utah medicaid pharmacy and therapeutics committee drug class … · · 2019-10-30introduction:...

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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

http://online.lexi.com/lco/action/search/pharmacat/essential_ashp?q=Dipeptidyl+Peptidase-4+Inhibitors

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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

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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

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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 sitagliptin compared to saxagliptin or linagliptin, as part of dual or triple therapy. Low-level evidence (indirect evidence from 5 NMAs) compared single-ingredient DPP-4i products versus each other in mono, dual, or triple therapy regimens (including comparison of alogliptin+pioglitazone versus empagliflozin/linagliptin. The majority of NMAs suggested no between-group differences with respect to HbA1c reduction, except one NMA (assessed by two different methodologies) suggesting differences in favor of alogliptin plus metformin. However, indirect results should be interpreted cautiously due to multiple limitations (e.g. weak links

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between interventions, clinical heterogeneity between studies, imprecision, multiple comparison complexity, etc.). No comparative evidence was found for saxagliptin/dapagliflozin. Additional head-to-head studies are required to strengthen the confidence in making conclusions concerning the relative efficacy among DPP-4 inhibitor products.

Adverse Drug Reactions: DPP-4 inhibitors are well tolerated and rarely induce hypoglycemia. The most commonly reported adverse events include headache, nasopharyngitis, and upper respiratory tract infection. Case reports of acute pancreatitis, hypersensitivity, heart failure hospitalizations, and severe arthralgia have been rarely described with the use of DPP-4 inhibitors.

Identified direct evidence reported similar incidences of adverse events among DPP-4 inhibitors, although one meta-analysis showed a higher incidence of arthralgia with sitagliptin compared to saxagliptin. Indirect evidence suggested (a) an increased incidence of gastrointestinal adverse events with linagliptin compared to alogliptin and sitagliptin, and (b) a higher risk of heart failure with alogliptin compared to sitagliptin, and linagliptin compared to saxagliptin and sitagliptin. Additional direct comparative evidence is required.

With respect to DPP-4 inhibitor combination products, safety profiles differ depending on the agent added to the DPP-4 inhibitor. Metformin combinations include a Black Box Warning regarding the risk of metformin-induced lactic acidosis and are contraindicated in patients with severe renal impairment. Combinations containing pioglitazone contain a Black Box Warning for the risk of congestive heart failure.

Summary: Clinical evidence suggests similar glycemic control among sitagliptin, saxagliptin, linagliptin and alogliptin. Guidelines do not specify a preference for one particular DPP-4i agent over another.

Some pharmacokinetic and safety nuances are identified among the DPP-4i products. Regarding dosage adjustments, linagliptin may be a preferable treatment option in patients with chronic kidney disease since it does not require dose adjustments for renal impairment, as do the other DPP-4i agents. Regarding safety outcomes, safety profiles were similar among DPP-4i products, although some specific differences with respect to arthralgia, heart failure hospitalizations, and gastrointestinal adverse events were found.

Therapy for T2DM should be individualized for each patient in order to achieve optimal glycemic control. Metformin remains the first-line recommendation for oral treatment of T2DM as it is effective, safe, and reduces cardiovascular events. DPP-4i products are alternative treatment options as monotherapy and can be used as part of dual and triple therapy regimens. Clinicians should choose a specific DPP-4 inhibitor product over another based on issues related to individual patient characteristics (comorbidities, patient’s preferences, and adherence), and issues related to the specific product (pharmacokinetic characteristics, safety concerns, contraindications, and cost).

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Introduction

Type 2 diabetes mellitus (T2DM) is a chronic disease state characterized by deterioration of glucose homeostasis requiring intervention with pharmacotherapies that simulate cellular targets among glucose regulation pathways. Table 1 of Appendix A lists the twelve drug classes available for the management of T2DM. The dipeptidyl peptidase-4 (DPP-4) inhibitors target a key enzyme responsible for incretin degradation among the glucose hemostasis response pathway. Four single-ingredient DPP-4 inhibitors are approved by the FDA: alogliptin, linagliptin, saxagliptin, and sitagliptin.

Since most patients eventually require dual-therapy regimens during their lifetime, many antihyperglycemic fixed dose combination (FDC) products are available, involving agents from multiple drug classes (e.g. biguanide; DPP-4 inhibitors; sulfonylureas; sodium-glucose cotransporter-2 (SGLT-2) inhibitors; and thiazolidinediones [TZD]). Ten DPP-4 inhibitor (DPP-4i) FDC products have gained FDA approval, however, one (sitagliptin/simvastatin) is no longer produced by the manufacturer. The first DPP-4i combination product (sitagliptin/metformin) was approved in 2007—following the 2006 approval of the first single-ingredient, sitagliptin product. Most recently, in February of 2017, a second DPP-4i/SGLT-2 inhibitor FDC product was approved (saxagliptin/dapagliflozin). Nomenclature used in this report includes a slash ('/') to separate the different active substances contained in a FDC product and a plus sign (‘+’) to define separate products used in combination.

Each DPP-4i is available in a combination with metformin. Linagliptin/metformin and sitagliptin/metformin are available as both immediate release (IR) and extended-release (XR) formulations, while alogliptin/metformin is available only as an IR form and saxagliptin/metformin only as an XR product. Linagliptin and saxagliptin are additionally available co-formulated with an SGLT-2 inhibitor: linagliptin/empagliflozin and saxagliptin/dapagliflozin. One DPP-4i is available in a combination with a thiazolidinedione: alogliptin/pioglitazone. With the exception of the immediate-release DPP-4i/metformin FDC products dosed twice daily, all other DPP-4i products are dosed once daily; this includes the single-ingredient products, the extended-release formulations, and combinations containing an SGLT-2 inhibitor or pioglitazone.

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. Table 1 details the preparations, indications, and dosing for these medications.

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Table 1. DPP-4 Inhibitor Containing Products Generic Name & Approval Date

Brand Name & Preparations

Indication & Dosage*

DPP-4 Inhibitor Single Ingredient Products

Alogliptin1

Approved 2013

Nesina Oral Tablet • 6.5mg • 12.5mg • 25mg

Labeled Indication: • Diabetes, type 2 in adults, as an adjunct to diet/exercise as monotherapy or in

combination therapy with other glucose lowering agents.

Adult Dose: 25mg orally, once daily

Linagliptin2

Approved 2011

Tradjenta Oral Tablet • 5mg




Saxagliptin3

Approved 2009

Onglyza Oral Tablet • 2.5mg • 5mg



Adult Dose: 2.5mg to 5mg orally, once daily; Use 2.5mg daily when administered with strong CYP3A4/5 inhibitors (i.e. ketoconazole, atazanavir, clarithromycin, ritonavir etc.)

Sitagliptin4

Approved 2006

Januvia Oral Tablet • 25mg • 50mg • 100mg

Labeled Indication: • Diabetes, type 2 in adults: as an adjunct to diet/exercise as monotherapy or in



Table 1 continues on next page

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DPP-4 Inhibitor Combinations with Metformin

Alogliptin/ Metformin5

Approved 2013

Kazano Oral Tablet • 12.5 - 500mg • 12.5 -1,000mg

Labeled Indication: • Diabetes, type 2 in adults, as an adjunct to diet/exercise to improve glycemic

control when treatment with both alogliptin and metformin is appropriate. Adult Dose: Initial doses should be based on the patient’s current doses of alogliptin and metformin, titrated gradually per glycemic response • Range: alogliptin 12.5mg/metformin 500 to 1,000mg twice daily

Linagliptin/ Metformin6,7

Approved 2012 and 2016 (XR)

Jentadueto Oral Tablet • 2.5 - 500mg • 2.5 - 850mg • 2.5 - 1000mg

Jentadueto XR Oral Tablet • 2.5 - 1000mg • 5 - 1000mg


control when treatment with both linagliptin and metformin is appropriate. Adult Dose: Initial doses should be based on the patient’s current doses of linagliptin and metformin, titrated gradually per glycemic response • Range: linagliptin 2.5mg/metformin 500 to 1,000mg twice daily (IR tablet); or

linagliptin 2.5mg/metformin 1,000 to 2,000mg once daily (XR tablet) • Patients currently on metformin: Initiate linagliptin 5mg daily with current daily

dose of metformin • Patients not on metformin: Initiate linagliptin 5mg daily with metformin 1,000mg

per day

Saxagliptin/ Metformin8

Approved 2010

Kombiglyze XR Oral Tablet • 2.5 - 1000mg • 5 - 500mg • 5 - 1000mg


control when treatment with both saxagliptin and metformin is appropriate. Adult Dose: Initial doses should be based on the patient’s current doses of saxagliptin and metformin, titrated gradually per glycemic response • Range: saxagliptin 2.5 to 5mg/metformin 1,000 to 2,000mg once daily • Patients inadequately controlled with metformin monotherapy: Initiate saxagliptin

2.5 to 5mg once daily plus the nearest current daily dose of metformin. Note: patients requiring saxagliptin 2.5mg and metformin >1,000mg/day should not be switched to the combination product.

• Patients inadequately controlled on saxagliptin 5 mg alone: Initiate saxagliptin 5mg with metformin 500 mg ER once daily. Note: patients requiring saxagliptin 2.5mg and are metformin-naïve or require metformin >1,000mg/day should not be switched to the combination product.

• Concomitant use with strong CYP3A4/5 inhibitors: Maximum dose should be saxagliptin 2.5mg/metformin 1,000mg once daily

Sitagliptin/ Metformin9,10

Approved 2007 and 2012 (XR)

Janumet Oral Tablet • 50 - 500mg • 50 - 1000mg •

Janumet XR Oral Tablet • 50 - 500mg • 50 - 1000mg • 100 - 1000mg

Labeled Indication: • Diabetes, type 2 in adults: as an adjunct to diet/exercise to improve glycemic

control when treatment with both sitagliptin and metformin is appropriate. Adult Dose: Initial doses should be based on the patient’s current doses of sitagliptin and metformin, titrated gradually per glycemic response • Max dose: sitagliptin 100mg/metformin 2,000mg per day • Patients currently on metformin: Initiate sitagliptin 100mg daily and the nearest

dose of metformin already being taken; use twice daily dosing with IR tablets and once daily dosing with XR tablets

• Patients not on metformin: Initiate sitagliptin 100mg daily with metformin 1,000mg daily


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DPP-4 Inhibitor Combinations with an SGLT2-Inhibitor

Linagliptin/ Empagliflozin11

Approved 2015

Glyxambi

Oral Tablet • 5 - 10mg • 5 - 25mg

Labeled Indication: • Diabetes, type 2 in adults: as adjunct to diet/exercise to improve glycemic control

when use of both linagliptin and empagliflozin is appropriate. Note: empagliflozin reduces cardiovascular mortality in patients with T2DM and CVD

Adult Dose: The recommended dose is linagliptin 5mg/empagliflozin 10mg once daily; the dose can be increased to the 5/25mg dosage strength, taken once daily, if tolerated

Saxagliptin/ Dapagliflozin12

Approved 2017

Qtern

Oral Tablet • 5 - 10mg

Labeled Indication: • Diabetes, type 2 in adults: as adjunct to diet/exercise to improve glycemic control

when treatment with both saxagliptin and dapagliflozin is appropriate. Adult Dose: saxagliptin 5mg/dapagliflozin 10mg once daily • Do not use this product with strong CYP3A4/5 inhibitors

DPP-4 Inhibitor Combination with Pioglitazone

Alogliptin/ Pioglitazone13

Approved 2013

Oseni

Oral Tablet • 12.5 - 15mg • 12.5 - 30mg • 12.5 - 45mg • 25.5 - 15mg • 25.5 - 30mg • 25.5 - 45mg

Labeled Indication: • Diabetes, type 2 in adults, as an adjunct to diet/exercise to improve glycemic control

when treatment with both alogliptin and pioglitazone is appropriate Adult Dose: Initial doses should be based on current doses of alogliptin and pioglitazone

• Patients inadequately controlled on diet/exercise, metformin monotherapy, or alogliptin monotherapy: Initiate as alogliptin 25 mg/pioglitazone 15 to 30mg once daily

• Patients inadequately controlled on pioglitazone alone: Initiate as alogliptin 25mg per day plus current daily dose of pioglitazone once daily

• Patients with NYHA Class I or II heart failure: Initiate as alogliptin 25mg with pioglitazone 15 mg once daily

• Patients switching from individual alogliptin and pioglitazone administration: Initial doses should be based on current dose of alogliptin and pioglitazone given once daily

• With strong CYP2C8 inhibitors (e.g., gemfibrozil) the maximum recommended dose is alogliptin 25 mg/pioglitazone 15 mg once daily

* Refer to additional dosing guidance for renal and hepatic impairment in Table 4 Abbreviations: ALO, alogliptin; CVD, cardiovascular disease; DPP-4i, dipeptidyl-peptidase-4 inhibitor; ER, extended release; IR, immediate release; LIN, linagliptin; MET, metformin; SAX, saxagliptin; SIT, sitagliptin; T2DM, diabetes type 2; XR, extended release Note: With respect to all DPP-4i combination products listed, if used concomitantly with insulin or insulin secretagogues, dose reduction of insulin or insulin secretagogues (e.g. sulfonylureas) may be necessary

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Disease Overview

Type 2 diabetes accounts for 90 to 95% of all diagnosed diabetes cases (other types include Type 1, gestational, monogenic syndromes, etc.).14 A large portion of Americans with diabetes remain undiagnosed (about 25%).14 According to 2015 data from the Centers for Disease Control and Prevention (CDC), the prevalence of diagnosed diabetes in the Utah adult population was 7.5% (not specifying diabetes type).15

Type 2 diabetes is a chronic disease state, characterized by peripheral insulin resistance and gradual loss of pancreatic beta-cell ability to secrete insulin.14 Patients may go undiagnosed in the early stage of the disease with unnoticeable symptoms. Eventually hallmark symptoms including hyperglycemia, polydipsia, polyphagia, polyuria, ketonuria, frequent infections, and slowed wound healing may prompt diagnosis.16 Although rare, a patient with long-standing undiagnosed T2DM may present with diabetic ketoacidosis precipitated by the stress of an infection.14

Modifiable risk factors for T2DM include overweight/obesity, low physical activity level, hypertension, and hypercholesterolemia.17 Non-modifiable risk factors include age (>45 years), history of gestational diabetes, race/ethnicity (higher risk for African-Americans, Latinos/Hispanic Americans, Native Americans, and Pacific Islander Americans), and a family history of diabetes.17 If the disease is mismanaged, negative microvascular and macrovascular complications ensue. Microvascular deterioration includes retinopathy, nephropathy, and neuropathies that may lead to pain and/or sensory loss, serious foot lesions, genitourinary dysfunction, and gastroparesis.14 Diabetes is the leading cause of adult blindness in the U.S.18 Negative macrovascular effects include coronary heart disease, cerebrovascular disease, and peripheral arterial disease.14

The diagnosis of T2DM is derived by assessing fasting plasma glucose (FPG), 2-hour post glucose challenge, and hemoglobin A1c (HbA1c).14 Adult screening for T2DM should begin at age 45 and be considered for overweight or obese patients. The FPG and HbA1c serve as target markers for establishing therapeutic goals, as described further in the guideline section of this report.14

Insulin resistance may be improved with weight reduction, however, it does not usually return to normal.14 Pharmacotherapy choices and treatment goals (target blood glucose and hemoglobin A1c levels) are tailored to the patient’s age, co-morbidities, and risk of hypoglycemia. The American Academy of Clinical Endocrinology and American College of Endocrinology (AACE/ACE) supports targeting an HbA1c of ≤ 6.5% for most patients, while the American Diabetes Association (ADA), sets the HbA1c goal to <7%.14,19 Nonetheless, each guideline highlights the importance of individualizing the HbA1c target according to the person’s disease onset/duration, presence of co-morbidities (e.g. cardiovascular disease, renal impairment or other macrovascular complications), age/life expectancy, past experience of hypoglycemia, and the patient’s motivation/adherence to the treatment regimen. Minimizing the risk of both hypoglycemia and weight gain are treatment priorities.14,19

During the early stages, management can take place with metformin monotherapy. Metformin improves insulin sensitivity and decreases hepatic glucose output. As beta-cell

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function progressively declines, patients may require combination regimens with additive and complimentary mechanisms of action. Eventually exogenous insulin replacement may be required. Table 1 of Appendix A lists the medications available among the 12 drug classes FDA-approved for T2DM: alpha-glucosidase inhibitors; amylin analogue; the biguanide, metformin; the bile acid sequestrant, colesevelam; the dopamine agonist bromocriptine; DPP-4 inhibitors; glucagon-like peptide-1 receptor agonists; insulins; meglitinides; SGLT-2 inhibitors; sulfonylureas; and thiazolidinediones. Compared to other non-insulin drug classes used for T2DM, the DPP-4 inhibitors have a lower risk of hypoglycemia compared to the sulfonylureas, amylin mimetics, and meglitinides.14

Treatment Guidelines for Type 2 Diabetes Mellitus

Two American clinical guidelines for the treatment of diabetes were updated recently in 2017: one from the American Association of Clinical Endocrinologists & American College of Endocrinology19 and the other by the American Diabetes Association.14 Additional national guidelines include those by National Institute for Health and Care Excellence20 (updated in 2017), and the Canadian Diabetes Association21 (updated in 2016). The European Association for the Study of Diabetes had collaborated with the ADA in a position statement published in 2015.22

Among the aforementioned guidelines, preference for one particular DPP-4i agent over another is not specified; recommendations are provided on a drug class level with regard to the DPP-4i agents. When intensifying treatment from first-line metformin monotherapy, the DPP-4i drug class is listed as an option for add-on therapy to metformin (add-on therapy is preferred over stopping metformin). Likewise, preference for a particular DPP-4i/metformin product is not specified among the guidelines. Regarding other agents formulated in DPP-4i combinations, several guidelines recommend considering empagliflozin in patients with atherosclerotic cardiovascular disease, since it has been shown to improve cardiovascular outcomes in patients with T2DM and clinically established cardiovascular disease.14,21 Although there is an ongoing cardiovascular outcomes study with dapagliflozin, it is not yet known if this agent will confer similar benefits.23

U.S. guidelines recommend DPP-4 inhibitors as 1) 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, or thiazolidinediones, SGLT-2i), and 4) as add on therapy to basal insulin regimens.

Table 2 provides an overview of the DPP-4i related recommendations provided in the U.S. guidelines by the ADA and the AACE/ACE. Each guideline describes treatment strategies based on the patient’s HbA1c level at diagnosis. Different HbA1c thresholds are specified by each guideline to differentiate when to initiate mono, dual, triple, or insulin-based regimens. A stepwise intensification approach is presented for the patient who does not meet the HbA1c goal after 3 months in the setting of disease state progression. The ADA guideline provides less preference statements pertaining to one drug class over another, while the AACE/ACE guideline

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provides a suggested hierarchy of usage when deciding between drug classes as treatment is intensified.

Table 2. U.S. Guidelines Pertaining the Treatment of Diabetes Type 2 with DPP-4 Inhibitors

Guide l ine Recommendat ion

2017 American Diabetes Association (ADA) Standards of Medical Care in Diabetes14

Monotherapy (C ons i der du al the ra py f or A1c ≥ 9% at d ia gno s i s or a n insu l i n -b ase d r eg i men f o r

A1c ≥ 10% a t d ia gn os i s ) Preferred: Metformin monotherapy (evidence rating: A) Secondary options: SUs, TZDs, DPP-4i, SGLT-2i, GLP-1 RA, basal insulin Consider insulin therapy (with or without additional agents) in newly-diagnosed symptomatic

patients with an A1c ≥10% or with BG> 300 mg/dL (evidence rating: E) If after 3 months target A1c is not achieved/maintained, add a second agent

Dual Therapy Dual therapy with metformin may include an agent of the following drug class: (e.g. DPP-4i, SGLT-

2i, TZD, SU), a GLP-1 RA, or basal insulin (evidence rating: A). A patient centered approach should be used to guide the choice of pharmacologic agents

(evidence rating: E) If after 3 months target A1c is not achieved/maintained, add a third agent

Tr ip le Therapy For patients unable to achieve glycemic goals with noninsulin dual therapy regimens, insulin

therapy should be started (evidence rating B); Patients may also consider a non-insulin, triple therapy regimen.

The guideline lists complementary option regimens (all including metformin preferably), however, overall does not specify one complementary regimen over another Optional Regimens Listed (all given equal weight of preference; must individualize therapy):

o MET + SU + (either TZD, DPP-4i, SGLT-2i, GLP-1 RA, or basal insulin) o MET + TZD + (either SU, DPP-4i, SGLT-2i, GLP-1 RA, or basal insulin) o MET + DPP-4i + (either SU, TZD, SGLT-2i, or basal insulin) o MET + SGLT-2i + (either SU, TZD, DPP-4i, GLP-1 RA, or basal insulin) o MET + GLP-1 RA + (either SU, TZD, SGLT-2i, or basal insulin) o MET + basal insulin + (either SU, TZD, DPP-4i, SGLT-2i, or GLP-1 RA)

Other Cons idera t ions o For patients not achieving glycemic goals, avoid delaying insulin therapy. (evidence rating: B)

- For example a patient may be started on basal insulin + an additional agent which may include a DPP-4i

o In patients with long-standing suboptimally controlled T2DM and established atherosclerotic cardiovascular disease, consider empagliflozin or liraglutide, as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care. (evidence rating: B)

- Note: empagliflozin is available in the DPP-4i combination product with linagliptin o “When initiating combination injectable therapy, metformin therapy should be maintained while

other oral agents may be discontinued on an individual basis to avoid unnecessarily complex or costly regimens (i.e., adding a fourth antihyperglycemic agent). In general, GLP-1 receptor agonists should not be discontinued with the initiation of basal insulin. Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are typically stopped once more complex insulin regimens beyond basal are used. In patients with suboptimal blood glucose control, especially those requiring large insulin doses, adjunctive use of a thiazolidinedione or SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed, though potential side effects should be considered.”


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Table 2. U.S. Guidelines Pertaining the Treatment of Diabetes Type 2 with DPP-4 Inhibitors

Guide l ine Recommendat ion

2017 Consensus Statement by the American Association of Clinical Endocrinologists & American College of Endocrinology (AACE/ACE) on the Comprehensive Type 2 Diabetes Management Algorithm19

Monotherapy Entry A1c < 7 . 5%

Preferred: Metformin monotherapy Secondary options: GLP-1 RA, SGLT-2i, DPP-4i, TZD, AGi, SU/GLN (listed in order of suggested

hierarchy of usage) If after 3 months, target A1c is not achieved/maintained, add a second oral agent

Dual & Tr ip le Therapy Con s ider du al or t r ip l e th e rap y i f A 1c i s ≥ 7 . 5% at ent ry

Dual therapy with metformin: may include an agent from the following drug classes: GLP-1 RA, SGLT-2i, DPP-4i, TZD, basal insulin, colsevelam, bromocriptine, AGi, SU/GLN (listed in order of suggested hierarchy of usage)

In metformin-intolerant patients, two drugs with complementary mechanisms of action from other classes should be considered.

If after 3 months, target A1c is not achieved/maintained, add a third agent Triple therapy regimen options: MET or other 1st line agent + 2nd line agent + (either GLP-1 RA,

SGLT-2i, TZD, basal insulin, DPP-4i, colesevelam, bromocriptine, AGi, SU/GLN (listed in order of suggested hierarchy of usage)

If after 3 months, target A1c is not achieved/maintained, consider insulin regimens

Insu l in Therapy Con s ider insu l i n -b as ed r eg imen f or an A1 c ≥9% at en t ry i f s ym pto mat ic First start basal insulin and up-titrate every 2 to 3 days to reach glycemic goal Patients not achieving goals may add a GLP-1 RA, SGLT-2i, or DPP-4i, if not already taking

one of these agents Prandial insulin should be considered to cover postprandial hyperglycemia See full guideline for further details on insulin therapy (basal and prandial regimen

approaches)

Other Cons idera t ions The benefits of empagliflozin or liraglutide with respect to cardiovascular disease is highlighted.

Abbreviations: A1c: hemoglobin A1c; AGi, alpha glucosidase inhibitor; BG, blood glucose; T2DM, type 2 diabetes mellitus; DPP-4i, dipeptidyl-peptidase-4 inhibitor; GLN, meglitinide analog; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione; Note: some products that specifically pertain to the drug class reviewed are bolded to highlight their mention in treatment guidelines, however, not to display preference where otherwise stated by the guideline itself.

14

Pharmacology & Special Populations DPP-4 inhibitors are indicated for diabetes type 2 only, and lack FDA approval for

diabetes type 1 or diabetic ketoacidosis. Moreover they have not been studied in patients with a history of pancreatitis.1-4 These agents block a key enzyme (Dipeptidylpeptidase-4) responsible for the breakdown of two major incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP).6,13 Thus, upon DPP-4i administration, the action of incretin hormones is prolonged, exaggerating the influence on glucose homeostasis pathways. As blood-glucose levels rise, GLP-1 and GIP stimulate synthesis and release of insulin from pancreatic beta-cells while also lowering glucagon secretion and hepatic glucose output.6,13 The sensation of satiety is enhanced as these incretin-based, DPP4i agents delay gastric emptying.24

In general, when a DPP-4i is combined with metformin, an SGLT-2 inhibitor, or pioglitazone, the additive and complementary mechanisms of action improve glucose regulation and the ability to achieve HbA1c targets. Metformin improves insulin sensitivity, decreases intestinal absorption of glucose, and reduces hepatic glucose production.9 The SGLT-2 inhibitors (dapagliflozin and empagliflozin) block the reabsorption of glucose via sodium-glucose cotransporters in the proximal renal tubule, resulting in a net increase of glucose excretion into the urine.12 Pioglitazone, a thiazolidinedione, increases insulin sensitivity at muscle and adipose tissue and down-regulates hepatic glucose output.13 The ADA treatment guideline notes, “each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0.9–1.1%.”14

Table 3 outlines pharmacokinetic information for the components among the DPP-4i single ingredient and combination products. A main pharmacokinetic difference between the DPP-4i agents is the primary route of metabolism and excretion. Saxagliptin undergoes metabolism through the hepatic cytochrome P450 enzymes (primarily via CYP3A4/5), while the others are metabolized by CYP enzymes to a lesser degree. Alogliptin, saxagliptin, and sitagliptin rely heavily on renal excretion while linagliptin primarily relies on fecal excretion. Thus, linagliptin does not require dose adjustments for renal impairment, as do the other DPP-4i agents.19,25 There is no dosing guidance for pediatric patients since all DPP-4i products are indicated only for adults. There are no particular dosing adjustments based solely on age, however other considerations such as renal/hepatic function should be considered for the geriatric population. Table 4 outlines special population considerations for the individual components among the DPP-4i single ingredient and combination products. Table 5 outlines drug-drug interaction concerns.

15

Table 3. Pharmacokinetics for Individual Agents in DPP-4i Containing Products5,6,9,11-13,26 Single Ingredient

(FDC product) Bioavail-

ability Volume of

Distribution Metabolism Excretion Half-life (hours)

DPP-4 Inhibitor Component

Alogliptin

(alogliptin/metformin) (alogliptin/pioglitazone)

100% Single dose (12.5mg IV) VD: 417 L

Minor pathway of elimination (<40%):

CYP2D6 CYP3A4

Renal excretion: 76% of total dose

Fecal excretion:13% of total dose

21

Linagliptin

(linagliptin/empagliflozin) (linagliptin/metformin)

30% Single dose (5mg IV) VD: 1,110 L

Minor pathway of elimination (≤10%)

CYP3A4

Renal excretion % unchanged: 5%

Fecal excretion: 80% of total dose

>100

Saxagliptin

(saxagliptin/dapagliflozin) (saxagliptin/metformin)

75% 151 L Primary pathway

CYP3A4/5



2.5 hours for the parent molecule and 3.1 hours for the active metabolite

Sitagliptin

(sitagliptin/metformin)

87% Single dose (100mg IV) VD: 198 L

Minor pathway of elimination (16%)

CYP3A4, CYP2C8



12.4

SGLT-2i, Metformin, and TZD Components

Dapagliflozin

(saxagliptin/dapagliflozin)

78% NA Primarily pathway by UGT1A9

Minor pathway by CYP



12.9

Empagliflozin

(linagliptin/empagliflozin)

NA Steady state VD: 74 L

Minor pathway of elimination (10%) by UGT enzymes: glucuronide conjugation

Renal excretion: 54% of total dose, half as unchanged drug

Fecal excretion: 41% of total dose, majority unchanged drug

12.4

Metformin

(alogliptin/metformin) (linagliptin/metformin) (saxagliptin/metformin) (sitagliptin/metformin)

50-60% Single dose (850mg tab) VD: 654 ± 358 L

Does not undergo hepatic metabolism


No biliary excretion

17.6

Pioglitazone

(alogliptin/pioglitazone)

NA Single dose VD: 0.6 L/kg

Major pathway of elimination:

CYP2C8 CYP3A4

Renal excretion: 15 to 30% of total dose, half as unchanged drug

Fecal excretion: majority of total dose

3 to 16 hours for parent molecule and 7 to 24 hours for active metabolites

Abbreviations: CYP, cytochrome P450 enzyme; FDC, fixed dose combination; IV, intravenous; NA, not available among package inserts or Lexicomp monograph; SGL-2i, sodium glucose transporter- 2 inhibitor; SQ, subcutaneous; tab, tablet; TZD, thiazolidinedione; UGT, uridine 5'-diphospho-glucuronosyltransferases; VD, volume of distribution

16

Table 4. Special Population Considerations for Individual Agents in DPP-4i Containing Products5,6,9,11-13,26 Single Ingredient

(FDC product) Age Adjustment for Kidney disease

Adjustment for Hepatic disease Pregnancy

DPP-4 Inhibitor Component

Alogliptin

(alogliptin/metformin)


No pediatric indication

No dose adjustments based on age (≥65 years), gender, or race

CrCL 30 to <60mL/min: • Use up to 12.5mg of

ALO per day • See metformin renal

dosing concerns CrCL <30mL/min: • Use up to 6.25mg of

ALO per day; Combination products are contraindicated since the strength of ALO in FDCs is too high; metformin is contraindicated

None per manufacturer for the single ingredient product

See the hepatic dosing concerns for pioglitazone for the respective combination product

Data is insufficient to determine major birth defects/miscarriage risk.

No adverse developmental effects observed in pregnant rats/rabbits, per manufacturer studies.

Linagliptin


(linagliptin/metformin)



No adjustments per manufacturer for the single ingredient product

See the renal dosing recommendations for the combination products based on the non-DPP-4i ingredient:

eGRF <30 mL/min: metformin and empagliflozin are contraindicated




Saxagliptin




eGRF ≤45 mL/min: • Use up to 2.5mg of

SAX per day

eGRF <30 mL/min: metformin and dapagliflozin are contraindicated




Sitagliptin




CrCL 30 to 49 mL/min: • use up to 50mg of SIT

per day

CLCR <30 mL/min: • use up to 25mg SIT per

day; metformin is contraindicated


Pregnancy Category B: Data is insufficient to determine major birth defects/miscarriage risk.

May affect development based on rat/rabbit studies using doses 100 times the normal human exposure


17

Table 4. Special Population Considerations for Individual Agents in DPP-4i Containing Products5,6,9,11-13,26 Single Ingredient

(FDC product) Age Adjustment for Kidney disease

Adjustment for Hepatic disease Pregnancy

Products with SGLT-2 inhibitors, Metformin, and TZD Components

Dapagliflozin




eGRF < 60 mL/min: • not recommended for

initial therapy; discontinuation should be considered

eGRF <30 mL/min: • contraindicated in

SRD, ESRD, and dialysis

None per manufacturer

Pregnancy Category C: Data is insufficient to determine major birth defects/miscarriage risk.

May affect development based on rate studies using doses at 15 times the normal human exposure

Empagliflozin




eGRF <45 mL/min: • not recommended for


eGRF <30 mL/min: • contraindicated in

SRD, ESRD, and dialysis

None per manufacturer

Not recommended during the second and third trimester of pregnancy based on animal models showing adverse renal effects; Data is insufficient to determine major birth defects/miscarriage risk.

Metformin




Consider dose adjustment recommendations for the DPP-4i as listed above for eGRF>45 to 60mL/min

eGRF 30 to <45 mL/min: • not recommended for


eGRF <30 mL/min: • contraindicated

Pharmacokinetic studies of MET are lacking in patients with hepatic impairment



Pioglitazone




None per manufacturer No adjustment for pre-existing stable impairment If liver enzymes become elevated (3X ULN) during therapy and no alternative etiology is present, then PIO should be discontinued



Abbreviations: ALO, alogliptin; CrCL, creatinine clearance (mL/min); CYP, cytochrome P450 enzyme; eGFR, estimated glomerular filtration rate (mL/min/1.73m2); ESRD, end stage renal disease; FDC, fixed dose combination; IV, intravenous; MET, metformin; NA, not available among package inserts or Lexicomp monograph; PIO, pioglitazone; SAX, saxagliptin; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; SIT, sitagliptin; SQ, subcutaneous; SRD, severe renal disease; tab, tablet; TZD, thiazolidinedione; UGT, uridine 5'-diphospho-glucuronosyltransferases; ULN, upper limit of normal; VD, volume of distribution

18

Table 5. Labeled Drug Interactions for Individual Agents in DPP-4i Containing Products5,6,9,11-13,26,27 Single Ingredient

(FDC product) Drug Interactions

DPP-4 Inhibitor Component Alogliptin

(alogliptin/metformin)


Alogliptin: no clinically significant drug interactions are expected to occur with the CYP-substrates/inhibitors or with renally excreted drugs. Nonetheless, the product labeling information does not address the implications of strong CYP enzyme inducers.

Linagliptin

(linagliptin/empagliflozin) (linagliptin/metformin)

Linagliptin: The exposure of linagliptin may be reduced by the co-administration with strong P-glycoprotein or CYP3A4 inducers (e.g. rifampin).

Saxagliptin


Saxagliptin: Strong CYP 3A4/5 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir) may increase the concentration of saxagliptin.

Sitagliptin


Sitagliptin: sitagliptin may increase the exposure to digoxin, however no dose adjustment for sitagliptin is required. No clinically significant drug interactions are expected to occur with the CYP-substrates or inhibitors, or with p-glycoprotein handled drugs.

SGLT-2i, Metformin, and TZD Components

Dapagliflozin


Dapagliflozin: there are no significant drug interactions expected for this agent per the prescribing information (package insert)

Empagliflozin


Empagliflozin: there are no significant pharmacokinetic drug interactions expected for this agent per the prescribing information (package insert)

Metformin


Metformin Hydrochloride: Interacting drugs include: a) carbonic anhydrase inhibitors (e.g. topiramate, zonisamide, acetazolamide) which can decrease in serum bicarbonate and induce nonanion gap, hyperchloremic metabolic acidosis (must increase monitoring of patients taking these); b) drugs inhibit clearance of metformin (e.g. organic cationic transporter-2 and multidrug and toxin extrusion inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine); c) alcohol, which is known to potentiate metformin/lactate metabolism effect; d) other drugs that may have additive blood glucose lowering effects; and e) agents that my stimulate hyperglycemia/loss of glycemic control (e.g. thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid.

Pioglitazone


Pioglitazone: Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone exposure; thus it is recommended to limit the pioglitazone dose to 15 mg daily. CYP2C8 inducers (e.g., rifampin) can reduce pioglitazone concentrations.

Abbreviations: CYP, cytochrome P450 enzyme; FDC, fixed dose combination; IV, intravenous; NA, not available among package inserts or Lexicomp monograph; SGL-2i, sodium glucose transporter- 2 inhibitor; SQ, subcutaneous; tab, tablet; TZD, thiazolidinedione; UGT, uridine 5'-diphospho-glucuronosyltransferases; VD, volume of distribution

19

Methods

Literature Search

Search strategies were developed by an Informational Scientist for OVID Medline and EMBASE. Strategies consisted of controlled vocabulary, such as MeSH, and keyword phrases. Two methodological filters were used, one for systematic reviews and another for randomized controlled trials (RCT). Results were limited to English language. Databases were searched from date of inception forward. In EMBASE, we excluded conference abstracts. Searches were conducted in September, 2017. The complete search strategies and terms are available in Appendix B.

We also screened the reference lists of related systematic reviews and other relevant websites for further information:

1. For guidelines addressing the treatment of T2DM: websites of The American Diabetes Association, The American Association of Clinical Endocrinologists, The American College of Endocrinology, The National Institute for Health and Care Excellence, the Canadian Diabetes Association, and The European Association for the Study of Diabetes

2. For prescribing information package inserts: The Food and Drug Administration website (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/)

3. Evidence-based drug information databases (Micromedex, Lexicomp, and UpToDate)

Screening

At least two review authors screened titles and abstracts. The full text for all citations receiving two inclusion votes was retrieved; screening and inclusion were determined by the two lead authors. Conflicts were resolved via discussion between the two lead authors. Figure 1 shows the PRISMA flow chart28 for the review process.

Inclusion and Exclusion Criteria

Systematic reviews and RCTs providing head-to-head efficacy and safety comparisons (for the approved indication) among the DPP-4i products were included. For product comparisons where a systematic review provided robust data, we examined only those trials or systematic reviews published after the search date of the robust systematic review. Trials comparing monotherapy with combination regimens are excluded. A list containing the excluded references is provided in Appendix D.

20

Figure 1. PRISMA Systematic Literature Search Flow Chart

Records identified through database searching n = 937

Scre

enin

g In

clud

ed

Elig

ibili

ty

Iden

tific

atio

n Additional records identified through other sources

n = 2 (Scheen 2010, Li 2014)

Records screened n = 928

Records excluded n = 896

Full-text articles assessed for eligibility

n = 32

Full-text articles excluded, with reasons

n = 18 11 Wrong comparator 3 Wrong study design 3 Wrong methodology 1 Newer more robust SR available

Studies included in qualitative synthesis n = 14

10 efficacy/safety (1 MA, 3 RCTs, 5 NMAs, 1 reanalysis of a NMA) + 4 safety studies (1 SR, 3 NMAs)

Records after duplicated removed n = 928

21

Efficacy and Safety Comparative Evidence Clinical evidence involving head-to-head comparisons among DPP-4 inhibitor containing

products is presented for the products currently available in the United States. From a total of 937 references identified, 14 studies containing direct and indirect evidence met the inclusion criteria (2 SR/MA, 3 RCTs, 8 NMAs, and one reanalysis of a NMA). The majority of studies evaluated change in HbA1c levels as primary endpoint; one SR and 3 NMAs mainly evaluated safety outcomes. No studies evaluating FDC products versus the individual components administered concomitantly were identified.

Direct Evidence

Traditional Direct-Comparison Meta-analyses

COMPARISON OF DPP-4i PRODUCTS AS PART OF DUAL & TRIPLE THERAPY REGIMENS

Sitagliptin versus Saxagliptin

• In 2016, Zhao et al29 performed a meta-analysis including head-to-head RCTs with DPP-4i products. They identified 2 RCTs comparing sitagliptin to saxagliptin as part of dual therapy with metformin (Scheen et al30) or triple therapy with metformin and other oral hypoglycemic agents (Li et al31). Mantel-Haenszel meta-analytics found no differences between sitagliptin and saxagliptin in terms of the primary endpoints: HbA1c, fasting plasma glucose, and 2 hour postprandial plasma glucose levels. Safety profiles were comparable between treatments; however, a higher incidence of arthralgia was reported with sitagliptin compared to saxagliptin.

Head-to-head Randomized Control Trials

COMPARISON OF DPP-4i PRODUCTS AS PART OF DUAL THERAPY REGIMENS

Sitagliptin versus Saxagliptin + Metformin

• In 2010, Scheen et al30 conducted an 18-week, non-inferiority study to evaluate the efficacy and safety of saxagliptin 5 mg once daily versus sitagliptin 100 mg once daily as part of dual therapy with metformin in 801 adult patients with T2DM inadequately controlled on metformin. The trial demonstrated non-inferiority of saxagliptin plus metformin compared to sitagliptin plus metformin in reducing HbA1c from baseline to week 18 (primary endpoint in the per-protocol population). This result was confirmed in the full analysis set. No significant differences were reported for the secondary endpoints (i.e. percentage of patients achieving target HbA1c [HbA1c≤6.5%], changes from baseline in fasting plasma glucose, fasting insulin, glucagon, proinsulin, C-peptide, and β-cell function). Both treatments were well tolerated, with similar incidences of adverse events and low risk of hypoglycemia and weight gain.

22

COMPARISON OF DDP-4i PRODUCTS AS PART OF TRIPLE THERAPY REGIMENS

Linagliptin versus Sitagliptin + Insulin + (Metformin or Acarbose)

• In 2015, Tang et al32 conducted a 12-week, randomized, open-label study to evaluate the efficacy and safety of vildagliptin, sitagliptin, and linagliptin as add-on therapy to any insulin and metformin or acarbose in 535 Chinese adults patients with T2DM inadequately controlled on dual combination of insulin and metformin or acarbose. There was no significant difference between linagliptin and sitagliptin as part of triple therapy for the primary endpoints (change from baseline in HbA1c at week 12 and proportion of patients reaching the target Hb1Ac level of < 7%). For the secondary endpoints, linagliptin produced a significantly greater reduction in fasting plasma glucose at week 12 and postprandial plasma glucose levels at week 6 and 12, compared to sitagliptin. Adverse events were mostly mild and were reported similarly between groups.

Sitagliptin versus Saxagliptin + Metformin + Other Oral Hypoglycemic Agent

• In 2014, Li et al31 conducted a 24-week, randomized, open-label study to evaluate the efficacy and safety of vildagliptin, saxagliptin or sitagliptin as part of a triple therapy with metformin and other traditional oral hypoglycemic agents (OHA) in 207 Chinese patients with T2DM inadequately controlled with dual combination of metformin and OHAs. At week 24, the reduction in HbA1c and postprandial blood glucose, and the proportion of patients reaching Hb1Ac < 7% were not statistically significantly different in the saxagliptin group compared to sitagliptin group. The reduction in fasting blood glucose was significantly lower with sitagliptin compared to saxagliptin at week 24 (p < 0.001). Similar adverse events were reported between groups.

Indirect Evidence— Network Meta-analyses

COMPARISON OF DPP-4i PRODUCTS AS PART OF DUAL & TRIPLE THERAPY REGIMENS

DPP-4i (alone or in a combination) + Meformin (addresses all DPP-4i agents, alogliptin+pioglitazone and empagliflozin/linagliptin)

• In 2015, Mearns et al33 performed a network meta-analysis to compare DPP-4i products (alone or in a combination) as add-on therapy to metformin in patients with T2DM inadequately controlled on metformin alone.

o Regarding DPP-4i single-ingredient products as add on therapy to metformin, network meta-analysis results showed no differences among alogliptin, linagliptin, saxagliptin, and sitagliptin in terms of (a) changes from baseline in HbA1c and body weight, and (b) risk of hypoglycemia, and urinary tract infections. In addition, no differences were reported among linagliptin, saxagliptin, and sitagliptin with respect to changes in systolic blood pressure.

o Concerning DPP-4i combination products as add on therapy to metformin, no significant differences were reported between alogliptin+pioglitazone and empagliflozin/linagliptin with respect to HbA1c reductions from baseline and risk

23

of urinary tract infections. For the endpoint of changes in body weight, clinically significant weight gain was reported with alogliptin+pioglitazone compared to empagliflozin/linagliptin.

o Some study limitations include incoherence, under-reporting of some endpoints (e.g. urinary tract infections), multiple hypothesis testing in the same network meta-analysis, and weak links between some DPP-4i products.

COMPARISON OF DPP-4i PRODUCTS AS PART OF TRIPLE THERAPY REGIMENS

DPP-4i +Metformin+Sulfonylurea (addresses all DPP-4i agents)

• In 2017, Kay et al34 performed a network meta-analysis to compare alogliptin 25 mg once daily to linagliptin, saxagliptin, sitagliptin, and vildagliptin among a triple therapy regimen with metformin and a sulfonylurea in patients with T2DM inadequately controlled on metformin and sulfonylurea dual therapy. No differences were found among individual DPP-4i agents with respect to the primary efficacy outcome (percent change in HbA1c from baseline) using fixed effects and quasi-random effects models. No differences in terms of change in weight, hypoglycemia risk, and adverse events leading to discontinuation were reported. A limitation of the study is that there was low network connectedness. All DPP-4i, except sitagliptin were connected by only one RCT to the placebo comparator node-in-common; whereas sitagliptin was connected by two RCTs.

DPP-4i +Metformin+Sulfonylurea (addresses linagliptin, saxagliptin, & sitagliptin)

• In 2015, Mearns et al35 performed a network meta-analysis to compare antihyperglycemic drug regimens added to metformin and sulfonylurea therapy in T2DM patients inadequately controlled on dual treatment with metformin and sulfonylurea. Results included comparisons between linagliptin, saxagliptin, and sitagliptin. With respect to the outcomes (a) change in HbA1c from baseline, (b) change in body weight from baseline, (c) risk of confirmed hypoglycemia, and (d) risk of urinary tract infections, no significant differences were found between these three agents. Study limitations include a low number of links contributing to certain pairwise network estimates and heterogeneity in study design, duration, and quality of reporting.

DPP-4i +Metformin+thiazolidinedione (addresses linagliptin versus sitagliptin only)

• In 2015, Saulsberry et al36 performed a network meta-analysis to compare DPP-4i products among triple therapy regimens with metformin and a thiazolidinedione (rosiglitazone or pioglitazone) in patients with T2DM inadequately controlled on metformin-TZD dual therapy. No significant difference was found between linagliptin and sitagliptin with respect to the primary efficacy outcome, change in HbA1c from baseline, using a random effects model. No differences in body weight or hypoglycemia risk were reported. Limitations of the study include (a) an inadequate search strategy, which may increase the risk of publication bias, (b) a low connectedness of the network with respect to indirect comparisons for linagliptin versus sitagliptin (1:3 RCT ratio), and (c) a potential presence of heterogeneity and inconsistency.

24

COMPARISON OF DDP-4i PRODUCTS AS MONOTHERAPTY, DUAL & TRIPLE THERAPY REGIMENS

DPP-4i as monotherapy (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin), dual therapy (with metformin, sulfonylurea, pioglitazone or insulin), triple therapy (with metformin and sulfonylurea)

• In 2014, Craddy et al37 conducted a network meta-analysis to compare DPP-4i products as mono, dual and triple therapy in patients with T2DM. Overall, no differences were reported between the DPP-4i products in terms of HbA1c change from baseline, proportion of patients achieving HbA1c of <7%, body weight change, and hypoglycemia events. The proportion of patients achieving HbA1c of <7% was statistically significantly higher with alogliptin plus metformin compared to saxagliptin plus metformin. Nevertheless, this result should be cautiously considered because authors compared odds ratios from different trials and the odds ratio for alogliptin plus metformin was very wide.

• This network dataset from Craddy et al, was reanalyzed by Messori et al38 (2014) for therapeutic equivalence assessment between all DPP-4i (alogliptin, linagliptin, saxagliptin, sitagliptin or vildagliptin) as monotherapy or in combination with metformin in patients with T2DM. All DPP-4i agents met the equivalence criteria (±0.25% change in HbA1c), with the exception of saxagliptin given as monotherapy (possibly less efficacious) and alogliptin in combination with metformin (possibly more efficacious).

25

Safety DPP-4i products are well tolerated and rarely induce hypoglycemia.14,19 The most

commonly reported adverse events include headache, nasopharyngitis, and upper respiratory tract infection.25

Post-marketing reports of acute pancreatitis, hypersensitivity (e.g. angioedema and urticaria), exacerbated heart failure requiring hospitalization, severe arthralgia, and bullous pemphigoid leading to hospitalization have been rarely described in patients using DPP-4 inhibitors.5,6,9,11-14,26,27 The FDA announced two drug safety communications associated with DPP-4 inhibitors in 2014 (for risk of heart failure) and 2015 (for severe joint pain). Regarding heart failure, the FDA assessed 2 clinical trials in diabetic patients with heart disease. They found an increased risk of heart failure hospitalizations (especially in those patients with a history of heart failure or kidney disease) in the group of patients receiving saxagliptin or alogliptin-containing products compared to placebo group.39 With regard to joint pain, a review of the FDA Adverse Event Reporting System database and the medical literature indicated a higher incidence of severe arthralgia associated with the use of sitagliptin, saxagliptin, linagliptin, and alogliptin.40 Hepatic impairment (increased liver enzymes) were uncommonly reported with the use of alogliptin,1,13 and some cases of acute renal failure were reported with the use of sitagliptin-containing products.4,9,10

Metformin combinations include a Black Box Warning regarding the risk of metformin-induced lactic acidosis.5,6,8-10 The combination containing pioglitazone contains a Black Box Warning for the risk of congestive heart failure.13

Further information concerning DPP-4 inhibitor single-ingredient and combination products are outlined in Table 6 and 7: Table 6 outlines the warnings and contraindications and Table 7 includes a summary of the most common adverse events.

Studies described in the ‘Efficacy and Safety Clinical Evidence’ section found no significant differences among DPP-4 inhibitor products, with the exception of a meta-analysis reporting a higher incidence of arthralgia with sitagliptin versus saxagliptin as part of a dual therapy with metformin.29 Four safety articles including direct or indirect head-to-head comparison among the DPP-4 inhibitors were identified. One systematic review identified a single direct head-to-head trial reporting no differences in the incidence of adverse events between saxagliptin and sitagliptin.41 Three network meta-analysis with several limitations suggested (a) an increased incidence of gastrointestinal adverse events with linagliptin compared to alogliptin and sitagliptin,42 (b) a similar incidence of diarrhea and hypoglycemia with saxagliptin+metformin versus sitagliptin+metformin,43 and (c) an increased risk of heart failure with alogliptin compared to sitagliptin, and linagliptin compared to saxagliptin and sitagliptin.44 The risk of heart failure hospitalizations with the use of DPP-4 inhibitors remains controversial. Several studies and meta-analyses have evaluated this concern showing uncertainties regarding the association between DPP-4 inhibitors and risk of heart failure hospitalizations.45-49 Further confirmatory evidence is needed.

26

Table 6. Combination DPP-4 Inhibitor Products Warnings & Precautions*5,6,9,11-13,26,27

Warnings

Warnings in common

for a l l DPP-4 Inh ibi tor

Products

Heart failure: Some cases of exacerbated heart failure requiring hospitalization were reported in clinical trial and/or postmarketing stages for alogliptin and saxagliptin, however a warning for this is among each DPP4-I package insert

Additive hypoglycemic effect with other agents: Use caution with other medications known to cause hypoglycemia (e.g. sulfonylureas)

Severe & Disabling Arthralgia: there are some postmarketing cases of severe arthralgia upon the use of DPP4-Is, with onset varying from one day to years and relief experienced upon discontinuation of the DPP4-I

Bullous Pemphigoid: there are some postmarketing cases of bullous pemphigoid requiring hospitalization upon the use of DPP4-Is, with relief experienced upon discontinuation of the DPP4-I and administration of topical or systemic immunosuppressive treatment.50

Macrovascular Effects: there are no studies establishing conclusive evidence of macrovascular risk reduction with these agents or any other antidiabetic agent

Pancreatitis: there have been postmarketing reports of patients taking DDP4-Is who experienced acute pancreatitis

Addit iona l warn ings for DPP-4 Inh ib i tors

combined with Metformin

Alogliptin/

Metformin

Linagliptin/ Metformin

Saxagliptin/ Metformin

Sitagliptin/ Metformin

Black Box Warning: Risk of metformin-induced lactic acidosis

Risk factors include: renal impairment, concomitant use of certain drugs, age 65 or above, radiological contrast studies (must discontinue medication in patients with LA risk factors undergoing contrast imaging), surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment

Contraindications: severe renal impairment: eGFR < 30 mL/min/1.73 m2 metabolic acidosis & diabetic ketoacidosis, hypersensitivity to component medications

Warnings: Drug Interactions: consider drugs (and alcohol intake) that may impair renal function, result in significant hemodynamic change,

interfere with acid-base balance or increase metformin accumulation Laboratory Abnormalities: metformin may lower serum B12 and folic acid concentrations; annual serum monitoring is advised Additional contraindications and warnings unique to alogliptin with metformin product Hepatic Effects: some patients experienced fatal or nonfatal hepatic failure while on alogliptin, however probable cause is unclear Additional contraindications and warnings unique to sitagliptin with metformin product Acute Renal Failure: there have been postmarketing reports of worsening renal function, including acute renal failure,

sometimes requiring dialysis

27

Table 6. Combination DPP-4 Inhibitor Products Warnings & Precautions*5,6,9,11-13,26,27

Warnings

Add i t iona l warn ings for DPP-4 Inh ib i tors

combined with an SGLT-2 Inhib itor

Linagliptin/

Empagliflozin

Saxagliptin/ Dapagliflozin

Contraindications: severe renal impairment

Warnings: Acute Kidney Injury: there have been postmarketing reports of acute kidney injury in patients taking empagliflozin and

dapagliflozin, as these agents can cause volume contraction. Hypotension: SGL2 inhibitors may cause hypotension, particularly in patients with renal insufficiency. Volume status should be

normalized prior to initiation and monitored during treatment. Ketoacidosis: there have been postmarketing reports of patients taking empagliflozin and dapagliflozin that have experienced

fatal ketoacidosis. Urosepsis and Pyelonephritis: there are postmarketing reports of serious urinary tract infections including urosepsis and

pyelonephritis requiring hospitalization in patients receiving empagliflozin and dapagliflozin Genital Mycotic Infections: SGL2 inhibitors increase the risk of genital mycotic infections. Increased LDL-C: SGL2 inhibitors can increase LDL levels

Additional contraindications and warnings unique to saxagliptin with dapagliflozin product Contraindications: also contraindicated in moderate renal impairment (eGFR <45 mL/min/1.73 m2), along with severe & end-

stage renal disease, or patients on dialysis. Warning: Bladder Cancer: May increase the risk of bladder cancer; do not use in patients with bladder cancer and use caution

when in persons with a prior history of bladder cancer.

Add i t iona l warn ings for DPP-4 Inh ib i tors

combined with a Thiazo l id ined ione

Alogliptin/ Pioglitazone

Black Box Warning: Congestive heart failure Thiazolidinediones (e.g. pioglitazone) may cause/exacerbate heart failure, via dose related fluid retention. Combined use with

insulin and existing HF may increase risk. Contraindications:

Do not initiate in NYHA Class III or IV heart failure Warnings: Drug Interactions: strong CYP2C8 inhibitors (e.g. gemfibrozil) and inducers (e.g. rifampin) may affect pioglitazone concentrations. Hepatic Effects: some patients experienced fatal or nonfatal hepatic failure while on alogliptin, however probable cause is unclear Bladder cancer: May increase the risk of bladder cancer; do not use in patients with bladder cancer and use caution when in persons

with a prior history of bladder cancer. Macular edema: Postmarketing reports of macular edema have occurred in patients taking pioglitazone. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with

OSENI or any other antidiabetic drug. Fractures: pioglitazone is associated with an increased risk of fracture in female patients

*Refer to prescribing information for full details and recommended monitoring with respect to warnings/precautions Abbreviations: CVD, cardiovascular disease; DPP4-I, dipeptidyl-peptidase-4 inhibitor; eGRF, estimated glomerular filtration rate; ER, extended release; HF, heart failure; RCT, randomized controlled trial; SGL2-I, SLG2 inhibitor;

28

Table 7. Combination DPP-4 Inhibitor Products Adverse Events*5,6,9,11-13,26,27,51 Substance

(Brand Name) Adverse Events

DPP-4 Inhibitor Single Ingredient Products

Alogliptin

(Nesina)

1% to 10%: Cardiovascular: Cardiac failure (4%) Central nervous system: Headache (4%) Genitourinary: Decreased estimated GFR (5%) Hepatic: Increased serum ALT (>3 times ULN: 1%) Renal: Renal function abnormality (3%; patients with high cardiovascular risk: 23%), renal disease (patients with high cardiovascular risk: 17%), renal insufficiency (patients with high cardiovascular risk: 8%) Respiratory: Nasopharyngitis (5%), upper respiratory tract infection (5%)

Linagliptin

(Tradjenta)

1% to 10%: Endocrine & metabolic: Hypoglycemia (7%), increased uric acid (3%) Gastrointestinal: Increased serum lipase (8%; >3x upper limit of normal) Respiratory: Nasopharyngitis (7%), cough (2%)

Frequency not defined: Dermatologic: Urticaria Neuromuscular & skeletal: Myalgia Respiratory: Asthma

Saxagliptin

(Onglyza)

1% to 10%: Cardiovascular: Peripheral edema (4%) Central nervous system: Headache (7%) Endocrine & metabolic: Hypoglycemia (6%) Genitourinary: Urinary tract infection (7%) Hematologic & oncologic: Lymphocytopenia (2%) Hypersensitivity: Hypersensitivity reaction (2%; including facial edema and urticaria)

Sitagliptin

(Januvia)

1% to 10%: Endocrine & metabolic: Hypoglycemia (1%) Respiratory: Nasopharyngitis (5%)

Frequency not defined: Gastrointestinal: Diarrhea, nausea Renal: Increased serum creatinine

DPP-4 Inhibitor Combinations with Metformin

Alogliptin/ Metformin

(Kazano)

1% to 10%: Central nervous system: Headache (5%) Endocrine & metabolic: Hypoglycemia (2% to 5%) Gastrointestinal: Diarrhea (6%) Genitourinary: Urinary tract infection (4%) Neuromuscular & skeletal: Back pain (4%) Respiratory: Upper respiratory tract infection (8%), nasopharyngitis (7%)

Linagliptin/ Metformin

(Jentadueto)

1% to 10% or frequency not defined Dermatologic: Pruritus Gastrointestinal: Diarrhea (6%), decreased appetite, nausea, pancreatitis, vomiting Hypersensitivity: Hypersensitivity reaction Respiratory: Nasopharyngitis (6%), cough

29

Table 7. Combination DPP-4 Inhibitor Products Adverse Events*5,6,9,11-13,26,27,51 Substance

(Brand Name) Adverse Events

Saxagliptin/ Metformin

(Kombiglyze)

Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered saxagliptin and metformin and more commonly than in patients treated with metformin alone are: headache (8%) and nasopharyngitis (7%)

Sitagliptin/ Metformin

(Janumet)

1% to 10%: Central nervous system: Headache (6%) Gastrointestinal: Diarrhea (8%), nausea (5%), abdominal pain (3%), vomiting (2%) Respiratory: Upper respiratory tract infection (6%)

DPP-4 Inhibitor Combinations with an SGL2-Inhibitor

Linagliptin/ Empagliflozin

(Glyxambi)

>10%: Genitourinary: Urinary tract infection (11% to 13%)

1% to 10%: Endocrine & metabolic: Hypoglycemia (2% to 4%), increased serum cholesterol Hematologic & oncologic: Increased hematocrit Respiratory: Upper respiratory tract infection (7%), nasopharyngitis (6% to 7%)

Saxagliptin/ Dapagliflozin

(Qtern)

>10%: Respiratory: Upper respiratory tract infection (14%) 1% to 10%:

Cardiovascular: Headache (4%) Endocrine & metabolic: Dyslipidemia (5%), hypoglycemia (2%) Gastrointestinal: Diarrhea (4%) Genitourinary: Urinary tract infection (6%; including Escherichia urinary tract infection, prostatitis, and pyelonephritis; mostly reported in females) Infection: Localized fungal infection (3%; genital infections, including vulvovaginal mycotic infection, balanoposthitis, genital fungal infection, vaginal infection, and vulvovaginitis; mostly reported in females) Neuromuscular & skeletal: Back pain (3%), arthralgia (2%) Renal: Renal insufficiency (2%)

DPP-4 Inhibitor Combination with Pioglitazone

Alogliptin/ Pioglitazone

(Oseni)

1% to 10%: Endocrine & metabolic: Hypoglycemia (≤4%) Neuromuscular & skeletal: Back pain (4%) Respiratory: Nasopharyngitis (5%), upper respiratory tract infection (4%)

AEs specific to pioglitazone: <1%, postmarketing, and/or case reports: Bladder carcinoma (FDA Safety Alert, Dec. 19,

2016) *Refer to prescribing information for full details and recommended monitoring with respect to adverse reactions Abbreviations: AE, adverse events; DPP4-I, dipeptidyl-peptidase-4 inhibitor; SGLT2-inhibitor, sodium glucose transporter- 2 inhibitor

30

Summary DPP-4i agents, as monotherapy or add-on therapy, are effective for lowering blood

glucose levels in patients with T2DM. Guidelines do not specify a preference for one DPP-4i agent over another. Metformin remains the first-line recommendation for oral treatment of T2DM as it is effective, safe, and reduces cardiovascular events. DPP-4i products are recommended as treatment options for initial monotherapy in patients with metformin contraindications or intolerance (e.g. severe renal impairment, hypersensitivity, risk of lactic acidosis, gastrointestinal concerns). If glycemic control is not achieved with metformin or DPP-4i monotherapy, DPP-4i agents may be used as part of dual and triple therapy regimens. Fixed-dose combinations of DPP-4i agents are available with the SGLT-2 inhibitors, dapagliflozin and empagliflozin, and with the thiazolidinedione, pioglitazone, which may be used as dual therapy or in triple-therapy regimens.

Four DPP-4i agents are available as single-ingredient products. Nine fixed-dose combinations containing a DPP-4 inhibitor with metformin, dapagliflozin, empagliflozin, or pioglitazone are also available.

Following a systematic search for head-to-head comparisons among DPP-4 inhibitor containing products, 14 efficacy/safety studies (2 SR/MA, 3 RCTs, 8 NMAs, and one reanalysis of a NMA) were identified. The majority evaluated the change in HbA1c levels as the primary endpoint, except one SR and 3 NMAs that mainly evaluated safety outcomes. The usable efficacy findings included the following:

• Sitagliptin versus Saxagliptin as part of dual or triple therapy (1 MA, 2 RCTs): One MA including 2 RCTs of interest for this report showed no differences between sitagliptin and saxagliptin in reducing HbA1c levels. Comparable efficacy results were reported by the 2 single RCTs identified in the aforementioned MA.

• Sitagliptin versus Linagliptin as part of triple therapy (1 RCT): No between-group differences in decreasing HbA1c from baseline were reported.

• Alogliptin+pioglitazone versus empagliflozin/linagliptin as add-on therapy to metformin (1 NMA): No significant differences were reported between treatment groups with respect to HbA1c reductions from baseline. Greater weight gain was reported with alogliptin+pioglitazone compared to empagliflozin/linagliptin.

• Comparisons among all DPP-4 inhibitor products as part of dual or triple therapy (5 NMAs): No differences among DPP-4 inhibitors were identified for the endpoint of change in HbA1c from baseline. One NMA with several limitations reported a statistically significantly higher proportion of patients achieving HbA1c of <7% with alogliptin plus metformin compared to saxagliptin plus metformin.

• DPP-4i as monotherapy and as add-on therapy to metformin (1 reanalysis of a NMA): With respect to the change in HbA1c, all DPP-4i agents met the equivalence criteria except saxagliptin given as monotherapy and alogliptin in combination with metformin.

Although direct-comparative clinical evidence suggests similar glycemic control among sitagliptin, saxagliptin, linagliptin and alogliptin, some pharmacokinetic and safety nuances are identified. Saxagliptin undergoes metabolism primarily through cytochrome P450 (CYP) 3A4/5

31

enzymes, while the others are metabolized by CYP enzymes to a lesser degree. Alogliptin, saxagliptin, and sitagliptin rely heavily on renal excretion while linagliptin primarily relies on fecal elimination. Thus, linagliptin may be a preferable treatment option in patients with chronic kidney disease since it does not require dose adjustments for renal impairment, as do the other DPP-4i agents.

Regarding safety, DPP-4 inhibitors are well tolerated and rarely induce hypoglycemia. The most commonly reported adverse events include headache, nasopharyngitis, and upper respiratory tract infection. Direct evidence reported similar incidences of adverse events among DPP-4 inhibitors, with one meta-analysis showing a higher incidence of arthralgia with sitagliptin compared to saxagliptin. Indirect evidence suggested (a) an increased incidence of gastrointestinal adverse events with linagliptin compared to alogliptin and sitagliptin, and (b) a higher risk of heart failure with alogliptin compared to sitagliptin, and linagliptin compared to saxagliptin and sitagliptin. Further direct comparative evidence is required. With respect to DPP-4i combination products, safety profiles differ depending on the agent added to the DPP-4 inhibitor. Metformin combinations include a Black Box Warning regarding the risk of metformin-induced lactic acidosis and are contraindicated in patients with severe renal impairment. The combination containing pioglitazone contains a Black Box Warning for the risk of congestive heart failure

In summary, 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 sitagliptin compared to saxagliptin or linagliptin, as part of dual or triple therapy. Low-level evidence (indirect evidence from 5 NMAs) compared single-ingredient DPP-4i products versus each other in mono, dual, or triple therapy regimens (including comparison of alogliptin+pioglitazone versus empagliflozin/linagliptin). The majority of these NMAs suggested no between-group differences with respect to HbA1c reduction, except one NMA (assessed by two different methodologies) suggesting differences in favor of alogliptin plus metformin. However, indirect results should be interpreted cautiously due to multiple limitations (e.g. weak links between interventions, clinical heterogeneity between studies, imprecision, multiple comparison complexity, etc.). Safety profiles were similar among DPP-4 inhibitor products, with some specific differences between them (arthralgia, heart failure hospitalizations, and gastrointestinal adverse events). No comparative evidence was found for saxagliptin/dapagliflozin. Additional head-to-head studies are required to strengthen the confidence in making conclusions concerning the relative efficacy among DPP-4 inhibitor products.

Therapy for T2DM should be individualized for each patient in order to achieve optimal glycemic control. Metformin remains the first-line recommendation for oral treatment of T2DM as it is effective, safe, and reduces cardiovascular events. DPP-4i products are alternative treatment options as monotherapy and can be used as part of dual and triple therapy regimens. Clinicians should choose a specific DPP-4 inhibitor product over another based on issues related to individual patient characteristics (comorbidities, patient’s preferences and adherence), and issues related to the specific product (pharmacokinetic characteristics, safety concerns, contraindications, and cost).

32

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Appendix A

Table 1. Glucose lowering agents for type 2 diabetes mellitus*14,51 Orals Subcutaneous In jectables

o Alpha-glucosidase inhibitors Acarbose Miglitol

o Amylin mimetic Pramlintide

o Biguanide Metformin

o GLP-1 receptor agonists Albiglutide Dulaglutide Exenatide Liraglutide Lixisenatide

o Bile acid sequestrant Colesevelam

o Dopamine-2 agonist Bromocriptine

o DPP-4 Inhibitors Alogliptin Linagliptin Saxagliptin Sitagliptin

o Insulins Rapid acting

• inhaled insulin • insulin glulisine • insulin lispro • insulin aspart

Short acting (Regular) Intermediate acting (NPH) Long acting

• Insulin detemir • Insulin glargine

Ultra-long acting • Insulin glargine U300 • Insulin degludec

Combination insulin products

o SGLT-2 inhibitors Canagliflozin Dapagliflozin Empagliflozin

o Sulfonylurea 1st Generation:

Chlorpropamide Tolazamide Tolbutamide

2nd Generation: Glimepiride Glipizide Glyburide

o Meglitinides Nateglinide Repaglinide

o Thiazolidinediones Pioglitazone Rosiglitazone

*Some glucose lowering agents are also available as fixed-dose combinations Abbreviations: DPP-4, dipeptidyl peptidase 4; GLP-1; glucagon-like peptide 1; SGL-2, sodium-glucose co-transporter 2

36

Appendix B

Table 1. Medline Literature Search Strategy (via Ovid) for SRs and RCTs Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions(R). Search Strategy Date: September 13th, 2017 SR results: 257; RCT results with 2015 date limit: 396 1 (alogliptin* or linagliptin* or saxagliptin* or sitagliptin*).ti,ab,kw,kf. (2656) 2 (nesina* or 'syr 322' or syr322 or vipidia*).ti,ab,kw,kf. (15) 3 ("tradjent*" or trajent* or "bi 1356" or "bi1356" or "ondero*").ti,ab,kw,kf. (31) 4 ("bms 477118" or bms477118 or onglyza* or onglysa*).ti,ab,kw,kf. (22) 5 ("mk 0431" or "mk 431" or "mk0431" or "mk431" or "ono 5435" or "ono5435" or januvia* or ristaben* or tesabel* or tesavel* or xelevia*).ti,ab,kw,kf. (74) 6 linagliptin/ or sitagliptin phosphate/ (1383) 7 or/1-6 [single drugs] (2836) 8 dipeptidyl-peptidase iv inhibitors/ or gliptin*.ti. or (("dipeptidyl peptidas*" or "dipeptidyl-peptidas*" or dipeptidylpeptidas*) adj1 ("bms 477118" or bms477118 or onglyza* or onglysa* or iv)).ti. or (dppiv.ti. or dpp4 or "dpp iv" or "dpp 4").ti. [drug class] (4434) 9 7 or 8 [single drugs + drug class] (5877) 10 ((alogliptin* adj3 metformin*) or kazano* or vipdomet*).ti,ab,kw,kf. (24) 11 ((linagliptin* adj3 metformin*) or jentadueto*).ti,ab,kw,kf. (47) 12 ((metformin* adj3 saxagliptin*) or kombiglyz* or komboglyz*).ti,ab,kw,kf. (70) 13 (Metformin* adj3 sitagliptin*).mp. or (efficib* or janumet* or "mk 0431a" or "mk0431a" or ristfor or "metformin hydrochloride drug combination" or velmetia*).ti,ab,kw,kf. (214) 14 ((dapagliflozin* adj3 saxagliptin*) or qtern).ti,ab,kw,kf. (23) 15 ((Empagliflozin* adj3 linagliptin*) or glyxambi).ti,ab,kw,kf. (26) 16 ((Alogliptin* adj3 pioglitazon*) or (actos adj2 nesina) or incresync* or oseni*).ti,ab,kw,kf. (36) 17 or/10-16 [Drug combos] (405) 18 or/9,17 [ALL DRUGs = single drugs + drug class + drug combos] (5880) 19 exp animals/ not humans.sh. [Cochrane RCT Filter 6.4.d Sens/Precision Maximizing] (4583014) 20 (animal? or beaver? or beef or bovine or breeding or bull or canine or castoris or cat or cattle or cats or chicken? or chimp$ or cow or dog or dogs or equine or foal or foals or fish or insect? horse or horses or livestock or mice or monkey? or mouse or murine or plant or plants or pork or porcine or protozoa? or purebred or rat or rats or rodent? or sheep or thoroughbred).ti. or veterinar$.ti,ab,kw,kf,hw. (2234866) 21 or/19-20 [Animal filter, combined] (5080926) 22 (systematic adj2 (review? or overview? or scoping)).ti,ab,kw,kf. or (metaanaly$ or meta-analy$).pt,ti,ab,kw,kf. [SR filter] (214312) 18 or/9,17 [ALL DRUGs = single drugs + drug class + drug combos] (5880) 19 exp animals/ not humans.sh. [Cochrane RCT Filter 6.4.d Sens/Precision Maximizing] (4583014) 20 (animal? or beaver? or beef or bovine or breeding or bull or canine or castoris or cat or cattle or cats or chicken? or chimp$ or cow or dog or dogs or equine or foal or foals or fish or insect? horse or horses or livestock or mice or monkey? or mouse or murine or plant or plants or pork or porcine or protozoa? or purebred or rat or rats or rodent? or sheep or thoroughbred).ti. or veterinar$.ti,ab,kw,kf,hw. (2234866) 21 or/19-20 [Animal filter, combined] (5080926) 22 (systematic adj2 (review? or overview? or scoping)).ti,ab,kw,kf. or (metaanaly$ or meta-analy$).pt,ti,ab,kw,kf. [SR filter] (214312) 23 (randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti. [RCT filter] (1179537) 24 18 not 21 [ all drugs, NOT animal] (4744) 25 limit 24 to english language (4467) 26 remove duplicates from 25 (4131) 27 26 and 22 [SR set] (257)

37

Table 1. Medline Literature Search Strategy (via Ovid) for SRs and RCTs 28 (26 and 23) not 27 [ RCT set ] (1090) Note: A date limit (2015) was then set for the RCT subset only:

• RCT 2015-present = 396 (results on 10/04/17) • RCT pre-2015 = 709 (results on 10/04/17) (Not imported to Covidence)

38

Table 2. Embase Literature Search Strategy for SRs and RCTs EMBASE.com. Search Strategy Date: September 13th, 2017 SR results: 235; RCT results with 2015 date limit: 498 #29 #26 AND #25 NOT #27 AND [english]/lim 1,148 #28 #26 AND #25 NOT #27 1,148 #27 #26 AND #24 235 #26 #19 NOT (#20 OR #21) AND [english]/lim 4,857 #25 'clinical study'/mj OR 'clinical trial'/mj OR 'controlled clinical trial'/mj OR 'controlled study'/mj OR 'major clinical study'/mj OR controlled OR multicentre OR multicenter OR 'multi centre' OR 'multi center') NEAR/3 (study OR trial)):ab) OR placebo:ab,ti OR 2,561,618 #24 #22 OR #23 197,759 #23 metaanaly*:ti,ab OR 'meta-analy*':ti,ab OR ((systematic NEAR/2 review):ti) 197,334 #22 'systematic review'/mj OR 'meta analysis'/mj 21,638 #21 'conference abstract'/it OR 'conference review'/it 2,703,612 #20 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell'/de)) 6,299,629 #19 #11 OR #18 9,297 #18 #12 OR #13 OR #14 OR #15 OR #16 OR #17 552 #17 'alogliptin plus pioglitazone'/de OR ((actos NEAR/2 nesina):ab,ti,tn) OR incresync*:ab,ti,tn OR oseni*:ab,ti,tn 40 #16 'empagliflozin plus linagliptin'/de OR glyxambi:ab,ti,tn 50 #15 'dapagliflozin plus saxagliptin'/de OR qtern:ab,ti,tn 20 #14 'metformin plus saxagliptin'/de OR kombiglyz*:ab,ti,tn OR komboglyz*;:ab,ti,tn OR 'metformin plus sitagliptin'/de OR 'metformin velmetia*:ab,ti,tn 409 #13 'linagliptin plus metformin'/de OR jentadueto*:ab,ti,tn 62 #12 'alogliptin plus metformin'/de OR kazano*:ab,ti,tn OR vipdomet*:ab,ti,tn 51 #11 #6 OR #7 OR #10 9,137 #10 #8 OR #9 4,951 #9 gliptin*:ti OR ((('dipeptidyl peptidas*' OR 'dipeptidyl-peptidas*' OR dipeptidylpeptidas*) NEAR/1 (4 OR iv)):ti) OR dppiv:ti OR dpp4:ti OR 4,527 #8 'dipeptidyl peptidase iv inhibitor'/mj 2,076 #7 'alogliptin'/mj OR 'linagliptin'/mj OR 'saxagliptin'/mj OR 'sitagliptin'/mj 3,294 #6 #1 OR #2 OR #3 OR #4 OR #5 5,610 #5 'mk 0431':ti,ab,tn OR 'mk 431':ti,ab,tn OR 'mk0431':ti,ab,tn OR 'mk431':ti,ab,tn OR 'ono 5435':ti,ab,tn OR 'ono5435':ti,ab,tn OR 908 #4 'bms 477118':ti,ab,tn OR bms477118:ti,ab,tn OR onglyza*:ti,ab,tn OR onglysa*:ti,ab,tn 351 #3 'tradjent*':ti,ab,tn OR trajent*:ti,ab,tn OR 'bi 1356':ti,ab,tn OR 'bi1356':ti,ab,tn OR 'ondero*':ti,ab,tn 233 #2 nesina*:ti,ab,tn OR 'syr 322':ti,ab,tn OR syr322:ti,ab,tn OR vipidia*:ti,ab,tn 167 #1 alogliptin*:ti,ab,tn OR linagliptin*:ti,ab,tn OR saxagliptin*:ti,ab,tn OR sitagliptin*:ti,ab,rn 4,873 Note: A date limit (2015) was then set for the RCT subset only:

• RCT 2015-present = 498 (results on 10/04/17) • RCT pre-2015 = 660 (results on 10/04/17) (Not imported to Covidence)

39

Appendix C

Direct Evidence

Table 1. Direct Evidence: Systematic Reviews/Meta-analyses Including DPP-4i Containing Products Study Reference and Design

Objective(s) Treatment Interventions

Clinical Efficacy Clinical Safety Limitations

1. Zhao et al29 (2016)

• Meta-analysis using Mantel-Haenszel method

• Literature search: 1 May 2015 (6 studies were included. Only 2 of interest: Scheen 201030 and Li 201431)

To evaluate the hypoglycemic efficacy and safety of sitagliptin with other DPP-4i directly in patients with T2DM

• Sita 100 mg/day • Saxa 5 mg/day

Change in HbA1c from baseline: Mean difference (95% CI) of sita vs. saxa (fixed effects model): -0.10 [-0.20, 0.01] FPG and P2HG (random effect model): no significant difference between sita and saxa

No statistical differences in total AEs • Arthralgia: OR, 5.17, 95% CI, 1.13 to 23.74 [Scheen 2010] (Higher incidence in sitagliptin than saxagliptin)

• Limited number of trials

• Individual methodological quality not good enough

• Different eligibility requirements of HbA1c, additional treatment and treatment duration

Abbreviations: AE, adverse events; CI, confidence interval; DPP-4i, dipeptidyl peptidase-4 inhibitors; FPG, fasting plasma glucose; OR, odds ratio; P2HG, 2-h postprandial plasma glucose; Saxa, saxagliptin; Sita, sitagliptin; T2DM, type 2 diabetes mellitus

40

Table 2. Direct Evidence: Randomized Controlled Trials Including DPP-4i Containing Products Study Reference and Design



1. Tang et al32 (2015)

• 12-week, randomized, open-label, parallel clinical study

• 1 center: Patients were recruited from the Metabolic Diseases Hospital of Tianjin Medical University between January 2013 and January 2015

To evaluate the efficacy and safety of the three DPP-4i (vildagliptin, sitagliptin, and linagliptin) as add-on therapy in Chinese patients with T2DM inadequately controlled on dual combination of insulin and metformin or acarbose.

• Sita 100 mg QD+ background therapy (OHA*+insulin)

• Lina 5 mg QD + background therapy (OHA*+insulin)

• Vildagliptin 50 mg BID + background therapy (OHA*+insulin)

*OHA may be metformin or acarbose

Primary endpoint: • Change in HbA1c from baseline Sita: -0.84 ± 0.08% Lina: -0.81 ± 0.008% • % patients that reached the target

HbA1c Sita: 52.73% Lina: 55.49% Secondary endpoints: Mean FPG values at week 12: Lina: 6.90 ± 1.55 mmol/L Sita: 8.02 ± 4.48 mmol/L; (p<0.05) (FPG levels significantly lower with lina than sita) Mean PPG values at week 6 and 12: The value was significantly lower in the lina group than in the sita group Insulin dosage at week 6 and 12: similar between groups

AEs: no significant difference between groups in terms of reported AEs. • The most

commonly reported AEs were GI AEs (11.52 % for sita and 9.15 % for lina)

• Hypoglycemia: 10.3% for sita, and 7.29% for lina

• Low incidences of renal and hepatic toxicity, infections, and chest discomfort

• Small number of patients

• No placebo group

2. Li et al31 (2014) • 24-week,

randomized, open-label, parallel clinic study

To assess the efficacy and safety of three DPP-4 inhibitors (Saxagliptin, Sitagliptin and Vildagliptin) as add-on therapy to dual combination of traditional oral hypoglycemic agents in Chinese type 2 diabetes patients

• Saxa 5 mg QD + background therapy (MET + other OHA*)

• Sita 100 mg QD + background therapy (MET + other OHA*)

*OHA may be glimepiride, or acarbose, or pioglitazone

Primary endpoint: • Change in HbA1c from baseline at 24

week (no differences between groups) • % patients that reached the target

HbA1c at 24 week Saxa: 59% (39 patients) Sita: 59% (36 patients) (no differences between groups) Secondary endpoints: Mean FPG values at week 24: (sitagliptin showed the smallest reductions) Mean PPG values at week 24: (no differences between groups)

AEs: No significant between-group differences • Mild

hypoglycemia was commonly reported among all groups (saxa: 6%, sita: 3%

• Too short study to evaluate long-term glycemic control, weight loss, and β-cell preservation

• Small study • Open-label design • Patients enrolled

based on specific criteria (may be different from the real clinical use)

41

Study Reference and Design



3. Scheen et al30 (2010)

• 18-week, phase 3b, multicentre, randomized, double-blind, noninferiority parallel-group, active-controlled

• 99 sites in South America, Mexico, Europe and South Africa

To compare the efficacy and safety of two DPP-4i, saxagliptin and sitagliptin, in 801 patients whose glycaemia was inadequately controlled with metformin, with mean age ranged from 58.1 to 58.8 y; mean duration of type 2 diabetes of 6.3 y; mean HbA1c ranged from 7.68% to 7.69%

• Saxa 5 mg + Met QD

• Sita 100 mg + Met QD

Primary endpoint: PP analysis: Adjusted Mean Change in HbA1c (%): Saxa: -0.52% (±0.039); 95% CI, -0.60 to -0.45% Sita: -0.62% (±0.038); 95% CI, -0.69 to -0.54%). Difference between groups: 0.09%; 95% CI, -0.01 to 0.20%. (The upper limit of this 95% CI was below the predefined criterion for noninferiority of <0.3) (Non-inferiority demonstrated) Full cohort analysis: Difference between groups in mean change from baseline in HbA1c: 0.17%; 95% CI, 0.06-0.28% (Non-inferiority demonstrated) Secondary endpoints: No differences between groups for % patients achieving target HbA1c, changes from baseline in fasting insulin, glucagon, proinsulin, or C-peptide, and in homeostasis model assessment-2β.

% Patients With Symptoms of Hypoglycemia: 3.2% with Saxa 2.8% with Sita Skin AEs: higher with Sita than Saxa (differences not clinically relevant) Body weight: declined from baseline by a mean of 0.4 kg in both treatment groups (Safety profiles are comparable, frequency of serious AEs is low)

• Exclusion of a placebo group

Abbreviations: AE, adverse events; DPP-4i, dipeptidyl peptidase-4 inhibitors; FPG, fasting plasma glucose; GI, gastrointestinal; Lina, linagliptin; OHA; oral hypoglycemic agents; PPG, postprandial plasma glucose; Saxa, saxagliptin; Sita, sitagliptin; T2DM, type 2 diabetes mellitus

42

Indirect Evidence

Table 3. Indirect Evidence: Network Meta-analyses Including DPP-4i Containing Products

Study Reference, Design and Search Date



1. Kay et al34 (2017)

• Bayesian NMA (using Markov Chain Monte Carlo) combining direct and indirect treatment comparisons

• Literature search: January 2016 (8 studies included)

To assess the relative efficacy and safety of alogliptin vs. other DPP-4i (lina, sita, saxa, alo) in combination with metformin and sulfonylurea.

• Linagliptin 5 mg • Sitagliptin 100

mg • Saxagliptin 5 mg • Alogliptin 25 mg

Plus metformin and sulfonylurea

Main analysis:

• No significant differences between groups in mean HbA1c (%) change from baseline

• No significant differences between groups in mean change in body weight from baseline

Main analysis:

Comparability between alogliptin and other DPP-4i in terms of key safety outcomes:

• number of patients experiencing hypoglycemic events

• number of patients experiencing adverse events leading to study discontinuation

• Indirect comparison

• The data for alogliptin is from a post hoc subgroup analysis from the EXAMINE trial (It did not have as its primary objective to evaluate the effects of alogliptin on glycemic control)

2. Mearns et al35 (2015)

• Frequentist NMA model, using random-effects model for heterogeneity

• Literature search up to May 2014

To assess the efficacy and safety of third-line adjuvant antihyperglycemic agents in people with T2DM failing metformin and sulphonylurea combination therapy

• Linagliptin • Saxagliptin • Sitagliptin NMA connections: Lina vs. PBO: 1 study Saxa vs. PBO: 1 study Sita vs. PBO: 2 studies with HbA1c data and hypoglycemia data. 1 study with body weight and urinary tract infection data

Network Meta-Analysis Results (Weight Mean Differences, 95% CI):

• Change in HbA1c from Baseline: - Lina vs. Saxa: -0.06 (-0.45, 0.33) - Lina vs. Sita: -0.13 (-0.43, 0.16) - Saxa vs. Sita: -0.07 (-0.42, 0.28) • Change in Body Weight From

Baseline: - Lina vs. Saxa: 0.47 (-1.49, 2.43) - Lina vs. Sita: 1.15 (-0.58, 2.89) - Saxa vs. Sita: 0.68 (-1.09, 2.46) (no significant differences between groups)

Network Meta-Analysis Results (Relative Risk, 95% CI):

• Risk of Confirmed Hypoglycemia:

- Lina vs. Saxa: 3.06 (0.13, 72.98)

- Lina vs. Sita: 1.19 (0.48, 2.98)

- Saxa vs. Sita: 0.39 (0.02, 8.89)

• Risk of Urinary Tract Infections

- Lina vs. Saxa: 0.81 (0.21, 3.07)

• Many agents were only compared in one or two trials, and certain endpoints were sparsely reported

• Authors did not assessed other agent-specific endpoints due to lack of data

• Most trials only followed

43




- Lina vs. Sita: 2.44 (0.8, 7.38)

- Saxa vs. Sita: 3.0 (0.68, 13.33)

(no significant differences between groups)

patients for 24 weeks

• Incoherence cannot be ruled out

3. Mearns et al33 (2015)

• NMA using random-effects model

• Literature search up to May 2014

To assess the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2DM on metformin alone

• Alogliptin • Linagliptin • Sitagliptin • Saxagliptin • Alo/Pio • Empa/Lina Plus metformin

Network Meta-Analysis Results (Weight Mean Differences, 95% CI):

• Change in HbA1c from Baseline: - Alo vs. Lina: -0.07

(-0.3,0.16) - Alo vs. Sax: 0.07

(-0.16,0.29) - Alo vs. Sita: -0.07

(-0.27,0.13) - Alo/Pio vs. Empa/Lina: 0.11 (-

0.19,0.4) - Lina vs. Saxa: 0.14

(-0.03,0.31) - Lina vs. Sita: 0 (-0.14,0.14) - Saxa vs. Sita: -0.13 (-0.25,

-0.01) • Change in Body Weight From

Baseline (Kg) - Alo vs. Lina: -0.13

(-0.98,0.71) - Alo/Pio vs. Empa/Lina:

-4.46 (-5.67,-3.26) - Alo vs. Saxa: -0.03

(-0.84, 0.77 - Alo vs. Sita: 0.12

(-0.58, 0.82) - Lina vs. Saxa: 0.1

Network Meta-Analysis Results (Relative Risk, 95% CI):

• Risk of Confirmed Hypoglycemia:

- Alo vs. Lina: 2.82 (0.27,29.61)

- Alo vs. Sax: 5.38 (0.46,63.47)

- Alo vs. Sita: 7.95 (0.82,77.14)

- Saxa vs. Sita: 1.48 (0.47,4.61)

• Risk of Urinary Tract Infections:

- Alo vs. Lina: 0.9 (0.38,2.11)

- Alo vs. Sax: 1.13 (0.48,2.65)

- Alo vs. Sita: 0.91 (0.39,2.1)

- Alo/Pio vs. Empa/Lina: 0.69 (0.25,1.9)

- Saxa vs. Sita: 0.81 (0.51,1.27)

• Certain endpoints were sparsely reported

• Incoherence cannot be ruled out

• Type I error. NMA cross- compared 25 therapies plus placebo on 6 different endpoints

• Publication bias may be present

44




(-0.66, 0.87) - Lina vs. Sita: 0.25

(-0.37,0.87) - Saxa vs. Sita: 0.15

(-0.43, 0.73) • Change in Systolic Blood Pressure

From Baseline (mmHg) - Lina vs. Saxa: 2.23

(-2.02,6.48) - Lina vs. Sita: -0.3

(-3.65,3.05) - Saxa vs. Sita: -2.52

(-5.67,0.63) (no significant differences between groups)

• Risk of genital tract infections: Lina vs. Sita: 3.05 (0.33,27.76) (no significant differences between groups)

4. Saulsberry et al36 (2015)

• NMA using random-effects model

• Literature search: January 2015 (11 RCTs evaluating DPP4i, SUs, GLP-1, and SGLT2 were included)

To determine the efficacy and safety of antidiabetic agents added-on to metformin and a TZD in T2DM patients inadequately controlled on metformin-TZD dual therapy

• Linagliptin • Sitagliptin

Plus metformin and TZD

Indirect comparisons:

• Weighted mean differences on change in Hb1Ac:

Lina vs. Sita: -0.2; 95% CI:-0.58, 0.19

(no significant differences between groups)

• Weighted mean differences on change in weight:

Lina vs. Sita: 0.46, 95% CI:-0.61, 1.53

Indirect comparisons:

Weighted mean differences on relative risk of confirmed hypoglycemia:

Lina vs. Sita: 5.19, 95% CI: 0.73, 36.89

• Heterogeneity and inconsistency in the network.

5. Craddy et al37 (2014)

• Bayesian NMA (using Markov Chain Monte Carlo)

Mixed treatment comparison meta-analyses Were performed to demonstrate the relative

• Monotherapy (alo, lina, saxa, sita, vilda)

• All DPP-4+Met • All DPP-4+SU • Lina, sita,

vilda+Met+SU

Mixed treatment comparison: • Weighted mean differences on

change from baseline in Hb1Ac (95% CrI): No differences between DPP-4i

• Weighted mean differences on change in weight:

• Hypoglycemia: No differences between DPP-4i

• Comparison of OR from different studies

• Imprecision: very wide interval for alo+met

45




• Literature search: November 2012 (83 RCTs)

treatment effects of each DPP-4 inhibitor (alo, lina, saxa, sita, vilda) as monotherapy, dual or triple therapy

• Lina, sita, vilda+Pio

• Sita, vilda +Insulin

No differences between DPP-4i • % patients achieving HbA1c <7%;

OR (95% CrI): 6.41 (3.15 to 11.98) with alo+met vs. 2.17 (1.56 to 2.95) with saxa+met (CrI do not overlap; statistically significant difference between groups)

• Small number of studies in some network

6. Messori et al38 (2014)

• Therapeutic equivalence study using data drom Craddy et al37

To evaluate the degree of therapeutic equivalence for DPP-4 inhibitors given in T2DM as monotherapy or in combination with metformin

• Alo, lina, saxa, sita, vilda as monotherapy

• Alo, lina, saxa, sita, vilda as dual therapy with metformin

Endpoint: HbA1c change from baseline (equivalence margin= ±0.25% change in HbA1c) • “Given as monotherapy, lina, sita,

and vilda (but not saxa) met the equivalence criterion when compared with one another”

• “Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion”

Not reported • Analysis based on the same clinical material already published by Craddy et al.

Abbreviations: Alo, alogliptin; AE, adverse events; CrI, credible interval; DPP-4i, dipeptidyl peptidase-4 inhibitors; Empa, empagliflozin; FPG, fasting plasma glucose; GI, gastrointestinal; GLP-1, glucagon-like peptide-1 analogues; Lina; linagliptin; NMA, network meta-analysis; OHA; oral hypoglycemic agents; OR, odds ration; PBO, placebo; Pio, pioglitazone; PPG, postprandial plasma glucose; RR, relative risk; Saxa, saxagliptin; Sita, sitagliptin; SGLT2, sodium-glucose cotransporter-2; SU, sulfonylureas; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione

46

Appendix D

Table 1. List of Excluded References Wrong study design 1. Aroda VR, Henry RR, Han J, et al. Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis

and Systematic Review. Clinical Therapeutics. 2012;34(6):1247-1258.e1222. 2. Cai X, Gao X, Yang W, et al. DPP-4 Inhibitor Treatment in Chinese Type 2 Diabetes Patients: A Meta-

Analysis. Diabetes Technology and Therapeutics. 2016;18(12):784-793. 3. Esposito K, Chiodini P, Maiorino MI, et al. A nomogram to estimate the HbA1c response to different DPP-4

inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. BMJ open. 2015;5(2):e005892.

Wrong Comparator 4. Berhan A, Berhan Y, Author A, et al. Efficacy of alogliptin in type 2 diabetes treatment: A meta-analysis of

randomized double-blind controlled studies. BMC Endocrine Disorders. 2013;13 Article Number: 9. 5. Clar C, Gill JA, Court R, et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in

type 2 diabetes. BMJ open. 2012;2:5 Article Number: e001007. 6. Dai X, Wang H, Jing Z, Fu P. The effect of a dual combination of noninsulin antidiabetic drugs on lipids: a

systematic review and network meta-analysis. Current medical research and opinion. 2014;30(9):1777-1786.

7. Deacon CF, Mannucci E, Ahrén B, et al. Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis. Diabetes, Obesity and Metabolism. 2012;14(8):762-767.

8. Esposito K, Cozzolino D, Bellastella G, et al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: Meta-analysis of randomized controlled trials. Diabetes, Obesity and Metabolism. 2011;13(7):594-603.

9. Gamble JM, Clarke A, Myers KJ, et al. Incretin-based medications for type 2 diabetes: an overview of reviews. Diabetes, obesity & metabolism. 2015;17(7):649-658.

10. Goldman-Levine JD, Author A, McPhs U, Boston US, Correspondence A, J.D. Goldman-Levine MUBUS. Combination Therapy When Metformin Is Not an Option for Type 2 Diabetes. Annals of Pharmacotherapy. 2015;49(6):688-699.

11. Monami M, Iacomelli I, Marchionni N, et al. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials. Nutrition, Metabolism and Cardiovascular Diseases. 2010;20(4):224-235.

12. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: A Randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapaglif lozin to metformin. Diabetes care. 2015;38(3):376-383.

13. Wang T, Wang F, Zhou J, et al. Adverse effects of incretin-based therapies on major cardiovascular and arrhythmia events: meta-analysis of randomized trials. Diabetes/metabolism research and reviews. 2016;32(8):843-857.

14. Wu D, Li L, Liu C, et al. Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes, Obesity and Metabolism. 2014;16(1):30-37

Newer more robust SR available 15. Gerrald KR, Van Scoyoc E, Wines RC, et al. Saxagliptin and sitagliptin in adult patients with type 2 diabetes:

A systematic review and meta-analysis. Diabetes, Obesity and Metabolism. 2012;14(6):481-492.

47

Wrong methodology 16. Gross JL, Rogers J, Polhamus D, et al. A novel model-based meta-analysis to indirectly estimate the

comparative efficacy of two medications: An example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus. BMJ open. 2013;3:3 Article Number: e001844.

17. Kania DS, Gonzalvo JD, Weber ZA. Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. Clinical Therapeutics. 2011;33(8):1005-1022.

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