Steering Patients to Glycemic Control Using GLP-1 Receptor Agonists

Transcription

1 Steering Patients to Glycemic Control Using GLP-1 Receptor Agonists IMPROVING T2DM OUTCOMES IN THE PHARMACY SETTING Release Date: July 31, 2015 Expiration Date: July 31, 2016 Presented by Creative Educational Concepts, Inc. Supported through an independent educational grant from AstraZeneca.

2 Target Audience This initiative is targeted towards managed care pharmacists, and other healthcare professionals caring for patients with T2DM. Learning Objectives At the conclusion of this knowledge-based activity, participants should be able to: 1. Using the newest, more individualized treatment guidelines, appraise appropriate treatment plans incorporating various glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapies, alone or in combination, including the optimal initiation of long-acting GLP-1 RAs. 2. Explore efficacy, safety, and dosing information regarding currently available GLP-1 RAs to enhance individualized treatment decisions and recommendations for T2DM patients. 3. Examine strategies to overcome barriers to poor patient adherence in T2DM patients that engage patients in self-management of T2DM to improve long-term outcomes. Faculty Ashley Johnson, PharmD, BCPS Adjunct Assistant Professor of Pharmacy Practice Lloyd L. Gregory School of Pharmacy Palm Beach Atlantic University West Palm Beach, FL Dr. Johnson is an Adjunct Assistant Professor of Pharmacy Practice, specializing in drug information at Palm Beach Atlantic University in West Palm Beach, Florida where she teaches in the drug information and literature evaluation courses. She earned her Doctorate of Pharmacy and completed a PGY1 Pharmacy Practice Residency with emphasis in ambulatory care and academia at Palm Beach Atlantic University. Her other professional achievements include Board Certification in Pharmacotherapy (BCPS), faculty member for the American Society of Health-System Pharmacists (ASHP) Ambulatory Care Board Certification review course, serving as the President elect of the Palm Beach Society Chapter of the Florida Society of Health-System Pharmacists and was the recipient of the Mylan Institute of Pharmacy 2011 Excellence in Pharmacy Award. Dr. Johnson has no financial relationships to disclose in relation to the content of this activity. Fee This activity is complimentary. Accreditation Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. This knowledge-based activity is approved for 1.5 contact hours (.15 CEUs) of continuing pharmacy education credit (UAN H01-P). Pharmacy credit will be reported directly to the National Association of Boards of Pharmacy (NABP ) CPE Monitor electronic CE tracking system. Disclosure Declaration It is the policy of CEC to ensure independence, balance, objectivity, scientific rigor, and integrity in their continuing education activities. Those involved in the development of this continuing education activity have made all reasonable efforts to ensure that information contained herein is accurate in accordance with the latest available scientific knowledge at the time of accreditation of this continuing education activity. Information regarding drugs (e.g., their administration, dosages, contraindications, adverse reactions, interactions, special warnings, and precautions) and drug delivery systems is subject to change, however, and the reader is advised to check the manufacturer s package insert for information concerning recommended dosage and potential problems or cautions prior to dispensing or administering the drug or using the drug delivery systems. Fair balance is achieved through ongoing and thorough review of all presentation materials produced by faculty, and all educational and advertising materials produced by supporting organizations, prior to educational offerings. Approval of credit for this continuing education activity does not imply endorsement by CEC for any product or manufacturer identified. UNLABELED USE DISCLOSURE This activity may include discussions of products or devices that are not currently approved for use by the Food and Drug Administration (FDA), or are currently investigational. SUPPORTING ORGANIZATION This activity is supported by an educational grant from AstraZeneca. Instructions To receive a statement of credit, you must: Review the full content of the activity and reflect upon its teaching. Complete the questions and evaluation at the end of the activity. You must have a passing score of 70% on the post-test. You will have two (2) opportunities to complete the post-test. 1

3 INTRODUCTION Approximately 29.1 million individuals in the United States (U.S.) have diabetes, this comprises 9.3% of the population. In 2012 diabetes was estimated to cost $245 billion dollars. 1 With the availability of newer therapies for the management of diabetes, the percentage of patients with diabetes using only oral medications increased from 42.1% to 50.3% from 1997 to 2011, whereas the percentage of patients using only insulin decreased from 26% to 17.8%. The data from the National Health Interview Survey does not take into account the use of newly approved injectable therapies including the glucagon-like receptor agonists (GLP-1 RAs) which assist in minimizing some of the adverse effects seen with insulin therapy. 2 Patients may be more willing to utilize injectable glucose lowering medications if they are more effective in achieving HbA1c targets, despite previous concerns that this may not be viewed as an appealing dosage form. 3 This article will review the current guideline recommendations from the American Diabetes Association/ European Association for the Study of Diabetes and the American Association of Clinical Endocrinologists (ADA/ EASD/AACE) for the management of type 2 diabetes mellitus (T2DM) with a focused review on the safety and efficacy of the five available GLP-1 RAs. In addition, potential considerations for the use of GLP-1 RAs in clinical practice and strategies pharmacists can employ to improve adherence with diabetes therapies will be explored. PATHOPHYSIOLOGY OF T2DM There are numerous metabolic pathophysiologic abnormalities that contribute to the development of T2DM. Genetic factors, lack of physical activity, and increased consumption of refined carbohydrates predispose individuals to developing insulin resistance. This primarily occurs within the muscle, however it also occurs in the liver where these organs become desensitized to the effects of insulin resulting in impaired glucose metabolism and reduced glycogen production within the muscles and overproduction of glucose in the liver. 4 Initially the pancreatic β cells compensate by increasing insulin production, but this is not sustainable long-term and progressively leads to β cell burn out. In fact, upon diagnosis, individuals with T2DM have already lost approximately 80% of their β cell function. 4 Impaired glucose tolerance is also propagated by increased glucagon secretion from the pancreatic α cells, increased glucose reabsorption in the kidneys, increased lipolysis in adipocyte tissue, and insulin resistance. Furthermore, impaired GLP-1 secretion within the gastrointestinal tract leads to impaired neurotransmitter regulation of appetite and decreased incretin effect. 4 DeFronzo and colleagues endorse the early use of multiple antidiabetic therapies based on known abnormalities. 4 Prompt identification of patients who may be at increased risk of diabetes including those who are overweight or obese and have additional risk factors such as physical inactivity, first degree relative with diabetes, and high-risk ethnicities (e.g., African American, Asian American, Latino, Native American, Pacific Islander) is essential to preserving existing β cell function. 5 THE AMERICAN DIABETES ASSOCIATION AND EUROPEAN ASSOCIATION FOR THE STUDY OF DIABETES (ADA/EASD) RECOMMENDATIONS Glycemic goals for nonpregnant adults with diabetes include HbA1c goal of <7%, preprandial plasma glucose goal of 80 to 130 mg/dl, and peak postprandial blood glucose goal of <180 mg/dl. 5 These HbA1c goals should be individualized to be more or less stringent depending on potential risks associated with hypoglycemia and adverse effects from drug therapy, disease duration, life expectancy, presence of comorbid conditions, established vascular complications, patient attitude, and expected treatment efforts, and available resources and support system. 5 For example, patients with long-standing diabetes, short life expectancy, or who are unable to reach glycemic targets while on multiple optimized glucose-lowering medications and receiving diabetes self-management education may benefit from a less stringent HbA1c goal of <8%. 5 The ADA standards of care recommend a blood pressure goal of <140/90 mmhg and assessing cardiovascular risk factors in conjunction with age to determine if moderate or high potency statin therapy is warranted. 5 Annually patients with T2DM should receive a dilated eye exam, assessment of urinary protein, foot exam, and influenza vaccination. 5 Other preventive measures include the pneumococcal vaccine, counseling on smoking cessation if using nicotine products, and antiplatelet therapy as indicated. 5 Lifestyle modifications Due to the significant role that dietary habits can play in glycemic control, individualized medical nutrition therapy should be provided by a registered dietitian who can provide education on choosing healthy food options, ideal macronutrient (i.e., carbohydrates, protein, and fat) distribution and portion control. 5 Patients should be encouraged to engage in moderate-intensity physical activity at least 3 days per week with no gap in exercise greater than 2 consecutive days, perform resistance training twice weekly, and attempt to break up time spent sitting that is greater than 90 minutes. 5 Implementing these lifestyle changes is a foundational component of diabetes management and pharmacists should encourage patients in adopting healthier lifestyle practices to not only improve glycemic control but also reduce overall cardiovascular risk. With the progressive nature of insulin resistance seen in T2DM, deteriorating β-cell function often necessitates intervention with multiple glucose lowering medications. 5 Initiating Drug Therapy Metformin remains the first line option for the management of T2DM in the absence of any contraindications due to its robust effect in lowering HbA1c, low risk of hypoglycemia, weight neutrality, low cost, and a favorable side effect profile which mostly involves GI disturbances (e.g., diarrhea and nausea). 5 If the individualized HbA1c target is not achieved after 3 months of monotherapy a 2-drug regimen is recommended. 5 Alternatively, initial dual therapy may be considered if HbA1c is >9%. Dual therapy options include metformin plus a sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 RA, or basal insulin. 5 The decision as to what add-on agent is best necessitates balancing the individual benefits in terms of efficacy and the potential risks with hypoglycemia, adverse effects, influence on weight, and costs. In developing a dual or triple regimen to improve glycemic control, medications with complementary mechanisms of action should be selected. A brief review of the advantages and disadvantages of these individual classes of glucose lowering medications is described below. 5 Sulfonylureas (e.g., glyburide, glipizide, glimepiride) along with metformin have been a mainstay of therapy due to high efficacy in reducing HbA1c and low cost. 5 However, sulfonylureas are associated with a potentially undesirable side effect profile entailing weight gain and hypoglycemia which may be especially problematic in elderly patients. 5 Alpha glucosidase inhibitors (e.g., acarbose, miglitol), also referred to as meglitinides, may be substituted in place of sulfonylureas for patients experiencing postprandial hypoglycemia or those with irregular eating 2

4 habits. 5 Thiazolidinediones (e.g., pioglitazone) are effective in lowering HbA1c but use in clinical practice is limited by their adverse effects of weight gain, peripheral edema, increased incidence of heart failure, and increased risk of bone fractures in women. 5 Dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin) are oral agents that offer HbA1c lowering with a low risk of hypoglycemia, adverse effects, and weight gain. 5 Sodium-glucose co-transporter 2 (SGLT-2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) are the newest class of glucose lowering medications that reduce HbA1c by 0.5% to 1% compared to placebo by reducing glucose reabsorption and increasing urinary excretion of glucose within the kidneys independent of insulin release. 5 Use of SGLT-2 inhibitors is associated with weight loss of approximately 2 kg over 6-12 months and lowering of systolic and diastolic blood pressure by approximately 2-4/1-2 mmhg respectively. 5 A drawback of these agents, based on their mechanism of action, is an increased risk of genital mycotic infections and urinary tract infections. SGLT-2 inhibitors are not suitable to use when the estimated GFR is <45-60 ml/min/1.73 m 2. 5 Basal insulin therapy (e.g., glargine, detemir) offers the greatest potential reduction in HbA1c but is coupled with a high risk of hypoglycemia and weight gain. 5 GLP-1 RAs are analogs of the endogenous glucagon-like peptide-1 that is secreted from the L-cells located within the ileum and colon which inhibit abnormally high glucagon secretion in response to food intake and enhance pancreatic β-cell function by increasing glucose-dependent insulin secretion to lower fasting and postprandial glucose in T2DM. 6,7 Unique from other incretin-based therapies including the DPP-4 inhibitors, GLP-1 RAs also reduce weight by suppressing appetite and slowing gastric emptying. 8,9 Other agents in the management of T2DM less commonly employed because of their modest effects on lowering HbA1c, adverse effects and/or frequent administration schedule are amylin mimetics (e.g., pramlintide), bile acid sequestrants (e.g., colesevelam) and dopamine agonists (bromocriptine). 5 If the individualized HbA1c target is still not achieved after approximately 3 months of optimized dual therapy then the ADA/EASD recommends triple therapy should be initiated. In the event glycemic control remains inadequate after triple therapy on oral medications it is recommended to proceed to the use injectable medications. 5 If the triple regimen contained a GLP-1 RA the ADA/EASD endorses adding on basal insulin. If the triple regimen contained optimized basal insulin then it is recommended to add either a GLP-1 RA or rapid-acting mealtime insulin (e.g., lispro, aspart, glulisine). 5 AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS (AACE) RECOMMENDATIONS The AACE recommendations differ slightly from those of the ADA with an endorsed target HbA1c goal of <6.5% for patients with T2DM who are otherwise healthy without other comorbid conditions and at low risk for hypoglycemia. 10 An HbA1c goal of >6.5% is recommended for individuals with comorbid conditions and hypoglycemia risk. 10 In conjunction with lifestyle modifications, pharmacotherapy with a single agent for patients with an HbA1c <7.5% and a conservative approach of initiating dual therapy if HbA1c is >7.5% is recommended. 10 Unique to the AACE consensus statement, a suggested hierarchy of usage for specific medication classes is provided along with a notation indicating either few adverse events possible benefits exist or conversely that the class should be used with caution. 10 For monotherapy, similar to the ADA/EASD recommendations, metformin is recommended first as monotherapy given there are no contraindications followed by GLP-1 RAs, SGLT-2 inhibitors, DPP-4 inhibitors, alpha-glucosidase inhibitors, TZDs, and sulfonylureas/meglitinides. 10 GLP-1 RAs are the first agents recommended in hierarchical order for dual or triple therapy. 10 For patients presenting with an HbA1c >9% and who are symptomatic, initial therapy of insulin with or without other agents is preferred. 10 The AACE also advocates that consideration of safety and efficacy should be given greater weight in determining the optimal medication to initiate for a patient rather than acquisition costs since there are also costs incurred with stringent monitoring and managing adverse events such as hypoglycemia. 10 GLP-1 RAs can be used as an adjunct to diet and exercise or in combination with antidiabetic medications including metformin, a sulfonylurea, thiazolidinedione, metformin and a sulfonylurea or thiazolidinedione, or with insulin glargine with or without metformin and/or a thiazolidinedione for glycemic management in T2DM. 10 GLP-1 RAs are not indicated for the management of type 1 diabetes mellitus, children less than 17 years of age or for diabetic ketoacidosis. 10 Additionally, the use of GLP-1 RAs in combination with rapid-acting prandial insulins (i.e., insulin lispro, insulin aspart), DPP-4 inhibitors, or SGLT2 inhibitors has been insufficiently studied and co-administration is not recommended at this time. GLP-1 RAS Incretin-based therapies including GLP-1 RAs and DPP-4 inhibitors are unique options available in the management of T2DM that act to prolong the action of GLP-1. Due to their low risk of hypoglycemia, significant reduction in HbA1c and potential for weight loss, GLP-1 RAs may be considered in individuals who have poor glycemic control despite implementing lifestyle changes with diet, exercise and adherence to metformin. 5,10 GLP-1 is a gut peptide that is rapidly degraded by DPP-4 within a few minutes and is found to be present in deficient quantities in T2DM. 11 Because GLP-1 is a small molecule, it is also prone to renal elimination. 11 GLP-1 RAs are administered via a subcutaneous injection to avoid degradation in the gastrointestinal tract. The first GLP-1 RA, twice daily formulated exenatide was approved by the FDA in Exenatide is a synthetic form of the naturally DPP-4 resistant GLP-1 analog of the Gila monster but requires twice daily administration due to relatively quick renal elimination. 11 In 2010 once daily liraglutide was approved as an adjunct to diet and exercise to improve glycemic control in T2DM. Liraglutide has an amino acid substitution and is bonded to albumin to prevent DPP- 4 degradation and increase half-life. 12 An elevated dose of liraglutide is also FDA approved for chronic weight management in combination with diet and exercise. Further modifications of the GLP-1 RA molecules conferred resistance to degradation by dipeptidyl peptidase-4, prolonging the half-life to allow for once weekly dosing. Multiple once weekly formulated GLP-1 RAs have received FDA approval including exenatide in 2012 which is encapsulated in a microsphere to allow for once weekly dosing. 13 In 2014 both albiglutide and dulaglutide were approved, which were modified through conjugation to recombinant human albumin and a modified Fc fragment of immunoglobulin G, respectively. 14,15 Additional GLP-1 RAs that are currently in development include once-weekly taspoglutide, once-weekly semaglutide, and lixisenatide, which is approved in the European Union, Australia, 3

5 Japan and Mexico for use once daily before a meal in combination with basal insulin under the brand name (Lyxumia ). 16 In a Cochrane systematic review of 17 randomized trials including 6,899 patients with T2DM inadequately controlled with metformin and/or a sulfonylurea, GLP-1 RAs (albiglutide, exenatide twice daily, exenatide once weekly, liraglutide, lixisenatide, taspoglutide) resulted in average HbA1c reductions of 0.47% to 1.56% when compared to placebo. 17 A brief review of the clinical evidence regarding the use of GLP-1 RAs as monotherapy or add-on therapy with other glucose lowering therapies will be presented. Most of the clinical trials examining GLP-1 RAs use are designed as non-inferiority trials, to determine if GLP-1 RAs are no worse than other anti-diabetic therapies by a pre-specified margin which is typically an HbA1c margin of 0.3% to 0.4%. This study design and non-inferiority margin is in accordance with FDA guidance for drug development for T2DM. 18 Of the clinical trials that have been performed to date, a majority use exenatide as a comparator since it has been on the market a decade compared to the newer, longer acting formulations. GLP-1 RA monotherapy A summary of numerical efficacy results from clinical trials evaluating GLP-1 RAs as a monotherapy option for T2DM is provided in Table 1. As monotherapy, exenatide twice daily resulted in greater HbA1c reductions and more weight loss compared to placebo. Liraglutide decreased HbA1c and weight compared to glimepiride. 19,20 Exenatide once weekly was found to be noninferior to metformin, not noninferior to pioglitazone, and superior to sitagliptin in decreasing HbA1c. 21 Weight loss with exenatide was similar to that of metformin and was greater when compared to pioglitazone and sitagliptin. 21 Overall, HbA1c lowering and weight loss was found to be similar between dulaglutide 0.75 mg, dulaglutide 1.5 mg and metformin, except less weight loss was observed with dulaglutide 0.75 mg. 22 There are no clinical trials available assessing the use of albiglutide alone without metformin or another oral antidiabetic agent. GLP-1 RA IN COMBINATION WITH METFORMIN Exenatide twice daily in combination with metformin was found to be more effective at lowering HbA1c compared to metformin alone. 23 Exenatide once weekly in conjunction with metformin was found to be more effective in lowering HbA1c and in reducing weight compared to both pioglitazone and sitagliptin. 24 In a trial investigating patients receiving metformin as baseline therapy, the addition of liraglutide was more effective at lowering HbA1c compared to placebo and sitagliptin. 25 In another trial, liraglutide was also shown to be non-inferior compared to glimepiride and more effective at reducing body weight than all other treatment arms. 26 In comparison to placebo and sitagliptin, with all patients receiving concurrent metformin, dulaglutide was more effective in reducing HbA1c and body weight. 27 Dual therapy with albiglutide and metformin was more effective than metformin alone or dual therapy of metformin and either sitagliptin or glimepiride. 28 In this dual therapy comparison, albiglutide was more effective at reducing body weight than glimepiride but did not show significant weight loss compared to metformin alone or dual therapy of metformin and sitagliptin. 28 To summarize, GLP-1 RAs in combination with metformin are more effective in reducing HbA1c than placebo, TZD and DPP-4 inhibitors and were found to be non-inferior to sulfonylureas through a total of six trials. GLP-1 RA IN COMBINATION WITH METFORMIN AND AN ADDITIONAL ORAL ANTIDIABETIC MEDICATION As a part of a triple therapy regimen, GLP-1 RAs were more effective than placebo and noninferior to both TZD and insulin in reducing HbA1c. Similar to dual therapy, triple therapy with GLP-1 RAs resulted in greater weight loss than TZDs or insulin GLP-1 RA VERSUS INSULIN GLARGINE Overall, GLP-1 RAs including exenatide twice daily, exenatide weekly, liraglutide, and albiglutide were similar to insulin glargine titrated to a fasting glucose level of <100 mg/dl in HbA1c lowering ability in patients who failed to achieve glycemic controls despite using oral antidiabetic medication Of note, the reduction in postprandial glucose levels was greater with GLP-1 RAs (i.e., mg/dl to mg/dl with GLP-1 RAs versus mg/dl to -45 mg/dl with insulin glargine) whereas insulin glargine reduced fasting glucose levels to a greater extent (i.e., mg/dl to -38 mg/dl with GLP-1 RAs versus -32 mg/dl to mg/dl with insulin glargine) Local injection site reactions are more common with GLP-1 RAs than with insulin, approximately 10% vs. 1-5% respectively. 37,38 COMPARATIVE EFFICACY AND SAFETY OF GLP-1 RAS Once a decision has been made to initiate a GLP-1 RA to improve glycemic management, a second choice must be made in selecting which GLP-1 RA is best suited for an individual patient. In addition to patient specific characteristics, the selection of the optimal GLP-1 agent should take into consideration the distinct nuances in efficacy, safety, and patient satisfaction that each individual GLP-1 RA agent possesses. GLP-1 RAs have been compared head-to-head with other GLP-1 RAs in phase III noninferiority clinical trials. The heterogeneous trials ranged from weeks in patients with T2DM, HbA1c levels ranging from 8% to 8.5% and BMI ranging from approximately 32 to 35 kg/m 2 who were concurrently receiving metformin with or without a sulfonylurea and/or TZD. 13,33,39-42 A brief summary of the efficacy and safety results will be discussed. Of note, there is currently a lack of evidence comparing different once weekly formulations. All of the trials that will be reviewed compare once weekly formulations to either exenatide twice daily or liraglutide once daily. Efficacy in lowering HbA1c and obtaining HbA1c goals Exenatide twice daily versus exenatide once weekly In the DURATION-1 trial, exenatide once weekly significantly reduced HbA1c by -1.9% compared to a reduction of -1.5% within 30 weeks with the exenatide twice daily formulation (P=.023) while more patients achieved goal HbA1c of <7% with exenatide once weekly (77% versus 61% respectively, P=.0039). 13 Similarly, in the DURATION-5 trial, exenatide once weekly significantly reduced HbA1c by -1.6% in comparison with a -0.9% reduction within 24 weeks in the exenatide twice daily treatment group and more patients achieved goal HbA1c of <7% with exenatide once weekly (58% versus 30% respectively, P<.0001). 39 Exenatide twice daily versus liraglutide Liraglutide significantly reduced HbA1c by -1.6% compared to a reduction of -0.9% within 24 weeks with exenatide twice daily (P<.0001) in the LEAD-6 trial. 40 Liraglutide use also resulted in more patients achieving HbA1c goals of <7% (54% versus 43% respectively, P=.0015). 40 4

6 Exenatide twice daily versus dulaglutide The AWARD-1 trial demonstrated use of dulaglutide 0.75 mg and 1.5 mg resulted in superior HbA1c lowering at 26 weeks compared to exenatide twice daily (HbA1c reduction of -1.51%, -1.30%, -0.99% respectively, P<.001 for each comparison) and patients were more likely to achieve HbA1c goal of <7% with both doses of dulaglutide (78% and 66%) compared to exenatide (52%; P<.001 for each comparison). 33 Liraglutide versus albiglutide In the HARMONY-7 trial, the criteria for noninferiority was not met with a reduction in HbA1c from baseline to week 32 of -0.99% with liraglutide and -0.78% with albiglutide (noninferiority P-value=.0846). 41 Liraglutide versus dulaglutide Liraglutide was found to be noninferior to dulaglutide in lowering HbA1c at 26 weeks with HbA1c lowering of -1.36% and -1.42% respectively (noninferiority p-value <0.0001). HbA1c goal of <7% was achieved in 68% of both liraglutide and dulaglutide treatment groups in the AWARD-6 trial. 42 Efficacy in lowering weight Exenatide twice daily versus exenatide once weekly In the DURATION-1 trial, exenatide once weekly reduced weight similarly to exenatide twice daily (-3.7 kg versus -3.6 kg, p=0.89). 13 In the DURATION-5 trial, similar weight loss was observed between exenatide once weekly compared with exenatide twice daily treatment (-2.3 kg versus -1.4 kg). 39 Exenatide twice daily versus liraglutide Weight loss observed with liraglutide of kg was similar to exenatide twice daily of kg (p=0.22) in the LEAD-6 trial. 40 Exenatide twice daily versus dulaglutide Dulaglutide 1.5 mg and exenatide twice daily were associated with weight loss of -1.3 kg and kg respectively, whereas an average weight gain of 0.2 kg was observed with dulaglutide 0.75 mg. 33 Liraglutide versus albiglutide In the HARMONY-7 trial, more weight loss was seen with liraglutide when compared with albiglutide (-2.16 kg and kg, P<.0001). 41 Liraglutide versus dulaglutide Liraglutide use was found to be associated with greater weight loss of kg as compared with average weight loss of -2.9 kg with dulaglutide (p=0.011) in the AWARD-6 trial. 42 Adverse Effects Hypoglycemia GLP-1 RAs have a very low propensity for contributing to hypoglycemia, with no significant differences between investigated GLP-1 RA therapies ranging overall from 0% to 0.7% for major hypoglycemic episodes and 0% to 15.9% for minor hypoglycemic episodes. 13,33,39-42 An increase in the incidence of hypoglycemia was observed when GLP-1 RAs were used concurrently with sulfonylureas. 13,33,39-42 GI disturbances The most commonly reported adverse effects reported with GLP-1 RAs were nausea, vomiting, and diarrhea. In two trials, a higher incidence of nausea and vomiting with exenatide twice daily (ranging from 34.5% to 35% and 9.9% to 18.6%) was observed as compared with exenatide once weekly (ranging from 14% to 26.4% and 4.7% to 10.8%). 13,39 Furthermore, exenatide twice daily was associated with a slightly higher incidence of nausea when compared to liraglutide (28% versus 25.5%) whereas there was a decreased incidence of nausea with exenatide once weekly compared to liraglutide (9.3% versus 20.7%). 43 Rates of nausea and vomiting were similar for the following comparisons: exenatide twice daily versus liraglutide, dulaglutide versus liraglutide, exenatide twice daily versus dulaglutide 1.5 mg, and dulaglutide versus liraglutide. 33,40,42 In the HARMONY-7 trial, an increased incidence of nausea was observed with liraglutide therapy when compared to albiglutide (29.2% versus 9.9%). Short and long acting GLP-1 RAs (e.g., exenatide twice daily and liraglutide) may be more likely to cause symptoms of nausea and vomiting than prolonged-acting GLP-1 RAs (e.g., exenatide once weekly, albiglutide, and dulaglutide.) 41 Of note, GI adverse effects are more likely to occur during the first two weeks of initiation of GLP-1 RAs and are typically transient, diminishing after 1-2 months of therapy. 13,33,39-42 Injection site reactions Conflicting evidence is available concerning the differences in injection site reactions when comparing short and long acting GLP-1 RA formulations to prolonged-acting formulations. In trials comparing once weekly GLP-1 RAs, there was a higher incidence of injection site reactions observed compared with exenatide twice daily or liraglutide once daily. 13,41-43 However, in the AWARD-1 trial rates of injection site reactions were 0.4% for both dulaglutide 1.5 mg weekly and exenatide twice daily. 33 Additionally, exenatide once weekly was found to have a slightly lower incidence of injection site reactions when compared to exenatide twice daily (10% versus 13% respectively). 39 Attributed to its microsphere formulation, exenatide once weekly is the only GLP-1 RA associated with transient subcutaneous pea sized injection site nodules. 52 Upper respiratory tract infections Although the exact causal method is unknown, GLP-1 RAs have been associated with an increased incidence of upper respiratory tract infections (URIs). In the DURATION-1 and DURATION-5 trials, more patients using exenatide once weekly (17.2% and 7%) reported URIs compared with exenatide twice daily (8.1% and 4.1%). 13,39 Rates of URIs were similar among exenatide once weekly, exenatide twice daily, and albiglutide compared to liraglutide. 40,43 POTENTIAL BENEFITS OF GLP-1 RA THERAPY Clinical benefits and improved outcomes from using GLP-1 RAs in addition to HbA1c lowering of 1.7% are important to consider and weigh against the potential adverse effects of this drug class. Fasting and postprandial glucose levels are effectively lowered to a similar magnitude compared to insulin treatment. At low glucose levels there is no insulin secretion which helps avoid the risk of hypoglycemia. Most patients who take GLP-1 RAs have been shown to consistently lose between 2-4 kg of body weight. Additionally, systolic blood pressure has been shown to be lowered by 2-5 mmhg for patients taking GLP-1 RAs. It is currently unclear what impact the reductions in clinical parameters of weight and blood pressure 5

7 have on long term outcomes. 44 Evidence of macrovascular risk reduction with GLP- 1 RAs or any other glucose lowering medications have not been conclusively established in clinical trials. However, there are currently clinical trials underway that will provide needed insight and evidence regarding the impact of evidence-based therapies on long-term cardiovascular outcomes. 45 In a meta-analysis of 37 trials, GLP 1-RAs were not associated with an increased risk for major cardiovascular events in adults with T2DM compared to oral antidiabetes medications. 46 POTENTIAL ADVERSE EFFECTS OF GLP-1 RA THERAPY Adverse effects associated with individual GLP-1 RA agents are similar to those reported in the head-to-head comparison trials mentioned above with the most commonly occurring effects including GI disturbances, injection site reactions, and upper respiratory tract infections. The following adverse effects were noted with >5% incidence in clinical trials comparing the use of GLP-1 RAs with placebo. Exenatide twice daily was associated with nausea (8%), vomiting (4%), and dyspepsia (3%). Liraglutide use was shown to cause nausea (28.4%), diarrhea (17.1%), vomiting (10.9%), constipation (9.9%), and headache (9.1%). Exenatide once weekly resulted in nausea (11.3%), diarrhea (10.9%), injection-site nodule (10.5%), constipation (8.5%), headache (8.1%), and dyspepsia (7.3%). Albiglutide differed slightly from other GLP-1 RAs by sometimes causing URIs (14.2%), diarrhea (13.1%), nausea (11.1%), injection site reaction (10.5%), cough (6.9%), back pain (6.7%), arthralgia (6.6%), sinusitis (6.2%), and influenza (5.2%). Finally, clinical trials studying dulaglutide looked at two dosages. For the 0.75 mg dose, nausea (12.4%), diarrhea (8.9%), vomiting (6.0%), abdominal pain (6.5%), decreased appetite (4.9%), dyspepsia (4.1%), and fatigue (4.2%) were reported. The 1.5 mg dose was associated with nausea (21.1%), diarrhea (12.6%), vomiting (12.7%), abdominal pain (9.4%), decreased appetite (8.6%), dyspepsia (5.8%), and fatigue (5.6%). In response to GLP-1 RA therapy some patients develop antibodies to these agents which typically decline with time and do not impact glucose lowering efficacy, although cases of decreased glycemic response have been reported with exenatide twice daily. 47 Albiglutide, dulaglutide, exenatide once weekly and liraglutide have Risk Evaluation and Mitigation Strategy (REMS) risk management communication plans to reduce the potential risk of medullary thyroid carcinoma and acute pancreatitis associated with GLP-1 RA use. In rodent studies, rats and mice exposed to GLP-1 RAs developed dose-dependent and treatment-duration-dependent thyroid C-cell tumors, although it is important to note that rodents possess more C-cells which contain 22 to 45 fold more GLP-1 receptors than humans. 48,49 In rodents given exenatide and liraglutide, dose dependent increases of calcitonin were observed. 48,49 The AACE/ACE 2015 diabetes guidelines state, In rodents, GLP-1 receptor agonists may increase the frequency of benign and malignant C-cell neoplasms; however, in humans, neither acute pancreatitis nor medullary thyroid carcinoma has been convincingly shown to be caused by incretin-based therapies. 10 Episodes of acute pancreatitis in patients treated with liraglutide have been reported in spontaneous postmarketing reports and in some clinical trials there were more cases of pancreatitis in patients using liraglutide compared to other antidiabetic therapies. In a prospective cohort study with a median follow-up time of 15 months, liraglutide was not associated with an increased risk of acute pancreatitis or pancreatic cancer compared to other antidiabetic medications. 50 The FDA has extensively reviewed over 200 clinical trials involving 41,000 patients and there was no compelling evidence to indicate that GLP-1 RAs cause an increased risk in pancreatitis or pancreatic cancer compared to other glucose lowering agents. 51 It is important to recognize that there is an increased risk of pancreatitis in T2DM alone without the use of medication. 50,51 GLP-1 RAs are contraindicated in those with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN 2) Additionally, GLP-1 RAs have not been studied in patients with a history of pancreatitis and therefore a history of pancreatitis should be considered during the shared clinical decision making process. Patients should be counseled on the above mentioned risks and instructed to report any signs or symptoms that may indicate the presence of potential thyroid cancer or pancreatitis such as dysphagia, dyspnea, persistent hoarseness, a mass in the neck region or persistent severe abdominal pain radiating to the back respectively. If pancreatitis is suspected discontinue the GLP-1 RA promptly and do not restart if pancreatitis is confirmed. Clinicians are encouraged to report any adverse events to the FDA at FDA-1088 or www. fda.gov/medwatch. OPTIMAL CANDIDATES FOR GLP-1 RA THERAPY Determination of what therapy should be initiated in a patient with inadequately controlled T2DM should be given careful consideration taking into account numerous factors such as individualized HbA1c goals, patient specific characteristics, patient s previous experiences with antidiabetic medications, and cost. In the context of determining if GLP-1 RAs may be an option for a specific patient, it is important to examine the following factors. Individualized HbA1c goals The decision whether to initiate one or two medications is contingent upon what a patient s individualized HbA1c goal is in comparison with their current HbA1c level. GLP-1 RAs offer a significant and competitive reduction in HbA1c compared to other available antidiabetic therapies when used alone or as a component of dual or triple therapy. Patient specific characteristics There are many specific factors that determine the suitability of an antidiabetic medication for a particular patient including age, body weight, and concurrent conditions. The age of a patient is important to consider since mental acuity and presence of vision impairment could potentially complicate the safe administration of injectable medications. If these issues are present and the patient has a designated caregiver, the caregiver should be educated and trained in how to administer these medications. GLP-1 RAs are an attractive option for patients that are overweight or obese due to their ability to cause weight loss where many other antidiabetic agents that can be used as add-on therapy with metformin are known to cause weight gain (e.g., sulfonylureas, TZDs, and insulin). Clinicians should consider alternative therapeutic options for individuals with a history of pancreatitis since GLP-1 RAs have not been studied in this population or in patients with a history of GI disease such as gastroparesis since gastrointestinal 6

8 adverse effects are commonly reported upon initiation of GLP-1 RAs. All GLP-1 RAs are classified as pregnancy category C and are not recommended for use while pregnant or breastfeeding since it is unknown if GLP-1 RAs are excreted into the breast milk. 47,52-55 In patients with severe renal impairment (i.e., CrCl <30 ml/min) exenatide twice daily and exenatide once weekly are not recommended. GLP-1 RAs have not been shown to cause direct nephrotoxicity, however there have been reports of acute renal failure or renal insufficiency in patients taking exenatide. It is challenging to ascertain a definitive cause in these cases since other factors were also present that can contribute to declining renal function such as dehydration and use of angiotensin-converting enzyme inhibitors or diuretics. 56 Other GLP-1 RAs have not been extensively studied in patients with impaired renal function. 47,52-55 In regards to patients who have hepatic impairment, GLP-1 RAs may be used without modification of the dose since these medications are primarily metabolized via other pathways. Potential drug interactions are not a frequent deterrent to the use of GLP-1 RAs because they have few known interactions. Orally administered medications may be affected by GLP-1 RA induced delayed-gastric emptying, so caution should be exercised in using medications with a narrow therapeutic index or those that require rapid absorption in order to maintain efficacy although, with the exception of exenatide twice daily, no definitive interactions with clinical implications have been identified. 47,52-55 Antibiotics and oral hormonal contraceptives should be administered 1 hour prior to exenatide twice daily to ensure appropriate absorption of these medications. 47 Administration of GLP-1 RAs in combination with rapid-acting prandial insulins, DPP-4 inhibitors, or SGLT2 inhibitors has been insufficiently studied and is not recommended at this time. Previous experiences with antidiabetic agents Patients preference and willingness to use specific medications may be based on their personal past experiences and the experiences of their family and friends. For example, patients who have experienced adverse effects such as hypoglycemia may be reluctant to try alternative therapies that may also cause similar adverse effects. Clear communication with patients regarding their previous experiences and preferences can be helpful in replacing potentially inaccurate preconceived ideas. Factual information and identifying therapeutic options that address the patients concerns so that shared decision making can take place. The goal is to collaboratively create a treatment plan which the patient is comfortable and therefore is more likely to be adherent. Cost Increased costs are associated with GLP-1 RA therapy compared to other oral antidiabetic therapies that are available in generic formulations such as metformin and sulfonylureas. In analyzing the cost of therapy, patients and healthcare providers should also consider potential costs of nonadherence, frequent self-monitoring of blood glucose and, adverse event management. OPTIMAL TIMING OF INITIATION OF GLP-1 RAS In patients who are appropriate candidates a GLP-1 RA may be started in combination with another antidiabetic therapy in treatment naïve patients with T2DM and an HbA1c >7.5-9%. Initiation of a GLP-1 RA may also be considered for patients with T2DM who have failed to achieve glycemic control despite adherence with lifestyle modifications and optimized dosing of one or more antidiabetic medication. GLP-1 RAs can be administered as part of a dual or triple therapy regimen with oral antidiabetic medications (i.e., metformin, sulfonylureas, and/or TZD) or in combination with basal insulin prior to initiating a complex prandial or mealtime insulin regimen. Initiation of a GLP-1 RAs may be a particularly desirable option compared to prandial insulin for use in conjunction with basal insulin for patients who are obese or unable to appropriately use a complex multi-dose insulin regimen. Dosing Patients have the flexibility of selecting different GLP-1 dosing regimens based on their individual needs and preferences. Specific information pertaining to starting doses, maximum doses, and instructions for missed doses for each GLP-1 RA is provided in Table 3. Exenatide is unique in that it must be administered one hour prior to a meal twice daily. The other GLP-1 RAs can be administered anytime that is most convenient for the patient irrespective of meals. Liraglutide is administered once daily and the prolonged-acting GLP-1 RAs including exenatide extended release, albiglutide and dulaglutide are administered once weekly. If used concurrently with a sulfonylurea, insulin, or any glucose-independent insulin secretagogue such as meglitinides, a reduction in the dose of the sulfonylurea or insulin may be warranted if hypoglycemia is experienced. Administration All GLP-1 RAs are administered subcutaneously in the abdomen, thigh or upper arm using the device supplied by the manufacturer. Prior to use, the manufacturer of exenatide extended release recommends gently cleaning the injection site area with an alcohol swab or soap and water. 52 In preparing to administer exenatide twice daily, exenatide once weekly, liraglutide, and albiglutide, patients should be instructed to first wash their hands. 47,52-54 GLP-1 RAs that are available in a pen formulation that do not require reconstitution, including exenatide twice daily, liraglutide, and dulaglutide should be inspected prior to administration to ensure the medication containing liquid is clear and free of particles. 47,53,55 Patients should be counseled to rotate injection sites and, if using concurrently with insulin, to administer the medications as separate injections. With the differing reconstitution and administration instructions, it is essential that pharmacists are well-versed in how to appropriately use these products. A summary of required steps needed prior to injection for each GLP-1 RA is provided in Table 3. Exenatide twice daily and liraglutide are available as prefilled pen devices and are administered in a similar fashion to that of insulin pens. These GLP-1 RAs are relatively easy to use, only requiring the attachment of a pen needle and dialing to the required dose prior to administration. Exenatide once weekly is available in two different formulations, a single use vial, requiring multiple steps for reconstitution and a prefilled pen that also requires reconstitution. Likewise, albiglutide also must be reconstituted but unlike any other GLP-1 RA, also requires a waiting period of 15 or 30 minutes prior to use depending upon the dose. Dulaglutide is available as a prefilled pen that does not require reconstitution and is the only GLP-1 RA delivery device that comes pre-loaded with the needle so patients do not have to touch the needle prior to administration. For additional information on device-specific administration instructions, the respective medication guides provide step-bystep guidance. 47,52-55 While demonstrating appropriate use of the GLP-1 devices it 7

9 is pertinent to discuss the importance of properly disposing of pen needles and not reusing or sharing the drug delivery device or needles to avoid the transmission of blood-borne pathogens. Storage Refrigerate all GLP-1 RAs prior to use and do not freeze. After initial use GLP-1 RAs may be stored in the refrigerator or at room temperature. If stored at room temperature, dulaglutide should be protected from light by storing in provided packaging and discarded after a total of 14 days. If albiglutide or exenatide once weekly is stored in the refrigerator, allow the pen to sit at room temperature for 15 minutes prior to administration. 47,52-55 ADHERENCE CONSIDERATIONS Barriers to adherence with antidiabetic therapies include confusion regarding dosing and administration of medications, insufficient time spent with healthcare professionals receiving instruction, feelings of insecurity regarding management of chronic conditions, and cost. 57 Pharmacists play a significant role in improving adherence to therapies in order to obtain target HbA1c goals with the intent of preventing complications resulting from diabetes through the use of medication therapy management (MTM) services. MTM services encompass a multifaceted approach that incorporates problem-solving strategies, emphasizes realistic, habitual changes in diet and exercise and tailors pharmacotherapy based on patient specific needs or preferences, educates on self-monitoring of blood glucose and appropriate administration techniques to employ with injectable antidiabetic therapies. 57 In a systematic review, pharmacist involvement in diabetes management was found to result in significant decreases in HbA1c of approximately 1% and systolic blood pressure ranging from -4 to -8 mmhg in patients with T2DM. 58 Furthermore, the Asheville project was instrumental in demonstrating that community pharmacist-directed services for diabetes management and education can also lower annual direct medical costs. 59 Strategies that have been used to increase medication adherence for patients with T2DM include telephone reminders, electronic pill boxes with text message alerts for missed doses, one-on-one counseling sessions using the teach back method and the use of pictorial images for patients with low literacy, and counseling following discharge from an acute care setting. 60 Barriers to the use of injectable antidiabetic therapies Internationally, the estimated rates of insulin omission are 19.9% in France, 42% in the U.S., and 44% in Japan, highlighting the need to simplify regimens, provide counseling, and emphasize the importance of adherence with patients. 57 Barriers that may deter patients from using insulin or other injectable therapies include needle phobia, fear of injection, negative beliefs or experiences, fear of potential side effects including weight gain and severe hypoglycemia, anticipated needle pain, inconvenience, and concern regarding the impact on daily life. 61 Limited health literacy, lack of self-confidence in managing injection logistics, perceptions of disease severity, and poor counseling provided by clinicians are also possible barriers. 62 anxiety, which is considered by patients to be a major barrier. With new technological advances, injection devices are being redesigned with thinner needles, microtapering, and beveling to improve injection comfort. For patients with previous negative experiences with needles, it may be beneficial to point out or display the difference in the relatively small needle size used for injectable antidiabetic therapies compared with vaccinations or other intramuscular injections that require a larger and wider needle. Other tips to reduce injection-related pain include allowing sufficient time for the alcohol swabbed area to dry prior to injection, avoiding wiping needles with alcohol, and utilizing proper injection techniques. Additionally, recommending an angled injection may minimize accidental intramuscular injections. The use of motivational interviewing helps to not only reveal barriers but also illuminate potential strategies that will increase patient s confidence in appropriately managing glycemic levels with injectable therapies. First, assessing the nature or origin of the patient s concern by asking questions about their past experiences and perception regarding injectable therapy through open-ended questions or the Diabetes Fear of Injecting and Self-testing Questionnaire can provide insight that can ultimately be used to tailor counseling and therapy. 63 For patients using insulin, the use of GLP-1 RAs will not completely eliminate the need for basal insulin but can reduce the need for multi-dose daily prandial insulin injections which in turn may improve medication adherence. CONCLUSION GLP-1 RAs offer a novel therapeutic option for T2DM that enhances pancreatic β cell function resulting in substantial decreases in HbA1c ranging from 1% to 1.7%. This class of medications has a favorable side effect profile, lowers blood pressure, reduces body weight, possesses minimal drug interactions and most do not require specific dose adjustments for renal or hepatic impairment. Clinical trials have demonstrated the efficacy of using GLP-1 RAs with dual or triple therapy with oral antidiabetic medications as well as basal insulin regimens. GLP-1 RAs can have a synergistic effect in reducing HbA1c and can be valuable in mitigating adverse effects of hypoglycemia and weight gain when co-administered with other antidiabetic therapies. Adverse effects observed with GLP-1 RAs mostly include GI disturbances, injection site reactions, and URIs. Ongoing research will provide insight into potential cardiovascular benefits while also investigating concerns of pancreatitis and thyroid cancer associated with GLP-1 RA use. Pharmacists are an essential part of the healthcare team in providing diabetes education and counseling including reinforcing lifestyle modifications, explaining appropriate use of antidiabetic therapies and working with patients to resolve potential barriers that may impede adherence to antidiabetic therapies all in an effort to minimize diabetes related complications and improve quality of life. Administration with shorter and lower-gauge needles has not been shown to consistently minimize injection pain in clinical studies. However, there is a strong patient preference for thin, short needles (<6 mm) with a smaller diameter (>30 gauge) and using these types of needles may reduce injection-related fear and 8

10 Table 1: Summary of selected GLP-1 RA clinical trials Study Design Baseline therapy Treatment groups Change in HbA1c (%) Change in FBG (mg/dl) Change in weight (kg) GLP-1 RA monotherapy Moretto TJ, et al N=232 Drug naïve Exenatide 5 mcg twice daily weeks Exenatide 10 mcg twice daily Garber A, et al (LEAD-3 MONO) N= weeks Drug naïve or taking up to half of highest dose of one OAD prior to study Liraglutide 1.2 mg daily Liraglutide 1.8 mg daily Glimepiride 8 mg daily Russell-Jones D, et al (DURATION-4) N= weeks Drug naïve Exenatide 2 mg weekly Metformin 2,000 mg daily Pioglitazone 45 mg daily Sitagliptin 100 mg daily Umpierrez G, et al (AWARD-3) N= weeks Drug naïve or taking lowdose OAD prior to study Dulaglutide 0.75 mg weekly Dulaglutide 1.5 mg weekly Metformin 1, mg daily GLP-1 RAs in combination with metformin DeFronzo RA, et al. N= weeks Metformin Exenatide 5 mcg twice daily Exenatide 10 mcg twice daily Bergenstal RM, et al (DURATION-2) N= weeks Metformin Exenatide 2 mg weekly Pioglitazone 45 mg daily Sitagliptin 100 mg daily Nauck M, et al N=1,091 Metformin Liraglutide 0.6 mg daily (LEAD-2) 26 weeks Liraglutide 1.2 mg daily Liraglutide 1.8 mg daily Glimepiride 4 mg daily Pratley RE, et al N=497 Metformin Liraglutide 1.2 mg daily weeks Liraglutide 1.8 mg daily Sitagliptin 100 mg Nauck M, et al N=1,098 Metformin Dulaglutide 0.75 mg weekly (AWARD-5) 52 weeks Dulaglutide 1.5 mg weekly Sitagliptin 100 mg daily Ahren B, et al N=1,012 Metformin Albiglutide mg weekly (HARMONY-3) 104 weeks Glimepiride 2-4 mg daily Sitagliptin 100 mg daily

11 Study Design Baseline therapy Treatment groups Change in HbA1c (%) Change in FBG (mg/dl) Change in weight (kg) GLP-1 RAs in combination with metformin and one additional OAD Kendall DM, et al N=733 Metformin + SU Exenatide 5 mcg twice daily weeks Exenatide 10 mcg twice daily Home PD, et al (HARMONY-5) N= weeks Metformin + SU (glimepiride) Albiglutide mg weekly Pioglitazone mg daily Zinman B, et al N=533 Metformin + rosiglitazone Liraglutide 1.2 mg daily (LEAD-4 Met+TZD) 26 weeks Liraglutide 1.8 mg daily Reusch J, et al N=310 Pioglitazone + metformin Albiglutide 30 mg weekly (HARMONY-1) 52 weeks GLP-1 RAs versus insulin Heine RJ, et al N=551 Metformin + SU Exenatide 10 mcg twice daily weeks Insulin glargine (titrated to FBG <100 mg/dl) Diamant M, et al N=456 Metformin + SU Exenatide 2 mg weekly (DURATION-3) 26 weeks Insulin glargine (titrated to FBG <100 mg/dl) Russell-Jones D, et al (LEAD-5 MET+SU) N= weeks Metformin + SU (glimepiride) Liraglutide 1.8 mg daily Insulin glargine (titrated to FBG <100 mg/dl) Weissman PN, et al (HARMONY-4) N= weeks Metformin + SU Albiglutide 30 mg weekly Insulin glargine(titrated to FBG <100 mg/dl) Rosenstock J, et al. N= weeks Insulin glargine MET + PIO Albiglutide mg weekly Insulin lispro

12 Table 2: GLP-1 RA dose adjustment considerations, drug interactions, and pregnancy category classification 47,52-55 Medication Renal Dosing Adjustment Required Hepatic Dosing Adjustment Required Selected Drug Interactions Pregnancy Category Exenatide injection (twice daily) (Byetta ) Not recommended in endstage renal disease or in severe renal impairment (CrCl <30 ml/min). In moderate renal impairment (CrCl ml/min) caution should be exercised when initiating or increasing the dose of exenatide from 5 mcg to 10 mcg. No Orally administered medications with a narrow therapeutic index or require rapid GI absorption may be affected by exenatide-induced delayed gastric emptying, use with caution Oral hormonal contraceptives and antibiotics should be used be taken 1 hour before exenatide injection C Liraglutide injection (Victoza ) Exenatide extended release for injectable suspension (once weekly) (Bydureon ) Albiglutide for injection (Tanzeum ) Warfarin, monitor INR closely No No Orally administered medications may be affected by liraglutide-induced delayed gastric emptying, use with caution Not recommended in endstage No Orally administered medi- renal disease or in severe cations may be affected by renal impairment (CrCl <30 exenatide-induced delayed ml/min). In moderate renal gastric emptying, use with impairment (CrCl ml/ caution min) or renal transplantation use caution. No No Orally administered medications may be affected by albiglutide-induced delayed gastric emptying, use with caution C C C Dulaglutide injection (Trulicity ) If a patient with severe renal impairment or end-stage renal disease experiences adverse gastrointestinal side effects, monitor renal function closely. No Orally administered medications with a narrow therapeutic index may be affected by dulaglutide-induced delayed gastric emptying, use with caution C 11

13 Table 3: GLP-1 RA dosing and preparation instructions 47,52-55 Medication Dosing* Missed dose Exenatide (Byetta ) Starting dose: 5 mcg twice daily Maintenance dose: 5-10 mcg twice daily 60 minutes prior to 2 main meals spaced at least 6 hours apart Liraglutide (Victoza ) Starting dose: 0.6 mg once daily for 1 week to minimize GI discomfort Exenatide (Bydureon ) Albiglutide (Tanzeum ) Dulaglutide (Trulicity ) Maintenance dose: mg once daily Starting and Maintenance dose: 2 mg once weekly Starting dose: 30 mg once weekly Maintenance dose: mg weekly Starting dose: 0.75 mg once weekly Maintenance dose: mg once weekly Skip the missed dose and take the next dose at the next prescribed time Skip the missed dose and take the next dose at the next prescribed time. If there is >3 day time lapse between the last dose, reinitiate at a dose of 0.6 mg daily Take the missed dose as soon as possible within 3 days of the missed dose and then resume regularly scheduled weekly dose. If it has been >3 days since the missed dose, skip the missed dose and resume administration with the next scheduled dose. Requires reconstitution Requires waiting prior to administration Requires needle attachment Single-use device No No Yes No No No Yes No Yes** No Yes Yes**** Yes** Yes 15 minutes if using the 30 mg pen and 30 minutes if using the 50 mg pen No No No*** Yes Yes Yes *Dose may be increased if adequate glycemic control is not achieved with lower dosage. With the exception of exenatide (Byetta ), GLP-1 RAs can be administered anytime that is convenient for the patient without regard to meals. **The reconstitution process is specific to the each GLP-1 drug delivery device and requires shaking, tapping, or rocking to ensure the medication is sufficiently mixed. ***The dulaglutide drug delivery device also retracts the needle after the injection is complete. **** Exenatide once weekly is available in two formulations including a single-dose tray and a prefilled pen. 12

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