Second and Third-Line Therapy for Patients With Diabetes (Optimal Use Project)


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Health Technology Review
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In combination with lifestyle measures (weight control, proper nutrition, and adequate exercise), medications, such as metformin and sulfonylureas, play an important role in achieving glycemic control in patients with diabetes mellitus:

  • Metformin is a popular first-line oral antidiabetes drug that is used to help control glycemic levels in patients with diabetes when lifestyle modifications alone are insufficient.

Because diabetes is a progressive disease, metformin monotherapy may eventually fail to adequately control glycemic levels. At this point, most patients need one or more oral antidiabetes drug, or insulin, added as a second-line therapy to their treatment regimen. If, after time, second-line therapy fails, most patients will need one or more additional drugs added as a third-line therapy to achieve target glycemic levels. In Canada, seven classes of antidiabetes drugs are available that may be used as second- and third-line therapy: sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, incretin agents, weight loss agents, and insulins (human and insulin analogues).

Need for Recommendations

When metformin monotherapy is no longer effective, existing guidelines recommend several options. However, these guidelines generally lack specific recommendations regarding which drug(s) are optimal as second- and third-line therapy. Instead, they typically recommend that a stepwise approach be used to add drugs from various classes. Moreover, guideline recommendations in this area are based primarily on evidence regarding clinical efficacy and safety; cost-effectiveness is often not considered.

Given the large, growing population of patients with diabetes in Canada, suboptimal use of second- and third-line antidiabetes drugs is likely to have a detrimental effect on both health outcomes and the cost-effective use of drugs. There is a need for clear recommendations based on clinical- and cost-effectiveness evidence to guide the choice of second- and third-line therapy in patients with inadequately controlled diabetes.

Scope of CADTH Work on Second- and Third-Line Therapy Topics

CADTH's original work in this topic area concluded in 2010, with the publishing of several reports. Since then, new antidiabetes agents were approved for use in Canada. In particular, two glucagon-like peptide-1 analogues, exenatide (Byetta®) and liraglutide (Victoza®), and new dipeptidyl peptidase-4 inhibitors (e.g., linagliptin) were approved by Health Canada. Therefore, CADTH undertook and completed an update of the clinical research, pharmacoeconomic review, and optimal therapy recommendations to include the new agents.

Key Messages

CADTH's work on this project has resulted in the following key messages:

For most of your adult patients with type 2 diabetes, when proper diet and exercise are not enough to control hyperglycemia:

  • Start oral therapy with metformin.
  • Add a sulfonylurea to metformin when metformin alone is not enough to adequately control hyperglycemia.
  • Add neutral protamine Hagedorn (NPH) insulin when metformin and a sulfonylurea are not enough to adequately control hyperglycemia.*


    Add a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and a sulfonylurea in the rare instances when insulin is not an option.

Optimize the dose of the agent at each stage of therapy before moving to the next. Proper diet and exercise should be encouraged at every stage.

*Patients experiencing significant hypoglycemia during efforts to reach target glycated hemoglobin (A1C) with NPH insulin may benefit from a switch to a long-acting insulin analogue (i.e., insulin glargine or detemir).


The Canadian Agency for Drugs and Technologies in Health (CADTH) offers tools to assist with implementing its recommendations on optimal second-line therapies for patients with diabetes inadequately controlled on metformin, and third-line therapies for patients with diabetes inadequately controlled on metformin and sulfonylurea. The tools provide summaries of key clinical messages designed to support decision-making.

To make these tools relevant to different audiences, CADTH can tailor specific tools to individual needs and settings. Contact us if you would like our assistance in tailoring any of these tools to meet your unique needs as a health care provider, policy-maker, or consumer.

To help decision-makers evaluate optimal use initiatives, CADTH has also developed a series of generic tools that can be applied across health topics. These generic tools include an audit and feedback guide and an evaluation framework.

Second- and Third-line Therapy Tools

Published Articles

Cost-effectiveness of second-line antihyperglycemic therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin (Canadian Medical Association Journal)

Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A systematic review and mixed treatment comparisons meta-analysis (Open Medicine)

Choice of therapy in patients with type 2 diabetes inadequately controlled with metformin and a sulphonylurea: a systematic review and mixed-treatment comparison meta-analysis (Open Medicine)

Perspectives and experiences of health care professionals and patients regarding treatments for type 2 diabetes (Canadian Pharmacists Journal)


Our project on second- and third-line therapy for patients with inadequately controlled diabetes resulted in the following reports:

Third-Line Pharmacotherapy for Type 2 Diabetes — Erratum

Why are we issuing an erratum?

In July 2013, CADTH posted updated versions of the CADTH Optimal Use Report on third-line pharmacotherapy for patients with type 2 diabetes with inadequate glycemic control on metformin and a sulfonylurea (Third-Line Pharmacotherapy for Type 2 Diabetes — Update). As a result of an error identified in the 2013 report, CADTH has prepared an errata document that summarizes the error and provides revised results for the network meta-analysis of hemoglobin A1C and the pharmacoeconomic analysis.

Does this affect the recommendation report?

The Canadian Drug Expert Committee (CDEC) will be made aware of the erratum and the corrected analyses at an upcoming CDEC meeting. If any revisions need to be made to the recommendations or reasons for recommendations, a revised recommendation report will be drafted and posted on the CADTH website. If no revisions are required, we will issue a note indicating that the erratum had no effect on the recommendations. Any such revisions or note will be issued by the end of May 2014.

Final Updated Reports

Final Reports from 2010

Summary Reports

Second-Line Therapy

Third-Line Therapy

Current Practice and Use