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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
 
 

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