Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Single-Ingredient Prandial Insulins

Inhalable Insulin Insulin (Afrezza)

Injectable Insulin Insulin Aspart (Fiasp, Novolog) Insulin Glulisine (Apidra) Insulin Lispro (Admelog, Humalog) Insulin Regular, Human (Novolin, Humulin)

Report Finalized February 2019 Presented March 2019

Review prepared by: Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, Pharm.D., Clinical Pharmacist Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Joanne LaFleur, Pharm.D., MSPH, Associate Professor University of Utah College of Pharmacy

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2019 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved Contents Executive Summary ...... 2 Introduction ...... 4 Table 1. Prandial Insulin Products ...... 5 Methods ...... 8 Disease Overview ...... 9 Table 2. Glycemic Targets per ADA and AACE/ACE Guidelines ...... 10 Insulin Pharmacotherapy ...... 11 Table 3. American Guideline Recommendations Regarding the Use of Prandial Insulins ... 13 Pharmacology ...... 15 Table 4. Pharmacodynamic and Kinetic Parameters ...... 16 Table 5. Information Regarding Special Populations ...... 18 Direct Comparative Evidence of Prandial Insulins ...... 20 Adults with Type 1 Diabetes Mellitus ...... 22 Adults with Type 2 Diabetes Mellitus ...... 26 Special Populations...... 28 I. Pregnant Women with Pre-Existing Diabetes ...... 28 II. Pregnant Women with Gestational Diabetes ...... 28 III. Pediatric Population with Type 1 Diabetes Mellitus ...... 28 Safety ...... 30 Table 6. Warnings for Prandial Insulins ...... 31 Summary ...... 32 References ...... 33 Appendix A: Medline Literature Search Strategy ...... 37 Appendix B: Embase Search Strategy ...... 38 Appendix C: Excluded Studies ...... 39 Appendix D: Systematic Reviews ...... 41 Appendix E: Summary of Treatment-Effect Differences ...... 60

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Executive Summary

Prandial insulins are administered to control the post-meal blood glucose rise and are classified into two categories: (a) rapid-acting insulin analogs (RAIAs) and (b) short-acting insulins that contain regular human insulin. The single-ingredient RAIAs include inhaled human insulin (Afrezza) and the injectable products containing insulin aspart (Fiasp and Novolog), insulin glulisine (Apidra), and insulin lispro (Admelog and Humalog). Admelog is a biosimilar of the originator insulin lispro, Humalog. The regular human insulin (RHI) products (Novolin R and Humulin R U-100) generally have a longer time-to-onset and duration of action compared to the RAIAs when administered as bolus subcutaneous injections. Concentrated products include Humalog U-200 and Humulin R U-500. The Humulin R U-500 product has unique pharmacokinetic properties with rapid prandial onset and basal activity.

With the exception of Fiasp, only indicated for adults with DM, all other injectable U-100 and U-200 prandial insulins are indicated for adults and children with DM. Afrezza is indicated only for adults and should not be used with coexisting lung disease or for patients who smoke. Humulin R U-500 is indicated for adults or children requiring more than 200 units per day. Insulin dosing is highly individualized per administration route, the patient’s metabolic needs, and glycemic targets. Dose adjustments may be required during acute illness or when there are changes in the patient’s activity level, meal patterns, renal/hepatic functioning, or to concomitant medications.

According to the 2019 American Diabetes Association (ADA) practice guideline, most patients with type 1 diabetes mellitus (T1DM) should receive RAIAs, over RHI, to minimize the risk of hypoglycemia. While no preference is specified for one particular RAIA over another, authors highlight that the minimum dosing increment for inhaled insulin of 4 units could potentially limit the ability to fine-tune a patient’s dose. For patients with type 2 diabetes mellitus (T2DM), the ADA guideline describes that there are no important differences between RAIAs versus RHI, with respect to hemoglobin A1c (A1c) or hypoglycemia outcomes. In contrast, the 2018 American Academy of Clinical Endocrinologists and American College of Endocrinology practice guideline for T2DM management supports the use of RAIAs or inhaled insulin over the use of RHI. Additionally, the ADA notes that concentrated products may help improve adherence for patients with high insulin requirements.

The research objective of this report was to determine whether there are key efficacy or safety differences between the single-ingredient, prandial insulins for the outpatient management of T1DM, T2DM, or gestational diabetes mellitus (GDM), based on direct comparative evidence. Following our literature searches in Embase and Medline for systematic reviews (SRs) of randomized controlled trials (RCTs), we included evidence from 15 SRs. Results are provided per unique patient population and according to the delivery mode (multiple daily injections [MDI] or continuous subcutaneous infusion [CSII]):  RAIAs versus RHI in Adults with T1DM: Regarding adults with T1DM treated by MDI, the RAIAs tended to further reduce A1c from baseline compared to RHI; however, differences were marginal and unlikely to be clinically meaningful. This was also the case for lispro compared to RHI in the setting of CSII administration. Based on a Cochrane review assessing longer-term trials (of at least 24 weeks), meta-analysis showed RAIAs and RHI were similar with respect to the risk of severe hypoglycemia in T1DM patients treated by MDI.1-3 Authors further concluded that rates of overall

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hypoglycemia did not appear substantially different between aspart or lispro versus RHI, administered via MDI; available RCTs were rated low quality.1 In a single study reported for CSII aspart-treated adults, there were lower rates of symptomatic hypoglycemia and confirmed nocturnal hypoglycemia during the maintenance period with aspart compared to RHI.4,5 RCTs comparing CSII lispro with CSII RHI showed mixed results, either a lower or similar incidence of hypoglycemia with CSII lispro compared to CSII RHI.6  RAIA vs. RAIA in Adults with T1DM: Most studies of an RAIA versus RAIA in adults with T1DM apply to the CSII setting. Only two comparative studies were reported for the MDI therapy in adults with T1DM; no major differences were found between glulisine and lispro, or between the biosimilar products.7,8 In CSII studies, there were no clear differences regarding A1c control and hypoglycemia outcomes regarding comparisons between aspart versus glulisine or lispro. In a single study available for CSII lispro versus CSII glulisine there was no difference in the overall rate of severe hypoglycemic events; however, the rate of confirmed symptomatic hypoglycemic episodes were lower with LIS.9  Afrezza vs. Aspart in Adults with T1DM: One RCT showed that Afrezza was non-inferior to aspart for the reduction in A1c; yet, there were more aspart-treated patients who achieved an A1c <7.0%. There was a lower incidence of severe hypoglycemia and about 1 kg less weight gain with inhaled insulin compared to MDI aspart.10  Adults with T2DM: Meta-analyses conducted in a 2018 Cochrane Review resulted in no significant differences between any single RAIA vs. RHI with respect to A1c change or non-severe hypoglycemic episodes; studies were rated low to very low quality. Moreover, there were no clear differences in the risk of severe hypoglycemic events between agents. Only 2 studies were available comparing RAIAs versus each other for patients with T2DM (1 study each for ASP versus LIS, and Admelog vs. Humalog); no major differences were found.  Pediatric Patients: Based on a 2018 systematic review, there were no clear differences with respect to A1c control or risk of severe hypoglycemic events between aspart or lispro versus RHI, administered by MDI. Regarding nocturnal hypoglycemia, results from individual RCTs were mixed for lispro versus RHI (3 of 5 RCTs reported significant differences in favor of lispro) and no differences were reported for aspart versus RHI.6 In pediatric patients treated via CSII, no major differences were found between lispro versus RHI or between aspart versus lispro for A1c control or hypoglycemia-related outcomes.

According to the Medicaid fee-for-service utilization data, the majority of patients who received a prandial insulin in 2018 used the preferred drug products Humalog and Novolog. There were no fills for the non-preferred products, Fiasp and Afrezza. There was very low use of Apidra, a preferred product, and the non-preferred products, Admelog or regular human insulins, relative to the commonly used agents. Regarding possible preferred agents for inclusion on the Medicaid preferred drug list, maintaining at least 1 rapid-acting product as preferred should be considered.

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Introduction

Prandial insulins are used in diabetes mellitus (DM) to control the post-meal blood glucose rise and are generally classified into two categories: (a) rapid-acting insulin analogs (RAIAs) and (b) short-acting insulins.11 Table 1 details the specific formulations, indications, and dosing for the single-ingredient, prandial insulin products currently available in the United States (US). The prandial insulins listed in Table 1 are indicated for the treatment of adults and children with DM, with the exception of Afrezza and Fiasp that are indicated only for adults with DM. From here on, the letter “U” followed by a number stands for the insulin concentration as insulin units per milliliter (eg, U-200 means 200 units/mL).

The RAIAs include inhaled human insulin (Afrezza) and the injectable products containing insulin aspart (Fiasp and Novolog), insulin glulisine (Apidra), and insulin lispro (Admelog and Humalog). Afrezza is an inhalation powder formulation available in single-use cartridges. It should not be used in patients with coexisting lung disease or in patients who smoke. The remaining products in Table 1 are injectable agents that are administered subcutaneously in the outpatient setting. Admelog is a biosimilar of the originator insulin lispro, Humalog. Biosimilar products produce the same clinical effect as the reference product and are considered interchangeable by the US Food and Drug Administration (FDA).12 The regular human insulin products (Novolin R and Humulin R U-100), which are identical in structure to native human insulin, have a longer time-of-onset and duration-of-action compared to the RAIAs when administered as bolus subcutaneous injections. An advantage of RAIAs over regular human insulin is that they can be administered closer to mealtime; thus, patients can more easily match prandial insulin doses to their carbohydrate intake.

Available concentrated products include Humalog U-200 KwikPen and Humulin R U-500 vials and KwikPen. Humulin R U-500 is specifically indicated for patients requiring more than 200 units per day. The American Diabetes Association (ADA) guideline notes that “…concentrated preparations may be more comfortable for the patient and may improve adherence for patients with insulin resistance who require large doses of insulin.”11,13 The Humulin R U-500 product has unique pharmacokinetics that may be desired for certain patients. With subcutaneous dosing at >0.4 units/kg, the U-500 regular insulin product has a rapid onset (<15 minutes) with basal activity throughout the day.14 The U-500 product is available in a 20 mL multiple-dose vial and in a 3 mL prefilled pen (this is the only pen available containing regular human insulin). The dedicated syringe for the U-500 vial product must be used to reduce the risk of dosing errors.14

Insulin dosing is highly individualized per administration route, the patient’s metabolic needs, and glycemic targets. Dose adjustments may be required during acute illness or when there are changes in the patient’s activity level, meal patterns, renal/hepatic functioning, or to concomitant medications.

The research objective of this report is to determine whether there are key efficacy or safety differences between the single-ingredient, RAIAs for the outpatient management of type 1 DM (T1DM), type 2 DM (T2DM), or gestational diabetes mellitus (GDM), based on direct comparative evidence. The Utah Medicaid Preferred Drug List (PDL) groups all prandial insulins together under the “Rapid Acting Insulin” group, including regular human insulin. The following products are listed as preferred: Apidra vials and SoloStar pen; Novolog vials and pen; and Humalog vials and pen. Non-preferred products include Admelog, Afrezza, Fiasp, Humulin R, and Novolin R.

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Table 1. Prandial Insulin Products14-22 Agents

(Approval Year) Indications and Administration Information Formulations Rapid-Acting Human Insulin Analogs

Indication: for the treatment of adults with DM, to improve glycemic control Insulin Human • In patients with T1DM, must use with a long-acting insulin • Not recommended for the treatment of diabetic ketoacidosis or for patients Powder for Inhalation who smoke (2014) Dosing Single-use Cartridges • Use by a single inhalation per cartridge and at the beginning of a meal Afrezza 4 units, 8 units, and • For insulin naïve patients, start on 4 units of Afrezza at each meal 12 units per cartridge • For patients switching from another prandial insulin, see the package insert for a dose conversion table

Indication • Fiasp Insulin Aspart : for the treatment of adults with DM, to improve glycemic control • Novolog: for the improvement of glycemic control in adults and children with DM. The safety and effectiveness have not been established in pediatric (Fiasp, 2017; patients younger than 2 years or in pediatric patients with T2DM Novolog, 2000) Subcutaneous Injection • Fiasp : Inject at the start of a meal or within 20 minutes after starting a meal into the abdomen, upper arm or thigh Solution, 10mL Vial • Novolog: Inject subcutaneously within 5-10 minutes before a meal into the Fiasp U-100 abdominal area, thigh, buttocks or upper arm Novolog U-100 • Insulin aspart products should generally be used in regimens with an intermediate- or long-acting insulin Solution, 3mL Cartridge Fiasp PenFill U-100 Subcutaneous Infusion with Insulin Pump, Novolog only Novolog PenFill U-100 • Change the vial in the reservoir at least every 6 days, and the infusion set and the infusion set insertion site at least every 3 days • Solution, Pen-injector, 3mL Do not mix with other insulins or diluents Fiasp FlexTouch U-100 Intravenous Administration, Fiasp and Novolog Novolog FlexPen U-100 • Dilute to 0.05 unit/mL to 1 unit/mL insulin aspart in infusion systems using Novolog FlexTouch U-100 polypropylene infusion bags

Opened or unrefrigerated insulin aspart products expire in 28 days

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Table 1. Prandial Insulin Products14-22 Agents

(Approval Year) Indications and Administration Information Formulations

Indication: for the improvement of glycemic control in adults and children with DM. The safety and effectiveness have not been established in pediatric patients younger than 4 years old, or in children with T2DM Insulin Glulisine Subcutaneous Injection (2004) • Administer within 15 minutes before or within 20 minutes after starting a meal into the abdominal wall, the thigh, or upper arm. • Should generally be used with an intermediate or long-acting insulin Solution, 10mL Vial • Can be mixed with NPH human insulin Apidra U-100 Subcutaneous Infusion with Insulin Pump Solution, Pen-injector, 3mL • Change the reservoir and infusion set every 48 hours Apidra SoloStar U-100 • Do not mix with other insulins or diluents

Opened or unrefrigerated Apidra products expire in 28 days

Insulin Lispro Indication • Admelog: for the improvement of glycemic control in adults and children ≥ 3 (Admelog 2017; years of age with T1DM or in adults with T2DM • Humalog: for the improvement of glycemic control in adults and children Humalog 1996) with DM. The safety and effectiveness have not been established in pediatric patients younger than 3 years or in children with T2DM Solution, 3mL Vial Subcutaneous Injection Humalog U-100 • Inject subcutaneously within 15 minutes before a meal or immediately after a Solution, 10mL Vial meal into the abdominal area, thigh, buttocks or upper arm Admelog U-100 • Should generally be used with an intermediate- or long-acting insulin Humalog U-100 Subcutaneous Infusion with Insulin Pump, Admelog and Humalog U100 Solution, 3mL Cartridge • Change the vial in the reservoir at least every 7 days; and the infusion set and Humalog U-100 the infusion set insertion site at least every 3 days • Do not mix with other insulins or diluents in the pump Solution, Pen-injector, 3mL Intravenous Administration, Admelog and Humalog U100 Admelog SoloStar U-100 Dilute to 0.01 unit/mL to 1 unit/mL insulin lispro using normal saline Humalog Junior KwikPen

U-100 Humalog KwikPen U-100 Opened or unrefrigerated insulin lispro products expire in 28 days and U-200

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Table 1. Prandial Insulin Products14-22 Agents

(Approval Year) Indications and Administration Information Formulations Short-Acting Human Insulin Humulin R U-100 Insulin Regular Indication: as an adjunct to diet and exercise to improve glycemic control in adults and children with DM

Subcutaneous Injection (Humulin R 1982; • For subcutaneous use (in the abdomen, thigh, gluteal region or upper arm), Novolin R 1991) 30 minutes before a meal and should generally be used along with intermediate or long-acting insulin • Can mix with Humulin N Solution, 3mL Vial • No information is provided in the label regarding use in infusion pumps for the U- Humulin R U-100 100 product Solution, 10mL Vial Intravenous Administration Humulin R U-100 • Can be used intravenously at concentrations from 0.1 unit/mL to 1 unit/mL, Novolin R U-100 diluted with normal saline Novolin R ReliOn U-100 Humulin R U-500a Solution, 20mL Vial: Indication: to improve glycemic control in adults and children with diabetes mellitus Humulin R U-500 requiring more than 200 units of insulin per day Solution, Pen-injector, 3mL • For subcutaneous use (in the abdomen, thigh, buttock, or upper arm) usually Humulin R U-500a KwikPen administered 2 to 3 times daily 30 minutes before a meal • Safety and efficacy has not been established in combination with other insulins or when delivered by infusion pumps

Novolin R U-100

Indication: to improve glycemic control in adults and children with DM; The safety and effectiveness have not been established in pediatric patients less than 2 years

old or in pediatric patients with T2DM. Subcutaneous Injection • For subcutaneous use (in the abdomen, thigh, buttock, or upper arm) 30 minutes before a meal, and should generally be used along with intermediate or long- acting insulin • Can mix with NPH human insulin • Total daily insulin requirements vary and are usually between 0.5 and 1.0 units/kg/day. Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or co-administered medications • Use in insulin pumps is not recommended because of the risk of precipitation Intravenous Administration • Can be used intravenously at concentrations from 0.1 unit/mL to 1 unit/mL, diluted with normal saline, 5% dextrose or 10% dextrose with 40 mmol/L KCL

Expiration for opened or unrefrigerated products: Humulin R U-100 vials, 31 days; Humulin R U-500 vials, 40 days; Humulin R U-500 KwikPen, 28 days; Novolin R vials, 42 days Abbreviations: DM, diabetes mellitus; KCL, potassium chloride; SQ, subcutaneous; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus a Humulin R U-500 has a rapid onset and an extended duration of action, with both prandial and basal activity.

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Methods

Systematic Literature Search

Search strategies were developed for systematic reviews (SRs) in Ovid-Medline and Embase; databases were searched up to December 20th and 22nd, respectively. Strategies consisted of controlled vocabularies, such as Medical Subject Headings (MeSH), and keyword phrases. Independently derived filters by an Informational Scientist were used to identify SRs. In Embase, we excluded conference abstracts. Results were limited to English language. The complete search strategies, and terms are available in Appendices A and B. We also screened the reference lists and other relevant websites for further information:

I. For treatment guidelines addressing diabetes management with insulin therapy we searched websites of the American Diabetes Association (ADA) (https://professional.diabetes.org/), and the American Association of Clinical Endocrinologists (https://www.aace.com/publications/guidelines).

II. For professional prescribing information (ie, product labeling) we searched the drug sponsor’s website for each brand product, or websites such as Drugs@FDA and dailymed.nlm.nih.gov/dailymed/ if there was no sponsor website available (package inserts searched for on December 3rd to 6th, 2018)

III. Evidence-based drug information databases, Micromedex and Lexicomp

Screening

Two reviewers independently screened publication titles and abstracts for inclusion. Conflicts were resolved by consensus between reviewers. The full text for all citations receiving 2 inclusion votes were retrieved. The lead author made the final determination for inclusion upon full-text review. Figure 1 on page 20 shows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart for the literature screening process.

Inclusion and Exclusion Criteria

Considered for inclusion was evidence based on randomized controlled trials, among systematic reviews, comparing efficacy or safety outcomes between the prandial insulins for the outpatient management of T1DM, T2DM, or GDM. Direct, pair-wise meta-analysis (MA) statistical data was included, while mixed- or indirect-comparative statistical data (ie, network meta-analyses) was excluded. We considered studies in which the same insulin delivery mode was used for the comparator arm (eg, continuous subcutaneous insulin infusion [CSII] or by multiple daily doses [MDD]) and with matching concomitant antihyperglycemic agents in the comparator arm. We focused on evidence from trials with treatment lasting at least 12 weeks, since lesser durations would confound effects on hemoglobin A1c. SRs including the most up-to-date evidence was included; SR publications were excluded if they missed more recently published RCTs. For comparisons involving inhaled insulin, only studies with the current approved product (Afrezza with the Gen2 inhaler) were considered. Meta- analysis summary results were included if they reported separate estimates for each insulin agent and distinguished effects in key populations separately (eg, results in T1DM separate from those in T2DM).

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Disease Overview

Patients with diabetes mellitus have impaired glucose homeostasis that leads to hyperglycemia, hypertriglyceridemia, ketoacidosis, and tissue catabolism.13 Adequate glycemic control reduces microvascular complications (eg, retinopathy, nephropathy) and macrovascular complications (eg, myocardial infarction, stroke) that result from chronic hyperglycemia.11 In T1DM, insulin-producing, pancreatic beta-cells are destroyed by autoimmune processes (or idiopathic cause) and patients require exogenous insulin to thrive.23 The estimated prevalence of T1DM in the US is approximately 3 million patients.24 Patients with T2DM have varying degrees of insulin resistance and insufficiency of insulin secretion.13 Early on in the disease, patients with T2DM are usually managed with oral antihyperglycemic therapies, unless patients are markedly symptomatic or with a very high hemoglobin A1c (A1c) or blood glucose at diagnosis— requiring insulin expediently.13 While lifestyle management is at the core of T2DM treatment, the disease is progressive and eventually many patients will require exogenous insulin.11,23 The Centers for Disease Control and Prevention estimates that more than 30 million Americans have diabetes with the majority of cases (90% to 95%) being T2DM.25

In the ambulatory setting, patients receive prandial insulin (ie, rapid- or short-acting insulin for the management of the post-meal glucose rise), usually in combination with basal insulin (ie, insulin that controls blood glucose in between meals), with or without other non-insulin antihyperglycemic agents.11 Prandial U-100 insulins may also be used alone in a continuous infusion pump.

A1c “…has strong predictive value for diabetes complications…,” so is used as the major tool to evaluate glycemic control in patients with diabetes.13 A1c reflects the average blood glucose over approximately the preceding 3 months (ie, how well patients have been controlled over this period).13 Treatment guidelines recommend individualizing the patient’s A1c goal with consideration of patient-specific factors such as their age, duration of disease, co-morbidities, motivation, self-management ability, preferences, risk for hypoglycemia, and their hypoglycemia awareness.13,26 Once insulin therapy is initiated, appropriate control of fasting blood glucose generally relates the optimization of the basal insulin regimen; however, in some situations it can also depend on dosage/duration of action of the prandial insulin used. For patients requiring prandial insulin for the management of post-prandial blood glucose, the dose and timing must be tailored to match the patient’s carbohydrate intake, pre-meal glucose levels, and anticipated activity.13

Table 2 lists the glycemic targets described in US treatment guidelines for the management of diabetes along with other glycemic targets for fasting and post-prandial blood glucose levels.

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Table 2. Glycemic Targets per ADA and AACE/ACE Guidelines ADA Diabetes Care Guideline, 201913 Adults, non-pregnant • A1c target is generally <7% • A lower A1c target of <6.5% can be set for individuals at low risk for hypoglycemia, polypharmacy, or other adverse effects. Such patients may include those with shorter duration of diabetes, T2DM treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease • A1c target of <8% may be appropriate in individuals with a history of severe hypoglycemia, advanced macro- or micro-vascular complications, extensive comorbidities, long-standing diabetes and inability to achieve lower threshold targets • Pre-prandial capillary plasma glucose target is 80-130 mg/dL, but can set to a more or less stringent goal per the patient’s needs • Peak postprandial capillary plasma glucose (1-2 hours after beginning of the meal) target is <180 mg/dL, but can be set to a more or less stringent goal per patient need Older Adults • A1c target of <7.5 for older adults who are otherwise healthy older adults (eg, few coexisting chronic diseases, intact cognitive function and functional status) • A1c goal of <8% or <8.5% for older adults with multiple coexisting chronic illnesses, cognitive impairment, functional dependence Children and Adolescents with T1DM • A1c target of 7.5% should be considered but goals should be individualized based on patient/caregiver needs/situation; a lower goal (<7%) is reasonable if it can be achieved without hypoglycemia • Before meals serum glucose goal is 90 – 130 mg/dL and the bedtime/overnight goal is 90-150 mg/dL Pregnant Women • A1c goal of 6%-6.5% to reduce the risk of congenital anomalies; the goal can be set to <6% if it can be achieved without hypoglycemia, or can be relaxed to <7% to prevent hypoglycemia

AACE/ACE T2DM Management Guideline, 201826 Adults with T2DM • General A1c target is ≤6.5% if it can be achieved without significant hypoglycemia or other complications. • An A1c target of >6.5%-8% is recommended for those in whom the lower target cannot be achieved without adverse outcomes (eg, patients with history of severe hypoglycemia, limited life expectancy, advanced renal disease or macrovascular complications, extensive comorbid conditions, or long- standing T2DM with difficulty controlling A1C goal despite intensive effort)

Abbreviations: A1c, glycosylated hemoglobin A1c; AACE/ACE, American Academy of Endocrinologists and American College of Endocrinology; ADA, American Diabetes Association; T2DM, type 2 diabetes mellitus

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Insulin Pharmacotherapy

Preferences Specified Among ADA and AACE/ACE Guidelines Regarding Prandial Insulins

Regarding prandial insulins, the 2019 ADA guideline states that “[m]ost individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk.”13 While no preference is specified for one particular RAIA over another, authors highlight that the minimum dosing increment of 4 units for inhaled insulin, Afrezza, could potentially limit the ability to fine-tune a patient’s dose.11,13

For patients with type 2 diabetes, the 2019 ADA guideline cites two meta-analyses to describe that there are no important differences between RAIAs versus regular human insulin (RHI), with respect to A1c or hypoglycemia outcomes.13 In contrast, the 2018 American Academy of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guideline for T2DM supports the use of rapid-acting insulins or inhaled insulin, over the use of regular human insulin because, “…the former have a more rapid onset and offset of action and are associated with less hypoglycemia.”26 This statement, however, was not based on an independent systematic review of the literature.

Type 1 Diabetes Mellitus

The majority of patients with T1DM should be treated with multiple daily doses of prandial insulin and basal insulin, or by continuous subcutaneous insulin infusion (CSII).11,13,24 Children and adolescents, especially, should be treated with intensive insulin regimens. The ADA recommends considering CSII for all children and adolescents with T1DM, especially children under 7 years of age. Insulin pumps can improve glycemic control and reduce hypoglycemia in children.11,13 CSII devices have features that can benefit patients, especially children who may have unpredictable eating and exercise patterns.27

The ADA recommends the use of rapid-acting insulins analogs over RHI for all T1DM patients, in order to reduce hypoglycemia risk.13 Total daily insulin requirements are generally between 0.4 to 1 units/kg/day with higher doses needed during puberty, pregnancy, and medical illness. The benefit of intensive therapy must be balanced with the patient’s risk of hypoglycemia, and patient/caregiver preferences. Patients must match prandial insulin dosing to carbohydrate intake, pre-meal glucose levels, and anticipated activity.11

Type 2 Diabetes Mellitus

Metformin is the recommended first-line antihyperglycemic agent for all patients without contraindications.13 For newly diagnosed patients whose A1c is ≥1.5% above target or for patients who are not achieving their target A1c after 3 months of metformin monotherapy, the ADA recommends dual-therapy with metformin. Addition of the second glucose-lowering agent is selected according to patient co-morbidities, hypoglycemia risk, impact of potential weight gain, and patient preferences. For patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, the ADA recommended second agent is a glucagon-like peptide 1 (GLP-1) agonist or sodium-glucose co- transporter 2 inhibitor (SGLT2-I) with proven cardiovascular risk reduction; otherwise, the second therapy can be selected from any of the following drug classes: sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 agonists, SGLT2-I, or basal insulin. Early initiation of

11 insulin is recommended if at presentation the patient’s A1c is ≥10%, blood glucose is ≥300 mg/dL, or if the patient is symptomatic.13

For patients who go on to receive basal insulin, if glycemic targets are not achieved with basal insulin titrated to an appropriate fasting blood glucose level or if the basal insulin dose exceeds 0.5 units/kg/day, combination injectable therapy containing basal insulin plus either prandial insulin or a GLP-1 agonist (if not already on one) should be considered.13 When combination injectable regimens are employed, metformin is continued, while sulfonylureas and DPP-4 inhibitors are usually discontinued. Prandial insulin is initiated as one dose before the largest meal and can be up-titrated to twice or three times daily with meals according to the patient’s needs. Providers must balance the potential benefits of an intensive insulin regimen approach with the risk of hypoglycemia and weight gain.13

Type 2 Diabetes Mellitus in Pediatric Patients

According to the ADA treatment algorithm, there are generally two scenarios by which pediatric patients with T2DM may be started on basal insulin: 1) if patients are not meeting their A1c goal with metformin monotherapy, or 2) if patients are symptomatic (without acidosis or without ketosis) with hyperglycemia and A1c ≥8.5% at diagnosis.13 If patients remain uncontrolled with basal insulin titrated up to 1.5 units/kg/day, then prandial insulin is added or patients may be converted to pump therapy.13

Pregnant Women with Diabetes

Treatment of pregnant women with diabetes improves perinatal outcomes, reducing perinatal risks such as fetal anomalies, preeclampsia, macrosomia, and neonatal hypoglycemia associated with uncontrolled diabetes in pregnancy.11 Insulin is the first-line therapy for gestational onset diabetes mellitus (GDM) and for pregnant women with pre-existing type 1 or type 2 diabetes because it does not cross the placenta. Efficacy of oral agents is generally insufficient and/or ineffective during pregnancy; safety evidence on their long-term use in pregnant women is also lacking.11,13 The ADA cites a 2017 Cochrane Review by O’Neil et al describing no clear superiority of any specific insulin regimen over another for diabetes management during pregnancy.13,28

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Table 3. American Guideline Recommendations Regarding the Use of Prandial Insulins Professional Organization Statements  Guideline American Diabetes Association Type 1 DM • Insulin is the mainstay therapy, starting with 0.4-1 units/kg/day  Standards of Medical Care in • Most patients with T1DM should be treated with concomitant basal Diabetes; 201913 insulin with multiple daily injections of prandial insulin, or by continuous subcutaneous insulin infusion (Level A recommendation) • Most patients with T1DM should use rapid-acting insulin analogs to reduce hypoglycemia risk. (Level A recommendation) • Insulin requirements are higher during puberty, pregnancy and medical illness.

• Balance intensive therapy with hypoglycemia risk.

Type 2 DM

• With the progressive nature of T2DM, patients often require insulin- containing regimens. • Combination injectable therapy of basal insulin regimen plus either prandial insulin or a GLP-1 RA can be employed if patient is not meeting their A1c goal after already being titrated onto basal insulin. • Prandial insulin is initiated as one dose before the largest meal or with the greatest excursion in post prandial glucose. May increase to twice or three times daily dosing of prandial insulin if needed. o The prandial insulin dose per meal should be initiated at 4 units or 10% of the basal dose; if the patient has an A1c< 8%, consider decreasing the basal dose by the same amount. Dose adjustments by 1-2 units or 10%-15% up to twice weekly can be made to achieve A1c control. Dose adjustments by 2-4 units or 10-20% may be made to mitigate an unclear cause of hypoglycemia. Management considerations • “A patient-centered approach should be used to guide the choice of pharmacologic agents,” taking into consideration efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, administration method, cost, and patient preferences. • Patients should be provided an algorithm for insulin titration based on self-monitored blood glucose levels. Older Adults • For older adults at increased risk of hypoglycemia, ADA generally prefers medication classes with low risk of hypoglycemia. • Consider simplifying regimens of multiple daily injections that may be too complex for patients with diabetes complications, life-limiting coexisting chronic illnesses, or limited functional status. Children and Adolescents • The ADA states that most patients with T1DM should be treated with rapid-acting insulin analogs to reduce the risk of hypoglycemia. • “The majority of children and adolescents with type 1 diabetes should be treated with intensive insulin regimens, either via multiple daily injections or continuous subcutaneous insulin infusion.” • Prandial insulin can be considered for patients with T2DM who reach 1.5 units/kg/day of basal insulin and are not achieving their A1c target.

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Table 3. American Guideline Recommendations Regarding the Use of Prandial Insulins Professional Organization Statements  Guideline American Academy of Endocrinology and American Patients who remain uncontrolled while receiving combination therapy with College of Endocrinology basal insulin and oral agents or GLP-1 agonists may then require prandial insulin. Additionally, prandial insulin should be considered when the total  Consensus Statement by the daily dose of basal insulin is greater than 0.5 units/kg since the risk of American Association on hypoglycemia increases considerably beyond this dose without much A1c Clinical Endocrinologists and reduction. American College of • Rapid-acting analogs and inhaled insulin are preferred over regular Endocrinology on the human insulin “…because the former have a more rapid onset and Comprehensive Type 2 offset of action and are associated with less hypoglycemia (167).” Diabetes Management • Prandial insulin can be can be started with the largest meal of the day; Algorithm – 2018 Executive additional mealtime doses may be added later if needed. Summary26

Abbreviations: A1C; glycosylated hemoglobin; CSII, continuous subcutaneous insulin infusion with type 1; DM, diabetes mellitus; FBG, fasting blood glucose; GLP-1, glucagon-like peptide, GDM, gestational diabetes mellitus; MDI, multiple daily injections; PK, pharmacokinetics; PPG, post prandial glucose; RAIA, rapid acting insulin analog; RHI, regular human insulin; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

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Pharmacology

Insulin analogs bind to insulin receptors in peripheral sites of skeletal muscle and adipose tissue stimulating glucose uptake and protein synthesis, while inhibiting hepatic glucose production, lipolysis in adipocytes, and proteolysis.15,16 There is considerable variability in the pharmacodynamics of insulins between individuals or even within the same individual,15-17 and “[t]he rate of insulin absorption and onset of activity is affected by the site of injection, exercise, and other variables.”17

The inhaled human insulin product (Afrezza) utilizes a carrier protein technology for delivery into the lungs.15 The insulin molecule in Afrezza is identical to native human insulin,15 as are the regular human insulin injectable products (Novolin R and Humulin R). Humulin R labeling describes that “[t]he uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.”21

Insulin aspart, glulisine, and lispro are homologous to native human insulin differing by one or two amino-acid substitutions.16-20,22 Upon subcutaneous injection, these substitutions yield a quicker absorption into the blood stream compared to regular human insulin. The Fiasp formulation of insulin aspart has two excipients added, nicotinamide (ie, vitamin B3) and L-arginine, to shorten the onset of action compared to the originator insulin aspart product, Novolog. FDA reviewers explained, “…the earlier onset of action would allow for dosing closer to mealtime or even after the meal with resultant better matching to carbohydrate intake.”29 Compared to Novolog, pharmacokinetic studies showed a significantly faster onset of appearance, about twice as fast, and about 10 minutes faster in the time to maximum concentration.29

Concentrated products include Humalog U-200 KwikPen and Humulin R U-500 vials and KwikPen. The ADA guideline notes that “…concentrated preparations may be more convenient and comfortable for patients to inject and may improve adherence in those with insulin resistance who require large doses of insulin.”13 The U-200 Humalog product is bioequivalent to U-100 Humalog, as they have similar pharmacokinetic and pharmacodynamic (PK/PD) profiles when used at the same unit/kg dose.20,30 Humulin U-500 is approved for patients that require more than 200 units of insulin a day.14 It has a unique PK/PD profile, with both a rapid onset of action and long duration of action when used subcutaneously at doses between 0.4 to 1.3 units/kg; the mean time-of-onset is within 15 minutes and mean duration-of-action is 21 hours.14 Compared to an MDI prandial/basal regimen with multiple single- entity products, the U-500 regular human insulin product may allow for fewer daily injections since it can be used as the patient’s complete insulin regimen administered twice or three times daily.14,30

Table 4 provides a summary of pharmacodynamic and kinetic parameters for the prandial insulins. Regarding table 4 formatting, some parameters were provided with respect to a certain weight-based dosing (eg, values appear in line with doses), while some parameters were provided without the dose used (eg, values aligned with the drug name). Table 5 provides additional information pertaining to use in special populations.

15

Table 4. Pharmacodynamic and Kinetic Parameters15-20,22,31 First Measured Tmax Peak Effect T1/2 Duration of action Effect (minutes) (hours) Rapid-Acting Insulins

Insulin Human

Afrezza 10-20 120-206

4 U 12 35 1.5 12 U 12 45 3 48 U 12 55 4.5

Insulin Aspart

Fiasp

0.1 U/kg SQ 20 91 5 0.2 U/kg SQ 17 ̴63 (SQ) 122 68 (SQ) 6 0.4 U/kg SQ 16 133 7

Novolog 12-18 40-50 (SQ) 81 (SQ) 0.15 U/kg SQ 60-180 3-5

Insulin Glulisine Apidra 12-30 96-168 42 3-4 0.15 U/kg/SQ 60 (range 40-120) 0.2 U/kg SQ 100 (range 40-120)

Insulin Lispro 15-30 <5 Admelog 51-55 (based on 0.3 U/kg/SQ 50 124 “another lispro product”)

Humalog 60 60 20 units 168 and 144, with U-200 and U-100 respectively

16

Table 4. Pharmacodynamic and Kinetic Parameters15-20,22,31 First Measured Tmax Peak Effect T1/2 Duration of action Effect (minutes) (hours) Short-Acting Insulins Insulin Regular

8 Novolin R 30 90-210 5 0.1 U/kg 90-210

Humulin R 0.05- 0.4 U/kg SQ 30 (range 10 to 75) 120 (range 20 to 360) 180 (range 20-420) median 90 8 ( range 3-14)

50 U or 100 U 180 (range 60-480) mean 216 18 (range 12-24)

Humulin R U-500 50 U or 100 U <15 240-480 270 21 (range 13-24)

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Table 5. Information Regarding Special Populations14-22,32 Pediatric Patients Pregnant Women Geriatric Patients Renal or Hepatic Impairment

Human data is insufficient to determine risk; however, animal Inhaled data suggests low risk to fetus Human Not approved for pediatric Insulin patients Based on animal data, it is highly likely that the insulin and (Afrezza) carrier particle are excreted in human milk; use with caution

No differences in safety and Patients with renal or impairment may effectiveness were evident in be at increased risk of hypoglycemia. Insulin Aspart Not approved for pediatric subgroup analyses for patients Studies with human insulin have shown older than 65 years; however, increased exposure in patients with patients There is limited human data; (Fiasp) older adults should be treated renal or liver failure; thus, more probably compatible in more conservatively when frequent blood glucose monitoring and Indicated to improve glycemic pregnancy per Briggs et al32 initiating and titrating doses to dose adjustment may be necessary in Insulin Aspart control in adults and children with DM; has not been Compatible during avoid hypoglycemia patients with these co-morbidities breastfeeding per Briggs et al32 studied in pediatric patients (Novolog) below 2 years of age or in pediatric patients with T2DM Indicated to improve glycemic No human data; probably Insulin control in adults and children compatible in pregnancy per Glulisine with DM; has not been Briggs et al32

studied in pediatric patients Compatible during (Apidra) younger than 4 years old or in breastfeeding per Briggs et al32 pediatric patients with T2DM

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Table 5. Information Regarding Special Populations14-22,32 Pediatric Patients Pregnant Women Geriatric Patients Renal or Hepatic Impairment Humalog: Indicated to improve glycemic control in adults and children with DM; Retrospective data in pregnant No differences in safety and has not been studied in women have not found an effectiveness were evident in patients younger than 3 years Patients with renal or impairment may association between use of subgroup analyses for patients Insulin of age or in pediatric patients be at increased risk of hypoglycemia. insulin lispro and birth defects, older than 65 years; however, Lispro with T2DM Studies with human insulin have shown miscarriage, or adverse older adults should be treated increased exposure in patients with

(Admelog and maternal or fetal outcomes. more conservatively when renal or liver failure; thus, more Humalog) Admelog: Indicated to Compatible during pregnancy initiating and titrating doses to frequent blood glucose monitoring and improve glycemic control in and breastfeeding per Briggs et avoid hypoglycemia. dose adjustment may be necessary in adults and pediatric patients al32 patients with these co-morbidities ≥ 3 years of age with T1DM

and in adults with T2DM.

The U-100 products are The effects of age on Insulin indicated to improve glycemic pharmacodynamics of regular Regular control in adults and children Compatible during pregnancy insulin have not been with DM. The U-500 product and breastfeeding per Briggs et conducted. Older adults should 32 (Humulin R is indicated for adults and al be treated more conservatively and Novolin R) children requiring more than when initiating and titrating 200 units/day. doses to avoid hypoglycemia Abbreviations: DM, diabetes mellitus, T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus

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Direct Comparative Evidence of Prandial Insulins

Our literature search yielded a total of 261 unique titles from which 15 systematic reviews were included. Figure 1 displays the preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart for the publication screening process.33 The majority of SRs excluded during full-text review either did not include a systematic literature search methodology, did not report direct meta- analysis results (ie, network MAs focusing on indirect or mixed comparisons), or missed more recently published RCTs captured in the included systematic reviews. Appendix C provides a list of studies excluded in the full-text review stage. Figure 2, on the next page, shows the systematic reviews included and the patient population for which they apply. Appendix D provides a table describing the design and findings for each systematic review. Appendix E provides an abbreviated summary of the treatment- effect differences between agents that were consistently reported among the comparative evidence.

Figure 1. PRISMA Flow chart for Publication Screening

Records identified from search strategies in Appendix A and B • Embase 224 • OvidMedline 120

Identification

Records screened, duplicates removed in Covidence Records excluded

Screening (261) (225)

Full-text articles assessed Full-text articles excluded, a

Eligibility for eligibility with reasons (36) (21) Wrong population (1) Wrong comparator (4)

Wrong study design (8) Publications included in Other (8) qualitative synthesis (15) Included

a See Appendix C for descriptions

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Figure 2. Included Systematic Reviews Systematic review Indication Area first author and publication year

Yamada 2018 Tieu 2018 Ovalle 2017 Adults with T1DM Fullerton 2016 Treated by MDI Pittas 2015 Wojciechowski 2015 Sanches 2013 CADTH 2008

Norgaard 2018 Adults with T1DM CADTH 2008 Treated by CSII Colquitte 2003

Fullerton 2018 Tieu 2018 Comparative Yamada 2018 Evidence for Ovalle 2017 Prandial Insulins Adults with T2DM Pittas 2015 Wojciechowski 2015 Heller 2013 Mannucci 2009 CADTH 2008

Norgaard 2018 Pregnant Women O'Neill 2017 Brown 2017

Pediatric Patients Norgaard 2018 with T1DM CADTH 2008

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Section Format: The remainder this section is formatted to reflect data respective to the unique population studied and by which insulin was administered (ie, via multi-daily dosing [MDI] or continuous subcutaneous insulin infusion [CSII]. Adults with Type 1 Diabetes A.1. RAIAs versus RHI Administered via MDI for Adults with T1DM A.2. RAIAs versus RAIA via MDI for Adults with T1DM B.1. RAIA versus RHI Administered via CSII for Adults with T1DM B.2. RAIAs versus RAIAs via CSII for Adults with T1DM C. Inhaled Insulin (Afrezza) vs. RAIAs for Adults with T1DM

Adults with Type 2 Diabetes A. Inhaled Insulin (Afrezza) versus RAIAs for Adults with T2DM B.1. RAIA versus RHI for Adults with T2DM B.2. RAIAs versus RAIAs for Adults with T2DM via MDI

Special Populations I. Pregnant Women with Pre-Existing Diabetes Treated by MDI II. Pregnant Women with Gestational Diabetes Treated by MDI III. Pediatric Population with T1DM

ADULTS WITH TYPE 1 DIABETES MELLITUS

A. Multi Daily Dose Injection (MDI) Insulin Treated Adults with T1DM

A.1. RAIAs versus RHI Administered via MDI for Adults with T1DM

A 2016 Cochrane Review (Fullerton et al) included studies of at least 24 weeks duration and performed separate meta-analyses for insulin lispro (LIS) versus RHI and insulin aspart (ASP) versus RHI regarding A1c, severe hypoglycemia, and weight gain outcomes in adults with T1DM.1 Authors found no studies comparing insulin glulisine (GLU) versus RHI. LIS and ASP-treated groups experienced a significantly lower A1c at the end of treatment compared to the RHI treated groups: a) LIS vs. RHI mean treatment difference was -0.20% (95% CI -0.34, -0.05); and b) ASP vs. RHI mean treatment difference was -0.14% (95% CI -0.21, -0.06); evidence was graded as low quality.1 If we consider that a non-inferiority margin of 0.4% for the change in A1c from baseline to endpoint has been used by the FDA to determine clinically meaningful differences in non-inferiority trials34, then these marginal differences are unlikely to be clinically meaningful.

Meta-analyses by Fullerton et al showed no difference between ASP versus RHI or LIS versus RHI for the outcomes of severe hypoglycemia or weight gain (based on low quality evidence).1 Furthermore Cochrane review authors state the following regarding other hypoglycemia outcomes:

“For general hypoglycaemia, also taking into account mild forms of hypoglycaemia, the data were generally of low quality, but also did not indicate relevant group differences. For nocturnal severe hypoglycaemic episodes, two trials reported statistically significant effects in

22

favour of insulin aspart. However, due to inconsistent reporting in publications and study reports, the validity of the result remains questionable.”1

Authors note that all included studies (3 RCTs for ASP versus RHI, and 6 RCTs for LIS versus RHI) were at high risk of performance bias since these were all open-label studies. All studies also had high risk of bias scores in at least one other bias domain.1 The meta-analysis point estimate for the effect of ASP versus RHI on A1c found by Fullerton et al is consistent with other previously published SRs (Wojciechowski et al 20152, Rys et al 201135, and a 2008 SR published by the Canadian Agency for Drugs and Drug Technologies in Health [CADTH]). Wojciechowski et al and Rys et al found that ASP further reduced A1c by -0.11% over RHI in mixed populations of type 1 patients (adults and children with bolus or CSII regimens).2,35 The CADTH 2008 SR found that ASP further reduced A1c by -0.11% in MDI studies lasting at least 3 months, in adults with T1DM.5

Wojciechowski et al 2015, including studies of at least 12 weeks treatment duration, additionally reported meta-analyses results for the effect of ASP versus RHI on postprandial glucose from 4 RCTs of adults with T1DM.2 One of these RCTs was DeVries et al, in which the backbone NPH dosing differed between ASP and RHI treatment arms. Nonetheless, the other three RCTs, independently, consistently showed that post-prandial glucose levels after breakfast, lunch, and dinner were lower with ASP treatment compared to RHI treatment. Meta-analyses of the 4 RCTs resulted in the following weighted mean differences (WMD) for ASP versus RHI with respect to postprandial glucose (PPG): (a) PPG post breakfast WMD –1.40 mmol/L; 95% CI, –1.72, –1.07, (b) PPG post lunch WMD –1.01 mmol/L; 95% CI – 1.61, –0.41, and (c) PPG post dinner WMD –0.89 mmol/L; 95% CI –1.19, –0.59.2

Sanches et al 2013 reported 1 RCT comparing 12 weeks of GLU versus RHI treatment in 860 patients.3,36 When GLU was administered pre-meal (but not when administered post-meal) there was a significantly greater A1c reduction from baseline to endpoint compared to the pre-meal RHI group (treatment difference -0.13%, P=0.02). A greater reduction in 2-hour post-breakfast and post-dinner blood glucose resulted with pre-meal or post-meal GLU use compared to pre-meal RHI use, yet not in the 2-hour post- lunch time point:

• Pre-meal GLU vs. RHI: 140.9 ± 3.1 mg/dL versus 163.8 ± 3.1 mg/dL for post-breakfast BG; and 146.2 ± 3.5 mg/dL versus 166.1 ± 3.5 mg/dL for post-dinner BG; P = 0.0001 for both time points. 3 • Post-meal GLU versus RHI: 140.9 ± 3.1 mg/dL versus 154.3 ± 3.0mg/dL, P = 0.0017; and 146.2 ± 3.5 mg/dL versus 157.9 ± 3.4mg/dL, P = 0.0137, respectively). 3

While body weight increased by 0.3 kg in the pre-meal insulin groups (both with RHI or GLU), there was significantly less weight gain in the post-meal GLU group compared to the pre-meal insulin groups (treatment difference of -0.3 kg, P = 0.03).3 Authors report no differences in outcomes regarding symptomatic hypoglycemia, nocturnal hypoglycemia, or severe hypoglycemia. 3

A.2. RAIAs versus RAIAs via MDI for Adults with T1DM

Most studies identified that compare RAIAs with one another are in the setting of CSII delivery. Studies in the setting of MDI therapy for patients with T1DM compared GLU versus LIS, or the biosimilar Admelog versus Humalog (1 study per comparison).

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A.2.a. GLU versus LIS via MDI for Adults with T1DM

One RCT (identified by Sanches et al SR) with 267 Japanese patients treated for at least 12 weeks, showed that GLU and LIS similarly reduced A1c and 2-hour post-prandial glucose values.7 Moreover, there were no significant differences with respect to events per patient-month of all symptomatic hypoglycemia, severe symptomatic hypoglycemia, or severe symptomatic hypoglycemia.7

A.2.b. LIS (Admelog) vs. LIS (Humalog) via MDI for Adults with T1DM

Two SRs comparing the safety and efficacy of the biosimilar, Admelog, to its originator showed that Admelog and Humalog similarly reduced A1c by 26 weeks in patients with DMT1 and DMT2, based on 1 RCT in each population (ie, no significant difference was found).8,37 For adults with T1DM, Admelog and Humalog reduced the A1c by about 0.4 to 0.5 from baseline.37 There were no significant differences between Admelog and Humalog for additional outcomes including fasting plasma glucose, hypoglycemia, severe hypoglycemia, anti-insulin antibody positivity, injection site reactions and allergic reactions in patients with T1DM.8

B. Continuous Subcutaneous Insulin Infusion (CSII) Treated Adults with T1DM

B.1. RAIA versus RHI Administered via CSII for Adults with T1DM

B.1.a. ASP vs. RHI via CSII for Adults with T1DM

A single RCT (Bode et al)4 for ASP versus RHI (identified by Norgaard et al SR) showed no significant difference in the change of A1c from baseline after 16 weeks of treatment; however, authors report that the end of study post-dinner blood glucose was significantly lower with ASP compared to the RHI group.4,6 There were no significant differences reported for blood-glucose confirmed hypoglycemia (<50 mg/dL) or severe hypoglycemia episodes. The RCT study authors report a significant difference in symptomatic hypoglycemia rates in favor of ASP when data was evaluated only for the maintenance period; yet, authors do not report p-values for the difference between treatment arms with respect to the entire treatment period or during the dose-adjustment phase.4 Thus, it is difficult to determine the overall safety effect of these treatments. A 2008 CADTH SR evaluated the rates of nocturnal hypoglycemia reported in Bode et al RCT and found a lower rate in favor of ASP (rate ratio 0.55, 95% CI 0.43, 0.70).5

B.1.b. LIS vs. RHI via CSII for Adults with T1DM

Norgaard et al 2018 SR identified 7 RCTs comparing LIS versus RHI for at least 3 months. Individual studies either showed that A1c was similar or better controlled with LIS compared to RHI.6 In 2003, Colquitt et al performed a meta-analysis with 6 RCTs which showed that the end of study A1c was significantly less with LIS compared to RHI (treatment effect difference -0.25%, 95% CI -0.47, -0.06). A lower or similar incidence of hypoglycemic events was observed with LIS compared to RHI based on results from individual RCTs, but severe hypoglycemia rates were similar.6,38 Colquitt et al note that only 1 of the 6 included RCTs were of high quality, while the rest had more than 3 quality categories rated as unknown or inadequate.38

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B.2. RAIAs versus RAIAs via CSII for Adults with T1DM

B.2.a. ASP vs. GLU via CSII for Adults with T1DM

Two RCTs were identified, showing similar control of A1c with ASP and GLU treatment, assessed by either the change in A1c from baseline to study endpoint or by comparing the A1c at study endpoint6 (ie, no significant difference in treatment effect). One trial reported BG measurements in the last week of therapy and found that “…there were no significant differences between most points of the seven- point PG profiles in the last week, except after lunch, where PG was higher for GLU compared with ASP (166.1 vs. 155.5 mg/dL, P<0.021).”9 Severe hypoglycemic events were similar between treatments in both trials.9,39 There were mixed results between the 2 RCTs for symptomatic hypoglycemia and nocturnal hypoglycemia showing either similar rates or lower rates with ASP compared to GLU.6

B.2.b. ASP vs. LIS via CSII for Adults with T1DM

Norgaard et al report 4 studies involving comparison of LIS to ASP.6 Only 1 of the 4 studies (Tamborlane et al 2002 Substudy 2) suggested greater A1c reduction with ASP; nonetheless, the treatment difference does not appear clinically meaningful (considering the FDA non-inferiority margin). One study showed that at the end of the trial, the 1 ½ -hour post-dinner blood glucose was lower with ASP compared to LIS (P=0.019, treatment difference not reported).4 Results between studies were conflicting, regarding whether there were more or less hypoglycemic events with LIS compared to ASP.4,9,40

B.2.c. GLU vs. LIS via CSII for Adults with T1DM

One RCT was identified (van Bon et al, 2011, including 288 patients) which showed no significant difference in the mean A1c at treatment end between LIS and GLU groups.9 There was no difference in the overall rate of severe hypoglycemic events. However, the rate of symptomatic hypoglycemic events (BG confirmed <70 mg/dL) per patient year were lower with LIS compared to GLU (62.7 vs. 73.8, P<0.001), along with the rate of symptomatic nocturnal hypoglycemia (12.8 vs. 9.48, P<0.001).9

C. Inhaled Insulin (Afrezza) vs. RAIAs for Adults with T1DM

One RCT of 528 patients compared Afrezza (with the Gen2 inhaler) versus ASP, both arms in combination with basal insulin.10,41 After 24 weeks of treatment, Afrezza was non-inferior to ASP for the mean change in A1c from baseline; the between-group difference was 0.19% and was within the 0.4% non-inferiority margin. The mean change in A1c (from a baseline of 7.94%) in the Afrezza arm was - 0.21%, compared to -0.40% in the ASP arm (treatment difference 0.19%; 95% CI 0.02, 0.36). There were more ASP patients achieving an A1c <7.0% (31% vs. 18% of patients, respectively, P=0.016). The inhaled insulin group experienced marginal weight loss (–0.4 kg) compared to the gain (+0.9 kg) observed in the ASP group (P = 0.0102). The incidence of severe hypoglycemia was lower with inhaled insulin (18% vs. 29%; P < 0.016).10

The 2019 ADA guideline highlighted preliminary evidence from a 4 week pilot study in patients with type 1 DM: “[a] pilot study found evidence that compared with injectable rapid-acting insulin, supplemental doses of inhaled insulin taken based on postprandial glucose levels may improve blood glucose

25 management without additional hypoglycemia or weight gain, although results from a larger study are needed for confirmation.”13,42

D. Concentrated Insulins

There are no head-to-head studies reported in the SRs involving LIS U-200 or RHI U-500.

ADULTS WITH TYPE 2 DIABETES MELLITUS

A. Inhaled Insulin (Afrezza) versus RAIAs for Adults with T2DM

There was only one very small study, with 39 patients found for the T2DM population comparing Afrezza (with the Gen2 inhaler) to ASP.41 This is an unpublished study with treatment duration lasting 16 weeks (identified in the SR of Pittas et al 2015). There was no significant difference with respect to the change in A1c between treatment arms.41

B. Multi Daily Dose Injection (MDI) Insulin Treated Adults with T2DM

B.1. RAIA versus RHI for Adults with T2DM

A 2018 Cochrane Review was conducted for adults with T2DM to compare RAIAs versus RHI in RCTs of at least 24 weeks duration. Authors concluded that there are no clear benefits of rapid-acting insulin analogues over regular human insulin.43 Meta-analyses showed no significant differences between any single RAIA vs. RHI with respect to A1c change or symptomatic hypoglycemic events, based on low to very low quality studies. Moreover, there were no clear differences in the risk of severe hypoglycemic events between agents. Results regarding patient-relevant outcomes, such as all-cause mortality, microvascular, or macrovascular complications were lacking.43 Authors of the 2008 CADTH report also found no difference in the A1c treatment effect when comparing ASP or LIS versus RHI in adults with T2DM.5

The 2019 ADA guideline cites two meta-analyses (Heller et al 2013 and Mannucci 2009) comparing RAIA with RHI in patients with type 2 diabetes and states that there were no important differences in A1c or hypoglycemia between RAIA and RHI for patients with T2DM.13,44,45

• The 2009 Mannucci et al SR/MA showed that when data was assessed by individual RAIAs separately, there was no significant difference between any single RAIA (aspart, lispro, glulisine) versus RHI.44 Only when data was combined for all RAIAs was significance achieved for the reduction in A1c in favor of RAIAs vs. RHI: treatment difference 0.4% (95% CI 0.1% to 0.6%, P=0.027).44 • Heller et al, 2013 SR, reported 3 RCTs for T2DM that all individually showed no difference in the change in A1c between ASP and RHI treatment.46 However, authors go on to report an MA- effect estimate, combining data from the T2DM RCTs with other trials in T1DM populations, to arrive at significant findings in favor of ASP.46 This considerable clinical heterogeneity causes us to question the appropriateness of concluding that there is significant difference in effect for the type T2DM population specifically.

26

An additional SR/MA, found from our literature search (Wojciechowski et al, 2015) was also conducted with clinical heterogeneity. Authors included some RCTs in patients with T2DM who were not on basal insulin, which goes against current standard of care.46 Authors found a significant difference in favor of ASP versus RHI for the relative change in A1c in patients with T2DM (weighted mean difference -0.22%; 95% CI -0.39, -0.05).2 If we consider that a non-inferiority margin of 0.4% for the change in A1c from baseline to endpoint has been used by the FDA to determine clinically meaningful differences in non- inferiority trials34, then this marginal difference (a difference of change in the A1c by 0.22% between the two treatments) is unlikely to be clinically meaningful.

B.2. RAIAs versus RAIAs for Adults with T2DM via MDI

B.2.a. ASP vs. GLU via MDI for Adults with T2DM

There were no studies found among the included SRs for this comparison in the T2DM population.

B.2.b ASP vs. LIS via MDI for Adults with T2DM

A single study was identified for ASP versus LIS, comparing 12 weeks of treatment with biphasic aspart 30% (70/30) or biphasic lispro 25% (75/25). There were no significant differences for control of A1c, self- monitored blood glucose levels, or overall hypoglycemia.5,47

B.2.c GLU Comparisons via MDI for Adults with T2DM

There were no studies found among the included SRs comparing GLU vs. ASP or LIS for the T2DM population.

B.2.d Biosimilar Comparisons via MDI for Adults with T2DM

Two SRs comparing the safety and efficacy of the biosimilar, Admelog, to its originator, Humalog, for diabetes management in adults showed that Admelog and Humalog similarly reduced A1c by 26 weeks in patients with T1DM or T2DM, based on 1 RCT in each population (ie, no significant difference was found).8,37 For adults with T2DM Admelog and Humalog reduced the A1C by about 0.9 from baseline.37 Additionally, there were no significant differences between Admelog and Humalog for outcomes including fasting plasma glucose, hypoglycemia, severe hypoglycemia, anti-insulin antibody positivity, injection site reactions and allergic reactions.8

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SPECIAL POPULATIONS

I. Pregnant Women with Pre-Existing Diabetes Treated by MDI

Two SRs, Norgaard et al 2018 and a Cochrane Review by O’Neill et al 2017, identified the same 2 RCTs involving patients with pre-gestational type 1 diabetes.6,48 Cochrane review authors rated these two studies as very low quality evidence.48 The Cochrane review authors explain that firm conclusions regarding how rapid insulin compare to regular human insulin can not be made since studies were of low quality and were limited in size and number.48

• One RCT of 322 patients showed no difference in A1c control at the end of the second or third trimester with ASP versus RHI.49,50 Risk of major maternal hypoglycemia, preeclampsia, preterm labor, cesarean section, fetal loss, congenital malformations, and neonatal short-term complications were comparable between groups.49,50 • In an RCT of 33 patients, there was no difference between LIS versus RHI with respect to maternal A1c throughout pregnancy, perinatal outcomes, or neonatal complications.51 Complications during pregnancy such as the need for caesarean or pre-eclampsia, did not differ between the groups, nor did neonatal abnormalities.51 • No studies were found regarding head-to-head comparisons in pregnant women with pre-existing T2DM.48

II. Pregnant Women with Gestational Diabetes Treated by MDI

Meta-analyses of a 2017 Cochrane Review (Brown et al 2017) found no difference in maternal or infant outcomes comparing regular human insulin with insulin aspart or lispro.52 Three RCTs were identified for each comparison (ie, RHI vs. ASP, and RHI vs. LIS). Cochrane authors reviewed maternal outcomes including pre-eclampsia, caesarean section, maternal hypoglycemia, glycemic control (A1c), postprandial glucose, and weight gain. Infant outcomes included neonatal hypoglycemia, fetal death, macrosomia, preterm birth, congenital anomaly, respiratory distress, and risk of large birth weight for gestational age.

In addition, Norgaard et al 2018 SR reported head-to-head results for this population; however, the Cochrane review by Brown et al included more complete information (ie, more studies and details about the RCTs). No additional RCTs were found in the more updated search by Norgaard et al, that weren’t already included in the Cochrane Review.

III. Pediatric Population with Type 1 DM

III.a. Pediatric Patients Treated by MDI

A 2018 systematic review by Norgaard et al 2018 identified 9 head-to-head studies involving rapid- acting insulins in the pediatric population with T1DM.6 Meta-analysis was performed for the risk of severe hypoglycemia; however, not for efficacy endpoints in this population. Norgaard et al showed mixed results from 3 individual RCTs for ASP versus RHI regarding A1c control (1 small RCT (N=30) showing a difference and 2 RCTs showing no difference). Results from 5 RCTs consistently showed LIS

28 and RHI similarly controlled A1c. One RCT showed GLU similarly reduced A1c compared to LIS; there were also no differences between GLU and LIS for hypoglycemia-related outcomes.53

• ASP versus RHI: Individual study results from 3 RCTs were mixed as ASP was either similar in efficacy or significantly better at controlling A1c compared to RHI. Studies were small with less than 65 patients in each trial.6 The single study showing a greater A1c reduction with ASP included 30 patients. Authors did not report the treatment-effect difference, only a P-value; this study also showed no difference between groups in the mean 2-hour postprandial glucose.54 The other two studies showed no significant difference in the A1c at treatment end between ASP and RHI treated arms.

• LIS versus RHI: Individual study results from 5 RCTs consistently showed that LIS similarly controlled A1c compared to RHI, as no significant differences in A1c reduction from baseline or at endpoint were found after LIS or RHI treatment.6 There were mixed results for postprandial glucose: in two studies, the LIS group had a lower mean BG post breakfast and dinner55,56 measured on 2 days at the end of treatment, while Tupola et al57 suggested 2-hour PPG excursions, measured 1 day per month over the treatment period, were similar between LIS and RHI treatment groups.

• GLU vs. LIS: One study was found for this comparison in which GLU was non-inferior to LIS. There were no significant differences in the change in A1c from baseline or in the 2-hour post main meal glucose at study endpoint. After 26 weeks, there was a significant difference between groups in the percent of patients achieving the ADA age-specified A1c target favoring glulisine (38% vs. 32%, P =0.004). Nonetheless, it is unclear if authors adjusted for a potential confounder— differences in the proportion of children >12 years old between treatment arms (patients >12 years old had the most aggressive A1c target compared to younger pediatric age groups).Rates of “all” hypoglycemia, severe symptomatic hypoglycemia, nocturnal hypoglycemia, and severe nocturnal symptomatic hypoglycemia were also similar between treatment arms.53

Individual RCT study results consistently showed no significant difference in the risk of severe hypoglycemic events between RHI versus ASP or RHI versus LIS. Regarding nocturnal hypoglycemia, there were no significant differences reported from individual RCTs for ASP versus RHI. Results of RCTs were mixed for LIS versus RHI (3 of 5 reported a significant difference in favor of LIS). Norgaard et al performed a meta-analysis assessing the risk difference of severe hypoglycemia in patients treated with rapid acting insulin analogs versus RHI and also found no difference between groups (this summary estimate combined LIS and ASP data together).6

Meta-analyses of 4 RCTs in the 2008 CADTH SR also showed that for LIS versus RHI, there were no significant differences in A1c at study end, rates of severe hypoglycemia, rates of nocturnal hypoglycemia, or overall hypoglycemia between treatments.5

There were no head-to-head studies found for the pediatric population with T1DM directly comparing LIS or ASP bolus injections.6

29

III.b. Pediatric Patients Treated by CSII

Norgaard et al 2018 SR identified 2 RCTs: 1 small study (N=27) comparing LIS versus RHI and 1 study (N=298) of LIS versus ASP.6 Regarding the change in A1c from baseline, rates of severe or major hypoglycemia, or nocturnal hypoglycemia, no significant differences were found between LIS versus RHI or between ASP versus LIS.6,27,58

Safety

There are unique safety warnings Afrezza, compared to the injectable insulins, relating to involvement of the lungs for drug absorption.15 Before initiating Afrezza, patients must have a thorough evaluation for lung disease. Since acute bronchospasm has been observed in some patients with asthma or chronic obstructive pulmonary disease (COPD), the medication is contraindicated with either of these co- morbidities. Use of the medication is not recommended in patients who smoke or who have recently stopped smoking within the past 6 months because safety and effectiveness is unclear in this population.15 Regardless of chronic lung disease, Afrezza causes a small decline in lung function, measured by forced expiratory volume, usually observed within the first 3 months of use.15 It is unknown if lung function returns to baseline after the medication is discontinued.15

Common adverse reactions with the injectable prandial insulins include hypoglycemia, allergic reactions, hypersensitivity, injection-site reactions, and lipodystrophy.14-22 Weight gain is also possible with the use of insulins. The most common adverse reactions for Afrezza (with an incidence of ≥ 2% ) are hypoglycemia, cough, and throat pain or irritation.15

Hypoglycemia risk increases with intensification of glycemic control.13,59 Symptoms can vary across individuals but generally include inability to concentrate, sweating, palpitations, and tremor. Severe hypoglycemia is life-threatening with the potential to cause seizures, coma, and death. Patients may have difficulty realizing they are hypoglycemic (ie, hypoglycemia unawareness), especially patients with longstanding diabetes, recurrent hypoglycemia, diabetic neuropathy, or those prescribed certain medications such as beta-blockers.60-63 There are many factors that can influence the potential for hypoglycemia including but not limited to a history of prior hypoglycemia episodes, hypoglycemia unawareness, time-action profile of insulin agents (basal and prandial), intensity of the insulin regimen, changes in meal pattern, medication changes, illness, or renal/hepatic insufficiency. The patient’s insulin regimen should be regularly re-assessed for potential optimization opportunities in order to meet the changing metabolic needs of patients—especially children, older adults, and pregnant/post-partum women.13,59 Considering children, Tubiana-Rufi et al explained that children generally have lower fasting tolerance compared to adults; thus, basal infusion rates (CSII) may need to be lowered during the second part of the night to prevent nocturnal hypoglycemia.58

Table 6 summarizes the additional safety information for prandial insulin products.

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Table 6. Warnings for Prandial Insulins14-22 WARNINGS IN COMMON FOR PRANDIAL INSULINS Contraindicated during episodes of hypoglycemia or if patient has hypersensitivity to the insulin analog or any of the product excipients

• Hypokalemia: All insulins can induce intracellular potassium transport, possibly resulting in hypokalemia. Monitor potassium levels in patients at risk of hypokalemia. • Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones and Insulins • Hyper- or Hypoglycemia: Increase the frequency of glucose monitoring with changes to: insulin dosage, co- administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairments and hypoglycemia unawareness • Hypersensitivity reactions are possible with insulins • Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection • Never share devices between patients, even if the needle is changed; never share or reuse needles or syringes

WARNINGS UNIQUE TO SPECIFIC PRODUCTS Afrezza (human insulin, inhalation) Black Box Warning • Acute bronchospasm has been observed in patients with asthma and COPD; use is contraindicated in patients with chronic lung disease • Before initiating, perform a thorough examination to identify potential lung disease that may influence the response to inhalation therapy Other Warnings • Decline in Pulmonary Function: Assess pulmonary function before initiating, after 6 months of therapy, and annually, even in the absence of pulmonary symptoms. • Lung Cancer: Do not use in patients with active lung cancer. In patients with a history of lung cancer or at risk for lung cancer, the benefit should outweigh the potential risk. At this time, data is insufficient to determine whether Afrezza has an effect on the development of lung or respiratory tract tumors: there were 2 cases of lung cancer in non-smoking patients and 2 case in patients with a history of heavy smoking reported in the package insert. • Diabetic Ketoacidosis: DKA was more common in patients with type 1 diabetes receiving Afrezza than in the control group, although event rates were low (0.43% in the treated arm compared to 0.14% in the control arm)

DRUGS THAT CAN IMPACT INSULIN NEEDS AND/OR RECOGNITION OF HYPOGLYCEMIA SYMPTOMS

• Drugs that increase insulin sensitivity and therefore increase potential for hypoglycemia: oral and injectable antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics.

• Drugs that reduce the effect of insulins: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (eg, epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (eg, in oral contraceptives), protease inhibitors and atypical antipsychotic medications (eg, olanzapine and clozapine).

• Drugs that may have mixed effects (increase or decrease insulin effects): Beta-blockers, clonidine, lithium salts, and alcohol Drugs that hide hypoglycemia signs: beta-blockers, clonidine, guanethidine, and reserpine Abbreviations: COPD, chronic obstructive pulmonary disease; DKA, diabetic ketoacidosis

31

Summary

The injectable U-100 and U-200 prandial insulins are indicated for adults and children with DM, with the exception of Fiasp which is indicated only for adults. Afrezza is the only available inhalable-insulin product; it is indicated for adults and should not be used in patients who smoke or who have a chronic lung disease. Concentrated products include Humalog (lispro) U-200 and Humulin R U-500 (regular human insulin). The U-200 Humalog product is bioequivalent to U-100 Humalog, as they have similar pharmacokinetic and pharmacodynamic (PK/PD) profiles when used at the same unit/kg dose.20,30 The Humulin R U-500 product has unique pharmacokinetic properties, with a rapid prandial onset and basal activity; it is approved for adults or children requiring more than 200 units per day.14

Overall, there does not appear to be clinically meaningful differences in the treatment-effect of prandial insulins for the reduction of A1c. There were mostly unclear differences regarding hypoglycemia-related outcomes when RAIAs were compared to one another; however, a single RCT in adults with T1DM showed lower rates of confirmed symptomatic hypoglycemia with CSII lispro versus CSII glulisine and similar rates of severe hypoglycemic events.9

There have been mixed results (some RCTs showing a difference and some showing no difference) for hypoglycemia-related outcomes when comparing RAIAs versus RHIs. Two Cochrane reviews performed meta-analyses on the longer-term studies available (with treatment durations of at least 24 weeks); there did not appear to be substantial differences regarding rates of severe hypoglycemia and overall hypoglycemia.1,43 Authors commented that the validity of results regarding nocturnal hypoglycemia reported by individual RCTs was questionable.1,43 While also considering studies of shorter durations reported among other systematic reviews, there appears a trend favoring RAIAs over RHI, as some RCTs have reported lower hypoglycemia rates with RAIAs; however, such results have not been consistent across all RCTs and comparisons. Considering the preference stated in practice guidelines for the use of RAIAs over RHI in most patients with T1DM13, maintaining at least 1 RAIA product as preferred on the PDL should be considered.

32

References

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50. Mathiesen ER, Kinsley B, Amiel SA, et al. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;30(4):771-776. 51. Persson B, Swahn ML, Hjertberg R, et al. Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus. Diabetes Res Clin Pract. 2002;58(2):115-121. 52. Brown J, Grzeskowiak L, Williamson K, Downie MR, Crowther CA. Insulin for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews. 2017;2017(11). 53. Philotheou A, Arslanian S, Blatniczky L, Peterkova V, Souhami E, Danne T. Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a Basal-bolus insulin regimen in a 26-week trial in pediatric patients with type 1 diabetes. Diabetes Technol Ther. 2011;13(3):327-334. 54. Cherubini V, Iannilli A, Iafusco D, et al. Premeal insulin treatment during basal-bolus regimen in young children with type 1 diabetes. Diabetes Care. 2006;29(10):2311-2312. 55. Deeb LC, Holcombe JH, Brunelle R, et al. Insulin lispro lowers postprandial glucose in prepubertal children with diabetes. Pediatrics. 2001;108(5):1175-1179. 56. Holcombe JH, Zalani S, Arora VK, Mast CJ. Comparison of insulin lispro with regular human insulin for the treatment of type 1 diabetes in adolescents. Clin Ther. 2002;24(4):629-638. 57. Tupola S, Komulainen J, Jaaskelainen J, Sipila I. Post-prandial insulin lispro vs. human regular insulin in prepubertal children with Type 1 diabetes mellitus. Diabetic medicine : a journal of the British Diabetic Association. 2001;18(8):654-658. 58. Tubiana-Rufi N, Coutant R, Bloch J, et al. Special management of insulin lispro in continuous subcutaneous insulin infusion in young diabetic children: a randomized cross-over study. Hormone research. 2004;62(6):265-271. 59. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245-1249. 60. Levemir (insulin detemir) injection [package insert]. Plainsboro, NJ: Novo Nordisk; Revised February 2015. 61. Lantus (insulin glargine) injection [package insert]. Bridgewater, NJ: Sanofi-Aventus US LLC; Revised August 2015. 62. Toujeo (insulin glargine) injection [package insert]. Bridgewater, NJ: Sanofi-Aventis US LLC.; Revised October 2018. 63. Tresiba (insulin degludec) injection [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; Revised November 2018. 64. Pankowska E, Nazim J, Szalecki M, Urban M. Equal metabolic control but superior caregiver treatment satisfaction with insulin aspart in preschool children. Diabetes Technol Ther. 2010;12(5):413-418. 65. Danne T, Rastam J, Odendahl R, et al. Parental preference of prandial insulin aspart compared with preprandial human insulin in a basal-bolus scheme with NPH insulin in a 12-wk crossover study of preschool children with type 1 diabetes. Pediatr Diabetes. 2007;8(5):278-285. 66. Zinman B, Tildesley H, Chiasson JL, Tsui E, Strack T. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes. 1997;46(3):440-443. 67. Kabul S, Hood RC, Duan R, DeLozier AM, Settles J. Patient-reported outcomes in transition from high-dose U-100 insulin to human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes: analysis of a randomized clinical trial. Health and quality of life outcomes. 2016;14(1):139. 68. DeVries JH, Lindholm A, Jacobsen JL, Heine RJ, Home PD. A randomized trial of insulin aspart with intensified basal NPH insulin supplementation in people with Type 1 diabetes. Diabetic medicine : a journal of the British Diabetic Association. 2003;20(4):312-318.

36

Appendix A: Medline Literature Search Strategy

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to December 20, 2018>

1 insulin, short-acting/ or insulin aspart/ or insulin lispro/ (1468)

2 insulin, regular, human/ or isophane insulin, human/ (147)

3 (insulin? adj3 (short or rapid or aspart or glulisine or lispro or inhaled or regular or regular human)).ti,ab,kw,kf. (5732)

4 insulin/ and (rapid-acting or short-acting or aspart or glulisine or lispro or rapid HYPOGLYCEMIC*).ti,ab,kw,kf. (1944)

5 (FIASP or NOVOLOG or APIDRA or ADMELOG or HUMALOG or AFREZZA or HUMULIN or NOVOLIN).ti,ab,kw,kf. (358)

6 1 or 2 or 3 or 4 or 5 (6394)

7 Meta-Analysis/ (94951)

8 (metaanaly$ or meta-analy$).ti,ab,kw,kf. (140049)

9 ((systematic adj3 review) or (overview adj4 review)).ti,kw,kf. (97240)

10 (cochrane$ or systematic review?).jw. (16132)

11 (or/7-10) and English.la. (210024)

12 (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. (1186448)

13 exp animals/ not humans.sh. (4524057)

14 (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 feline? 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 simian? or thoroughbred).ti. or veterinar$.ti,ab,kw,kf,hw. (2232849)

15 (12 not (or/13-14)) and English.la. (989221)

16 6 and 11 (120) Systematic Reviews

17 6 and 15 (1609)

37

Appendix B: Embase Search Strategy

No. Query: Searched through December 22, 2018 Results

#16 #10 NOT (#13 OR #14 OR #15) [Systematic Reviews] 224

#15 'conference abstract'/it OR 'conference review'/it 3252550

animal*:ti OR beaver*:ti OR beef:ti OR bovine:ti OR breeding:ti OR canine:ti OR castoris:ti OR cat:ti OR cattle:ti OR cats:ti OR chicken*:ti OR cow:ti OR dog:ti OR dogs:ti OR equine:ti OR foal:ti OR foals:ti OR fish:ti OR insect*:ti OR livestock:ti #14 2687149 OR mice:ti OR mouse:ti OR murine:ti OR plant:ti OR plants:ti OR pork:ti OR porcine:ti OR protozoa*:ti OR purebred:ti OR rabbit*:ti OR rat:ti OR rats:ti OR rodent*:ti OR sheep:ti OR thoroughbred:ti OR veterinar*:ti,ab,de

('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT #13 (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal 6641296 model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell'/de))

#10 #8 AND #9 231

(cochrane*:jt OR 'systematic review*':jt OR 'meta analysis'/mj OR 'systematic review'/mj OR ((systematic NEAR/3 review):ti) OR 'meta analys*':ti,ab,kw #9 202462 OR metaanalys*:ti,ab,kw OR ((overview NEAR/4 (review OR reviews)):ti)) NOT ('conference abstract'/it OR 'conference review'/it) AND [english]/lim

#8 #2 OR #5 OR #6 OR #7 23677

'insulin'/mj AND ('rapid acting':ti,ab,kw OR 'short acting':ti,ab,kw OR aspart:ti,ab,kw #7 1615 OR lispro:ti,ab,kw OR glulisin*:ti,ab,kw OR 'human regular':ti,ab,kw)

fiasp:ti,ab,kw OR novolog:ti,ab,kw OR apidra:ti,ab,kw OR admelog:ti,ab,kw #6 725 OR humalog:ti,ab,kw OR afrezza:ti,ab,kw OR humulin:ti,ab,kw OR novolin:ti,ab,kw

aspart:ti,ab,kw OR glulisin*:ti,ab,kw OR lispro:ti,ab,kw OR ((insulin* NEAR/2 #5 16934 (human OR regular OR short OR fast OR rapid OR inhal*)):ti,ab,kw)

'short acting insulin'/exp OR 'insulin aspart'/exp OR 'insulin glulisine'/exp OR 'insulin #2 12495 lispro'/exp OR 'human insulin'/exp

38

Appendix C: Excluded Studies

Wrong comparators

1. Ceglia L, Lau J, Pittas AG. Meta-analysis: efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus. Annals of Internal Medicine. 2006.145(9):665-675. • Does not involve studies with Afrezza 2. Dailey G. Developing a pulmonary insulin delivery system for patients with diabetes. Clinical Therapeutics.2007, 29 Spec No:1271-1283. • Does not involve studies with Afrezza 3. Onady GM, Stolfi A. Insulin and oral agents for managing cystic fibrosis-related diabetes. The Cochrane database of systematic reviews. 2013;7:CD004730. 4. Royle P, Waugh N, McAuley L, McIntyre L, Thomas S. Inhaled insulin in diabetes mellitus. Cochrane Database of Systematic Reviews. 2009(3):CD003890. • Review withdrawn following removal of old inhaled insulin product from the market; this review did not contain information regarding Afrezza

Wrong study design

5. Brunelle BL, Llewelyn J, Anderson JH, Jr., Gale EA, Koivisto VA. Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care.1998; 21(10):1726-1731 • Not a systematic review 6. Cameron CG, Bennett HA. Cost-effectiveness of insulin analogues for diabetes mellitus. CMAJ Canadian Medical Association Journal.2009;180(4):400-407. • Not a systematic review 7. Davidson JA, Liebl A, Christiansen JS, et al. Risk for nocturnal hypoglycemia with biphasic insulin aspart 30 compared with biphasic human insulin 30 in adults with type 2 diabetes mellitus: a meta-analysis. Clinical Therapeutics.31(8):1641-1651. • No a systematic review 8. Insulin analogues of marginal, if any, benefit. Journal of the National Medical Association. 2009;101(8):822-823. • Not an SR 9. Jacobsen IB, Henriksen JE, Hother-Nielsen O, Vach W, Beck-Nielsen H. Evidence-based insulin treatment in type 1 diabetes mellitus. Diabetes Research & Clinical Practice. 2008;86(1):1-10. • Study focuses on comparing RAIA vs. RHI, without separating out MA results based on individual RAIAs. Also doesn’t provide a table of study characteristics for included studies. A more recent Cochrane review (Fullerton et al 2016) has been published regarding the comparison of RAIA vs. RHI, in which included study characteristics and quality assessments are provided.

10. Martis R, Crowther CA, Shepherd E, Alsweiler J, Downie MR, Brown J. Treatments for women with gestational diabetes mellitus: an overview of Cochrane systematic reviews. Cochrane Database of Systematic Reviews.2018(8):CD012327. • Addresses other study/treatment questions (eg, insulin vs. oral therapy) 11. Pontiroli AE, Miele L, Morabito A. Metabolic control and risk of hypoglycaemia during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis. Diabetes, Obesity & Metabolism. 2012;14(5):433-446. • Study does not include head-to-head comparisons between individual agents (instead reports group summary effect differences) 12. Rys P, Pankiewicz O, Lach K, Kwaskowski A, Skrzekowska-Baran I, Malecki MT. Efficacy and safety comparison of rapid- acting insulin aspart and regular human insulin in the treatment of type 1 and type 2 diabetes mellitus: a systematic review. Diabetes & Metabolism. 2011;37(3):190-200.

39

Wrong population

13. Andrade-Castellanos CA, Colunga-Lozano LE, Delgado-Figueroa N, Gonzalez-Padilla DA. Subcutaneous rapid- acting insulin analogues for diabetic ketoacidosis. Cochrane Database of Systematic Reviews. 2016(1):CD011281. • Outside the scope of our review that focuses on use in the ambulatory population (non-hospitalized)

More up-to-date SR available

14. Anonymous. Insulin lispro: new preparation. Faster acting. Prescrire International. 1998;7(35):67-68. 15. Brown J, Grzeskowiak L, Williamson K, Downie MR, Crowther CA. Insulin for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews. 2016;2016(1). • Study protocol; see publication for completed study results 16. Davey P, Grainger D, MacMillan J, Rajan N, Aristides M, Gliksman M. Clinical outcomes with insulin lispro compared with human regular insulin: a meta-analysis. Clinical Therapeutics. 1997;19(4):656-674. 17. Kerr D, Wizemann E, Senstius J, Zacho M, Ampudia-Blasco FJ. Stability and performance of rapid-acting insulin analogs used for continuous subcutaneous insulin infusion: a systematic review. Journal of Diabetes Science & Technology. 2013;7(6):1595-1606. • See Norgaard et al 2018 18. Plank J, Siebenhofer A, Berghold A, et al. Systematic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus. Archives of Internal Medicine. 2005;165(12):1337-1344. • See Norgaard et al 2018, Brown et al 2017, Fullerton et al 2018 and 2016; This SR includes studies of less than 3 months, and doesn’t not report results separately for data from studies of 3 months or longer. 19. Siebenhofer A, Plank J, Berghold A, Narath M, Gfrerer R, Pieber TR. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews. 2004(2):CD003287. • Review has been updated 20. Siebenhofer A, Plank J, Berghold A, Narath M, Gfrerer R, Pieber TR. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews. 2006(4):CD003287. • Review has been updated 21. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ Canadian Medical Association Journal. 2009;180(4):385-397. • More updated SRs are available for the T2DM population. In addition, for the T1DM population this SR does not separate out CSII evidence from MDI evidenced

40

Appendix D: Systematic Reviews Table 1. Systematic Reviews Study lead Title and author, Results Methods year Adults with T2DM Authors conclude that there are no clear benefits of short-acting insulin analogues over regular human insulin based on mostly poor quality trials. Results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications were lacking. Quality/certainty of evidence was rated low to Short-acting insulin analogues very low for the A1c and hypoglycemia outcomes versus regular human insulin • ASP vs. RHI, 3 RCTs (Hermann 2013; NCT01650129, Pfützner 2013), for adult, non-pregnant persons • GLU vs. RHI, 3 RCTs (Dailey 2004; Rayman 2007, Pfützner 2013) with type 2 diabetes mellitus • LIS vs. RHI, 5 RCTs: Altuntas 2003; Bastyr 2000; Ross 2001; Z012 1997; Z014 1997),

Searched CENTRAL, MEDLINE, A1c changes for different insulins: there were no significant differences in the meta-analysis effect Embase, the WHO ICTRP Search estimates between any single RAIA vs. RHI Portal, and ClinicalTrials.gov Non-severe hypoglycemic episodes (mean episode/patient/month) for different insulins: there were no Fullerton through October 2018, without significant differences in the meta-analysis effect estimates between any single RAIA vs. RHI 43 2018 restrictions on the publication Severe hypoglycemia: “Overall, the incidence of severe hypoglycaemic events was low, and language no trial showed a clear difference between the two treatment arms.” Cochrane Nocturnal Hypoglycemia: MA was not feasible. Cochrane authors note “[t]he results provided for nocturnal Review Included randomized controlled hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the trials with treatment of at least 24 two short-acting insulin analogues and regular human insulin.” weeks • GLU vs. RHI: Only 2 RCTs, Dailey 2004; and Rayman 2007 discuss nocturnal hypoglycemia, defined as occurring anytime in the night, however do not perform statistical evaluation to determine significance Comparison of interest was short- • LIS vs. RHI: 2 RCTs, Bastyr 2000 and Ross 2001, defined nocturnal hypoglycemia occurring between 12 acting insulin analogues vs. regular and 6 am. Only Ross 2001 reported statistical evaluation between events in each group: 0.08 nocturnal human insulin for treatment of episodes per participant per 30 days for the lispro group versus 0.16 for the regular human insulin group non-pregnant patients with type 2 (P = 0.057) diabetes Health related quality of life: • “Two trials assessed health-related quality of life, however, the results were generally unreliable (very low-certainty evidence (Bastyr 2000; Ross 2001)).” • “Data were insufficient for costs of treatment, health-related quality of life, and many adverse events, such as potential carcinogenic effects.”

41

Table 1. Systematic Reviews Study lead Title and author, Results Methods year

Children and Adolescents with T1DM MDI Treatment

A. RAIA vs. RHI Efficacy and Safety of Rapid-Acting Based on how products performed in the individual studies, authors summarized that glycemic control Insulin Analogs in Special (based on either HbA1c or PPG) were similar or better with insulin lispro or insulin aspart compared to RHI. Populations with Type 1 Diabetes or Authors refrained from performing a meta-analyses for these efficacy outcomes. Gestational Diabetes: Systematic • ASP vs. RHI, + NPH (3 RCTs): Review and Meta-Analysis One RCT (Cherubini 2006)54, of 30 patients and with parallel comparison group design, showed a o Norgaard, significant change in A1c from baseline with ASP but not with RHI (P=0.018). 6 Searched PubMed, Embase, and 2018 ASP arm (A1c from 7.5 ± 0.8 to 7.0 ± 0.4%) the Cochrane library from inception o RHI arm (from 7.5 ± 1.4 to 7.4 ± 0.5%) (P = 0.018) to June 1st 2016; reference lists o Authors report a P value (P=0.018), however it is not clear what difference this applies to (ie, A1c were also searched change from baseline for ASP arm, or the treatment difference between ASP and RHI). No difference

in the 2 hour PPG was found between groups. In addition rates of “severe” or “any” hypoglycemia Drug comparison of interest: rapid events were similar between groups. acting insulin analogs compared to Two other RCTs showed no difference in A1c control or risk of severe hypoglycemia between ASP each other or compared to regular o and RHI treatment. human insulin . Pankowska et al 201064 was a parallel group study of 61 patients, showing no difference in

A1c between treatment groups (ASP vs. RHI) after 26 weeks of treatment. Rates of server Included RCTs, either blinded or hypoglycemia appeared similar between groups. open-label and of parallel or . Danne et al 200765 was a cross-over study with 26 patients that showed no significant crossover design. Target difference in A1c after 3 months of treatment on each rapid insulin. Moreover there was no populations included pregnant significant difference in the risk of hypoglycemia between ASP and RHI. women (with DMT1 or GDM); • LIS vs. RHI (5 RCTs; Holcombe 2002, Deeb 2001, Fairchild 2000, Ford-Adams 2003, Tupola 2001) children or adolescents aged <18 • 4 studies included basal NPH, and 1 study had basal NPH, lente, or ultralente years with T1D; for the CSII All 5 studies showed no intergroup differences in the A1c control, either the reduction of A1c from population, people with T1D of any o baseline or A1c at endpoint.6 In two studies, the LIS group had some lower PPG results (eg, mean age using an insulin pump. BG post lunch and breakfast,55,56 measured on 2 days at end of treatment), while Tupola et al57

suggested 2-hour PPG excursions were similar between LIS and RHI treatment.

o All studies showed no significant difference regarding severe hypoglycemic rates between treatment groups.

42

Table 1. Systematic Reviews Study lead Title and author, Results Methods year o 3 of 5 studies reporting on nocturnal hypoglycemia (Holcombe 2002, Fairchild 2000, Ford-Adams 2003) showed outcomes in favor of LIS for a reduction in the incidence (per patient per 30 days) of nocturnal hypoglycemia

Children and Adolescents with T1DM MDI Treatment Norgaard, Continued 20186 • Meta-analysis for severe hypoglycemia risk with RAIA (LIS or ASP) vs. RHI Summary point estimate showed that there were no significant differences in the risk of severe Continued hypoglycemia between rapid insulin analog (LIS or ASP) versus RHI.

B. GLU vs. LIS, + NPH insulin or insulin glargine (1 RCT)53 • The single, parallel group, RCT identified (Philotheou 2011) in patients, mean age of 12 years and entering the study stable on an insulin regimen using either neutral protamine Hagedorn insulin (NPH)

or glargine, showed GLU was non-inferior to LIS for the reduction of A1c and there was no significant difference between groups for the reduction in A1c from baseline; results from the subgroup analysis by type of basal insulin remained consistent. o “For the glulisine and lispro groups, the adjusted mean change (mean±SD) from baseline to Week 12 was -0.01±0.07% and -0.03±0.06%, and that from baseline to Week 26 was

0.08±0.08% and 0.17±0.08%, respectively.”53 • However, there was a significant difference between groups in the percent of patients achieving the ADA age-specified A1c target favoring glulisine (38% vs. 32%, P =0.004); It is not clear however, • There was no significant difference in the mean 2-hour post main meal glucose at endpoint between treatment groups.

• Authors of original study, Philotheou et al, report that there were no relevant differences in rates of “all” hypoglycemia, “severe” symptomatic hypoglycemia, nocturnal hypoglycemia, and severe nocturnal hypoglycemia were similar between groups

Children and Adolescents with T1DM

CSII Treatment LIS vs. RHI (1 RCT, Tubiani-Rufi 2004, N=27)58, using Minimed 506/507/507C infusion pumps allowing the use of multiple daily basal rates (by Medtronic-Minimed, Boulogne,France)

43

Table 1. Systematic Reviews Study lead Title and author, Results Methods year o No difference was found for the reduction in A1c, mean post-prandial glucose levels, or for events of 58 severe hypoglycemia. LIS vs. ASP (1 RCT, Weinzimer 2018, N=298)27 Norgaard, Insulin aspart CSII was non-inferior to insulin lispro CSII for the reduction of A1C from baseline (aspart,- 20186 o 0.15±0.05%; lispro,-0.05±0.07%; P=0.241 for the treatment difference) In addition there were no Continued significant differences between treatment groups in the mean fasting BG at endpoint, or mean postprandial BG at endpoint. Rates of major hypoglycemia, nocturnal hypoglycemia, and minor 27 hypoglycemia were also similar between treatment groups (ie, no significant differences).

Adults with T1DM Treated with CSII ASP vs. RHI (1 RCT, Bode 2002): After 16 weeks of treatment, the RCT showed no significant difference in the change of A1c from baseline, between ASP and RHI treatment. Authors report that at the end of study the PPG after dinner was significantly lower with ASP compared to the RHI group. There were no significant differences in the numbers or rate of blood-glucose confirmed (<50mg/dl) hypoglycemia episodes.

Symptomatic hypoglycemic episodes (non-confirmed by BG) were significantly lower in the ASP group compared to RHI (mean number of hypoglycemic episodes per patient per 30 days: 6.7 with RHI vs. 10.5 with LIS; P=0.034). The rate of confirmed nocturnal hypoglycemic episodes was lower with ASP compared to RHI. “Clogs/blockages in pumps or infusion sets were infrequent; most subjects (76, 83, and 75% in the IAsp, BR, and lispro groups, respectively) had _1 clog or blockage per 4 weeks during the trial.”4

ASP vs. GLU (2 RCTs) • Two RCTs were identified (Hoogma 2006 and van Bon 2011), showing similar control of A1c with ASP

and GLU treatment, assessed by either the change in A1c from baseline to study endpoint (Hoogma 2006) or by comparing the A1c at study endpoint (van Bon 2011) • van Bon et al assessed BG measures in the last week of treatment and found that “…there were no significant differences between most points of the seven-point PG profiles in the last week, except after lunch, where PG was higher for GLU compared with ASP (166.1 vs.155.5 mg/dL, P<0.021).”9

• Severe hypoglycemic event rates were similar between treatments in both trials. One trial found a significantly higher per patient-year rate of BG confirmed (BG<70mg/dL) symptomatic hypoglycemia in favor of ASP (van Bon 2011), while Hoogma 2006 found no difference in symptomatic hypoglycemic events (non-BG confirmed).

44

Table 1. Systematic Reviews Study lead Title and author, Results Methods year • Nocturnal hypoglycemia was reported by both studies; results are inconsistent as Hoogma et al 2006 reported no significant difference between treatments, while van Bon et al 2011 reported significant differences in favor of ASP

ASP vs. LIS (4 RCTs): Individual studies show mixed results: there were either similar or greater reductions in A1c with ASP vs. LIS, and either similar or lower A1c at the end of treatment with ASP compared to LIS Norgaard, • RCTs showing a lower A1c at endpoint with ASP vs. LIS were Tamborlane 2015 Substudy 2 20186 • RCTs showing greater A1c reduction from baseline with ASP vs. LIS were Tamborlane 2015 Substudy 2 • Continued RCTs showing no significant difference in A1c at study endpoint were van Bon 2011, Tamborlane 2015 Sub-study 1

• RCTs showing no significant difference in A1c reduction between treatments were Bode 2002, van Bon 2011, and Tamborlane 2015 Sub-study 1 • Note that there were limitations to Tamborlane Substudy 1 which was a cross-over study of 8 week treatment periods which would be affected by carry over effects in the A1c endpoint. Hypoglycemia:

• Tamborlane 2015 substudy 1 and 2 show significantly less monthly symptomatic hypoglycemia episodes (BG confirmed <3.9mmol/L) and less “all reported” hypoglycemia episodes (non BG confirmed) with LIS vs. ASP • Bode 2002 showed differences in symptomatic hypoglycemia in favor of ASP over LIS: (mean number of hypoglycemic episodes per patient per 30 days: 6.7 with ASP vs. 10.5 with LIS; P=0.044)

• Van Bon assesses significance only for GLU vs. ASP or GLU vs. LIS (see GLU section below for results) • Nocturnal hypoglycemia: no significant difference reported in Tamborlane 2015 and Bode 2002

LIS vs. RHI (8 RCTs): Individual studies showed that insulin lispro was associated with similar or greater A1c reduction compared to RHI or a similar or lower A1c at endpoint for LIS compared to RHI. All were cross-

over studies which rarely had a washout period in between treatment periods of 3 months. Guerci 1999 and Johansson 2000 are problematic since they were less than 3 months duration (1 and 2 months, respectively). See Colquitt et al SR, which doesn’t include these two RCTs and provides meta-analysis for A1c endpoints. • RCTs showing a lower A1c at endpoint with LIS vs. RHI were Zinmann 199766, Renner 1999, and

Johansson 2000 • RCTs showing greater A1c reduction from baseline with LIS vs. RHI were Melki 1998, Johansson 2000, and Raskin 2001

45

Table 1. Systematic Reviews Study lead Title and author, Results Methods year • RCTs showing no significant difference in A1c at study endpoint were Schmauss 1998, and Guerci 1999 • RCT showing no significant difference in A1c reduction between treatments was Bode 2002

Mean PPG measures and hypoglycemic outcomes from individual studies were either similar, however, most were lower with LIS compared to RHI.

Norgaard, LIS vs. GLU (1 RCT) 20186 van Bon et al, 2011, including 288 patients, showed no significant difference in the mean A1c at endpoint between treatment groups, or the percentage of patient with an A1c<7% at study end. Continued • There was no difference in the overall rate of severe hypoglycemic events, severe nocturnal hypoglycemia, or symptomatic nocturnal hypoglycemia; however, the rate of symptomatic hypoglycemic events (BG confirmed <70 mg/dL) per patient year were lower with LIS compared to GLU (62.7 vs. 73.8, P<0.001)

Pre-Gestational T1DM (2 RCTs) LIS vs. RHI, + NPH: In Persson et al 2002,51 an open-label, parallel group, RCT of 33 patients, there was no difference in maternal A1c throughout pregnancy, perinatal outcomes, or neonatal complications. The mean 90 minute post-breakfast blood glucose (combined measure at weeks 21, 28, and 34) was significantly lower in the lispro group, however not post-lunch or post-dinner.

o Severe hypoglycaemia occurred in two RHI treated patients and none in the LIS group (significance unknown). Nonetheless, the rate of biochemical hypoglycaemia (blood glucose

o Significant differences included the following: . The mean 90 minute post-breakfast glucose was significantly lower with ASP vs. RHI at the end of the 1st and 3rd trimesters, respectively (treatment difference: –0.75 [95% CI - 1.25; - 0.25], p = 0.003 and - 0.40 [95% CI - 0.80; - 0.01], p = 0.044, respectively), but not after the second trimester.

46

Table 1. Systematic Reviews Study lead Title and author, Results Methods year Gestational Diabetes Mellitus (4 RCTs) Norgaard, • ASP vs. RHI (Di Cianni 2007). Authors did not identify Balaji 2005 and Balaji 2012 as found in Cochrane SR 20186 by Brown et al 2016 Continued • LIS vs. RHI (Di Cianni 2007; Jovanovic 1999; Mecacci 2003) • ASP/NPH vs. RHI/NPH (Pettitt 2007) Norgarrd et al did not conduct a meta-analyses and miss two publications identified by Brown et al 2016 Cochrane review. Since Brown et at is more complete and more thoroughly evaluates various outcomes, it will be used to describe effect differences in GDM.

Efficacy and safety of biosimilar insulins compared to their reference products: A systematic review

Searched PubMed, Cochrane Tieu et al report outcomes from individual studies without performing a meta-analysis CENTRAL, Embase, Latin America and Caribbean Health Sciences Efficacy of Admelog vs. Humalog (LILACS), South Asian Database of Adults with T1DM: 1 RCT (Garg 2017); The change in A1c at week 26 with Admelog was -0.42 (SD 0.05) and Controlled Clinical Trials (SADCCT) with Humalog was -0.47 (SD 0.05). The mean difference between treatment groups was 0.06 (-0.08, 0.2) Tieu and IndiaMED through January 14, and not significantly different. 201837 2018 Adults with T2DM: 1 RCT (Derwahl, 2018); The change in A1c at week 26 with Admelog was -0.92 (SD 0.05) and with Humalog was -0.85 (SD 0.05). The mean difference between groups was 0.07 (-0.22, 0.07) and not Included randomized controlled significantly different. trials (RCTs) comparing safety and efficacy of any biosimilar insulin Adverse events: Admelog vs. Humalog (3 RCTs; Kapitza 2016, Garg 2017, and Derwahl 2018); statistical with a reference product. significance not evaluated Excluded insulin pump studies

Participants were adults with type 1 or 2 diabetes

47

Table 1. Systematic Reviews Study lead Title and author, Results Methods year Biosimilar vs originator insulins: Systematic review and meta- analysis

Searched MEDLINE, Embase, and Cochrane library to December 2017. Also searched Clinicaltrials.gov, and Adults with T1DM or T2DM the databases of major diabetes No significant differences between insulin lispro biosimilar (Ademlog) and originator (Humalog) were found conferences. for any of the outcomes included, based on meta-analysis including 2 RCTs (Garg 2017, SORELLA 1; and Derwahl 2018, SORELLA 2): Included randomized controlled Yamada • HbA1c at 24 weeks −0.0% [95% CI –0.11, 0.10], I2 = 17%; 20188 studies of the biosimilar versus • Fasting plasma glucose 0.05 [95% CI –0.36, 0.46], I2 = 0%; originator insulins. Outcomes • Hypoglycaemia OR 0.99 [95% CI 0.97, 1.00], I2 = 43%; included for the clinical efficacy • Severe hypoglycaemia OR 1.05 [95% CI 0.69, 1.59], I2 = 0%; primary outcome was the change in • Injection site reactions OR 0.62 [95% CI 0.17, 2.24] I2 = 2%; glycated haemoglobin [HbA1c] • from baseline) and hypoglycemia Allergic reactions OR 1.28 [95% CI 0.32, 5.15], I2 = 0%; for the safety primary outcome.

Participants were adult patients (aged ≥18 years) with type 1 or type 2 diabetes.

Ovalle et al shows that there are no head-to-head RCTs of concentrated insulins versus the U-100 Understanding concentrated counterpart. Nonetheless, this article is used for background information regarding the PK of these agents insulins: a systematic and another interesting study: review of randomized controlled • One non-controlled study (Kabul et al 2016) that the authors point out is an open-label switch Ovalle trials study, in which patients previously taking Regular insulin U-100, were switched over to the 201730 Humulin U-500 twice daily (BID) or three times daily (TID) for 24 weeks.67 During the 4 week lead- Search of Medline, in phase, researchers captured patient reported outcomes using the TRIM-D validated outcome Embase, CENTRAL, searched measure for treatment-related impact on patients with T1DM and T2DM. TRIM-D measures five Trialtrove|Pharma Intelligence, domains including treatment burden, daily life impact, diabetes management, compliance,

48

Table 1. Systematic Reviews Study lead Title and author, Results Methods year ClinicalTrials.gov from January 2000 psychological health, and health status. Investigators compared patient’s TRIM-D baseline score to to April 2016 the scores at the end of the U-500 (BID or TID) treatment period. All TRIM-D domains were significantly improved from baseline in both U-500 groups. The Visual Analog Scale (EQ-5D VAS) Included RCTs, published in English, was also used which measures 5 dimensions (mobility, self-care, usual activity, pain/discomfort, of phase 1–4 clinical studies using and anxiety/depression), however is not disease specific like TRIM-D. There was no significant concentrated insulins change in the total EQ-5D VAS score from baseline to endpoint for either U-500 group or for the overall study population.67 Different insulin types and regimens for pregnant women with pre-existing diabetes (Review)

Searched CENTRAL, MEDLINE, Pregnant Women with Pre-Existing Diabetes Embase, CINAHL, handsearched 30 • ASP vs. RHI, + NPH (1 RCT) journals and conference abstracts; o Cochrane review authors rated Mathiesen et al 2007 et al as very low-quality evidence also searched Cochrane Pregnancy . In the parallel group design, RCT (N=322) with two publications (Mathiesen et al and Childbirth’s Trials Register 2007 and Hod et al 2008),49,50 the A1c was similar at the end of 2nd and 3rd by contacting their Information trimester with ASP or RHI treatment. Risk of major maternal hypoglycemia, Specialist preeclampsia, preterm labor, cesarean section, fetal loss, congenital O’Neill, malformations, pre-term birth were also comparable between groups.50 201748 Included studies RCTs and cluster • LIS vs. RHI, + NPH (1 RCT) randomized trials. Excluded quasi- o Cochrane review authors rated Persson et al as very low-quality evidence randomized controlled trials and o Cochrane review authors found, ”… no clear differences between those using cross-over design the groups for pre-eclampsia, abnormalities in the baby, or the need for a caesarean. Macrosomia, perinatal death, birth trauma including shoulder dystocia, nerve palsy, and Participants of interest included fracture, and the composite measure of neonatal morbidity were not reported.” women with pre-existing diabetes . See above summary section under SR Norgaard et al 2018 for more details on (type 1 or 2), regardless of age or the RCT by Persson et al 2002.51 parity. Excluded women with GDM

49

Table 1. Systematic Reviews Study lead Title and author, Results Methods year

Gestational Diabetes Mellitus (6 RCTs) • RHI versus ASP (Balaji 2005; Balaji 2012; Di Cianni 2007, Pettitt 2007) Insulin for the treatment of women • Meta-analyses of RCT evidence showed no clear difference in maternal hypertensive disorders with gestational diabetes (including preeclampsia or pregnancy induced hypertension), maternal hypoglycemia, caesarean section, neonatal risk of being born large for gestational age Searched Cochran Pregnancy and • RHI versus LIS (Di Cianni 2007; Jovanovic 1999; Mecacci 2003) Childbirth’s Trials Register (1 May • T Meta-analyses of RCT evidence showed no clear difference in caesarean section, maternal 2017; which includes reference that hypoglycemia, neonatal risk of being born large for gestational age have been extracted from CENTRAL,MEDLINE, Meta-Analysis Meta-analysis Comparison: RCTs Embase and CINAHL), Outcome Result ClinicalTrials.gov, WHO No significant (a) ASP vs. RHI: Balaji 2012 International Clinical Trials Registry Pre-eclampsia difference between Brown Platform (ICTRP) (1 May 2017) and treatments (NSD) 201752 reference lists of retrieved studies (a) ASP vs. RHI, Balaji 2012 NSD in 2017. Cesarean section (b) LIS vs. RHI: Jovanovic 1999, Mecacci 2003 NSD (c) RAIA vs. RHI: Balaji 2012, Jovanovic 1999, Mecacci 2003 NSD Included RCTs comparing different (a) ASP vs. RHI, Balaji 2012 NSD Large for insulin analogues for treating (b) LIS vs. RHI: Jovanovic 1999, Mecacci 2003 NSD Gestational Age women with diagnosed with GDM. (c) RAIA vs. RHI: Balaji 2012, Jovanovic 1999, Mecacci 2003 NSD Excluded cross-over trials, quasi- (a) ASP vs. RHI, Balaji 2012, Di Cianni 2007, Pettitt 2007 NSD Maternal randomized trials, and patients (b) LIS vs. RHI: Di Cianni 2007 NSD Hypoglycemia with pre-existing type 1 or type 2 (c) RAIA vs. RHI: Balaji 2012, Di Cianni 2007, Pettitt 2007 NSD diabetes. Glycemic control (a) ASP vs. RHI, Balaji 2012 NSD (by A1c) at study (b) LIS vs. RHI: Jovanovic 1999, Mecacci 2003 NSD endpoint (c) RAIA vs. RHI: Balaji 2012, Jovanovic 1999, Mecacci 2003 NSD Post-prandial (a) ASP vs. RHI, Balaji 2012, Di Cianni 2007, Balaji 2005 NSD glucose (b) LIS vs. RHI: Di Cianni 2007, Mecacci 2003 NSD

50

Table 1. Systematic Reviews Study lead Title and author, Results Methods year

Fullerton, Adults with T1DM Treated by MDI (non-pregnant) 20161 o All trials were open-label; most were parallel group design, 2 were cross over studies (Ferguson 2001 and Provenzano 2001). Authors explained that “[m]ost trials used NPH as basal insulin, one trial used Ultralente insulin (Z011 2007), and another trial allowed both, NPH or Ultralente insulin

Title: Short-acting insulin analogues (Z015 2007). Two trials did not specify the type of slow-acting insulin (Iwamoto 2001; Provenzano versus regular human insulin 2001).” In order to meet the SR inclusion criteria, the long- or intermediate-acting analog had to for adults with type 1 diabetes mellitus be “…given equally to both groups.” Authors noted that “[s]ome of the included trials found effects on post-prandial glucose values; (Review) o however, this outcome was not assessed because “…analyses of post-prandial glucose values Searched PubMed, EMBASE and leave a lot of leeway for subjective analysis and are often carried out posthoc.”1 Cochrane up to December 2014 Results: None of the trials found were designed to evaluate long-term effects on all-cause mortality or microvascular and macrovascular complications. Cochrane authors performed separate meta-analyses for

Included RCTs of blinded and LIS or ASP versus RHI with respect to outcomes of severe hypoglycemic episodes, A1c at endpoint, and open-label, parallel and cross-over weight gain. No studies were found that included glulisine. Cochrane authors report that while 3 trials design, with a treatment duration of suggest nocturnal hypoglycemia is lower with RAIAs, “…no trial provided convincing results to support this 24 weeks or more. claim.” LIS vs. RHI (6 RCTs) : Ferguson 2001; Provenzano 2001; Recasens 2003; Z011 2007; Z013 2007; o Drug comparisons of interest included Z015 2007

Short-acting insulin analogues (lispro, o ASP vs. RHI (3 RCTs): (Home 2000; Iwamoto 2001; Raskin 2000) aspart or glulisine) versus regular human insulin. • Description of results for individual studies Meta-Analysis Outcome Comparison: RCTs Meta-analysis for independent RAIA vs. RHI o Participants included adults (>18 Severe hypoglycemic • Individual RCTs consistently showed NSD (a) LIS vs. RHI (5 RCTs): years) with DMT1 who were not episodes between RHI versus LIS or ASP. Meta-analyses Ferguson 2001a; pregnant (eg, requiring third party also showed NSD between RHI versus ASP or LIS Recasens 2003; Z011 assistance, resolution (per Analysis 1.6 of review) 2007; Z013 2007; Z015 after glucagon injection, Meta-analysis any single RAIAs (LIS or ASP) vs. 2007 o resolution RHI showed also found NSD (b) ASP vs. RHI: Home after intravenous 2000; Raskin 2000 glucose and coma).

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year • Individual RCTs consistently showed NSD between RHI versus LIS. For ASP vs. RHI, two (a) LIS vs. RHI: RCTs (Iwamoto and Raskin) showed NSD, while Fullerton, Ferguson 2001a; the one (Home 2000) showed a significant 20161 Provenzano 2001, difference, with a lower A1c in the ASP group (- Recasens 2003; Z011 Continued 12%, 95% CI -0.22, -0.02). 2007; Z013 2007; Z015 A1c at endpoint Meta-analyses showed a significant difference, 2007 o with lower A1c in the ASP or LIS groups versus (b) ASP vs. RHI: Home RHI, in separate analyses (per Analysis 1.8 of 2000; Iwamoto 2001, review; LIS vs. RHI (6 RCTs): -0.20%, 95% CI - Raskin 2000 0.34, -0.05; ASP vs. RHI (3 RCTs): -0.14%, 95% CI

-0.21, -0.06).

Individual RCTs consistently showed NSD (a) LIS vs. RHI: o Recasens 2003; Z011 between RHI versus LIS. For ASP vs. RHI, 1 RCT

2007; Z013 2007; Z015 (Raskin) showed a difference, while the one Weight Gain 2007 (Home) showed NSD. (b) ASP vs. RHI: Home o Meta-analyses showed NSD in weight gain with LIS or ASP versus RHI, in separate analyses 2000; Raskin 2000 Abbreviation: NSD, no significant difference a Primary endpoint for the individual RCT

• Regarding other outcomes where meta-analyses couldn’t be performed for individual effect differences of each RAIA (eg, general hypoglycaemia) authors note that the evidence was 1 “…of low quality, but also did not indicate relevant group differences.” • “For nocturnal severe hypoglycaemic episodes, two trials reported statistically significant

effects in favour of insulin aspart. However, due to inconsistent reporting in publications and study reports, the validity of the result remains questionable.”1 • In addition, there was no clear evidence suggesting RAIA, over RHI, had substantial effect on health-related quality of life.

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year Title: Clinical efficacy and safety of insulin aspart compared with Type 1 DM (11 RCTs; adults and children, bolus and CSIII therapy) regular human insulin in patients • Note that authors do not separate out the population age (eg, pediatric, adult) or delivery method Wojciech- with type 1 and type 2 diabetes: (bolus or CSIII), as they merge all data together owski, a systematic review and meta- Efficacy: ASP vs. RHI 20152 analysis A1c Effect, ASP vs. RHI: Authors conduct meta-analysis regarding the relative change in A1c between ASP versus RHI (ie, change from baseline to end point in the ASP group relative to the RHI group). Search was conducted in Medline, • Authors included a study by DeVries et al68, which has a different dosing scheme in the NPH backbone EMBASE, and CENTRAL up to May of both treatment arms (confounding issue). Thus effects on A1c may not be solely attributed to the 2013. Authors also searched difference in prandial insulin, and maybe be partially due to the difference in the basal regimens

meeting proceedings by the between arms; sensitivity analysis was not performed.68

American Diabetes Association, o Authors state that ASP is superior at reducing A1c compared to RHI based on the meta-analysis European Association for the Study summary endpoint: HbA1c (weighted mean difference [WMD], –0.11%; 95% CI, –0.16 to –0.05; –1.2 of Diabetes mmol/mol; 95% CI, –1.7 to –0.5) with no evidence for between-study statistical heterogeneity (P = 0.59; I2 = 0%)

Drug comparisons of interest were insulin aspart with regular human PPG Effect, ASP vs. RHI: Four RCTs (all adults treated by MDI) were used to perform meta-analyses for insulin, with or without basal post-prandial glucose (ASP vs. RHI). One of these studies was DeVries et al, in which the backbone NPH insulin and provided with other dose differed between ASP and RHI treatment arms. Nonetheless, the other three studies consistently similar antidiabetic medications in show, independently, that post-prandial glucose levels after breakfast, lunch, and dinner were lower with each arm ASP treatment compared to RHI treatment. • postprandial glucose levels post breakfast (WMD, –1.40 mmol/l; 95% CI, –1.72 to –1.07), Patients included had either T1DM • postprandial glucose level post lunch (WMD, –1.01 mmol/l; 95% CI, –1.61 to –0.41) or T2DM. Excluded patients with • postprandial glucose level post dinner (WMD, –0.89 mmol/l; 95% CI, –1.19 to –0.59). pregestational or gestational diabetes Safety: ASP vs. RHI • Risk of severe hypoglycemia requiring third-party assistance (5 RCTs of mixed populations, adults, Included RCTs with at least 12 children, CSII, and MDI): No significant difference between ASP and RHI treatment arms. weeks of follow-up • Risk of nocturnal hypoglycemia (4RCTs of mixed populations, adults, children, CSII, and MDI): meta- analysis confirmed a lower risk of nocturnal hypoglycemia with ASP versus RHI (RR = 0.76; 95% CI, 0.64, Funded by Novo Nordisk 0.91), with no evidence for between-study statistical heterogeneity (P = 0.13, I2 = 46%).

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year Wojciech- T2DM, Adults (5 RCTs; insulin naive and experienced adults with basal insulin (4 RCTs) or without basal owski, insulin (1RCT)) 20152 5 RCTs (Bretzel 2004, Hermann 2013, Maiti 2012, Pala 2007, Raskin 1999): Maiti 2012 study doesn’t report Continued the type of basal insulin used, making it appear that no basal insulin was used. Hermann 2013 had either detemer or NPH for the basal therapy and do not report whether these were balanced among treatment arms.

Efficacy, ASP vs. RHI in Adults with T2DM There was a significant difference in the following clinical measures in favor of ASP compared to RHI; no sensitivity analyses were performed. • Relative change in A1c from baseline between treatment groups (WMD, –0.22%; 95% CI, –0.39 to – 0.05; –2.4 mmol/mol, –4.3 to –0.5); there was no significant between-study heterogeneity (P = 0.25; I2 = 26%). There is clinical heterogeneity as some trials were cross over design, and some did not include basal insulin therapy. • There was not enough numerical data provided in the RCTs to perform a meta-analysis for the effect on postprandial blood glucose. Safety, ASP vs. RHI in Adults with T2DM • The risk of overall hypoglycemia (based on meta-analysis) and sever hypoglycemia (based on individual study results) were comparable between the groups. Efficacy, safety, and patient Efficacy: comparative change in A1c from baseline between treatment arms acceptability of Technosphere T1DM inhaled insulin for people with Authors report result from studies using Afrezza in with two different inhalers (Gen2 and MedTone). After diabetes: a systematic review reviewing the FDA review documents, it was found the the Gen2 inhaler is the currently approved product. and meta-analysis Each inhaler provides different exposure, so only results with the currently approved inhaler will be discussed in the body of this report (Bode et al 2015, RCT comparing Afrezza and ASP10). Searched ClinicalTrials.gov, Medline Afrezza vs. ASP and CENTRAL up to 2015) • Results of individual RCTs were mixed with respect to the comparative change in A1c from baseline: 2 RCTs showed a significant difference in favor of ASP (ie, greater A1c reduction with ASP), while 1 RCT Pittas Included RCTs assessing the safety, (MK-TI-101) showed no difference between Afrezza and ASP. The three RCTs ranged from 12 to 52 41 2015 efficacy, and acceptability of weeks and included 107 to 539 patients; the two largest RCTs (MKC-TI-171 and MKC-TI-009) including Technosphere insulin (Afrezza) 528 and 539 patients, respectively, were the 2 showing a significant difference in favor of ASP compared with an active Afrezza vs. LIS

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year comparator, in patients with T1DM • One RCT was found (MKC-TI-117), which showed no significant difference between Afrezza and LIS for or T2DM the reduction of A1c. Excluded conference abstracts and T2DM

studies shorter than 11 weeks Authors report result from studies using Afrezza in with two different inhalers (Gen2 and MedTone). After reviewing the FDA review documents, it was found the the Gen2 inhaler is the currently approved product. SR authors received no outside Each inhaler provides different exposure, so only results with the currently approved inhaler will be funding discussed in the body of this report (non-published RCT: MKC-TI-162).

Afrezza vs. ASP • There were 2 RCTs found comparing ASP vs. Afrezza with inconsistent results; the very small study of 30 patients (MKC-TI-162, with the Gen2 inhaler) showed no significant difference in the change in A1c between treatment arms, while the large study of 309 (with the MedTone inhaler) patients showed a significant difference in favor of ASP over Afrezza.

Mixed Population Authors performed meta-analyses to assess the treatment difference between Afrezza versus any SQ insulin. They found no significant difference between Afrezza versus SQ insulin for adults with either T1DM or T2DM. However, when they combined data in T1DM and T2DM, the meta-analysis effect estimate showed a significant difference in favor of SQ insulin over Afrezza (net A1c difference 0.16%, 95% Ci 0.06, Pittas 0.25). 201541 Continued Safety Afrezza vs. SQ insulin in T1DM and T2DM (results were not reported separately with respect to each type of insulin or type of DM) • Authors state that “[s]evere hypoglycaemia was reported less frequently with Technosphere inhaled insulin than with subcutaneous insulin (OR 0·61, [95% CI 0·35–0·92]; 12% of patients with Technosphere insulin vs 19% with subcutaneous insulin).” Results were not provided separately for each type of SAIA. • Authors also report a pooled effect from 3 RCTs for the outcome weight gain, which favored Afrezza, as it was associated with significantly less weight gain compared to subcutenous insulin Insulin analogues versus human Authors identified studies with glulisine that were not found by some other authors. These glulisine trials Sanches insulin in type 1 diabetes: direct were incorporated into our report to fill in the evidence gap. 201336 and indirect meta-analyses of • GLU vs. RHI (1 RCT, Garg et al 2005; 12 week study, N-=866) showed no difference for the efficacy and safety reduction of A1c when pre and post meal GLU data was combined versus RHI. Original publication

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year of the RCT reports data separately for GLU, finding a significant difference in favor of GLU for the Searched Scopus, Medline, reduction in A1c only when administered premeal, and not when administered postmeal.3 Cochrane Library, Lilacs and • GLU vs. LIS (1 RCT, Kawamori 2009; 32 weeks of treatment, N=267) There was no significant International Pharmaceutical difference for the reduction of A1c Abstracts (IPA) o Kawamori et al report no differences in adjusted mean 2h-PPG and change in adjusted mean daily rapid-acting insulin dose at study endpoint. Included double-blinded o There were no differences in hypoglycaemia-related events (all symptomatic randomized controlled trials (RCTs) hypoglycaemia, severe symptomatic hypoglycaemic, or severe nocturnal) of adults with T1DM who received a long-acting insulin analogue (glargine or detemir), a short-acting insulin analog (aspart, lispro or glulisine), NPH insulin (either alone or in combination with rapid-acting human insulin [regular]) or insulin analogues (lispro or aspart) for at least 4 weeks. Meta-analyses were by random-effects modeling

Rapid-Acting Insulin Analogues for Adults with T1DM the A1C Outcome, Adults with T1DM Treatment of Diabetes Mellitus: LIS vs. RHI (Extracted data from studies ≥3 months) Meta-analyses of Clinical • Combined analysis of MDI and CSII studies ≥3 months (6 RCTs) A1c weighted mean difference (WMD) - Outcomes. 0.17%; 95% CI -0.30, -0.03 Update of CADTH Technology o MDI subgroup [4 RCTs] A1C WMD [95% CI] = –0.19% [–0.38 to -0.0]; NSD (Fullerton et al 2016 SR Report No. 87 includes some more recent RCTs and finds a difference) CSII subgroup MA [2 RCTs]: no significant difference found o Searched Cochrane Library ASP vs. RHI (Extracted data from studies ≥3 months) MEDLINE, Embase, and BIOSIS • Combined analysis of MDI and CSII studies ≥3 months [5 RCTs] A1c WMD –0.13%, 95% CI –0.21, -0.05 CADTH Previews. Results from 1990 to o MDI subgroup [4 RCTs] A1C WMD [95% CI] = –0.11% [–0.18 to -0.04] (Fullerton et al 2016 SR 20085 April 2007 were considered also find a significant difference) CSII subgroup [1 RCTs] A1C WMD= –0.20% [–0.66 to 0.26]; NSD o ASP vs. LIS: (1 RCT, Bode et al 2002, 16 week treatment with CSII, N=87)

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year Included RCTs of at least 4 weeks • No significant WMD in the A1C at treatment end; Since the publication of this SR, there have been duration, with patients diagnosed more recent RCTs published for this comparison (see Norgaard et al 2018) T1 or T2DM Hypoglycemia Outcomes, Adults with T1DM Comparators were prandial insulins Rate of overall hypoglycemia (LIS, ASP, or RHI; GLU not included LIS vs. RHI since it was not approved in Combined analysis of MDI and CSII studies (16 RCTs): no significant difference in event rates Canada). MDI subgroup MA [12 RCTs] no significant difference in event rates o “Studies containing insulin o CSII subgroup MA [4 RCTs] no significant difference in event rates premixed formulation or ASP vs. RHI combination therapy were included Combined analysis of MDI and CSII studies (8 RCTs): no significant difference in event rates only if the additional antidiabetic MDI studies MA (6 RCTs): no significant difference o agents were given equally to both o CSII studies (2 RCT): RR 0.58; 95% CI 0.40, 0.85—includes a study of 7 weeks duration the intervention and ASP vs. LIS: (1 RCT, Bode et al 2002, 16 week treatment with CSII, N=87) comparator groups” • Increase in the event rate with LIS compared to ASP, RR 1.49; 95% CI 1.37, 1.63; Since the publication Outcomes included: A1c, of this SR, there have been more recent RCTs published for this comparison (see Norgaard et al 2018)

hypoglycemia, quality of life, complications of diabetes, and mortality. Severe or major hypoglycemia LIS vs. RHI

Objectives included: Combined analysis of MDI and CSII studies (10 RCTs) Relative risk (RR) 0.80; 95% CI 0.67, 0.96 CADTH • Comparing RAIA to RHI for o MDI subgroup [6 RCTs] RR 0.7; 95% CI 0.65, 0.94 (Fullerton et al 2016 SR include a few more 20085 treatment of DMT1, DMT2, or recent RCTs and find no difference) GDM o CSII subgroup MA [4 RCTs]: no significant difference found • CSII of RAIA vs. RHI for special ASP vs. RHI Continued populations o MDI studies MA (3 RCTs): no significant difference (consistent with Fullerton 2016 SR) 4 • ASP vs. LIS for DMT1, DMT2, or o CSII studies (1 RCT): appeared similar bases results reported by the RCT authors Bode et al GDM ASP vs. LIS: (1 RCT, Bode et al 2002, 16 week treatment with CSII, N=87) • No difference reported by Bode et al. Since the publication of this SR, there have been more

recent RCTs published for this comparison (see Norgaard et al 2018) Nocturnal hypoglycemia LIS vs. RHI Combined analysis of MDI and CSII studies (4 RCTs) Relative risk (RR) 0.60; 95% CI 0.40, 0.90

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year o MDI subgroup [3 RCTs] RR 0.58; 95% CI 0.35, 0.98; however, there was a significantly large 2 degree of heterogeneity among studies (I = 95.6) o CSII study [1 RCT] RR 0.67; 95% CI 0.51, 0.88 (There have been at least 6 more recent RCTs published since this SR, thus data is incomplete—See Norgaard et al SR 2018) ASP vs. RHI o MDI studies (2 RCTs): no MA provided o CSII study (1 RCT, Bode et al 2002, 16 week treatment with CSII, N=118): rate ratio 0.55, 95% CI 0.43, 0.70 ASP vs. LIS: (1 RCT, Bode et al 2002, 16 week treatment with CSII, N=87) • No significant difference reported by Bode et al; Since the publication of this SR, there have been more recent RCTs published for this comparison (see Norgaard et al 2018)

Weight gain: no significant difference between LIS vs. RHI, data not available for ASP vs. RHI

Pre-adolescents with T1DM, MDI Treatment LIS vs. RHI, 4 RCTs (Deeb 2001, Fairchild 2000, Ford-Adams 2003, Tupola 2001) • Meta-analyses showed no significant differences in A1c at study end, rates of severe hypoglycemia, rates of nocturnal hypoglycemia, overall hypoglycemia between treatments CADTH Adolescents with DMT1, MDI Treatment 20085 • Authors identified 1 RCT (Holcombe 2002, LIS vs. RHI) showing no significant difference in A1c control or severe hypoglycemia rates. This single study showed a significant difference in favor of Continued LIS compared to RHI with respect to nocturnal and overall hypoglycemia: rate ratios (95% CI) were 0.61 (0.57, 0.64) and 0.90 (0.88, 0.93) respectively.

Adults with T2DM RAIA vs. RAIA: authors report only one available study, Niskanen et al comparing ASP vs. LIS, and finding no difference in A1c control or in the rates of overall hypoglycemia Pregnant Women with T1DM Authors identify Persson et al (LIS vs. RHI) and Mathiesen et al (ASP vs. RHI); See the sections for the systematic reviews by O’Neil et al 2017 and Norgaard et al 2018 for information on study outcomes

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Table 1. Systematic Reviews Study lead Title and author, Results Methods year Are analogue insulins better than soluble in continuous subcutaneous Adults with T1DM treated by CSII insulin infusion? Results of ASP vs. RHI (1 RCT) a meta-analysis No difference was found for the mean change in baseline A1c between ASP vs. RHI (this single study, Bode

2002 is also discussed in the Norgaard 2018 SR section above). Colquitt et al rank the RCT by Bode et al as

Colquitt high quality Searched Medline, Embase, Science et al Citation Index, BIOSIS, and Web of 200338 LIS vs. RHI (6 RCTs, with at least 3 months of treatment, with a patient sum of 500) Science Proceedings up to 2002 Meta-analysis of 6 RCTs showed that the end of study A1c was significantly less with LIS versus RHI

(treatment effect difference -0.25%, 95% CI -0.47, -0.06). Authors note that only one of the studies (Bode et Included RCTs with a minimum al 2002) is of high quality. This SR missed a newer RCT (Tubiana-Rufi 2004, N=18) identified in Norgaard et duration of 10 week treatment al 2018 SR phase, comparing rapid acting insulin analogs to RHI Abbreviations: A1C; glycosylated hemoglobin; ASP, insulin aspart; CSII, continuous subcutaneous insulin infusion with type 1; DMT1, diabetes mellitus type 1; GLU, insulin glulisine; GDM, gestational diabetes mellitus; HbA1c, hemoglobin A1c; LIS, insulin lispro; MDI, multiple daily injections; PPG, post prandial glucose; RAIA, rapid acting insulin analog; RCT, randomized controlled trial; RHI, regular human insulin; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

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Appendix E: Summary of Treatment-Effect Differences

Adults with T1DM

• RAIAs vs. RHI: Compared to RHI, the RAIAs may offer only marginal (ie, significant difference but unlikely to be clinically meaningful) improvements in A1c control in patients with T1DM treated by MDI and are similar with respect to the risk of severe hypoglycemia.1-3 In the setting of CSII for adults with T1DM, LIS also demonstrated marginal improvements in A1c control over RHI (based on data from an MA of 6 RCTs for LIS38, most with quality weaknesses).38 Based on a single study with ASP CSII there was a lower rate of nocturnal hypoglycemia reported in the ASP group compared to RHI.4,5 Study results reported from individual RCTs were mixed (ie, there was a lower or similar incidence of hypoglycemia with CSII LIS compared to CSII RHI).6

• RAISs vs. RAIAs: Most studies of RAIAs versus RAIAs in adults with T1DM apply to the CSII setting. Studies in the setting of MDI therapy for patients with T1DM compared GLU versus LIS or the biosimilar Admelog versus Humalog (1 study per comparison); no significant differences were found.7,8 In CSII studies, ASP was either better or similar at controlling the A1c compared to LIS, while ASP performed similar to GLU. GLU and LIS similarly control A1c and there were no differences in severe hypoglycemic events. Results were mixed regarding which agent, LIS or ASP, causes more risk of hypoglycemia. For LIS versus GLU there was no difference in the overall rate of severe hypoglycemic events; however, the rate of symptomatic hypoglycemic events (BG confirmed <70 mg/dL) per patient year were lower with LIS compared to GLU in the one available study.9

• Regarding Afrezza, one head-to-head trial was identified with the currently approved dosage form (with the Gen2 inhaler device) compared to ASP in adults with T1DM. While Afrezza was non- inferior to ASP for the mean change in A1c; there was a significantly greater change in A1c with ASP compared to Afrezza (-0.21% vs. -0.40%) and more ASP patients achieved an A1c <7.0% (31% vs. 18% of patients, respectively; P=0.016). The inhaled insulin group experienced marginal weight loss (–0.4 kg) compared to the gain (+0.9 kg) observed in the subcutaneous insulin group (P = 0.0102). The incidence of severe hypoglycemia was significantly lower with inhaled insulin versus ASP (18% vs. 29%; P < 0.016).10

Table 1 summarizes findings among MDI and CSII studies for the pediatric population.

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Table 1. Summary of Comparative Evidence for Injectable Prandial Insulin Comparisons in Adults with T1DM Comparison Reported differences where (Applicable A1c Post prandial Glucose (PPG) Hypoglycemia there is consistency among SRs Systematic or RCTs Reviews) Patients treated by MDI • Significantly lower A1c at Significantly lower A1c Meta-analysis and results from Meta-analyses showed no difference treatment end with ASP MDI1; at treatment end with independent RCTs consistently between ASP versus RHI for the however differences are ASP (3 RCTs) (TED: - showed that post-prandial glucose outcomes of severe hypoglycemia or unlikely to be clinically ASP vs. RHI 0.14%, 95% CI -0.21, - levels after breakfast, lunch, and weight gain.1 Fullerton et al also note meaningful based on the (Norgaard 0.06)1 dinner were lower with ASP that individual trials all show that overall historical non-inferiority 2018, treatment compared to RHI hypoglycemia rates are similar between margin of 0.4% A1c change Fullerton treatment2 treatments. used by the FDA 2016, Patients treated by CSII • Post-prandial glucose levels Wojciechowski NSD found from 1 RCT The end of study PPG after dinner Lower rate of nocturnal hypoglycemia were lower with ASP treatment 2 2015, CADTH for the reduction in was lower with ASP (1 RCT)4 with ASP, based on 1 RCT5 compared to RHI treatment 2008, Colquitt A1c4 2003) • Lower rate of nocturnal hypoglycemia with ASP CSII, based on 1 RCT • PPG after dinner: lower with ASP CSII Patients treated by CSII • PPG after lunch: lower with Two RCTs were One trial reported lower post- Severe hypoglycemic events were ASP, based on 1 CSII RCT ASP vs. GLU identified, showing lunch BG values during the last similar between treatments in both (Norgaard similar control of A1c week of treatment with ASP (166.1 trials. There were mixed results among 2 2018) with ASP and GLU vs.155.5 mg/dL, P<0.021).”9 RCTs regarding non-severe treatment6 hypoglycemia and nocturnal hypoglycemia.6 Patients treated by CSII 4 CSII RCTs One out of the 4 RCTs The end of study PPG after dinner Mixed results from 4 RCTs • Mixed results for A1c control reported greater A1c was lower with ASP (1 RCT)4 and hypoglycemia risk ASP vs. LIS reduction with ASP; (Norgaard however the 2018) difference does not appear clinically meaningful

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Table 1. Summary of Comparative Evidence for Injectable Prandial Insulin Comparisons in Adults with T1DM Comparison Reported differences where (Applicable A1c Post prandial Glucose (PPG) Hypoglycemia there is consistency among SRs Systematic or RCTs Reviews) Patients treated by MDI • Significantly lower A1c at Significantly lower A1c Cochrane reviewers note that they Meta-analyses showed no difference treatment end with ASP in both at treatment end with did not investigate post-prandial between LIS versus RHI for the MDI and CSII studie1,6; however LIS (TED LIS vs. RHI: - glucose as an outcomes since outcomes of severe hypoglycemia or differences are unlikely to be 0.20%, 95% CI -0.34, - these values “…leave a lot of weight gain. Most RCTs showed no clinically meaningful based on

0.05) 1 leeway for subjective analysis and difference in hypoglycemia episodes the historical non-inferiority LIS vs. RHI are often carried out posthoc.”1 between treatments.1 margin of 0.4% A1c change (Norgaard used by the FDA 2018, Patients treated by CSII Fullerton MA of 6 RCTs showed Mean PPG measures from A lower or similar incidence of 2016, Colquitt that LIS was associated individual studies were either hypoglycemic events was observed with 2003) with a lower A1c at similar; however, most were lower LIS compared to RHI based on results study end (TED with LIS compared to RHI.6 from individual RCTs.6 -0.25%, 95% CI -0.47, -0.06).38

Patients treated by MDI • Larger reductions in A1c were 1 RCT showed pre- 2-hour post-breakfast and 2-hour NSD in the rate or incidence of “all” achieved with pre-meal but not meal GLU use (but not post-dinner blood glucose levels symptomatic or nocturnal hypoglycemia. post-meal dosing of GLU, post-meal dosing) were significantly lower with pre- Rates of severe hypoglycemia were also compared to pre-meal RHI. reduced A1c meal or post-meal GLU use similar. • 2-hour post-breakfast and significantly more compared to RHI, based on 1 RCT post-dinner blood glucose compared to RHI levels were lower with pre- GLU vs. RHI (treatment difference - meal and post meal GLU use,

0.13%, P=0.02) compared to pre-meal RHI (Sanches 2013)

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Table 1. Summary of Comparative Evidence for Injectable Prandial Insulin Comparisons in Adults with T1DM Comparison Reported differences where (Applicable A1c Post prandial Glucose (PPG) Hypoglycemia there is consistency among SRs Systematic or RCTs Reviews) Patients treated by MDI The rate of confirmed No differences No differences reported from 1 No differences reported from 1 RCT7 symptomatic hypoglycemic reported from 1 RCT7 RCT7 events and symptomatic nocturnal hypoglycemia was GLU vs. LIS Patients treated by CSII lower with LIS CSII compared to NSD found from 1 RCT No differences reported6,9 NSD in the overall rate of severe GLU CSII, based on results from 1 (Norgaard for the A1c at hypoglycemic events; However, the rate RCT9 20186, treatment end9 of symptomatic hypoglycemic events Sanches (BG confirmed <70 mg/dL) per patient 201336) year were lower with LIS compared to GLU (62.7 vs. 73.8, P<0.001), along with the rate of symptomatic nocturnal hypoglycemia (12.8 vs. 9.48, P<0.001).9

Abbreviations: ASP, insulin aspart; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; FDA, US Food and Drug Administration; GLU, insulin glulisine; LIS, insulin lispro; MA, meta-analysis; MDI, multiple daily dose bolus insulin; NSD, no significant difference; RCT, randomized controlled trial; RHI, regular human insulin; SD, significant difference; TED, treatment effect difference

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Patients with T2DM

Meta-analyses conducted in a 2018 Cochrane Review included RCTs of at least 24 weeks duration. There were no significant differences between any single RAIA vs. RHI with respect to A1c change or non- severe hypoglycemic events (based on low to very low quality studies). Moreover, there were no clear differences in the risk of severe hypoglycemic events between agents. Results on patient-relevant outcomes, such as all-cause mortality, microvascular, or macrovascular complications were lacking.

There were limited studies comparing RAIAs versus each other for patients with T2DM. There was 1 study each for ASP versus LIS and Admelog vs. Humalog; no significant differences were found.

Pregnant Women

No clear differences were found between RAIAs vs. RHI. The rapid-acting insulins, aspart and lispro, similarly controlled A1c control compared to regular human insulin, with NPH background therapy in pregnant women with pre-existing T1DM.6 Meta-analyses of a 2017 Cochrane Review (Brown et al 2017) found no difference in maternal or infant outcomes comparing regular human insulin with insulin aspart or lispro.52 No head-to-head studies comparing rapid acting insulin analogs with on another were found.6,52

Pediatric Patients with T1DM

Most comparative studies in the pediatric population were in children with T1DM treated via MDI. No head-to-head studies were reported with GLU or for MDI ASP versus MDI LIS in children. A 2018 systematic review by Norgaard et al 2018 identified 9 head-to-head studies involving MDI administered, rapid-acting insulin comparisons in the pediatric population with T1DM.6 There were no clear differences between the prandial agents with respect to A1c control or severe hypoglycemia-related outcomes. Regarding nocturnal hypoglycemia, there were no significant differences reported from individual RCTs for ASP versus RHI. Results of RCTs were mixed for LIS versus RHI (3 of 5 RCTs reported significant differences in favor of LIS).

Two additional RCTs involving CSII were identified for the pediatric population with T1DM: 1 compared LIS versus RHI and one of LIS versus ASP.6 Regarding the change in A1c from baseline, no significant differences were found between LIS versus RHI or between ASP versus LIS.6 RCTs reported no significant differences for hypoglycemia-related outcomes between RHI versus ASP or RHI versus LIS.6 There were no studies found comparing CSII ASP versus CSII RHI.

Table 2 summarizes findings among MDI and CSII studies for the pediatric population.

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Table 2. Summary of Comparative Evidence for Prandial Insulin Comparisons in Pediatric Patients with T1DM Comparison A1c PPG prandial Hypoglycemia Summary Pediatric patients treated by MDI ASP vs. RHI Mixed results No difference NSD consistently Only small trials in patients from small RCTs reported among 3 reported among treated via MDI are for A1c control RCTs RCTs for the risk available for this ASP vs. RHI (ASP preformed of severe comparison, overall ASP (Norgaard similar in 2 RCTs hypoglycemia or and RHI appear similar 2018)6 and performed any better than RHI in hypoglycemia6 1 small study of 30 patients) 6 Pediatric patients treated by CSII ASP vs. LIS NSD found from 1 NSD found from 1 NSD found from 1 Products appear similar; RCT for the RCT RCT for major, although, available ASP vs. LIS reduction in A1c minor, or nocturnal evidence is very limited (Norgaard hypoglycemia (only 1 RCT for the 2018) pediatric CSII population and none available for MDI) Pediatric patients treated by MDI LIS vs. RHI NSD consistency Mixed results from NSD consistently LIS and RHI similarly among RCTs for individual RCTs (LIS reported among control A1c, however, PPG A1c control performed similar RCTs for the risk of levels following breakfast or better than RHI) severe and dinner were found in with respect to hypoglycemic some studies. There are LIS vs. RHI PPG post breakfast events. Three of the also mixed results (Norgaard and dinner 5 RCTs report lower regarding nocturnal 2018) rates of nocturnal hypoglycemia as 3 of 5 hypoglycemia with RCTs reported lower rates LIS with LIS in MDI treatment. Pediatric patients treated by CSII NSD found from 1 NSD found from 1 NSD found from 1 RCT for the RCT for mean PPG RCT for severe reduction in A1c58 levels58 hypoglycemia58 Pediatric patients treated by MDI GLU vs. LIS NSD found from 1 NSD found from 1 NSD in “all”, Products appear similar, GLU vs. LIS RCT for the RCT “severe, nocturnal, although, evidence is very (Norgaard reduction of A1c or severe nocturnal limited (only 1 RCT for the 2018) symptomatic T1DM pediatric MDI hypoglycemia found population; none available from 1 RCT for CSII) Abbreviations: ASP, insulin aspart; CSII, continuous subcutaneous insulin infusion; GLU, insulin glulisine; LIS, insulin lispro; MA, meta-analysis; MDI, multiple daily dose bolus insulin; NSD, no significant difference; PPG, post prandial glucose; RCT, randomized controlled trial; RHI, regular human insulin; SD, significant difference; TED, treatment effect difference

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