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Diabetes Treatment Failure May Actually Be Nonadherence

Oct 14, 2017

Second-line treatment is often initiated without evidence of recommended use of first-line treatment.

Metformin is the first-line agent for treating type 2 diabetes as recommended by American Diabetes Association and European Association for the Study of Diabetes. It is relatively safe and has great MedicationAdherenceevidence of efficacy lowering glucose levels in addition to microvascular and macrovascular benefits. However, some patients cannot tolerate it due to adverse GI effects, including nausea and diarrhea, and become noncompliant. One of the best counseling points is to take it with food and use of extended release forms. However, many patients without full knowledge of proper drug administration decide to become noncompliant leading to poor outcomes. In this scenario, prescribers fail to distinguish between non-adherence to metformin to therapeutic failure, and proceed to give other second-line anti-hyperglycemic medications. Current guidelines recommend combination therapy with additional antihyperglycemic agents if monotherapy with metformin fails to achieve the specified hemoglobin A1c target over 2–3 months.


The following retrospective study explored the treatment patterns of patients who received second-line therapy for diabetes, specifically by estimating their previous claims-based use of metformin. It specifically evaluated a large pool of patients diabetes who have Aetna health insurance and their membership claims data. It included a total of 52,544 participants who were prescribed a second-line agent such as a sulfonylurea, DPP-4 inhibitors, insulin or any other. Prescription drugs were recorded using the National Drug Code.

It was found that among patients who at least filed one second-line agent, 6,441 (28%) had no previous claim evidence of ever taking metformin. From this value, only a minority had contraindication to metformin; these included heart failure (2.9%), COPD (3.1%), liver diseases (4.3%), and renal diseases (4.1%). Also, only 8.2% of all participants had evidence of recommended use of metformin in the prior 60 days.

About one-third of patients, 7,382 (35%), received metformin before initiating second-line medication, but the duration of their metformin treatment before second-line treatment was less than 48 days, opposing the current guidelines, which recommend treatment and evaluation of metformin for at least 2 months before making therapy adjustments. Furthermore, patients were more likely to be prescribed an additional second-line agent or insulin if their initial second-line antihyperglycemic medication was prescribed without evidence of recommended use of metformin (P < 0.001). Also, male patients were found to be less likely to follow treatment plans than females (P < 0.001).

Regardless of the current guidelines, many patients are being prescribed 2nd line agents without evidence of metformin therapy. What could be understood as treatment failure by prescribers may instead portray not taking the metformin as prescribed to the diabetic treatment guidelines. This may lead to the use of insulin or additional second-line medications, which are generally more expensive increasing the risk again for not following treatment plans, poor outcomes, and diminished quality of life. Healthcare providers should focus their efforts on improving adherence to metformin treatment, instead of switching anti-diabetic agents.

Retrospective claims-based analyses have several limitations, including the exclusion  of uninsured patients, lack of detailed clinical or behavioral information, proof of medication counseling and no out-of-pocket medication cost data. The precise number of patients who lacked evidence cannot be directly measured because prescriptions filled through a low-cost generic prescription medication program are probably not included in this study. Although GI adverse effects related to metformin therapy may lead to guideline nonadherence and early second-line medication initiation, this study did not find evidence of GI adverse effects in the claims data. Despite the several limitations, this study unmasked the poor assessment by clinicians when switching drugs, instead of optimizing first-line drug treatment and monitoring for adverse effects and compliance, which can be clearly assessed by a registered pharmacist.

 Practice Pearls:

  • Metformin is first-line therapy for type 2 diabetes and should be evaluated for 2 months before considering adding or switching to other agents.
  • Patients who are prescribed a second-line agent without evidence of metformin use are more likely to receive insulin or an additional second-line agent.
  • Follow-up and medication adherence  assessment is essential in treating diabetes and preventing excessive high-cost medications.



Yi-Ju Tseng, Gregory Steinberg. Antihyperglycemic Medications: A Claims-Based Estimate of First-Line Therapy Use Before Initialization of Second-Line Medications. Diabetes Care August 2017.


Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy