Assessment of Glucagon-like Peptide-1 Receptor Agonists in Veterans Taking Basal/Bolus Insulin Regimens
Background: Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is well established as add-on therapy to oral medications and basal insulin. However, there is little published data regarding the use of GLP-1 RAs for longer than 12 months in patients taking basal/bolus insulin regimens. The primary goal of our study was to assess the long-term efficacy of GLP-1 RAs as add-on therapy to basal/bolus insulin regimens.
Methods: This study was a retrospective record review of all patients on basal/bolus insulin regimens who received additional therapy with a GLP-1 RA. The primary outcome was the change in glycosylated hemoglobin A 1c (HbA 1c ) at 3, 6, 12, 18, and 24 months after initiation of the GLP-1 RA. Secondary outcomes included change in weight and total daily dose (TDD) of insulin and incidence of hypoglycemia and other adverse effects (AEs).
Results: Ninety-two patient records were reviewed. Mean glycemic control changed from baseline −1.1% (95% CI, −1.3 to −0.8; P < .001) at 3 months; −1.0% (95% CI, −1.3 to −0.7; P < .001) at 6 months; −0.9% (95% CI, 1.3 to −0.6; P < .001) at 12 months; −0.9% (95% CI, −1.4 to −0.3; P = .002) at 18 months; and −0.7 (95% CI, −1.4 to 0.1; P = .07) at 24 months. A significant decrease in weight was also observed from baseline through 18 months, and a significant decrease in TDD of insulin was identified from baseline through 12 months. Hypoglycemia was documented in 29.8% of patients at any point during GLP-1 RA therapy, and gastrointestinal AEs were documented in 18.3% of patients.
Conclusions: Adding GLP-1 RAs to complex insulin regimens may help achieve glycemic control while decreasing insulin requirements and mitigating undesirable AEs, such as weight gain.
Discussion
Adding a GLP-1 RA to basal/bolus insulin regimens was associated with a statistically significant decrease in HbA1c at each time point through 18 months. The greatest improvement in glycemic control from baseline was seen at 3 months, with improvements in HbA1c diminishing at each subsequent period. The study also demonstrated a significant decrease in weight at each time point through 18 months. The greatest decrease in weight was observed at both 6 and 12 months. Statistically significant decreases in TDD were observed at 3, 6, and 12 months. Insulin changes after 12 months were not found to be statistically significant.
Few studies have previously evaluated the use of GLP-1 RAs in patients with T2DM who are already taking basal/bolus insulin regimens. Gyorffy and colleagues reported significant improvements in glycemic control at 3 and 6 months in a sample of 54 patients taking basal/bolus insulin when liraglutide or exenatide was added, although statistical significance was not found at the final 12-month time point.13 That study also found a significant decrease in weight at 6 months; however there was not a significant reduction in weight at both 3 and 12 months of GLP-1 RA therapy. There was not a significant decrease in TDD at any of the collected time points. Nonetheless, Gyorffy and colleagues concluded that reduction in TDD leveled off after 12 months, which is consistent with this study’s findings. The small size of the study may have limited the ability to detect statistical significance; however, this study was conducted in a population that was racially diverse and included a higher proportion of women, though average age was similar.13
Yoon and colleagues reported weight loss through 18 months, then saw weight increase, though weights did remain lower than baseline. The study also showed no significant change in TDD of insulin after 12 months of concomitant exenatide and insulin therapy.11 Although these results mirror the outcomes observed in this study, Yoon and colleagues did not differentiate results between basal and basal/bolus insulin groups.11 Seino and colleagues observed no significant change in weight after 36 weeks of GLP-1 RA therapy in Japanese patients when used with basal and basal/bolus insulin regimens. Despite the consideration that the population in the study was not overweight (mean body mass index was 25.6), the results of these studies support the idea that effects of GLP-1 RAs on weight and TDD may diminish over time.14
Within the VHA, GLP-1 RAs are nonformulary medications. Patients must meet certain criteria in order to be approved for these agents, which may include diagnosis of CVD, renal disease, or failure to reach glycemic control with the use of oral agents or insulin. Therefore, participants of this study represent a particular subset of VHA patients, many of whom may have been selected for consideration due to long-standing or uncontrolled T2DM and failure of previous therapies. The baseline demographics support this idea, given poor glycemic control at baseline and high insulin requirements. Once approved for GLP-1 RA therapy, semaglutide is currently the preferred agent within the VHA, with other agents available for select considerations. It should be noted that albiglutide, which was the primary agent selected for some of the patients included in this study, was removed from the market in 2017 for economic considerations.15 In the case for these patients, a conversion to a formulary-preferred GLP-1 RA was made.
Most of the patients included in this study (70%) were maintained on metformin from baseline throughout the study period. Fifty-seven percent of patients were taking TDD of insulin > 150 units. Considering the significant cost of concentrated insulins, the addition of GLP-1 RAs to standard insulin may prove to be beneficial from a cost standpoint. Additional research in this area may be warranted to establish more data regarding this potential benefit of GLP-1 RAs as add-on therapy.
Many adverse drug reactions were reported at different periods; however, most of these were associated with the gastrointestinal system, which is consistent with current literature, drug labeling, and the mechanism of action.16 Hypoglycemia occurred in about one-third of the participants; however, it should be noted that alone, GLP-1 RAs are not associated with a high risk of hypoglycemia. Previous studies have found that GLP-1 RA monotherapy is associated with hypoglycemia in 1.6% to 12.6% of patients.17,18 More likely, the combination of basal/bolus insulin and the GLP-1 RA’s effect on increasing insulin sensitivity through weight loss, improving glucose-dependent insulin secretion, or by decreasing appetite and therefore decreasing carbohydrate intake contributed to the hypoglycemia prevalence.
