Second- and Third-Line Therapy for Patients with Diabetes

Medication

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

As part of its overall diabetes priority theme, CADTH researched and developed recommendations for both second- and third-line diabetes therapies through two different processes. For the second-line therapy project, CADTH used its optimal use process; for the third-line therapy project, CADTH used a pilot therapeutic review process.

Key Messages

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

• A sulfonylurea should be added to metformin when metformin alone is not enough to adequately control hyperglycemia.

  • Second-line therapy = metformin + sulfonylurea

• Neutral protamine Hagedorn (NPH) insulin should be added to metformin and a sulfonylurea when this combination therapy is not enough to adequately control hyperglycemia.

  • Third-line therapy = metformin + sulfonylurea + NPH insulin

Refer to our Project Status web page to find out what stage we are at in this project.