Essential Medicines List (EML) 2017 Application for the revision of second line treatments of type II diabetes: considered agents that can be used in combination with metformin are sulfonylureas, meglitinides, alpha-glucosidase inhibitors, TZDs, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists, basal insulins, bolus insulins, and biphasic insulins. General items 1. Summary statement of the proposal for inclusion, change or deletion In type 2 diabetes, when initial therapy with lifestyle interventions and metformin monotherapy are unsuccessful, a second oral or injectable agent is recommended. This is referred to as ‘second-line therapy’. Historically, insulin or sulfonylureas have been preferred second-line agents because of efficacy, side-effect profiles, long-term safety, and relative cost. Both insulin and sulfonylurea are listed as essential medicines, along with metformin. In 2013 the Expert Committee of Essential Medicines Selection and Use evaluated evidence comparing four groups of oral hypoglycemics: (1) dipeptidyl peptidase-4 (DPP-4) inhibitors, (2) thiazolidinediones, (3) alpha-glucosidase inhibitors, such as acarbose, and (4) meglitinides, against metformin (biguanide) and sulfonylureas (WHO Technical Report Series 985). The results from the 2013 review indicated that there were no apparent differences in efficacy across drug classes, and that sulfonylureas were the most cost-effective treatment option. Based on these analyses, the Expert Committee recommended that “there was insufficient evidence to show that any of the medicines in the four groups (DPP-4 inhibitors, alphaglucosidase inhibitors, meglitinides, or thiazolidinediones) offered any efficacy or safety advantages over the existing medicines included in the EML”, (i.e. metformin first line and sulfonylurea second line). Since then, a new drug class has entered the market of several countries for the treatment of patients with T2D — sodium-glucose cotransporter-2 (SGLT-2) inhibitors. In addition, a fourth (Dipeptidyl peptidase-4) DPP-4 inhibitor (alogliptin) as well as a third Glucagon-like peptide-1 (GLP-1) analogue (dulaglutide) have appeared and new data on the impact on cardiovascular outcomes of some of the new drugs (e.g., GLP-1 agonists, DDP-4 inhibitors and SGLT-2 inhibitors) have been published. Given the newer agents recently approved in most countries and additional randomized controlled trial (RCT) evidence published over the last 5 years for the existing and newer agents, there is a need to revisit comparative efficacy, safety and cost. This application concerns the updating of section 18.5 Insulins and other medicines used for diabetes of the WHO Model List of Essential Medicines (WHO EML) for adults and children (WHO Model List of Essential Medicines, April 2015, 19th Edition). This application provides a comprehensive and comparative assessment of all available second-line therapies (to be used in combination with metformin): sulfonylureas, meglitinides, alpha-glucosidase inhibitors, TZDs, DPP-4 inhibitors, SGLT-2 inhibitors (Table 1), GLP-1 agonists, basal insulins, bolus insulins, and biphasic insulins, including analogues (Table 2). The comparative assessment is based on an update of a previous CADTH systematic review and network meta-analyses of second-line therapies for type 2 diabetes (. In addition, this application reviews pharmacologic treatments for patients with type 2 diabetes who are at high risk for cardiovascular events. Third-line therapies were not assessed. Based on Bayesian network meta-analyses, adjunctive second-line therapies were associated with possible reductions in glycemic control when compared to metformin monotherapy, with few differences between any of the active treatments. Sulfonylurea and GLP-1 analogues decreased glycated hemoglobin when compared to DPP-4; GLP-1 analogues and sulfonylurea decreased weight when compared to metformin monotherapy, while insulin and sulfonylurea increased weight when compared with the other classes. GLP- 1 analogues and insulins increased the number of adverse events and withdrawals. Sulfonylurea and insulins increased non-severe hypoglycemia when compared to metformin monotherapy and other classes. However basal insulin was associated with fewer non- severe hypoglycemia events when compared to sulfonylurea. Urinary tract infections were possibly increased with SLGT-2 when compared to metformin monotherapy and DPP-4. In high risk patients, SGLT-2 were possibly associated with a reduction in all-cause mortality when compared to placebo and to DPP-4 analogues, and SGLT-2 were not associated with severe hypoglycemia events. This review offers a set of analyses to assess and interpret multiple second line medicines used to treat T2D and to understand the relative merits of these multiple interventions. Compared with conventional pairwise meta-analysis, network meta-analysis has advantages: the technique borrows strength from indirect evidence to gain certainty about all treatment comparisons, including comparisons of estimated effects that have not been investigated head to head in randomized clinical trials. 2. 2. Name of relevant WHO department and focal point Management of Noncommunicable Diseases of the Department for Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention Essential Medicines and Health Products Department 3. Name of the organization(s) consulted and/or supporting the application Report Authors: 1,2George A. Wells, Shannon Kelly, Amy Johnston, Shuching Hsieh, Jesse Elliott, Zemin Bai, Li Chen, Alomgir Hossain, Becky Skidmore Contributors: 3Bradley Mitchelmore, Sumeet Singh, Mohammed Jabr, Hongbo Yuan, Melissa Severn, Brendan McIntosh, Karen Lee, Brent Fraser Clinical experts: 4Julia Lowe, 5Marshall Dahl 1. Methods and Applications Group for Indirect Treatment Comparisons (MAGIC), Ottawa, Canada. Sponsored by the Canadian Institutes for Health Research, Drug Safety and Effectiveness Program (CIHR-DSEN). 2. Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario. 3. CADTH, Ottawa, Canada. 4. Sunnybrook Hospital, University of Toronto, Toronto, Ontario. 5. University of British Columbia, Vancouver Hospital, Vancouver, British Columbia. 6. University of Calgary, Julia McFarlane Diabetes Research Centre, Calgary, Alberta. 4. International Non-proprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC) code of the medicine. This evaluation is based on the policy context currently prevailing in Canadian publicly funded drug programs for the reimbursement of drugs for T2D. Table 1: Oral medicines included in the application Drug Class INN Drug Name Anatomical DDD Therapeutic Chemical (ATC) codes DPP-4 Inhibitors Alogliptin A10BH04 25 mg Linagliptin A10BH05 5 mg Saxagliptin A10BH03 5 mg Sitagliptin A10BH01 100 mg SGLT-2 Inhibitors Canagliflozin A10BK02 200 mg Dapagliflozin A10BK01 10 mg Empagliflozina A10BK03 17.5 mg Sulfonylureas Chlorpropamide A10BB02 375 mg Gliclazideb A10BB02 160 mg 60 mg Glimepiride b A10BB12 2 mg Glyburide b A10BB04 10 mg Tolbutamide A10BB03 1,500 mg 30 mg TZDs Pioglitazone A10BG03 Rosiglitazone 6 mg A10BG02 360 mg Meglitinides Nateglinide A10BX03 Repaglinide 4 mg A10BX02 Acarbose 300 mg AGIs A10BF01 DPP-4 Alogliptin/metformin A10BD13 25 mg Inhibitors/Biguanides Linagliptin/metformin A10BD19 5 mg Saxagliptin/metformin A10BD21 5 mg Sitagliptin/metformin A10BD07 100 mg SGLT-2 Dapagliflozin/metformin A10BD15 10 mg Inhibitors/Biguanides Empagliflozin/metformin A10BD20 17.5 mg Canagliflozin/metforminc A10BD16 200 mg a Not included in Therapeutic Choices. b Generic products also available. c Pre-Notice of Compliance CADTH Common Drug Review submission received on February 3, 2016 (https://www.cadth.ca/canagliflozin-and-metformin-hydrochloride). Notes: Table adapted from Table 8 in Endocrine and Metabolic Disorders: Diabetes Mellitus Chapter of Therapeutic Choices. Canadian Pharmacists Association, 2015. All rights reserved. Source: https://www.e- therapeutics.ca/tc.showChapter.action?documentId=c0079#tablc0079n00043. Accessed: July 29, 2015.Other information sources include Product Monograph available from the Health Canada Drug Product Database (http://www.hc-sc.gc.ca/dhp- mps/prodpharma/databasdon/index-eng.php) as well as CADTH 2013 (Updated) Optimal Use Reports on the optimal use of second- and third line therapies for type 2 diabetes mellitus (https://www.cadth.ca/second-third-line-therapies-type-2-diabetes). Table 2: Injectable medicines: GLP-1 Analogues, Insulin and Insulin Analogues GLP-1 Analogue Products Anatomical Therapeutic DDD Chemical (ATC) codes Dulaglutide A10BJ05 0.16 mg Exenatide A10BJ01 15 ug Exenatide extended-release A10BJ01 15 ug Liraglutide A10BJ02 1.2 mg Albiglutide A10BJ04 5.7 mg Insulin and Insulin Insulin and Insulin DDD Analogue Productsa Analogue Types Insulin aspart Very rapid-acting A10AB05 insulin analogue Insulin glulisine Very rapid-acting A10AB06 insulin analogue Insulin lispro Very rapid-acting A10AB04 insulin analogue Insulin, regular Rapid-acting insulin A10AB01 Insulin, pork Rapid-acting insulin A10AB03 Insulin, NPH Intermediate-acting A10AC01 insulin Insulin, pork Intermediate-acting A10AC03 40 U insulin Insulin detemir Long-acting insulin A10AE05 analogue Insulin glargine Long-acting insulin A10AE04 analogue Insulin regular/insulin, Mixed (regular/NPH) A10AD01 NPH human insulin Insulin lispro/lispro Mixed insulin A10AD04 protamine analogue Insulin aspart/aspart Mixed insulin A10AD05 protamine analogue DDD = World Health