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Utah Medicaid Pharmacy and Therapeutics Committee Drug Utah Medicaid Pharmacy and Therapeutics Committee Drug Class Review DPP-4 Inhibitor Products AHFS Classification: 68:20.05 Dipeptidyl Peptidase-4 Inhibitors Alogliptin (Nesina) Alogliptin and Metformin (Kazano) Alogliptin and Pioglitazone (Oseni) Linagliptin (Tradjenta) Linagliptin and Empagliflozin (Glyxambi) Linagliptin and Metformin (Jentadueto, Jentadueto XR) Saxagliptin (Onglyza) Saxagliptin and Dapagliflozin (Qtern) Saxagliptin and Metformin (Kombiglyze XR) Sitagliptin (Januvia) Sitagliptin and Metformin (Janumet, Janumet XR) Final Report November 2017 Review prepared by: Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Assistant Professor University of Utah College of Pharmacy Michelle Fiander, MA, MLIS, Systematic Review/Evidence Synthesis Librarian Joanne LaFleur, Pharm.D., MSPH, Associate Professor University of Utah College of Pharmacy University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2017 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved 1 Contents List of Abbreviations .................................................................................................................................... 3 Executive Summary ...................................................................................................................................... 4 Introduction ................................................................................................................................................... 6 Table 1. DPP-4 Inhibitor Containing Products ................................................................................ 7 Disease Overview ................................................................................................................................... 10 Treatment Guidelines for Type 2 Diabetes Mellitus ............................................................................... 11 Table 2. U.S. Guidelines Pertaining the Treatment of Diabetes Type 2 with DPP-4 Inhibitors .... 12 Pharmacology & Special Populations ......................................................................................................... 14 Table 3. Pharmacokinetics for Individual Agents in DPP-4i Containing Products ....................... 15 Table 4. Special Population Considerations for Individual Agents in DPP-4i Containing Products ....................................................................................................................................................... 16 Table 5. Labeled Drug Interactions for Individual Agents in DPP-4i Containing Products .......... 18 Methods ...................................................................................................................................................... 19 Figure 1. PRISMA Systematic Literature Search Flow Chart ....................................................... 20 Efficacy and Safety Comparative Evidence ................................................................................................ 21 Direct Evidence ....................................................................................................................................... 21 Traditional Direct-Comparison Meta-analyses ................................................................................... 21 Head-to-head Randomized Control Trials .......................................................................................... 21 Indirect Evidence— Network Meta-analyses ......................................................................................... 22 Safety .......................................................................................................................................................... 25 Table 6. Combination DPP-4 Inhibitor Products Warnings & Precautions ................................... 26 Table 7. Combination DPP-4 Inhibitor Products Adverse Events ................................................. 28 Summary ..................................................................................................................................................... 30 References ................................................................................................................................................... 32 Appendix A ................................................................................................................................................. 35 Table 1. Glucose lowering agents for type 2 diabetes mellitus ...................................................... 35 Appendix B ................................................................................................................................................. 36 Table 1. Medline Literature Search Strategy (via Ovid) for SRs and RCTs .................................. 36 Table 2. Embase Literature Search Strategy for SRs and RCTs .................................................... 38 Appendix C ................................................................................................................................................. 39 Table 1. Direct Evidence: Systematic Reviews/Meta-analyses Including DPP-4i Containing Products ......................................................................................................................................... 39 Table 2. Direct Evidence: Randomized Controlled Trials Including DPP-4i Containing Products ....................................................................................................................................................... 40 Table 3. Indirect Evidence: Network Meta-analyses Including DPP-4i Containing Products ...... 42 Appendix D ................................................................................................................................................. 46 Table 1. List of Excluded References ............................................................................................ 46 2 List of Abbreviations AACE/ACE: American Association of Clinical Endocrinologists & American College of Endocrinology ADA: American Diabetes Association CDC: Centers for Disease Control and Prevention CYP: Cytochrome P450 DPP-4i: Dipeptidylpeptidase-4 inhibitors FDA: Food and Drug Administration FDC: Fixed-dose combination FPG: Fasting plasma glucose HbA1c: Hemoglobin A1c IR: Immediate release MA: Meta-analysis MeSH: Medical Subject Headings NMA: Network meta-analysis RCT: Randomized controlled trials SGLT-2: Sodium-glucose cotransporter-2 SR: Systematic reviews T2DM: Type 2 diabetes mellitus TZD: Thiazolidinediones XR: Extended-release 3 Executive Summary Introduction: Dipeptidylpeptidase-4 inhibitors (DPP-4i) are oral medications indicated for adults with type 2 diabetes mellitus (T2DM). In a glucose dependent manner, the DPP-4i agents inhibit the breakdown of two major incretin hormones, ultimately increasing insulin release from pancreatic beta-cells and down regulating hepatic-glucose synthesis and output. There are four single ingredient DPP-4i agents approved by the U.S. Food and Drug Administration (FDA): alogliptin, linagliptin, saxagliptin, and sitagliptin. The DPP-4 inhibitors are also formulated in fixed-dosed combination (FDC) products with other glucose lowering agents to intensify therapy. Each DPP-4i is available in a combination with metformin. Two products combine a DPP-4i with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor (linagliptin/empagliflozin and saxagliptin/dapagliflozin), and one combines a DPP-4i with a thiazolidinedione (alogliptin/pioglitazone). Some pharmacokinetic nuances differentiate the DPP-4 inhibitor class. Saxagliptin undergoes metabolism primarily through cytochrome P450 (CYP) 3A4/5 enzymes, while others are metabolized by CYP enzymes to a lesser degree. Alogliptin, saxagliptin, and sitagliptin rely heavily on renal elimination while linagliptin is primarily eliminated through the fecal route. Guidelines recommend DPP-4 inhibitors for treatment of T2DM in the following situations: 1) as monotherapy when patients have a contraindication or intolerance to metformin, 2) in dual therapy added to metformin when patients do not meet glycemic goals with metformin monotherapy (or added to other agents if metformin intolerance is present), 3) in triple-therapy non-insulin regimens (with metformin, sulfonylureas, thiazolidinediones, or SGLT-2 inhibitors), and 4) as add on therapy to basal insulin regimens. This report includes clinical efficacy and safety evidence for the DPP-4i single-ingredient and FDC products. A systematic methodology was used to identify head-to-head comparative evidence for the DPP-4i containing products available in the United States in order to differentiate their treatment effect for the management of T2DM. Fourteen efficacy/safety studies were identified: 2 systematic reviews (SR)/meta-analyses (MA), 3 randomized-controlled trials (RCTs), 8 network meta-analyses (NMA), and one reanalysis of a NMA. The majority evaluated the change in hemoglobin A1c (HbA1c) levels as a primary endpoint, except one SR and 3 NMAs that evaluated safety outcomes. Clinical Efficacy: Direct head-to-head comparisons between DPP-4 inhibitors as monotherapy or between combinations containing DPP-4 inhibitors are limited. High-level evidence (direct evidence from one MA and three RCTs) reported no significant differences in reducing HbA1c levels with
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