The Relationship between Timing of Initiation on a Glucagon-like Peptide-1 Receptor Agonist and Glycosylated Hemoglobin Values Among Patients with Type 2 Diabetes
Abstract
Purpose
This study examines the relationship between timing of initiation on a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and glycosylated hemoglobin (HbA1c) values.
Methods
The IBM MarketScan databases were used to identify adults with type 2 diabetes mellitus (T2DM) who initiated GLP-1 RA therapy and had multiple recorded HbA1c results. Time to GLP-1 RA initiation was proxied by the number of classes of glucose-lowering agents prescribed in the 2 years before GLP-1 RA initiation, with fewer glucose-lowering agents indicating initiation of a GLP-1 RA earlier in disease progression. Paired t tests examined differences in HbA1c values from preperiod to 2-year postperiod. Multivariable analyses examined the relationship between time to GLP-1 RA initiation and postperiod HbA1c values.
Findings
Initiation on a GLP-1 RA was associated with a 0.6% reduction in HbA1c values over 2 years (P < 0.0001). Earliest starts were associated with a 1.3% reduction in HbA1c levels (P < 0.0001) and the highest likelihood of achieving a postperiod HbA1c level <7% (odds ratio, 4.9; 95% CI, 3.0–8.1).
Implications
Results indicate that although initiation on a GLP-1 RA is generally associated with reduced HbA1c levels, there may be additional clinical benefits associated with earlier initiation of a GLP-1 RA.
Key words
Introduction
Findings from the United Kingdom Prospective Diabetes Study and ADOPT (A Diabetes Outcome Progression Trial) suggest that treatment failure is associated with a progressive decline in beta-cell function.
,
As a result, researchers have argued that “there is an urgent need for antidiabetic agents that improve, preserve or replace beta-cell function.”
-like peptide-1 receptor agonists (GLP-1 RAs) enhances beta-cell function, proliferation, and regeneration; diminishes beta-cell apoptosis; and, by these means, increases the mass of functional beta cells.
Research has also shown improved beta-cell functioning associated with the use of GLP-1 RAs in patients with T2DM as measured by using the proinsulin:insulin ratio and homoeostasis model assessment-B analysis.
A patient’s response to GLP-1 RAs may depend on several factors, including age, baseline HbA1c level, insulin use, and duration of diabetes.
In light of these findings and given that a shorter duration of diabetes is associated with better beta-cell function,
it is hypothesized that earlier initiation of GLP-1 RA therapy may be associated with improved patient outcomes.
Materials and Methods
The retrospective, observational study data came from the IBM MarketScan Commercial Claims and Encounters and the Medicare Supplemental databases (IBM Watson Health, Cambridge, Massachusetts). These databases provided information on patient demographic characteristics, enrollment, inpatient services, outpatient services, and prescription drug use. The MarketScan laboratory database provided laboratory test results, including HbA1c, for a subset of patients included in the MarketScan Commercial Claims and Encounters and the Medicare Supplemental databases. The data came from insurance claims and medical encounters dated from January 1, 2013, through December 31, 2017. All study data were fully de-identified and compliant with the Health Insurance Portability and Accountability Act. Given the use of retrospective and de-identified data, no institutional review board oversight was required.
Patients with T2DM were required to have been initiated on a GLP-1 RA in 2015, with the first such use identified as the index date. In addition, patients were required to have at least 1 recorded HbA1c value in the 6 months before the index date and another in the last 6 months of the 2-year postperiod. Patients were excluded if they were identified as pregnant at any time from 2 years before the index date (ie, the preperiod) through 2 years after the index date (ie, the postperiod), or if they were not continuously insured from the start of the preperiod through the end of the postperiod. The Supplemental Figure (see the online version at doi:https://doi.org/10.1016/j.clinthera.2020.06.019) illustrates how each of these inclusion and exclusion criteria affected sample size.
time to initiation on a GLP-1 RA was proxied by using the number of classes of GLAs prescribed in the 2 years before GLP-1 RA initiation, with fewer medications prescribed indicating earlier initiation on a GLP-1 RA. Ordinary least squares models examined the relationship between the timing of GLP-1 RA initiation and postperiod HbA1c, and logistic models examined the relationship between the timing of GLP-1 RA initiation and the likelihood of having a postperiod HbA1c below the American Diabetes Association recommended target of 7.0%.
All multivariable analyses controlled for patient characteristics (age, sex, region of residence, and insurance plan type), preperiod health (Charlson Comorbidity Index, Diabetes Complications Severity Index, anxiety, and depression), and preperiod resource utilization (visits to cardiologist, endocrinologist, nephrologist, or ophthalmologist; number of visits to family practitioner or internist; and number of HbA1c laboratory tests ordered).
All analyses were conducted by using SAS version 9.4 (SAS Institute, Inc., Cary, North Carolina). A P value < 0.05 was considered, a priori, to be statistically significant.
Results
To examine the relationship between use of a GLP-1 RA and HbA1c, the last HbA1c test result before initiation on a GLP-1 RA was compared with the last HbA1c test result in the 2-year postperiod for each patient. The results indicated that, in the overall population, initiation on a GLP-1 RA was associated with a 0.6% reduction in mean HbA1c level (8.5% [1.9%] preperiod HbA1c vs 7.9% [1.8%] postperiod HbA1c; P < 0.0001).
Figure 1The association between time to initiation on a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and postperiod glycosylated hemoglobin (HbA1c) values.
Figure 2The association between time to initiation on a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and likelihood of glycosylated hemoglobin (HbA1c) value < 7.0% in the postperiod.
As a test of the robustness of the results, all analyses were conducted with an alternative proxy for time to initiation on a GLP-1 RA. Specifically, rather than using the number of classes of GLAs prescribed in the preperiod, patients were classified based on the number of classes of GLAs they were prescribed most frequently in the preperiod. The results using this alternative proxy were generally consistent with the main study results, although not as strong. For example, in our primary analyses, the use of no GLAs in the preperiod was associated with a 1.3% lower HbA1c value in the postperiod compared with the use of ≥4 GLAs (P < 0.0001). In our sensitivity analyses, patients who used no GLAs most frequently in the preperiod had a postperiod HbA1c value 0.5% lower than those who were most frequently prescribed ≥3 GLAs (P = 0.0081).
this finding is consistent with the hypothesis that initiation of a GLP-1 RA earlier in disease progression is associated with lower HbA1c value.
Discussion
,
the results from the present analyses indicate that, on average, initiation on a GLP-1 RA is associated with improved glycemic control. Notably, the improvement in HbA1c value (−0.6%; P
,
potentially due to differences in study design, study length, and drug adherence rates. In addition, our findings suggest that earlier initiation on a GLP-1 RA, as proxied by the use of fewer classes of GLAs in the preperiod, is associated with a lower postperiod HbA1c value and an increased likelihood of having a postperiod HbA1c value
In addition, our findings are in accordance with reported research that among patients treated with a GLP-1 RA, longer duration of diabetes is associated with reduced odds of achieving HbA1c reduction ≥1%
and that reduced glycemic response to GLP-1 RAs was associated with a longer duration of diabetes and clinical markers of low beta-cell function.
and the associated results were generally consistent with those of an alternative proxy. In addition, as an intention-to-treat study, our findings did not examine how the duration of treatment with a GLP-1 RA may affect patient outcomes. The study was also unable to examine certain factors (eg, patient fear of injection, medication costs) that may potentially affect time to GLP-1 RA initiation. Another limitation was that the study data came from a well-insured population who had recorded HbA1c laboratory results. As such, the sample population may not be generalizable to all adults with T2DM. Finally, the analyses focused on association only and thus provide no information about causation.
Conclusions
The results from this research indicate that initiation on a GLP-1 RA is associated with a lower HbA1c value, translating to better glycemic control. In addition, earlier initiation on a GLP-1 RA, as proxied by use of fewer GLAs in the preperiod, was associated with both a lower HbA1c value and an increased likelihood of having a postperiod HbA1c value < 7%.
Conflicts of Interest
Drs. Boye, Mody, and Malik conducted this research as employees/shareholders at Eli Lilly and Company. Dr. Lage was compensated for her work on this research by Eli Lilly and Company. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Eli Lilly and Company provided funding for the data license in this study and reviewed the manuscript before submission for publication.
Acknowledgments
Eli Lilly and Company provided funding for this study.
The authors thank Patricia Platt for her assistance in the writing of the manuscript. Support for this assistance was provided by HealthMetrics Outcomes Research.
All authors have materially participated in the research and article presentation and approved the final version of the manuscript. Drs. Boye, Mody, and Malik had primary responsibility for study conception and design, data acquisition, interpretation of results, and manuscript revisions. Dr. Lage had primary responsibility for data analysis and drafting of the manuscript.
Appendix.
Supplementary Figure 1Inclusion-exclusion criteria and sample size.
Supplementary Table 1Patient Characteristics.
GLA – glucose-lowering agent; SD – standard deviation.
References
-
Beta cells—what they do, role in insulin.
-
UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group.
Diabet Med. 1998; 15: 297-303
-
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
N Engl J Med. 2006; 355: 2427-2443
-
An update on the effect of incretin-based therapies on β-cell function and mass.
Diabetes Metab J. 2016; 40: 99-114
-
The effects of glucagon-like peptide-1 on the beta cell.
Diabetes Obes Metab. 2009; 11: 11-18
-
Markers of β-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes.
Diabetes Care. 2016; 39: 250-257
-
Relationships between diabetes duration, metabolic control and beta-cell function in a representative population of type 2 diabetic patients in Sweden.
Diabet Med. 1994; 11: 794-801
-
A real-world study of the effect of timing of insulin initiation on outcomes in older Medicare beneficiaries with type 2 diabetes mellitus.
J Am Geriatr Soc. 2015; 63: 893-901
-
Trends in the incidence of diabetes, its clinical sequelae, and associated costs in pregnancy.
Diabetes Metab Res Rev. 2015; 31: 707-716
-
6. Glycemic targets: standards of medical care in diabetes—2020.
Diabetes Care. 2002; 43: S66-S76
-
Factors associated with long-term control of type 2 diabetes mellitus.
J Diabetes Res. 2016; 2016: 2109542
-
Treatment outcomes and tolerability following initiation of GLP-1 receptor agonists among type 2 diabetes patients in primary care practices in Germany.
J Diabetes Sci Technol. 2016; 11: 272-277
-
Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability.
Diabetes Care. 2011; 34: S279-S284
-
Glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: real-world evidence from a Mediterranean area.
Curr Med Res Opin. 2019; 35: 1735-1744
Article Info
Publication History
Published online: July 30, 2020
Accepted:
June 26,
2020
Publication stage
In Press Corrected Proof
Identification
Copyright
© 2020 The Authors. Published by Elsevier Inc.
User License
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) |
Permitted
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
Not Permitted
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article
Comments are closed.