Discussion
This study described weight change, adherence, and discontinuation patterns of GLP-1 RAs among patients with T2DM newly initiating injectable GLP-1 RA therapy in the UK; 33.4% and 43.5% of patients with weight assessments at 12 and 24 months of follow-up lost ≥5% of their baseline weight, respectively. While 59.2% of patients who remained on therapy were adherent to GLP-1 RA therapy at 24 months, 64.7% of patients discontinued therapy within that time. Patients with a BMI between 30 and 34 kg/m2 were more likely to discontinue therapy at 12 months (bivariate and multivariable model). However, no associations between adherence or discontinuation and BMI were observed at 24 months.
Past GLP-1 RA studies investigating individual GLP-1 RA agents reported weight change as mean kilograms lost and not as a proportion of patients who achieved ≥5% weight loss, have a study population with an comparatively lower BMI, and/or do not extend beyond 1 year.16–20 In these studies, mean weight change ranged from −1.0 kg to −3.78 kg over 6–12 months. Mean weight change in this study at 12 months was −4.6 kg. However, 80% of patients in the present study with available data had a BMI ≥35 kg/m2 and 56% had BMI ≥40 kg/m2 (median BMI 41.2 kg/m2) compared with mean BMIs in the low to mid 30s in most past studies. Thus, the populations and their weight changes are difficult to compare. Another retrospective analysis using CPRD is an exception; like the present analysis, patients with T2DM given liraglutide had a higher mean weight than those given sitagliptin (mean (SD) 114.3 kg (22.3) vs 95.4 kg (20.7), respectively); patients on liraglutide lost 3.78 kg compared with patients on sitagliptin who lost 1.12 kg over 6 months.20 An analysis of the effects of exenatide over 82 weeks reported that patients taking exenatide in dual therapy with metformin experienced a mean weight loss of 5.3 kg or 5.2% of baseline body weight.21 Comparatively, the present study found that only 33.4%–43.5% (at 12 and 24 months) of patients lost ≥5% of their baseline weight. This finding suggests that, compared with trials, patients in the real world may not frequently achieve clinically meaningful weight loss. It may also suggest that lifestyle interventions, including diet, physical exercise, and psychological support, remain an important component of a weight management strategy in patients with T2DM as pharmacological therapy alone is unlikely to help the majority of patients achieve clinically meaningful weight loss. Given weight loss is an important criterion for GLP-1 RA therapy persistence per NICE guidelines,5 this has important implications for the use of GLP-1 RAs in the UK.
Reported adherence to AHAs is generally highly variable. A meta-analysis of oral AHAs reported the pooled mean medication possession ratio (MPR) to be 75.3% over 6–24 months of follow-up.22 Adherence to GLP-1 RAs specifically has also been shown to vary widely across studies.8 Thus, the results of this study are overall consistent with previous reports.8 23 24 The finding that patients on weekly dosing regimens are more adherent than those on daily dosing regimens is also consistent with other studies using administrative and electronic medical records datasets across Europe and the USA.8 24
However, the discontinuation rates in this study were substantially higher than those reported in clinical trials.25 The SUSTAIN6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) trial reported that only 22.6% of patients prematurely discontinued semaglutide during the 24-month trial period.26 Comparatively, this study found that 45.2% and 64.7% of patients discontinued by 12 and 24 months, respectively. A sensitivity analysis expanding the allowable gap between end of days of supply of one prescription to start of a new prescription to 120 days did not substantially alter discontinuation rates (43.1% at 12 months, 63.3% at 24 months); this supports the conclusion that a majority of GLP-1 RA new users truly did discontinue therapy in those time periods. The results for discontinuation by dosing schedule (weekly vs daily) diverge from other real-world studies for reasons that are unclear. While other studies have reported greater discontinuation among patients prescribed daily doses compared with weekly doses,23 25 27 the present study found patients on weekly GLP-1 RAs were significantly more likely to discontinue therapy than those on daily GLP-1 RAs.
The high rates of discontinuation observed in this study prompt consideration of the real-world impact of GLP-1 RA on outcomes. In the LEADER trial, patients at risk for CVD experienced significantly fewer cardiovascular events and deaths than the placebo group after 36 months.6 The findings of the present study suggest that outside the context of randomized trials, patients prescribed GLP-1 RAs discontinue therapy sooner which may impact GLP-1 RAs effectiveness in the real world. The few studies that have evaluated real-world effectiveness of GLP-1 RAs have yielded inconsistent results.8 20 28–30 Future studies should consider evaluating the impact of adherence and persistence on glycemic control, weight, and other outcomes, in totality and by pharmacological agent or class, to better understand potential gaps in translating randomized trials efficacy into real-world effectiveness.
This study has several limitations. The sample sizes were relatively small: 589 patients met the inclusion criteria; 530 patients had at least two GLP-1 RA prescriptions to be included in the adherence analysis. The small study population was, in part, due to limiting the study to patients without evidence of AHAs other than metformin in the 90 days prior and 30 days after GLP-1 RA initiation. While this criterion reduced the impact of polypharmacy on assessments of weight, adherence, and discontinuation, it also reduced the applicability of its findings to the broader T2DM population. Additionally, patient weights over the follow-up period were available for a fraction of the full cohort and may be subject to unknown biases. It is also worth noting that the impact of lifestyle modifications on weight results could not be ascertained. Adherence was measured using data from electronic health records for prescriptions and calculating PDC. Determining whether patients actually took the medication or took the medication as prescribed would require intensive monitoring. That said, this study used the PDC method because of its increased sensitivity to capturing uncovered days compared with MPR, another commonly used method for estimating adherence.15 Identification of baseline comorbidities was subject to the presence of Read codes and thus may be under-reported. As with other observational studies, it is possible unaccounted for confounding factors may have influenced the results. It is also worth noting that this study investigated injectable GLP-1 RAs only; its findings may not be applicable to oral GLP-1 RAs. Additionally, the markedly higher rates of obesity in this study’s population may reflect a channeling bias; it is possible that physicians’ prefer to prescribe GLP-1 RAs to their patients with greater obesity given the medication’s demonstrated weight loss benefit in clinical trials.4 14 This may impact the generalizability of this study to a broader T2DM UK population. Finally, this was an observational research study of T2DM in the UK using primary care electronic medical records. Its findings, therefore, may not be applicable to other populations.
In conclusion, one in three patients with body weight measures available achieved clinically meaningful weight loss at 12 months. Although approximately 60% of the cohort was adherent during their observed time on therapy, nearly half of patients discontinued GLP-1 RA therapy within 12 months and nearly two-thirds discontinued within 24 months. Patients may benefit from additional support to improve more long-term adherence to GLP-1 RAs. Further investigation of the association between adherence and weight change on real-world effectiveness of GLP-1 RAs is warranted.