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Understanding The Gap Between Efficacy In Randomized Trials And Effectiveness In Real-World Use Of GLP-1RA and DPP-4 Therapies

Jan 13, 2018

Patients are not seeing the expected results because of medication adherence.

As the rate of obesity, type 2 diabetes, and cardiovascular disease steadily increases, so does the demand for accessible and effective treatment options. Over the last 10 years, approximately 40 new medications for the treatment of type 2 diabetes have been developed. Despite these advances, less than 50% of patients with type 2 diabetes in the United States have achieved an HbA1c < 7%. Randomized controlled trials often yield promising results with many patients experiencing significant reductions in HbA1c, fasting plasma glucose, and improved cardiovascular outcomes. However, when practitioners implement these new drugs into their practice, they are often met with significantly lower patient improvements. Some postulate that patients who agree to enroll in a clinical trial are more likely to be concerned about their health and are therefore more adherent to the medication regimen, which leads to better trial outcomes. Others propose that patients in trials are more likely to be on maximum dosing and in real-world scenarios practitioners may prescribe lower dosages. Recent studies have shown that adherence rates vary from 20-50% depending on the method of assessment and class of medication. Poor adherence is directly correlated to increased healthcare costs, reduced glycemic control, and ultimately poorer patient outcomes. Therefore, researchers aimed to compare the change in HbA1c between patients in a real-world setting and patients in a randomized control trial after the initiation of GLP-1 agonist or DPP-4 therapy.


An estimated multivariate model, combined with descriptive real-world and trial patient information was used to describe the differences between the two groups. Patient accounts of adherence are often inaccurate and to avoid potential bias, the critical measure used was based on the percentage of days covered (PDC). The PDC is currently endorsed by the National Quality Forum and the Medicare Star Ratings and is commonly used in quality measures and adherence literature. To evaluate the change in HbA1c, researchers accessed the Optum/Humedica Smartfile database. This database is one of the largest and most comprehensive databases that includes administrative claims and electronic records. The index date for real-world patients was the date of the first fill of a DPP-4 or GLP-1 agonist prescription with baseline measurements being 1 year prior to that fill. The follow-up period was the 1-year timeframe between baseline and subsequent HbA1c measurement. The GLP-1 agonists and DPP-4 medications selected were based on the number of real-world patients that were taking that drug. Because <5% of real-world patients were taking linagliptin and alogliptin, both of those drugs were excluded from the study. Publications of randomized controlled trials involving liraglutide, exenatide, sitagliptin and saxagliptin instead were selected. The primary outcome was changed in HbA1c measured from baseline (up to 90 days before initiation of therapy or 14 days after initiation of therapy) to a second HbA1c measurement (365 +/- 90 days after initiation of treatment). Adherence was estimated using the PDC with a non-overlapping supply of the medication. Adherence was classified as a PDC > 80%. Any changes in the patient’s medication regimen (i.e. discontinuance, change in regimen) was documented with discontinuance being defined as absence of the drug for 30 days with no subsequent fills through the end of the trial.

A total of 873 real-world patients met the inclusion criteria with 652 patients receiving DPP-4 therapy and 221 patients receiving GLP-1 agonist therapy. A total of 11 randomized controlled trials were selected and were comprised of 7 GLP-1 agonist trials and 4 DPP-4 trials. Baseline HbA1c levels were similar for real-world and trial patients taking a GLP-1 agonist, but the mean baseline HbA1c was lower for trial patients receiving DPP-4 therapy. During the follow-up period, approximately 29% of patients taking GLP-1 agonists and 37% taking DPP-4s were adherent to their medication regimen. Roughly 40% of real-world patients discontinued either a GLP-1 agonist or DPP-4 and less than half of that group was restarted on another medication. The overall reduction in HbA1c levels for real-world patients was similar between the two groups [GLP-1A: -0.52%, DPP-4: -0.51%]. This was in stark contrast to the trial patients [GLP-1A: -1.30%, DPP-4: -0.68%].

Adherent real-world patients taking GLP-1 agonists demonstrated more than double the decrease in HbA1c. The gap between real world and trial patients [GLP-1A: 0.51%, DPP-4: 0.18%] can be explained by differences in adherence, addition of other medications, and baseline characteristics. However, medication adherence accounted for approximately 75% of the estimated HbA1c gap between real-world and trial patients. We are not seeing real-world benefits in patients taking GLP-1 agonists or DPP-4s, and medication adherence is a primary reason. The results of this study stress the urgent need to reinforce medication adherence and evaluate how practitioners are educating patients on the importance of taking their medications.

Practice Pearls:

  • Medication adherence is 75% responsible for the difference between trial and real-world patient HbA1c improvement.
  • Less than half of patients discontinued on a GLP-1 agonist or DPP-4 were restarted on another regimen


Carls, Ginger S., et al. “Understanding the Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use of GLP-1RA and DPP4 Therapies in Patients With Type 2 Diabetes.” Diabetes Care(2017): dc162725.

Jessica Lambert, University of South Florida College of Pharmacy, Doctor of Pharmacy Candidate 2018