Type to search

Medicine Pharmacology

What is the current state of second- and third-line therapy for patients with type 2 diabetes?


This summary is based on comprehensive Optimal Therapy Reports on the topic prepared by Canadian Agency for Drugs and Technologies in Health (CADTH): Second- and Third-Line Therapy for Patients with Type 2 Diabetes

Report Summary (PDF)

Full Report (PDF)

The Canadian Agency for Drugs and Technologies in Health (CADTH) has released a series of Optimal Therapy Reports on the prescribing and use of second-line therapy for patients with type 2 diabetes inadequately controlled on metformin, and a therapeutic review of third-line therapy for patients with type 2 diabetes inadequately controlled with metformin and a sulfonylurea combination therapy. CADTH has also released intervention tools to support the uptake of this information.
Key Findings
In comparing the recommendations for  second- and third-line therapy with both the results of the current practice and current utilization analyses, several gaps emerge.
Practice Gaps
  • Metformin is discontinued, rather than continued, when second-line therapy is initiated in about a quarter of patients.
  • Insulin is underutilized as a third-line therapy.
  • Thiazolidinedione (TZD) utilization as a third-line intervention is prevalent although TZD is not indicated for this application in Canada.
Knowledge Gaps
  • Prescribers lack access to systematically reviewed findings on clinical effectiveness and cost-effectiveness of antidiabetes therapies.
  • There is a perception that hypoglycemia and weight gain are common or significant problems associated with the use of sulfonylureas.
  • Many patients lack awareness that diabetes is a progressive disease and that, even if they adhere to prescribed lifestyle changes and medications, they will likely need to add second- and third-line drugs to their therapy.
  • Prescribers may feel a need for a specialist consult before prescribing the start of insulin.
  • There is lack of awareness about the opportunity costs associated with therapeutic choices.
Summary Interpretation of the Data
Current Practice
  • Nearly all participating prescribers prefer to add a second-line drug to metformin rather than switching from metformin entirely, but that a consistently applied prescribing model is lacking.
  • To select a second-line drug, health care professionals described a complex decision-making process in which they consider efficacy, affordability, short-term side effects, long-term adverse effects, and convenience of the therapy.
  • There is considerable variability in the beliefs, perceptions, and considerations that underlie their choices. They also indicated that they rely on a wide variety of sources for information about second-line therapies, leading to diverse views and prescribing practices.
Second-line therapy
  • When metformin alone becomes insufficient for treating patients with type 2 diabetes, adding a sulfonylurea is the most cost-effective second-line therapy.
  • Sulfonylureas have a lower cost compared with insulin and newer drugs, and these cost-effectiveness results held true when the parameters in the analysis model were changed (as part of sensitivity analyses).
Third-line therapy
  • Adding NPH insulin to metformin and sulfonylurea combination therapy is the most cost effective third-line therapy.
  • Only when the parameters in the analysis model were considerably changed did another option emerge. In certain scenarios, adding DPP-4 inhibitors (sitagliptin) instead of insulin may be the most cost-effective option.
  • These scenarios include the following: if insulin lowers the quality of life in patients to a high degree (high disutility of insulin), if insulin users experience a higher risk of hypoglycemia, and if costs of long-acting insulin analogues are applied to the basal insulin option rather than the cost of NPH insulin.
  • It should also be noted that the quality of evidence informing the variations in model inputs is limited or of low quality; hence, results from sensitivity analyses should be interpreted with caution.
  • Further research is needed to more precisely understand the relative cost-effectiveness of third-line agents.
Long-term complications of diabetes
  • In both the CADTH clinical-effectiveness analyses, there was insufficient evidence to evaluate the comparative efficacy of second- and third-line antidiabetes drugs in reducing clinically important long-term complications of diabetes. Longer-term studies with larger sample sizes are required.
For further information, please visit the CADTH website

Do you need further information related to this subject? Do you have any comments or suggestions? Email us at oasisdiscussions@cda-adc.ca

Your are invited to comment on this post and provide further insights by posting in the comment box which you will find by clicking on “Leave a reply“ below. You are welcome to remain anonymous and your email address will not be posted.


Leave a Comment

Your email address will not be published. Required fields are marked *

%d bloggers like this: