuous release and serves as the basal component of the combination. This combination is the least expensive of the mixed insulins, however, is less desirable given the delayed onset of regular insulin and difficulties with meal timing 30 40 2 4 6 10 Taken 30 minutes before meals. Contains 500 units/ml. Rather than the standard 100 units/ml. weeks. In addition to improving glucose, TZDs have the added benefit of reducing triglycerides and improving high density lipoprotein cholesterol. When taken alone there is no risk of hypoglycemia. Patients must be warned that weight gain of up to 2 to 4 kg in the first year and peripheral edema are common (D Alessio & Hirsch, 2011). Heart failure risk is more prevalent in patients taking insulin in combination with a TZD (Garber et al., 2013). Patients with preexisting edema, heart failure, or hepatic impairment should not take a TZD. Increased risk of fracture due to bone demineralization has been reported in patients taking TZDs (Garber et al.). Rosiglitazone, one of the two available TZDs, has been withdrawn in Europe. Subsequent analysis by the Food and Drug Administration (FDA) concluded that the risk of myocardial infarction is no greater and comparable to that observed with standardof-care diabetes drugs (FDA, 2013). The risk of bladder cancer linked to Pioglitazone has been dispelled (Inzucchi et al., 2015) although the FDA has continued to recommend caution in patients with active or prior history of bladder cancer (FDA, 2011). Due to extensive liver metabolism, TZDs are not recommended in patients with hepatic disease. Liver function should be evaluated prior to initiation and periodically during use. June 2015 Home Healthcare Now 307

As Type 2 diabetes progresses and metformin fails to achieve the desired response, multiple treatment options are available and the approach to selection is not a one size fits all. Incretin-Based Therapies Dipeptidyl Peptidase-4 (DPP-4) Inhibitors The DPP-4 inhibitors are oral medications and include sitagliptin, saxagliptin, and others, each available as single component or as a combination product with metformin. They act with a glucose-dependent action targeting both fasting and postprandial glucose levels in part by inhibiting glucagon production. The effect of DPP-4 inhibitors ceases when glucose is within normal limits. These drugs differ slightly with respect to drug interactions and require dose adjustment for renal failure (Aschner, 2014). As a drug class, they are relatively more expensive than metformin and sulfonylureas, but may be preferred given they are well tolerated, often have daily dosing, low hypoglycemia risk, and are unlikely to cause weight gain. Glucose-Like Peptide-1 (GLP-1) Receptor Agonists GLP-1 is an endogenous incretin hormone that, in response to a high glucose level, stimulates the production of insulin, slows gastric emptying and postprandial release of glucagon. The GLP-1 receptor agonists (exenatide, liraglutide) are available only as injectable drugs. GLP-1 receptor agonists stimulate insulin production in a glucose-dependent manner and have a low risk of hypoglycemia. In addition, the GLP-1 receptor agonists slow gastric emptying, enhance satiety, and are associated with weight loss. Nausea and GI-related adverse effects are common with these agents, but often improve over time and are reported to occur less frequently with the longer-acting agents. Slow titration of doses diminishes symptoms of nausea. The primary disadvantages of the GLP-1 receptors agonists are their cost and route of administration by subcutaneous injection (Diab & D Alessio, 2014). The original drug in this class, exenatide, is given twice daily; however, a newer formulation has been approved for daily and weekly administration. Sodium Glucose Cotransport 2 (SGLT-2) Inhibitors The newest class of drugs available for glycemic control in T2DM is the SGLT-2 inhibitors. These agents (canagliflozin, dapagliflozin, and empagliflozin) inhibit SGLT-2, one of the transporters responsible for glucose reabsorption in the kidney. The resultant effect is promotion of urinary excretion of glucose, blood glucose lowering, and ultimately, improvement in HbA1c. Given their recent arrival to the diabetes drug treatment options, use is somewhat limited at the present time. They are generally well tolerated, have minimal to no risk of hypoglycemia, have minimal drug drug interactions, and provide an osmotic diuresis that has a modest blood pressure lowering effect. Disadvantages of the SGLT-2 inhibitors include their higher cost, lack of long-term use data, and a high incidence of genitourinary infections, especially in women (Abdul-Ghani et al., 2014). Because these drugs promote glycosuria, patients should be counseled regarding signs and symptoms of urinary tract and genital infections, which are common side effects. Generally, it is recommended to avoid the use of these drugs in those who have a history of frequent genitourinary infections. Less Commonly Used Agents There are several other classes of drugs used in the multimodal management of T2DM. These are used less often due to modest glucose lowering effect and relatively higher cost. The alpha-glucoside inhibitors, acarbose, and miglitol work by blocking the enzyme responsible for the breakdown of carbohydrates to glucose, which can lead to side effects such as flatulence, diarrhea, and bloating. An injectable amylin analog, pramlintide, slows gastric emptying and decreases postprandial glucagon secretion. It is used only in patients who are taking mealtime insulin. The bile acid sequestrant, colesevelam, has been used due to its potential effect on decreasing hepatic insulin resistance and reducing glucose absorption; however, it is associated with numerous drug drug interactions and has a relatively low level of efficacy of lowering glucose. Finally, bromocriptine, a dopamine agonist, may be utilized for its central effects that reverse metabolic changes observed with insulin 308 Volume 33 Number 6 www.homehealthcarenow.org

resistance and obesity. Data are limited with this agent and use is often associated with low blood pressure and syncope. Insulin Therapy Insulin is a naturally occurring hormone in the body and therefore is always effective in reducing glucose levels. With the progressive nature of T2DM beta cell function declines, insulin may be needed as a supplement to other agents or as primary treatment. Insulin may be administered by using a vial and syringe, an insulin pen device, a jet injector, subcutaneous injection ports, and insulin pumps. Hypoglycemia and weight gain are risks for all patients taking insulin. Self-glucose monitoring is required (ADA, 2015). It is valuable to include significant others in teaching related to hypoglycemia as the patient may not always be the first to recognize the symptoms. Insulin preparations are often divided into categories based on their time-action profile. Rapid, fast, intermediate, and long-acting insulin types are available as well as formulations that combine faster and longer-acting insulin in one solution (Table 2). Long-Acting (Basal) Insulin Analogs In the majority of patients with T2DM, basal or long-acting insulin is the first insulin type added to the medication regimen to enhance glycemic control. Basal insulin is intended to mimic the continuous supply of insulin secreted by the normally functioning pancreas. Normally, even during fasting, glucose is steadily released into the blood and a continuous supply of background insulin is required to maintain blood glucose levels. Long-acting insulin analogs provide a steady, continuous supply up to 24 hours. A common misconception often leading to hyperglycemia is that basal insulin administration must be held during periods of fasting. Under most circumstances, even when patients are NPO, there is a need for basal insulin to respond to basic metabolic needs and, thus, holding this therapy can result in hyperglycemia several hours later. The ISMP has published multiple reports of hyperglycemia resulting from well-intended caregivers who unnecessarily hold basal insulin (ISMP, 2014). There are two insulin analogs available in this category: detemir and glargine. For most patients, these are administered once daily and generally cover the basal insulin requirements for up to 24 hours. It is important that they be administered at the same time every day. Intermediate-Acting Insulin Prior to the availability of 24-hour basal insulin, neutral protein hagedorn insulin, an intermediateacting product, was routinely used as basal insulin. Given its shorter duration of action, it must be administered twice daily. The long-acting insulin analogs are preferred given their once-daily administration and lower risk of hypoglycemia, NPH is a less-expensive alternative that is still utilized due to its favorable cost relative to the long-acting insulin analogs. Rapid-Acting Insulin Analogs Over time, many patients require the addition of prandial or mealtime insulin to their basal insulin regimen to adequately manage their blood glucose. The insulin of choice is one of the three currently available rapid-acting insulin analogs: aspart, glulisine, or lispro. These agents have been molecularly manipulated to provide fast absorption. Each has an onset of less than 15 minutes, peaks in 1 to 2 hours, and a duration of about 2 to 4 hours. These rapid-acting insulin preparations allow people with diabetes to inject insulin at the time of their meal. Ideally, the dose should match the timing, size, and carbohydrate content of the meal (Olson et al., 2014). This offers great convenience and flexible dosing especially when administered with an insulin pen device. Rapid-acting insulin may also be used to correct elevated glucose in some circumstances. An additional benefit of rapid-acting insulin over regular insulin is that doses can be taken at each meal without fear of overlapping action. Short-Acting Insulin Regular insulin is the sole preparation in this category. It has been used as the bolus or mealtime insulin, historically (prior to the availability of rapid-acting agents) administered 30 to 45 minutes prior to a meal. The onset of action is 30 to 45 minutes with a peak effect at 4 to 6 hours (Deglin et al., 2011). Unlike rapid-acting insulin, regular insulin requires close attention to timing of administration in relation to an anticipated meal. Hypoglycemia can occur if the meal is delayed or omitted due to an unforeseen circumstance. For this reason, rapid-acting insulin is preferred June 2015 Home Healthcare Now 309

as the bolus or mealtime insulin. Regular insulin, however, is lower in cost than rapid-acting insulin analogs. Regular insulin also comes in a concentrated form when doses of greater than 200 units per day are required; however, it must still be administered two to three times daily. Rather than the traditional concentration of 100 units/ml, concentrated insulin contains 500 units/ml. Insulin is considered a high-risk medication in both community and acute care settings, but there has been special emphasis placed on this concentration (ISMP, 2014). Mixed Insulin Premixed insulin is a combination product of short/rapid-acting insulin along with longer-acting basal insulin. These products provide convenience, however, are generally reserved for those individuals with stable insulin regimens who are well controlled. They are administered with meals and contain a fixed amount of both short/rapid-acting and long-acting insulin in a specific ratio. Conclusion Diabetes is a complex and multifaceted disease. Drug classes and therapies within each class continue to expand. Patients with T2DM require an individualized approach and should expect their drug therapy to evolve. As caregivers, providing patient education regarding the disease and drug therapy will enhance glycemic control and minimize side effects. Knowledge of the everexpanding list of medications is critical to safely and successfully manage glucose control. Barbara Freeland, DNP, RN, ACNS-BC, CDE, is a Clinical Assistant Professor, School of Nursing, University of Michigan, Ann Arbor, Michigan. Margo S. Farber, PharmD, is a Director, Drug Information Service, University of Michigan Health System, Ann Arbor, Michigan. The authors and planners have disclosed no potential conflicts of interest, financial or otherwise. Address for correspondence: Barbara Freeland, DNP, RN, ACNS-BC, CDE, 400 North Ingalls, Second Floor, Division 1, Ann Arbor, MI 48109 (bfreelan@umich.edu). DOI:10.1097/NHH.0000000000000243 REFERENCES Abdul-Ghani, M., Norton, L., & DeFranzo, R. (2014). Sodiumglucose cotransporter-2 inhibitors and type 2 diabetes. In G. Umpierrez (Ed.), Therapy for Diabetes Mellitus and Related Disorders (6th ed., pp. 435-460). Alexandria, VA: American Diabetes Association. American Diabetes Association. (2015). Clinical practice recommendations: Standards of medical care in diabetes. Diabetes Care, 38(Suppl. 1), S1-S85. Aschner, P. (2014). Dipeptidyl-peptidase 4 inhibitors. In G. Umpierrez (Ed.), Therapy for Diabetes Mellitus and Related Disorders (6th ed., pp. 387-400). Alexandria, VA: American Diabetes Association. Bailey, C. (2014). Metformin. In G. Umpierrez (Ed.), Therapy for Diabetes Mellitus and Related Disorders (6th ed., pp. 341-358). Alexandria, VA: American Diabetes Association. D Alessio, D., & Hirsch, I. (2011). Glycemic management of type 2 diabetes. In R. Robertson & A. Powers (Eds.), Translational Endocrinology & Metabolism: Type 2 Diabetes Update, 2(1), 69-94. Chevy Chase, MD: The Endocrine Society. Deglin, J., Vallerand, A., & Sanoski, C. (Eds.). (2011). Davis s Drug Guide for Nurses (12th ed.) Philadelphia, PA: F. A. Davis. Diab, D., & Alessio, D. (2014). Glucagon-like peptide-1 receptor agonist therapy for type 2 diabetes. In G. Umpierrez (Ed.), Therapy for Diabetes Mellitus and Related Disorders (6th ed., pp. 401-415). Alexandria, VA: American Diabetes Association. Food and Drug Administration. (2011). FDA drug safety communication: Update to on-going safety review of pioglitazone and increased bladder cancer risk. Retrieved from http://www.fda. gov/drugs/drugsafety/ucm259150.html Food and Drug Administration. (2013). FDA drug safety communication: FDA requires removal of certain restrictions on the diabetes drug Avandia. Retrieved from http://www.fda.gov/drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatients andproviders/ucm376365.htm Garber, A. J., Abrahamson, M. J., Barzilay, J. I., Blonde, L., Bloomgarden, Z. T., Bush, M. A.,, Davidson, M. H. (2013). AACE comprehensive diabetes management algorithm 2013. Endocrine Practice, 19(2), 327-336. Institute for Safe Medication Practice. (2014). High-alert medications. Retrieved from https://www.ismp.org/tools/institutionalhighalert.asp Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck, M.,, Matthews, D. R. (2012). Management of hyperglycemia in type 2 diabetes: A patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care, 35(6), 1364-1379. doi:10.2337/dc12-0413 Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck, M.,, Matthews, D. R. (2015). Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the study of diabetes. Diabetes Care, 38(1), 140-149. doi:10.2337/ dc14-2441 Olson, D., Rhee, M., & Phillips, L. (2014). In G. Umpierrez (Ed.), Therapy for Diabetes Mellitus and Related Disorders (6th ed., pp. 461-479). Alexandria, VA: American Diabetes Association. Riddle, M., & Yuen, K. (2014). Combination therapy in type 2 diabetes. In G. Umpierrez (Ed.), Therapy for Diabetes Mellitus and Related Disorders (6th ed., pp. 508-521). Alexandria, VA: American Diabetes Association. Romeo, G., Abrahamson, M., & Goldfine, A. (2014). Insulin secretagogues: Sulphonylureas and glinides. In G. Umpierrez (Ed.), Therapy for Diabetes Mellitus and Related Disorders (6th ed., pp. 359-376). Alexandria, VA: American Diabetes Association. Unger, J., Hinnen, D., Schreiner, B., & Parkin, C. (2013). Putting medications where they belong: Practical advice for managing type 2 diabetes in clinical practice. Journal of the American Association of Nurse Practitioners, 25(2), 65-76. For 28 additional continuing nursing education activities on diabetes, go to nursingcenter.com/ce. 310 Volume 33 Number 6 www.homehealthcarenow.org