Chronic Disease Management Drug Shows Real-World Efficacy

February 11, 2020 - A chronic disease management drug used to treat type 2 diabetes showed real-world efficacy, even working slightly better among patients who would have been considered ineligible to participate in phase 3 randomized clinical trials, according to a new study. 

Published in JAMA Network Open on February 7, the cross-section analysis of 7,034 Denmark residents from January 2009 to December 2018 uncovered that empagliflozin – a sodium-glucose cotransporter 2 inhibitor used to lower glucose – was linked to a mean reduction in glycated hemoglobin (HbA1c) of 0.91 percent after six months. These findings were similar to phase 3 of randomized clinical trials (RTCs) results, researchers from Aarhus University Hospital in Denmark reported.

But patients who would have be eligible to participate in phase 3 RTCs of empagliflozin experienced lower HbA1c reductions compared to patients who would have been deemed ineligible due to characteristics, like comorbidities, use of other glucose-lowering drugs, or HbA1c levels outside the range required for RCT participation. 

Using linked population-based medical databases containing complete information on redeemed prescriptions, laboratory tests, and diagnosis for all residents in Northern Denmark, researchers compared the eligibility criteria of the four empagliflozin phase 3 RCTs with the characteristics of the study population.

More than 55 percent of first time empagliflozin initiators would have been ineligible for phase 3 RCT participation, the analysis showed. The most frequent reasons for ineligibility was the use of glucose-lowering drugs (GLD) concurrent with empagliflozin (27.8 percent), baseline blood sugar level outside the eligibility range (25.2 percent), and presence of comorbidities such as blood dyscrasias, cancer, and other clinical conditions that could harm a patient’s safety (15.3 percent). 

Yet this group experienced a mean reduction in HbA1c of 1.01 percent versus a reduction of 0.78 percent among patients who would have been eligible to participate in phase 3 RTCs. 

“These findings suggest that the efficacy of empagliflozin in reducing HbA1c in trials translates into real-world effectiveness, but they also underscore the importance of conducting studies after drug approval, given that real-world patients differ from randomized clinical trial participants,” the authors wrote.

The study calls into question strict rules that determine who can and cannot participate in clinical trials.

Researchers evaluated range of eligibility criteria from their healthcare databases, the study found. Using current baseline GLD therapy at the time of empagliflozin initiation, researchers uncovered which GLD prescriptions empagliflozin initiators were retrieved in the last 120 days.  

Patients under 18, those who received treatment with anti-obesity drugs or systemic steroids 90 days before RCT participation, and real-world initiators who used specific drugs 120 days before empagliflozin initiation, were all deemed ineligible for the study. 

But patients who received no GLD medication or therapy trial GLDs 12 weeks before RCT participation could only participate if their last blood sugar level was between seven and ten percent. 

Patients enrolled in phase 3 RTCs most likely showed healthier behavior, including higher medication adherence and could tolerate more side effects than real-world users. 

However, the study discovered that common glucose-lowering drugs (GLDs) regimen used after empagliflozin initiation were either noninsulin GLD combination therapy alone (34 percent) or metformin and insulin (15.2 percent).  But the proportion of initiators who received metformin or at least two other noninsulin GLDs decreased from 1,266 initiators to 935 initiators after empagliflozin initiation. 

These findings suggested that many patients used empagliflozin as a replacement therapy, which was not studied in the original clinical trials for the drug. “This could have biased our findings toward an underestimation of the real-world reduction in HbA1c levels compared with the reduction seen in RCTs,” the authors explained.

The authors also reported another limitation of the study. Because of the limitations of administrative data, some of the criteria used to determine RCT eligibility was not available for evaluation, including BMI outside range and uncontrolled endocrine disorders.

“Considering that these conditions may be frequent, we may have underestimated the proportion of ineligible patients in our study,” the authors stated. “Moreover, although empagliflozin was only approved for type 2 diabetes, we may have included some patients in our study who did not have true type 2 diabetes because of missing clinical and biochemical data (eg, antibodies) on exact diabetes type.”

Regardless, the authors highlighted that the chronic disease management drug did show real-world efficacy. “Further studies should examine clinical outcome effectiveness and drug safety in these patient groups in routine clinical care,” they concluded.