Proposed Preferred Drug List. Clinical Criteria

Transcription

1 Proposed Preferred Drug List with Clinical Criteria Proposal for TennCare November 18, 2008 Page 1 of 42

2 Responsibilities of the TennCare Pharmacy Advisory Committee Source: Tennessee Code/Title 71 Welfare/Chapter 5 Programs and Services for Poor Persons/Part 24 Tennessee TennCare Pharmacy Advisory Committee/ through Make recommendations regarding a preferred drug list (PDL) to govern all state expenditures for prescription drugs for the TennCare program. o The TennCare Pharmacy Advisory Committee shall submit to the bureau of TennCare both specific and general recommendations for drugs to be included on any state PDL adopted by the bureau. In making its recommendations, the committee shall consider factors including, but not limited to, efficacy, the use of generic drugs and therapeutic equivalent drugs, and cost information related to each drug. The committee shall also submit recommendations to the bureau regarding computerized, voice, and written prior authorization, including prior authorization criteria and step therapy. o The state TennCare pharmacy advisory committee shall include evidence-based research in making its recommendations for drugs to be included on the PDL. o The TennCare bureau shall consider the recommendations of the state TennCare pharmacy advisory committee in amending or revising any PDL adopted by the bureau to apply to pharmacy expenditures within the TennCare program. The recommendations of the committee are advisory only and the bureau may adopt or amend a PDL regardless of whether it has received any recommendations from the committee. It is the legislative intent that, insofar as practical, the TennCare bureau shall have the benefit of the committee s recommendations prior to implementing a PDL or portions thereof. Keep minutes of all meetings including votes on all recommendations regarding drugs to be included on the state preferred drug list The chair may request that other physicians, pharmacists, faculty members of institutions of higher learning, or medical experts who participate in various subspecialties act as consultants to the committee as needed. Page 2 of 42

3 PDL Decision Process The primary clinical decision that needs to be made is determining if the drugs within the therapeutic class of interest can be considered therapeutic alternatives. A Therapeutic Alternative is defined by the AMA as: drug products with different chemical structures but which are of the same pharmacological and/or therapeutic class, and usually can be expected to have similar therapeutic effects and adverse reaction profiles when administered to patients in therapeutically equivalent doses 1. The Committee should not feel obligated to decide if every drug within the therapeutic class is exactly equal to all other drugs within the class, nor should they feel obligated to decide if every drug within the therapeutic class works equally well in every special patient population or in every disease. In special situations (e.g., presence of comorbid conditions) and in special populations (e.g., pediatrics) use of a non-preferred drug might be the most appropriate therapy. These cases can be handled through prior authorization (PA). PA serves as a safety valve in that it facilitates use of the most appropriate agent regardless of PDL status. LENGTH OF AUTHORIZATIONS: Dependent upon diagnosis and length of therapy needed to treat. (Most medications are used chronically, and thus would be approved for 1 year.) 1. Is there any reason the patient cannot be changed to a medication not requiring prior approval within the same class? Acceptable reasons include: Allergy to medications not requiring prior approval Contraindication to or drug-to-drug interaction with medications not requiring prior approval History of unacceptable/toxic side effects to medications not requiring prior approval 2. The requested medication may be approved if both of the following are true: If there has been a therapeutic failure of at least two medications within the same class not requiring prior approval (unless otherwise specified) The requested medication s corresponding generic (if a generic is available and preferred by the State) has been attempted and failed or is contraindicated 3. The requested medication may be approved if the following is true: An indication which is unique to a non-preferred agent and is supported by peer-reviewed literature or an FDA approved indication exists The information provided for each drug class is organized into the following sections, when applicable: BACKGROUND: General overview Pharmacology Therapeutic effect(s) Adverse reactions Outcomes data Place in therapy according to current Treatment Guidelines RECOMMENDATION: General recommendation regarding utility and therapeutic equivalence among the agents in the class, as well as requirements for product availability (PDL placement) 1 AMA Policy H Drug Formularies and Therapeutic Interchange Page 3 of 42

4 ENDOCRINE AND METABOLIC AGENTS BACKGROUND RE-REVIEW: THIAZOLIDINEDIONES Thiazolidinediones act to improve glycemic control by increasing insulin sensitivity in target tissues, as well as decreasing glucose output in the liver. These actions help to improve glycemic control in adult patients with type 2 diabetes. Pioglitazone and rosiglitazone are the agents currently available. Thiazolidinediones are selective agonists of the peroxisome proliferator-activated receptor (PPAR y). PPAR y regulates the transcription of insulin-responsive genes involved in the control of glucose production, transportation and utilization. PPAR γ also plays a role in the regulation of fatty acid metabolism. Thiazolidinediones do not stimulate insulin secretion and their activity depends on the presence of insulin for their efficacy in controlling blood glucose. Both agents are FDA approved for monotherapy as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; both agents are also approved for combination therapy with a sulfonylurea, metformin or insulin in adults when diet and exercise plus a single agent do not result in adequate glycemic control. The most common adverse events include fatigue, headache, edema, sinusitis, and diarrhea. o Both agents carry a black box warning for congestive heart failure: Thiazolidinediones, including pioglitazone and rosiglitazone, cause or exacerbate congestive heart failure in some patients. After initiation of pioglitazone or rosiglitazone, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone or rosiglitazone must be considered. Pioglitazone or rosiglitazone are not recommended in patients with symptomatic heart failure. Initiation of pioglitazone or rosiglitazone in patients with established New York Heart Association Class III or IV heart failure is contraindicated. o Rosiglitazone carries an additional black box warning for myocardial ischemia: A meta-analysis of 42 clinical studies (mean duration 6 months: 14,237 total patients), most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. o Pioglitazone and rosiglitazone should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis because these agents are active only in the presence of insulin. o Therapy with thiazolidinediones may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking a thiazolidinedione. o Macular edema has also been reported in some diabetic patients who were taking thiazolidinediones. Any visual symptoms should be promptly referred to an ophthalmologist. o Significant drug interactions: Use of gemfibrozil with thiazolidinediones can inhibit the metabolism of thiazolidinediones causing an increase in plasma concentrations of thiazolidinediones, resulting in an increased risk of hypoglycemia and other adverse effects. If co-administration is necessary, the thiazolidinedione dose should be reduced and blood glucose should be monitored closely. Page 4 of 42

5 ENDOCRINE AND METABOLIC AGENTS Rifamycins can increase the metabolism of the thiazolidinediones, which can decrease the plasma concentration causing decreased glycemic control. Blood glucose should be monitored closely when initiating and terminating rifamycins. Observation in clinical trials showed an increased risk of myocardial ischemia when rosiglitazone was added to insulin therapy and when patients taking rosiglitazone had background nitrate therapy. Use with insulin should be monitored closely and use of rosiglitazone with nitrates is not recommended. Several head to head trials comparing the thiazolidinediones have been completed. Overall, the trial results demonstrated efficacy in improving glycemic control as well as more limited trials specifically showed improvements in HbA 1c. The primary difference shown in these trials between the two agents involves their effects on lipoproteins. Pioglitazone has shown more favorable effects on lipoproteins than rosiglitazone. Patients treated with pioglitazone experienced a decrease in triglycerides, increase in high density lipoprotein (HDL) cholesterol and no consistent change in low density lipoprotein (LDL) and total cholesterol. Rosiglitazone was associated with an increase in total, LDL and HDL cholesterol, and variable effects on triglycerides. One specific trial compared pioglitazone to rosiglitazone in 802 patients with type 2 diabetes, HbA 1c >7%, TG > 150 mg/dl, LDL < 130 mg/dl. Primary outcomes were effect on TG, lipoproteins and HbA 1c. TG levels significantly decreased ( 51.9 mg/dl) with pioglitazone while TG levels increased with rosiglitazone (13.1 mg/dl; P<0.001). Pioglitazone significantly increased HDL cholesterol (5.2 mg/dl) compared to rosiglitazone (2.4 mg/dl; P<0.001). Non-HDL cholesterol was significantly higher with rosiglitazone (25.7 mg/dl) compared to pioglitazone (3.6 mg/dl; P<0.001). Both treatment groups increased LDL cholesterol: however, smaller increases were observed with pioglitazone (12.3 vs 21.3 mg/dl; P<0.001). Similar reductions in HbA 1c were observed with pioglitazone ( 0.7%) and rosiglitazone ( 0.6%; P=0.129). Additionally, trials with these agents looking at cardiovascular outcomes have also been completed. In May 2007, the Food and Drug Administration (FDA) issued an alert informing healthcare professionals of a potential safety concern related to rosiglitazone. Safety data from a pooled analysis of controlled clinical trials noted a significant increased risk of myocardial infarction and cardiovascular-related deaths in patients taking rosiglitazone; however, other published and unpublished data from long-term clinical trials provided contradictory evidence. A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), showed rosiglitazone to be associated with an increased risk of myocardial ischemic events; the ADOPT, DREAM and RECORD studies (mean duration 41 months; 14,067 total patients) have not confirmed or excluded this risk. At this time, pioglitazone has not been associated with an increased risk of myocardial infarction and/or cardiovascular-related deaths. Both pioglitazone and rosiglitazone are FDA approved for use as monotherapy and in combination with other antidiabetic agents to improve glycemic control in adults with type 2 diabetes mellitus. The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend metformin as the first-line therapeutic agent with thiazolidinediones and sulfonylureas as second-line or add-on therapy for the management of type 2 diabetes mellitus. The recommendations by the American College of Endocrinologists (ACE) and American Association of Clinical Endocrinologists (AACE) medical guidelines and Diabetes Road Map task force differ slightly and recommend a thiazolidinedione as well as metformin, a secretagogue (i.e. a sulfonylurea or meglitinide), an α-glucosidase inhibitor, or a dipeptidyl peptidase-4 [DPP- 4] inhibitor as a preferred intervention to achieve glycemic goals in treatment naïve patients with a HbA 1c of 6%-7%. Thiazolidinediones are also listed among the treatment options for combination therapy based upon HbA 1c levels in treatment naïve patients as well as those already receiving antidiabetic agents. At this time, the clinical guidelines do not give preference to one thiazolidinedione versus the other; however, the ADA, EASD and ACE/AACE Diabetes Road Map Task Force guidelines do note a possible link of rosiglitazone to cardiovascular events. Page 5 of 42

6 ENDOCRINE AND METABOLIC AGENTS RECOMMENDATION Both pioglitazone and rosiglitazone are FDA approved for use as monotherapy and in combination with other antidiabetic agents to improve glycemic control in adults with type 2 diabetes mellitus. The ADA and EASD recommend metformin as the first-line therapeutic agent with thiazolidinediones and sulfonylureas as second-line or add-on therapy for the management of type 2 diabetes mellitus. The recommendations by the ACE and AACE medical guidelines and Diabetes Road Map Task Force differ slightly and recommend a thiazolidinedione as well as metformin, a secretagogue (i.e. a sulfonylurea or meglitinide), an α-glucosidase inhibitor, or a dipeptidyl peptidase-4 [DPP-4] inhibitor as a preferred intervention to achieve glycemic goals in treatment naïve patients with a HbA 1c of 6%-7%. At this time, the clinical guidelines do not give preference to one thiazolidinedione versus the other; however, the ADA, EASD and ACE/AACE Diabetes Road Map Task Force do note a possible link of rosiglitazone to cardiovascular events. The current evidence and guidelines show that pioglitazone and rosiglitazone appear to be comparable in efficacy and are beneficial to patients when other first-line agents are not tolerated, are contraindicated or do not provide adequate glycemic control. Data regarding the risk of myocardial ischemia with rosiglitazone is inconclusive; however, pioglitazone has not been associated with this risk. Additionally, pioglitazone seems to have a more favorable effect on lipoproteins. For these reasons, pioglitazone can be considered a superior agent in this class. Therefore, it is recommended that at least pioglitazone be available for use. Given that current guidelines from the ADA and EASD do not recommend the TZDs as first line agents, and more cost-effective first-line treatments are available, it is recommended that this class be subject to step therapy criteria. PREFERRED Actos (pioglitazone) Avandia (rosiglitazone) ST, QL ST, QL Quantity Limits Actos all strengths 1 tablet per day Avandia all strengths 1 tablet per day RE-REVIEW: THIAZOLIDINEDIONES NON-PREFERRED Step Therapy for Thiazolidinediones Therapy with a TZD will be approved for either monotherapy or combination therapy in recipients who have had a failure, contraindication, drug to drug interaction, or intolerance to an adequate trial of metformin AND a sulfonylurea. References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; Accessed October, MedMetrics Thiazolidinediones single agents class review. October 1, US Food and Drug Administration Center for Drug Evaluation and Research. Summary minutes of the joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee held on July 30, Page 6 of 42

7 ENDOCRINE AND METABOLIC AGENTS 4. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA Sep 12;298(10): American Diabetes Association. Standards of medical care in diabetes 2008 [guideline on the Internet]. Diabetes Care Jan [cited 2008 Sep 16];31 Suppl 1:S Nathan DM, Buse JB, Davidson MB, Heine RJ, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care Aug; 29(8): Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: Update regarding the thiazolidinediones. Diabetologia Jan;51(1): AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus: Endocr Pract May-Jun;13(Suppl 1): Jellinger PS, Davidson JA, Blonde L, Einhorn D, Grunberger G, Handelsman Y, et al; ACE/AACE Diabetes Road Map Task Force. Road maps to achieve glycemic control in type 2 diabetes mellitus: ACE/AACE Diabetes Road Map Task Force. Endocr Pract May-Jun [updated 2008 Apr 18; cited 2008 Sep 16];13(3): Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al; for the GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care Jul;28(7): Derosa G, D Angelo A, Ragonesi PD, Ciccarelli L, Piccinni MN, Pricolo F, et al. Metformin-pioglitazone and metformin-rosiglitazone effects on nonconventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndrome. J Clin Pharm Ther Aug;31(4): Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al; for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Eng J Med Dec 7;355(23): Home PD, Jones NP, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, et al; for the RECORD Study Group. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med. 2007;24: Page 7 of 42

8 BACKGROUND ENDOCRINE AND METABOLIC AGENTS RE-REVIEW: THIAZOLIDINEDIONES COMBINATION PRODUCTS Combination thiazolidinedione products merge two antidiabetic agents with different mechanisms of actions to improve glycemic control in type 2 diabetic patients. Currently, there are four products available with pioglitazone and rosiglitazone paired with either glimepiride or metformin: o pioglitazone/glimepiride o pioglitazone/metformin o rosiglitazone/glimepiride o rosiglitazone/metformin Thiazolidinediones are selective agonists of the peroxisome proliferator-activated receptor γ (PPARγ). PPAR γ is found in adipose tissue, skeletal muscle and the liver. The PPAR γ regulates the transcription of insulin-responsive genes involved in the control of glucose production, transportation and utilization. PPAR γ also plays a role in the regulation of fatty acid metabolism. Glycemic control is improved by increasing insulin sensitivity in target tissues, as well as decreasing glucose output in the liver. Glimepiride is a sulfonylurea that stimulates the release of insulin from pancreatic β cells. Metformin is a biguanide that decreases endogenous hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral uptake and utilization of glucose. The thiazolidinedione combination products are FDA indicated as adjunctive therapy to diet and exercise as a once daily combination therapy to improve gylcemic control in patients with type 2 diabetes who are already being treated with a combination of each individual component and whose diabetes is not adequately controlled by the single agent. In addition to the common adverse reactions of the thiazolidinediones (fatigue, headache, edema, sinusitis, and diarrhea), the combination products are also associated with hypoglycemia, flatulence, nausea and vomiting. o Both thiazolidinediones carry a black box warning for congestive heart failure: Thiazolidinediones, including pioglitazone and rosiglitazone, cause or exacerbate congestive heart failure in some patients. After initiation of pioglitazone or rosiglitazone, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone or rosiglitazone must be considered. Pioglitazone or rosiglitazone are not recommended in patients with symptomatic heart failure. Initiation of pioglitazone or rosiglitazone in patients with established New York Heart Association Class III or IV heart failure is contraindicated. o Rosiglitazone carries an additional black box warning for myocardial ischemia: A meta-analysis of 42 clinical studies (mean duration 6 months: 14,237 total patients), most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. o Metformin carries black box warning for lactic acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/l), decreased blood ph, electrolyte disturbances with an increased anion gap, and an Page 8 of 42

9 ENDOCRINE AND METABOLIC AGENTS o o o o o o increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/ml are generally found. Glimepiride, the sulfonylurea component of the thiazolidinedione combination products, carries a special warning (not a black boxed warning) for an increased risk of cardiovascular mortality. This warning was based on a study where patients treated with a fixed dose of tolbutamide 1.5 gm daily for 5-8 years had a rate of cardiovascular mortality approximately 2.5 times that of patients treated with diet alone. Metformin is contraindicated in patients with renal disease or renal dysfunction and metabolic acidosis. Metformin products should be temporarily discontinued in patients undergoing radiologic studies involving parental administration of iodinated contrast materials since use of these products may alter renal function. Pioglitazone and rosiglitazone should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis because these agents are active only in the presence of insulin. Therapy with thiazolidinediones may result in ovulation in some premenopausal anovulatory women. These patients may be at an increased risk for pregnancy while taking a thiazolidinedione. Caution with therapy is advised if patient has hepatic dysfunction. Therapy should not be initiated if there is clinical evidence of active liver disease or increased serum transaminase levels (> 2.5 times upper limit of normal range). Significant drug interactions: Use of gemfibrozil with thiazolidinediones can inhibit the metabolism of thiazolidinediones causing an increase in plasma concentrations of thiazolidinediones. There is increased risk of hypoglycemia and other adverse effects. If co-administration is necessary, the thiazolidinedione dose should be reduced and blood glucose should be monitored closely. Rifamycins can increase the metabolism of the thiazolidinediones, which can decrease the plasma concentration causing decreased glycemic control. Blood glucose should be monitored closely when initiating and terminating rifamycins. Insulin therapy and nitrate therapy with rosiglitazone has shown in observational trials an increased risk of myocardial ischemia. Concomitant use with insulin should be monitored closely and use of rosiglitazone with nitrates is not recommended. Angiotensin converting enzyme (ACE) inhibitors may temporarily increase insulin sensitivity. When initiating ACE inhibitors in patients receiving sulfonylureas, carefully observe for symptoms of hypoglycemia. Chloramphenicol may reduce hepatic clearance of certain sulfonylureas and cause an increased hypoglycemic response. Monitor for hypoglycemia and blood glucose concentrations and adjust sulfonylurea doses as needed. Clofibrate may cause an increased hypoglycemic response to certain sulfonylureas through an unknown mechanism. Monitor for hypoglycemia and blood glucose concentrations and adjust sulfonylurea doses accordingly. Fluconazole may inhibit the metabolism of certain sulfonylureas (including glimepiride), increasing the hypoglycemic effects. Monitor blood glucose concentrations when coadministered. MAOIs may enhance the hypoglycemic action of sulfonylureas through an unknown mechanism. Monitor blood glucose concentrations and adjust the doses of the sulfonylurea accordingly. Salicylates can reduce plasma glucose levels and enhance insulin secretion, adding to the hypoglycemic effects of sulfonylureas. Monitor blood glucose concentrations and adjust the doses of the sulfonylurea accordingly. Sulfonamides may impair the metabolism of certain sulfonylureas and enhance the hypoglycemic effects of sulfonylureas. Monitor blood Page 9 of 42

10 ENDOCRINE AND METABOLIC AGENTS glucose concentrations and adjust the doses of the sulfonylurea accordingly. Glyburide may be a noninteracting alternative. Thiazide diuretics may increase fasting blood glucose levels resulting in decreased glycemic control. Dose increases of the sulfonylurea may be required to maintain glycemic control. The studies that evaluated combination therapy administered the medications as add-on agents and not as fixed-dose combination products. In limited trials comparing add-on therapy with either pioglitazone or rosiglitazone to glimepiride or metformin, the thiazolidinediones demonstrated comparable effects with regards to glycemic control but the pioglitazone combinations had a more favorable effect on lipoproteins than the rosiglitazone combinations. Metformin, second generation sulfonylureas and thiazolidinediones produced similar reductions in glycosylated hemoglobin (HbA 1c ) compared with one another when used as monotherapy, and combination therapies were more effective in reducing HbA 1c than monotherapy. The majority of the published studies that evaluated a fixed-dose regimen were with the rosiglitazone products. The addition of pioglitazone or rosiglitazone to metformin therapy significantly reduced HbA 1c and fasting plasma glucose (FPG) levels compared to metformin monotherapy. Glimepiride added to pioglitazone or rosiglitazone therapy significantly reduced HbA 1c and FPG compared to monotherapy. The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) discuss the potential role of combination products when patients are not achieving adequate glycemic control with a single agent. Thiazolidinediones, sulfonylureas and insulin are the primary agents recommended for add on therapy to metformin. The guidelines and Diabetes Road Map Task Force for the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinologists (ACE) agree these agents should be used for add on therapy; however, they also recommend the use of fixed-dose combination products as first line therapy for patients with type 2 diabetes mellitus who are naïve to pharmacologic therapy and have HbA 1c levels at 7%-8%. The guidelines do not give preference to one thiazolidinedione versus the other; however, the ADA, EASD and ACE/AACE Diabetes Road Map Task Force guidelines do note a possible link of rosiglitazone to cardiovascular events. RECOMMENDATION Based on the current evidence pioglitazone and rosiglitazone fixed-dose combination products appear to be comparable in efficacy and are beneficial to patients when other first-line agents are not tolerated, are contraindicated or do not provide adequate glycemic control. The ADA and EASD discuss the potential role of combination products when patients are not achieving adequate glycemic control with a single agent. The guidelines and Diabetes Road Map Task Force for the AACE/ACE agree these agents should be used for add on therapy; however, they also recommend the use of fixed-dose combination products as first line therapy for patients with type 2 diabetes mellitus who are naïve to pharmacologic therapy and have HbA 1c levels at 7%- 8%. Pioglitazone combination products have demonstrated a more favorable effect on lipoproteins than rosiglitazone combination products. The guidelines do not give preference to one thiazolidinedione versus the other; however, the ADA, EASD guidelines and AACE/ACE guidelines and Diabetes Road Map Task Force do note a possible link of rosiglitazone to cardiovascular events. Although the data regarding the risk of myocardial ischemia with rosiglitazone is inconclusive, pioglitazone has not been associated with this risk. For these reasons, pioglitazone combination products can be considered superior agents in this class. Therefore, it is recommended that at least pioglitazone combination products be available for use. Given that current guidelines from the ADA and EASD do not recommend TZDs as first line agents, and more cost-effective first-line treatments are available, it is recommended that the TZD combination products be subject to step therapy criteria. Page 10 of 42

11 ENDOCRINE AND METABOLIC AGENTS RE-REVIEW: THIAZOLIDINEDIONES COMBINATION PRODUCTS PREFERRED NON-PREFERRED Actoplus Met ST, QL (pioglitazone/metformin) N/A Duetact ST, QL (pioglitazone/glimepiride) Avandamet ST, QL (rosiglitazone/metformin) Avandaryl (rosiglitazone/glimepiride) ST,QL QUANTITY LIMITS Actoplus Met 2 tablets per day Duetact 1 tablet per day Avandamet 2 tablets per day Avandaryl 1 tablet per day STEP THERAPY Therapy with a TZD combination product will be approved for either monotherapy or combination therapy in recipients who have had a failure, contraindication, drug to drug interaction, or intolerance to an adequate trial of metformin AND a sulfonylurea. References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; Accessed October, MedMetrics Health Partners. Thiazolidinediones Combination agents class review. October 1, American Diabetes Association. Standards of medical care in diabetes 2008 [guideline on the Internet]. Diabetes Care Jan [cited 2008 Sep 16];31 Suppl 1:S Nathan DM, Buse JB, Davidson MB, Heine RJ, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care Aug;29(8): Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: Update regarding the thiazolidinediones. Diabetologia Jan;51(1): AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus: Endocr Pract May-Jun [cited 2008 Sep 16];13(Suppl 1): Jellinger PS, Davidson JA, Blonde L, Einhorn D, Grunberger G, Handelsman Y, et al; ACE/AACE Diabetes Road Map Task Force. Road maps to achieve glycemic control in type 2 diabetes mellitus: ACE/AACE Diabetes Road Map Task Force [guideline on the Internet]. Endocr Pract May-Jun [updated 2008 Apr 18; cited 2008 Sep 16];13(3): Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Page 11 of 42

12 ENDOCRINE AND METABOLIC AGENTS Am J Med. 2001;111: Chou HS, Palmer JP, Jones AR, Waterhouse B, Ferreira-Cornwell C, Krebs J, Goldstein BJ. Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes. Diabetes Obes Metab Aug;10(8): McCluskey D, Touger MS, Melis R, Schleusener DS, McCluskey D. Results of a randomized, double-blind, placebo-controlled study administering glimepiride to patients with type 2 diabetes mellitus inadequately controlled with rosiglitazone monotherapy. Clin Ther. 2004;26(11): Derosa G, Cicero AFG, Gaddi A, Ragonesi PD, Fogari E, Bertone G, et al. Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month, multicenter, double-blind, randomized, controlled, parallel-group trial. Clin Ther. 2004;26(5): Page 12 of 42

13 ENDOCRINE AND METABOLIC AGENTS BACKGROUND RE-REVIEW: INCRETIN MIMETICS Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are both incretin hormones secreted from intestinal cells in response to a meal to help regulate glucose homeostasis. Exenatide is the only incretin mimetic that selectively mimics the action of endogenous GLP-1. The incretin hormones increase insulin secretion in a glucose-dependent manner through activation of their specific receptors on pancreatic β-cells. They also suppress glucagon secretion during periods of hyperglycemia, slow gastric emptying, and thus in turn reduce overall food intake. Exenatide is FDA approved for adjunctive therapy in type 2 diabetes mellitus patients with poor glycemic control taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione. The most common adverse effects with exenatide include: diarrhea, nausea, and vomiting. o More severe adverse effects include: hypoglycemia and the development of antiexenatide antibodies. o In October 2007, the Food and Drug Administration (FDA) published an alert regarding an association between exenatide and pancreatitis. Subsequently, the FDA issued an update to this alert in August 2008, referencing 6 cases of hemorrhagic or necrotizing pancreatitis in patients who had a history of Byetta therapy. o Due to reports of pancreatitis, patient triglycerides should be evaluated prior to initiation of therapy with exenatide. If pancreatitis is suspected, exenatide should be discontinued; if pancreatitis is confirmed, exenatide should not be restarted and appropriate treatment should be initiated. o Exenatide is not a substitute for insulin in insulin-requiring patients. It should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. o If exenatide is used in combination with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia. o Due to slowing of gastric emptying, exenatide may delay absorption of oral medications administered concomitantly. Caution should be used for oral medications that require rapid gastrointestinal absorption or require specific concentrations for efficacy (the latter should be taken 1 hour prior to or 2 hours after exenatide administration). o Patients should be observed for signs of altered renal function, including those who are taking concomitant agents known to affect renal function/hydration status, such as diuretics, angiotensin-converting enzyme inhibitors, and nonsteroidal anti-inflammatory drugs, or those experiencing significant vomiting and/or diarrhea, which may lead to dehydration. o Exenatide is not recommended for use in patients with severe renal impairment or end-stage renal disease; also not recommended for use in patients with gastrointestinal disorders. o At this time, safety and efficacy have not been established in children. o There are no significant drug-drug interactions identified with exenatide. Of the 3 placebo controlled trials submitted for exanetide s FDA approval, 5 additional trials have also been published as extensions of those original 3 trials. Results from these trials demonstrated reductions in glycosylated hemoglobin (HbA 1c ) values as the primary endpoint ranged from 0.7% to 1.1% with the addition of exenatide to existing diabetic therapies. Page 13 of 42

14 ENDOCRINE AND METABOLIC AGENTS A randomized trial compared the change in HbA 1c from baseline in stable type 2 diabetic patients who were receiving either titrated dose of exenatide and metformin/sulfonylurea or titrated insulin glargine and metformin/sulfonylurea. Study patients had HbA 1c values in the range of 7-11% and had been on metformin/sulfonylurea therapy for at least 3 months. Significant changes from baseline HbA 1c were reported in both treatment groups (mean -1.11%). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide than insulin glargine. Gastrointestinal symptoms were more common in the exenatide group vs the insulin glargine group, including nausea (57.1% vs 8.6%), vomiting (17.4% vs 3.7%), and diarrhea (8.5% vs 3.0%); no P values reported. Another trial compared exenatide and metformin/sulfonylurea with insulin aspart twice daily and metformin/sulfonylurea therapy. Patients had a diagnosis of type 2 diabetes with suboptimal glycemic control with metformin and sulfonylurea therapy. There was not a significant change from baseline HbA 1c between the two treatment groups. Patients in the exenatide group experienced a gradual weight loss of -2.5 kg, compared with a gradual weight gain of 2.9 kg in the insulin aspart group. Patients in both exenatide and insulin aspart groups had a significant decrease in fasting serum glucose compared with baseline (P<0.001 for both groups). There was not a significant difference between groups. Adverse events that were more commonly reported in the exenatide vs insulin aspart group included: nausea (33.2% vs 0.4%), vomiting (15% vs 3.2%), and diarrhea (9.5% vs 2%); no p values reported. The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the American Association of Clinical Endocrinologists (AACE) do not include incretin mimetics in the their primary treatment algorithms for diabetes mellitus due to their generally lower glucose-lowering effectiveness and limited clinical data at this time. The American College of Endocrinologists (ACE)/AACE Diabetes Road Map Task Force also does not list incretin mimetics as a first line treatment option. Exenatide is recommended only when patients are not achieving HbA 1C goals despite maximal therapy on effective doses of a sulfonylurea and/or metformin or a thiazolidinedione. The recently published 2007 International Diabetes Federation guidelines for the management of post-meal glucose also include the DPP-4 inhibitors as an available treatment option with alpha-glucosidase inhibitors, amylin analogs, exenatide, insulins and meglitinides. All current guidelines state that the incretin mimetics may be appropriate for use in select patient populations where primary treatment strategies have not achieved adequate glycemic control. RECOMMENDATION Exenatide is an incretin mimetic that selectively mimics the action of endogenous GLP-1. The incretin mimetics are approved for the treatment of type 2 diabetes mellitus in patients who have not achieved adequate glycemic control with diet, exercise, and first-line therapy. The ADA, the EASD, and the AACE do not include incretin mimetics in their primary treatment algorithms for diabetes mellitus due to their generally lower effectiveness in glucose reduction and limited clinical data at this time. The ACE/AACE Diabetes Road Map Task Force also does not list incretin mimetics as a first line treatment option. Given that the incretin mimetics are not considered first line therapy for diabetes mellitus, and due to continuing study on the appropriate place in therapy for this class, it is recommended that the incretin mimetics be subject to clinical criteria to restrict their use to appropriate patients. Page 14 of 42

15 ENDOCRINE AND METABOLIC AGENTS PREFERRED RE-REVIEW: INCRETIN MIMETICS NON-PREFERRED CC, QL Byetta QUANTITY LIMITS Byetta 5 mcg (1.2 ml per 26 days) Byetta 10 mcg (2.4mL per 26 days) CLINICAL CRITERIA FOR BYETTA Byetta will be approved for recipients who meet ALL of the following criteria: Hemoglobin A1c > 7% (for initial approval only) Has failed to obtain glycemic control on an adequate trial of the following agents: A biguanide product (metformin) - unless the patient has a contraindication or history of intolerance to metformin At least one other oral hypoglycemic agent (i.e., a sulfonylurea, TZD, meglitinide, alpha glucosidase inhibitor, or DPP-4 inhibitor), OR insulin. Byetta will NOT be covered for the following: Diagnosis of Type I diabetes Treatment of diabetic ketoacidosis Use for weight loss Patient has end-stage renal disease or CrCl 30 ml/min. References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; Accessed October, MedMetrics. Incretin mimetics class review. October 1, Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143: Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A, et al. A comparison of twicedaily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50: American Diabetes Association. Standards of medical care in diabetes 2008 [guideline on the Internet]. Diabetes Care Jan [cited 2008 Aug 18]; 31:S International Diabetes Federation (IDF). Guideline for management of postmeal glucose [guideline on the Internet]. Brussels (Belgium): International Diabetes Federation, 2007 [cited 2007 Nov 29] Available from: 7. Jellinger PS, Davidson JA, Blonde L, Einhorn D, Grunberger G, Handelsman Y, et al. Page 15 of 42

16 ENDOCRINE AND METABOLIC AGENTS ACE/AACE Diabetes Road Map Task Force [guideline on the Internet]. Endocr Pract May-Jun [cited 2008 Aug 18]; 13(3): Available from: 8. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care Aug; 29(8): Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: update regarding the thiazolidinediones. Diabetologia. 2008;51: AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract May-Jun [cited 2008 Aug 18]; 13(suppl1): Page 16 of 42

17 ENDOCRINE AND METABOLIC AGENTS BACKGROUND RE-REVIEW: DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS SINGLE AND COMBINATION AGENTS Dipeptidyl peptidase-4 (DPP-4) inhibitors represent one of the newer classes of oral antidiabetic medications. The class reversibly blocks the inactivation of incretin hormones. Sitagliptin and sitagliptin/metformin are currently the only DPP-4 inhibitor and DPP-4 inhibitor combination product available in the United States. Incretin hormones are produced by the gastrointestinal tract in response to meals and are involved in the regulation of insulin. The inhibition of this inactivation enzyme results in an increase in insulin production and release from pancreatic β cells. Decreased glucagon secretion from pancreatic α cells occurs, thus decreasing hepatic glucose production. Delayed gastric emptying and increased satiety can also occur. In the combination product, metformin improves glycemic control by decreasing endogenous hepatic glucose production, decreasing intestinal absorption of glucose and increasing peripheral uptake and utilization of glucose. Sitagliptin is FDA approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Sitagliptin/metformin is FDA approved as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone, or in patients already being treated with the combination of sitagliptin and metformin. The most common adverse reactions experienced with sitagliptin therapy alone are headache, hypoglycemia, nasopharyngitis, and upper respiratory infection. The most common adverse reactions reported in patients simultaneously started on sitagliptin and metformin are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia and headache. o Sitagliptin does not carry any black box warnings at this time; however the combination of sitagliptin/metformin does carry a warning in regards to metformin and lactic acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation; when it occurs, it is fatal in approximately 50% of cases. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/ml are generally found. o The combination product containing sitagliptin and metformin is contraindicated in patients with renal disease or dysfunction, and acute or chronic metabolic acidosis including diabetic ketoacidosis, with or without coma. o Patients undergoing radiologic studies with iodinated contrast material should temporarily discontinue the combination product. o Caution is advised when using sitagliptin as a single agent in patients with moderate to severe renal insufficiency, as well as in patients with end-stage renal disease (ESRD) on dialysis. Dosage adjustments are recommended in these patient populations. o When using sitagliptin in combination with a sulfonylurea, a decreased dose of the sulfonylurea is recommended to reduce the risk of hypoglycemia. o Post-marketing reports of serious hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin conditions including Steven- Johnson syndrome, have been reported with use of sitagliptin. o Neither the single agent nor combination product has been studied in children less than 18 years old. o Significant drug-drug interactions: Sitagliptin may increase the concentration of digoxin. Patients should be monitored appropriately. No dosage adjustment of digoxin or sitagliptin is recommended. Page 17 of 42

18 ENDOCRINE AND METABOLIC AGENTS A 2007 meta analysis continued to support the placebo controlled findings that showed a significant decrease in HbA 1c. However, the DPP-4 inhibitors were slightly less effective in regards to glycemic outcomes when compared to other hypoglycemic agents. DPP-4 inhibitors were found to be weight neutral and the incidence of hypoglycemia with this class of medications was low. Additional trials: Drug Regimen Study Design Sample Size Endpoint Results Sitagliptin vs. Glipizide vs. Placebo Sitagliptin + glimepiride vs. Sitagliptin + glimepiride + metformin vs. Glimepiride + placebo Sitagliptin + metformin vs. Glipizide + metformin Sitagliptin+ metformin vs. Sitagliptin vs. Metformin Sitagliptin + metformin vs. Metform = placebo Sitagliptin + metformin vs. Metformin + placebo DB, RCT N=743 Change from baseline in HbA 1c, changes in weight and adverse effects DB, RCT N=441 HbA 1c change from baseline DB, RCT, NI N=1172 NI of sitagliptin to glipizide (change in baseline HbA 1c ) DB, RCT N= weeks DB, RCT N= weeks DB, RCT N= weeks Change in baseline HbA 1c Change in baseline HbA 1c Reduction in HbA 1c at 18 weeks of sitagliptin therapy All sitagliptin treatment groups demonstrated a significant reduction in HbA 1c over placebo ( 0.38% to 0.77%; P<0.001) No significant changes in baseline body weight in the sitagliptin groups compared to placebo; glipizide group demonstrated modest weight gain vs placebo (no P value reported). Hypoglycemia highest in glipizidetreated group (17%) compared to placebo (2%) and sitagliptin (4%), no P value reported. The addition of sitagliptin significantly decreased HbA 1c (P<0.001) from baseline. No significant difference was noted between glimepiride and sitagliptin vs glimepiride and placebo in patients who reached an HbA 1c level <7.0% (10.8% vs 8.7%; P<0.638). Results demonstrated no significant difference in change from baseline in either treatment group. Sitagliptin demonstrated NI to glipizide. Changes in baseline HbA 1c were statistically significant in all active treatment groups as compared to placebo and for combination therapy compared to monotherapy (P<0.001) Adverse events were similar among combination treatments and metformin monotherapy No change in weight in the sitagliptin monotherapy group as compared to all other active treatment groups. Sitagliptin+ metformin showed significant reduction from baseline in HbA 1c compared with placebo (P<0.001). Significantly more patients reached an HbA 1c <7% with sitagliptin + metformin (47%) than with placebo (18.3%); P< There was no increased risk of hypoglycemia or weight increase compared with placebo. At week 18 the sitagliptin and metformin group significantly reduced HbA 1c from baseline (P<0.001). No statistically significant differences between the two groups in hypoglycemia or in GI adverse events. *DB=double blind; RCT=randomized control trial; NI=non-inferior; GI=gastrointestinal Page 18 of 42