GLP-1 (-like -1) Agonists (Byetta®, Bydureon™, ® Tanzeum™, Trulicity™, Victoza ) Step Therapy and Quantity Limit Criteria Program

Summary

Commercial and Health Insurance Marketplace formularies target all agents listed in the program. For GenPlus formulary the target is Victoza. All other agents are non-formulary.

OBJECTIVE The intent of the GLP-1 (glucagon-like peptide-1) Agonists (Byetta/, Bydureon/ exenatide extended-release, Tanzeum/, Trulicity/dulaglutide, and Victoza/) Step Therapy (ST) program is to ensure appropriate selection of patients based on product labeling, and/or clinical guidelines, and/or clinical studies. Appropriate patients for exenatide or liraglutide therapy are those who are concurrently receiving or have tried , a , an oral combination product containing metformin or a sulfonylurea, or . The step edit allows continuation of therapy when patients have been receiving albiglutide, dulaglutide, exenatide or liraglutide. Patients without prerequisite agents in claims history or those who are unable to take a prerequisite agent due to documented intolerance, FDA labeled contraindication, or hypersensitivity will be reviewed when patient-specific documentation has been provided.

TARGET DRUGS Byetta® (exenatide) Bydureon™ (exenatide extended-release) Tanzeum™ (albiglutide) Trulicity™ (dulaglutide) Victoza® (liraglutide)

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Byetta, Bydureon, Tanzeum, Trulicity, or Victoza will be approved when ONE of the following is met: 1. The patient’s history includes one or more of the following antidiabetic agents; metformin, sulfonylurea, any combination with metformin or sulfonylurea, or insulin in the past 90 days OR 2. There is documentation that the patient is currently using the requested medication, Byetta, Bydureon, Tanzeum, Trulicity, or Victoza OR 3. The prescriber states the patient is using the requested medication, Byetta, Bydureon, Tanzeum, Trulicity, or Victoza AND is at risk if therapy is changed OR 4. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one of the following antidiabetic classes: metformin, sulfonylurea, or insulin

Length of approval: 12 months

NOTE: If Quantity Limit program also applies, please refer to Quantity Limit documents.

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FDA APPROVED INDICATIONS AND DOSAGE1,2,5,7,8

GLP-1 Indication Important limitations for Dosage and Agonist use Administration Byetta Adjunct to diet and  Not a substitute for insulin.  Inject subcutaneously (exenatide) exercise to improve Should not be used in within 60 minutes prior Injection glycemic control in patients with type 1 to morning and adults with or for the evening meals (or Available as: diabetes mellitus. treatment of diabetic before the 2 main 250 mcg/mL ketoacidosis. meals of the day, in: 5 mcg per  Concurrent use with approximately 6 hours dose, 60 doses, prandial insulin has not or more apart). 1.2 mL prefilled been studied and cannot  Initiate at 5 mcg per pen be recommended. dose twice daily;  Byetta has not been increase to 10 mcg 10 mcg per studied in patients with a twice daily after 1 dose, 60 doses, history of pancreatitis. month based on clinical 2.4 mL prefilled Consider other antidiabetic response. pen therapies in patients with a history of pancreatitis.

Bydureon Adjunct to diet and  Not a substitute for insulin.  Inject subcutaneously (exenatide exercise to improve Should not be used in 2 mg once weekly at extended- glycemic control in patients with type 1 any time of day, with release) adults with type 2 diabetes or for the or without meals. The Injection diabetes mellitus. treatment of diabetic day of weekly ketoacidosis. administration can be Available as:  Concurrent use with insulin changed if necessary 2 mg vial in has not been studied and as long as the last dose single-dose cannot be recommended. was administered 3 or tray with  Bydureon has not been more days before. syringe of studied in patients with a  Injection should be in diluent and history of pancreatitis. the abdomen, thigh or needle; 4 trays Consider other antidiabetic upper arm. per carton therapies in patients with a history of pancreatitis. 2 mg single- dose pen supplied in cartons with 4 pens and needle

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© Copyright Prime Therapeutics LLC. 01/2016 All Rights Reserved GLP-1 Indication Important limitations for Dosage and Agonist use Administration Tanzeum Adjunct to diet and  Tanzeum is not indicated in  Administer once weekly (albiglutide for exercise to improve the treatment of patients at any time of day, injection, for glycemic control in with type 1 diabetes without regard to subcutaneous adults with type 2 mellitus or for the meals. (SC) use diabetes mellitus. treatment of patients with  Initiate at 30 mg diabetic ketoacidosis; it is subcutaneously once Available as: not a substitute for insulin weekly. Dose can be single-dose in these patients. increased to 50 mg pens for  Not recommended as first- once weekly in patients injection, in line therapy for patients requiring additional cartons of 4 inadequately controlled on glycemic control. syringes plus diet and exercise.  Inject subcutaneously needles, in  Has not been studied in in the abdomen, thigh, doses of 30 mg patients with a history of or upper arm. and 50 mg pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.  Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Use is not recommended in patients with pre-existing severe gastrointestinal disease.  Has not been studied in combination with prandial insulin. Trulicity Adjunct to diet and  Not recommended as first-  Administer once weekly (dulaglutide for exercise to improve line therapy for patients at any time of day SC injection) glycemic control in inadequately  Inject subcutaneously adults with type 2  controlled on diet and in the abdomen, thigh, Available as: diabetes mellitus. exercise or upper arm Single dose  Has not been studied in  Initiate at 0.75 mg pens and patients with a history of subcutaneously once prefilled pancreatitis. weekly. Dose can be syringes  Consider another increased to 1.5 mg antidiabetic therapy once weekly for  Not for treatment of type 1 additional glycemic diabetes mellitus or control diabetic ketoacidosis.  Not for patients with pre- existing severe gastrointestinal disease.  Has not been studied in combination with basal insulin Victoza Adjunct to diet and  Victoza is not a substitute  Administer once daily (liraglutide exercise to improve for insulin. Victoza should at any time of day. [rDNA origin] glycemic control in not be used in patients  The injection site and injection), adults with type 2 with type 1 diabetes timing can be changed

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© Copyright Prime Therapeutics LLC. 01/2016 All Rights Reserved GLP-1 Indication Important limitations for Dosage and Agonist use Administration solution for diabetes mellitus. mellitus or for the without dose subcutaneous treatment of or diabetic adjustment. (SC) use ketoacidosis, as it would  Initiate at 0.6 mg per not be effective in these day for one week. This Available as: settings. dose is intended to Solution for  Concurrent use with reduce GI symptoms subcutaneous prandial insulin has not during initial titration, injection, pre- been studied. and is not effective for filled, multi-  Not recommended as first- glycemic control. After dose pen that line therapy for patients 1 week, increase the delivers doses inadequately controlled on dose to 1.2 mg. If 1.2 of 0.6 mg, 1.2 diet and exercise. mg dose does not mg, or 1.8 mg  Has not been studied result in acceptable (6 mg/mL, 3 sufficiently in patients with glycemic control, dose mL) a history of pancreatitis. can be increased to 1.8 Consider other antidiabetic mg. therapies in patients with a  When initiating, history of pancreatitis. consider reducing the dose of concomitantly- administered insulin secretagogues to reduce the risk of .

CLINICAL RATIONALE

Guidelines3,4 The American Diabetes Association (ADA) Standards of Medical Care in Diabetes recommend lowering A1C to < 7.0% in most patients to reduce the incidence of microvascular disease. If implemented soon after the diagnosis of diabetes, A1Clowering is associated with long-term reduction in macrovascular disease.3,6 To achieve and maintain this goal, the ADA/European Association for the Study of Diabetes (EASD) created a position statement for the management of hyperglycemia in type 2 diabetes mellitus. This statement is considered a patient-centered approach.6

Metformin is considered the optimal first-line drug unless there are prevalent contraindications. After metformin, there are limited data to guide therapy. Combination therapy with an additional 1-2 oral or injectable agents is reasonable, aiming to minimize side effects where possible. The choice is based on patients and drug characteristics, with the overriding goal of improving glycemic control while minimizing side effects.6

The options given for two-drug combination therapy include combining metformin with either a sulfonylurea (SU), a (TZD), dipeptidyl peptidase 4 (DPP-4) inhibitors, a glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose co-transport 2 (SGLT-2) inhibitors, or insulin (usually basal, e.g., NPH, , or ). SUs have a high efficacy in lowering A1C and have a moderate risk of hypoglycemia but cause weight gain and hypoglycemia. TZDs have high efficacy in lowering A1C and a low risk of hypoglycemia but cause weight gain, edema, heart failure, bone fracture, increased LDL () are major side effects. DPP-4 inhibitors have only an intermediate efficacy in lowering A1C, but have a low risk of hypoglycemia, and are neutral in terms of weight gain and major side effects are rare. SGLT-2 inhibitors have an intermediate efficacy in lowering A1C and a low risk of

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© Copyright Prime Therapeutics LLC. 01/2016 All Rights Reserved hypoglycemia, but are associated with weight loss but cause genitourinary infections and dehydration.6 The GLP-1 receptor agonists main advantage is weight loss, which is modest in most patients but may be significant in some. They do have a high efficacy in lowering A1C, a low risk of hypoglycemia, but and issues are the major side effect, particularly early in the course of treatment. Concerns regarding an increased risk of pancreatitis remain unresolved. C-cell hyperplasia and medullary thyroid tumors in animals have occurred. Insulin has the highest efficacy in decreasing A1C, but the disadvantages include both weight gain and hypoglycemia. Rapid-acting secretagogues () may be used in place of SUs. Other drugs may be used where available in selected patients but have modest efficacy and/or limiting side effects.6

If the goal is not met with two-drug combination, a third agent can be added. The essential consideration is to use agents with complementary mechanisms of action. Increasing the number of drugs heightens the potential for side effects and drug-drug interactions and negatively impacts patient adherence. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when A1C is very high (e.g., > 9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies.6

The statement notes that the injectable GLP-1 receptor agonists mimic the effects of endogenous GLP-1, thereby stimulating pancreatic insulin secretion in a glucose-dependent fashion, suppressing pancreatic glucagon output, slowing gastric emptying, and decreasing appetite. The guidelines do not prefer one GLP-1 receptor agonist over the other.6

The American Association of Clinical Endocrinologists (AACE) consensus algorithm for diabetes management also recommends metformin as the cornerstone of monotherapy and combination therapy. The algorithm recommends GLP-1 agonists, DPP-4 inhibitors, SGLT-2 inhibitors, and alpha-glucosidase inhibitors as acceptable alternatives if metformin cannot be used first line and as second line agents to add to metformin. TZDs, , and glinides may also be used, but these agents should be used with caution owing to the potential for weight gain, hypoglycemia, or other risks. The GLP-1-RA provides A1C lowering of 0.8 to 2.0% and weight loss ranges from 1-4 kg across studies. The risk of hypoglycemia is low when used as monotherapy or with metformin or with other low-risk but increases when used with SUs. Triple therapy may be used if A1C is not controlled by dual therapy. The AACE consensus algorithm does not prefer one GLP-1-RA over another.4

REFERENCES 1. Byetta prescribing information. AstraZeneca Pharmaceuticals, Inc. March 2015. 2. Victoza prescribing information. Novo Nordisk A/S. March 2015. 3. American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes Care 2015; 38(Supp 1): S1-S99. 4. Handelsman Y, Bloomgarden ZT, Grunberger G et al. American Association of Clinical Endocrinology- clinical practice guidelines for developing a diabetes mellitus comprehensive care plan – 2015. Endocrin Pract 2015; 21 (Suppl 1): 1-87. 5. Bydureon prescribing information. AstraZeneca Pharmaceuticals, Inc. September 2015. 6. Inzucchi SE, Bergenstal RM, Buse JB, et al. 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 2015; 38: 140-149. 7. Tanzeum prescribing information. GlaxoSmithKline LLC. July 2015. 8. Trulicity prescribing information. . July 2015.

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