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Cover of Second- and Third-Line Pharmacotherapy for Type 2 Diabetes: Update

Second- and Third-Line Pharmacotherapy for Type 2 Diabetes: Update

CADTH Optimal Use Report, No. 3.1

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In August 2010, the Canadian Agency for Drugs and Technologies in Health (CADTH) published an Optimal Therapy Report which assessed the clinical and cost-effectiveness of second-line therapies for patients with type 2 diabetes inadequately controlled on metformin. The results from the CADTH 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 Canadian Optimal Medication Prescribing and Utilization Service (COMPUS) Expert Review Committee (CERC) recommended that most patients requiring a second treatment after metformin should be prescribed a sulfonylurea. CADTH followed this report with a Therapeutic Review which examined the evidence for third-line treatment options for adults with type 2 diabetes inadequately controlled on metformin and a sulfonylurea. The results demonstrated that insulins (basal, biphasic, bolus), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, and thiazolidinediones (TZDs) all produced statistically significant reductions in hemoglobin A1C in combination with metformin and a sulphonylurea. Meglitinides and alpha-glucosidase inhibitors, however, did not. The addition of insulin neutral protamine Hagedorn (NPH) to metformin plus a sulfonylurea was associated with the most favourable cost-effectiveness estimates. CADTH’s Therapeutic Review Panel (TRP) recommended that, for most adults with type 2 diabetes inadequately controlled on metformin and a sulfonylurea, insulin NPH should be added as the third-line agent. Long-acting insulin analogues at prices similar to insulin NPH were also considered an option for patients inadequately controlled on metformin and a sulfonylurea.

The original clinical reviews of second- and third-line pharmacotherapy for type 2 diabetes included GLP-1 analogues and DPP-4 inhibitors currently available in Canada; however, the cost-effectiveness analyses and subsequent recommendations could not address the use of GLP-1 analogues, as there were no agents approved for use in Canada at the time of the reviews. Two GLP-1 analogues, exenatide (Byetta) and liraglutide (Victoza), are now approved for use in Canada. As well, sitagliptin and saxagliptin were the only DPP-4 inhibitors considered in the original economic analyses and recommendations, while agents in this class that were not yet approved by Health Canada (e.g., linagliptin) were excluded. Therefore, there is interest in updated optimal therapy recommendations for second- and third-line therapy in diabetes that incorporate the GLP-1 analogues and newer DPP-4 inhibitors.

Since the original CADTH reports were published, interest has emerged in the combined use of incretins and insulin, and some incretins have received regulatory approval for combined use with insulin in Canada and other jurisdictions. Hence, the updated clinical reviews will also address a supplemental research topic regarding the combination use of incretin agents with insulin.


This report is prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). The report contains a comprehensive review of the existing public literature, studies, materials, and other information and documentation (collectively the “source documentation”) available to CADTH at the time of report preparation.

The information in this report, when finalized, is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. The information in this report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process, nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of this document to ensure that its contents are accurate, complete, and up to date as of the date of publication, CADTH does not make any guarantee to that effect. CADTH is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document or in any of the source documentation.

This document and the information provided are prepared and intended for use in the context of the Canadian health care system. Other health care systems are different; the issues and information related to the subject matter of this document may be different in other jurisdictions and, if used outside of Canada, it is at the user’s risk. This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.

CADTH takes sole responsibility for the final form and content of this document, subject to the limitations noted above. The statements and conclusions in this document are those of CADTH and not of its advisory committees and reviewers. The statements, conclusions, and views expressed herein do not necessarily represent the views of Health Canada or any Canadian provincial or territorial government. Production of this document is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon.

This report is shared for feedback and comments and should not be used for any purposes other than for consultation. The report may change following this consultation.

Please contact CADTH’s Vice-President of Corporate Services at ac.htdac@secivresetaroproc with any inquiries about this notice or other legal matters relating to CADTH’s services.

Copyright © CADTH 2013.

PMID: 24278998

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