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Non-adherence to Metformin Versus Therapeutic Failure: When is it Appropriate to Switch to Second-Line Therapies?

Jan 20, 2018

Patients who skipped initial treatment with metformin and were instead started on second-line antihyperglycemic medication more likely to need dual therapy or insulin to control T2.

Both the American Diabetes Association and European Association for the Study of Diabetes support the use of metformin as the initial therapy for glycemic control, labeling all other pharmacologic therapies as second-line options, in absence of specific contraindications to metformin use such as chronic or acute metabolic acidosis, eGFR less than 60 mL/min, heart failure, or gastrointestinal intolerances to the drug.  Metformin is a safe and effective therapy costing consumers a fraction of cost when compared to some newer anti-diabetic agents on the market. In the instances when 3-month-long monotherapy with metformin is not sufficient to achieve the target HbA1c ranges, guidelines recommend the addition of a second-line therapy to the patient’s medication regimen. However, non-compliance with metformin therapy may be the reason for inadequate glycemic control.  Due to difficulty for providers to distinguish between the true metformin therapeutic failure and patients’ medication non-adherence, this study investigated treatment patterns of patients treated with second-line anti-diabetic medications.

A retrospective cohort study compiled the data from millions of beneficiaries from the insurance company Aetna. The study included beneficiaries diagnosed with type 2 diabetes within the previous 365 days after insurance enrollment who had at least 2 physician claims coded with ICD-9 codes corresponding to diabetes. Excluded from the study were the beneficiaries who were not followed up within 180 days following the first diabetes diagnosis, or patients who had at least one ICD-9 code corresponding to pregnancy. Metformin was labeled as the first-line medication, while all other anti-diabetic medications were labeled as second-line treatments. In the instances where the subjects received two second-line therapies, the original second-line therapy was identified based on the dispensed date. Moreover, if both of the second-line therapies were dispensed on the same day, the original second-line therapy was labeled as the medication, which was prescribed for a longer period of time. The proportion of days covered (PDC) was used to measure medication compliance. The standard of good adherence was set at PDC of 0.80, as defined by Centers for Medicare and Medicaid Services. Subjects were considered to be treated with a second-line therapy if they had metformin PDC less than 0.8, or if they never received metformin.

At the conclusion of the study, it was found that only 8.2% of subjects (1,875 beneficiaries) who were receiving second-line therapies had evidence of recommended metformin use in prior 2 months. There were 30.6% of subjects (6,441 beneficiaries) who received a second-line therapy without receiving single-agent metformin, or dual therapy with metformin and an additional anti-diabetic drug. However, out of 6,441 beneficiaries, contraindications and gastrointestinal intolerances to metformin were found in only 14.4% and 2.6% of subjects, respectively. Additionally, insufficient duration of metformin monotherapy was seen in 35% of subjects, who were either prescribed both metformin and a second-line antihyperglycemic therapy on the same day, or were receiving single-agent metformin for a duration of less than 2 months (48 days). More importantly, it was found that the subjects who were started on a second-line therapy without a prior appropriate metformin therapy were more likely to need insulin or a dual therapy to control their type 2 diabetes (p<0.001).

It has been proven difficult for providers to differentiate between metformin non-compliance and therapeutic failure. Regardless of cause, second-line anti-diabetic medications are often initiated either prematurely, or instead of metformin monotherapy, as shown in this study. Changes on a population health level are needed as well as the point-of-care support in order to increase compliance to metformin, and therefore, increase patient outcomes. Limitation of the claims presented in this study include the retrospective nature of the study, exclusion of a subset of patients who are uninsured or not beneficiaries of Aetna, and out-of-pocket medications costs.

Practice Pearls:

  • Metformin is the only first-line antihyperglycemic medication supported by both the American Diabetes Association and European Association for the Study of Diabetes. Other antihyperglycemic agents are indicated for use in instances where the patient has a contraindication to metformin, or HbA1c levels are not achieved within 3 months of metformin monotherapy.
  • Patients who are prescribed an anti-diabetic medication other than metformin as the initial treatment of type 2 diabetes have an increased risk of needing insulin or dual medication therapy for glycemic control.
  • Population health-level tools and point-of-care decision support should be implemented to increase compliance to metformin.


Yi-Ju Tseng.  “Antihyperglycemic Medications: A Claims-Based Estimate of First-line Therapy Use Prior to Initialization of Second-line Medications”. Diabetes Care, American Diabetes Association. Nov. 2017. Accessed Jan. 2018.

Centers for Medicare & Medicaid Services. Quality rating system measure technical specifications 2015. Accessed Jan. 2018.

Lamija Zimic PharmD(c), University of South Florida, College of Pharmacy