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Second and Third-line Therapies for Type 2 Diabetes

Published on: December 29, 2010
Product Line: Optimal Use


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).

For the full recommendations and detailed information on their development, see the recommendations report.

CADTH also offers knowledge mobilization tools to support the implementation of recommendations and to assist health care professionals, policy-makers, and consumers in making well-informed decisions.


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