Abstract
BACKGROUND:
In 2014, the US Food and Drug Administration approved the first glucagon-like peptide-1 (GLP-1) receptor agonist product, liraglutide injection, for obesity treatment. Many GLP-1 obesity treatment clinical trials report significant weight loss and medication adherence at more than 85%. Little is known about the real-world GLP-1 obesity treatment adherence, persistence, and switch rates.
OBJECTIVE:
To measure GLP-1 therapy persistence, adherence, and switch rates in a real-world cohort of members without diabetes using these drugs for obesity treatment.
METHODS:
Integrated pharmacy and medical claims data from 16.5 million average monthly commercially insured membership were used to identify obese members without diabetes newly initiating GLP-1 therapy between January 1, 2021, and December 31, 2021. Members were required to be continuously enrolled 1-year before and after the GLP-1 therapy start date and aged 19 years of age or older. Persistence was measured as no greater than or equal to 60-day gap with allowance for GLP-1 switching. Adherence was measured as the proportion of days covered (PDC) and members with a PDC greater than or equal to 80% were considered adherent. GLP-1 product switching was also assessed descriptively.
RESULTS:
4,066 commercially insured obese members without diabetes that newly initiated GLP-1 therapy met all study criteria. The mean age was 46 years, and 81% were female. Overall, GLP-1 persistence was 46.3% at 180 days and 32.3% at 1 year. The highest and lowest persistence rates at 1 year were observed for semaglutide (Ozempic) at 47.1% and liraglutide (Saxenda) 19.2%, respectively. Average PDC during the 1-year assessment was 51.0% with 27.2% adherent to therapy and 11.1% switched GLP-1 drugs.
CONCLUSIONS:
This GLP-1 weight loss treatment real-world analysis, among obese individuals without diabetes, found poor 1-year persistence and adherence and low rates of switching between products. These findings will aid in assessing products cost-effectiveness, understanding obesity care management program needs, forecasting future GLP-1 use and cost trends, and negotiating GLP-1 pharmaceutical manufacturer value-based purchasing agreements.
Plain language summary
This study assessed if people without diabetes stayed on glucagon-like peptide-1 (GLP-1) therapy for weight loss and if they took it as intended. At 1 year, among 4,066 people, we found 1 in 3 stayed on their GLP-1 and 27% took their medication as intended. We found some GLP-1 products were associated with more people staying on therapy than others. Reasons for low rates of staying on GLP-1 therapy may include shortages as well as side effects.
Implications for managed care pharmacy
During the first year of GLP-1 therapy for weight loss, two-thirds of commercially insured members were nonpersistent, defined as a more than 60-day gap, and only 27% were adherent. GLP-1 therapy persistence varied between products. These findings of poor persistence and adherence will aid in assessing GLP-1 products’ cost-effectiveness, understanding obesity care management program needs, forecasting future GLP-1 use and cost trends, and negotiating GLP-1 pharmaceutical manufacturer value-based purchasing agreements.
Obesity remains a significant health problem in the United States and globally. Commonly defined as a body mass index (BMI) greater than or equal to 30 kg/m2, obesity is both highly prevalent, with 41.9% of the US population reporting the condition between 2017 and 2020, and exceptionally costly, with estimates of obesity-related health care costs at nearly $173 billion annually.1 To address obesity, treatment guidelines begin with lifestyle modification. When insufficient to achieve a healthy weight, antiobesity pharmacotherapy is recommended as an adjunctive treatment in individuals with a BMI of 30 kg/m2 or greater, as well as individuals with a BMI of 27 kg/m2 or greater who have at least 1 obesity-related comorbidity.2-5
Historically, antiobesity pharmacotherapy has been infrequently used because of lack of sustained clinically significant weight loss, medication adverse events, and challenging administration issues.6 In 2021, antiobesity medications (AOMs) US Food and Drug Administration (FDA) approved for chronic overweight and obese treatment included oral naltrexone-bupropion (Contrave), oral orlistat (Xenical), oral phentermine-topiramate (Qsymia), oral lorcaserin (Belviq), and the high dose glucagon-like peptide-1 (GLP-1) receptor agonist products daily injectable maximum dose liraglutide 3.0mg (Saxenda) and weekly injectable semaglutide maximum dose 2.4mg (Wegovy). These AOM product labels indicate a modest 5% to 9% weight loss at 52 to 56 weeks, except for Wegovy, which demonstrated approximately 15% weight loss at 68 weeks.7-9 Other GLP-1 products available in 2021, which were FDA approved only for type 2 diabetes mellitus (T2DM), include weekly injectable semaglutide maximum dose 2.0mg (Ozempic), oral semaglutide (Rybelsus), weekly injectable dulaglutide (Trulicity), weekly injectable exenatide (Bydureon), daily injectable lixisenatide (Adlyxin), and daily injectable liraglutide maximum dose 1.8 mg (Victoza).
Use of T2DM GLP-1 products off-label to treat obesity, especially Ozempic, began to rise rapidly in the fall of 2022, driven in large part by social media trends.10 On-label GLP-1 prescribing for obesity rose substantially as well, with the rate of new prescriptions for Wegovy increased 7-fold from April 2022 to April 2023.10 These trends in GLP-1 obesity drug use and cost have resulted in self-insured employers questioning if they can afford to continue providing weight loss medication coverage.11 At a wholesale acquisition cost of more than $12,000 a year, often with substantial member out-of-pocket cost share, this increased GLP-1 weight loss treatment is driving up US employers’ health care spending, among employers covering weight loss medication.10-12
Currently, the only evidence GLP-1 therapy among patients without diabetes reduces obesity-related disease is from the SELECT study,13 a 3-year randomized controlled trial (RCT) evaluating the effectiveness of Wegovy to reduce major adverse cardiovascular events among individuals with preexisting cardiovascular disease (CVD), BMI greater than or equal to 27, and without diabetes. The study found a significant 1.5 percentage point reduction in major adverse cardiovascular events, which began to appear at 6 months.
It is known antiobesity GLP-1 RCTs have consistently shown high 1 year persistence rates of more than 85% with more favorable findings for weekly semaglutide (Wegovy) injection compared with daily liraglutide (Saxenda) injection.9 As self-insured employers and health plans weigh the value of covering weight loss medication, they need real-world data on persistence to therapy to determine the extent to which individuals are likely to receive the expected weight loss and related disease reduction benefits. In a real-world AOM persistency analysis of 26,522 adults newly initiating therapy between April 2015 and March 2016, only 41.8% who started liraglutide (Saxenda) were still on therapy at 6 months, whereas persistence was even lower for non-GLP-1 weight loss pharmacotherapies, with 15.9% for lorcaserin, 18.1% for naltrexone/bupropion, and 27.3% for phentermine/topiramate.14 Real-world T2DM treatment GLP-1 studies have found 1 year persistence rates at around 50%.15,16 By comparison, similarly expensive and self-injectable proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitor products to treat hyperlipidemia were found to have a real-world 60-day persistency of only 67.7%.17
Without current real-world research describing obesity without diabetes GLP-1 treatment persistency, adherence, and switch rates, forecasting cost-effectiveness evaluations and use will rely on the RCT persistency rates or approximations of persistency rates based on other therapies. In addition, if real-world GLP-1 weight loss without diabetes persistency is poor, this should be a focus for obesity care management programs and considered as an outcome for GLP-1 pharmaceutical manufacturer value-based purchasing agreements. The purpose of this analysis is to measure GLP-1 obesity treatment persistence, adherence, and switching in a real-world cohort of members without diabetes using these drugs.
Methods
Integrated medical and pharmacy claims plus enrollment data from January 1, 2020, to December 31, 2022, across 16 commercial health plans covering all regions of the United States were obtained for the study. During the study index period, the database contained a monthly average of 16.5 million members. Data obtained for this study included medical claims (date of service, diagnoses received, and procedures performed), pharmacy claims (fill dates, days supply, and National Drug Code numbers), and eligibility information (member demographics and enrollment history). This study was conducted to address the objectives stated for health insurance business purposes and, therefore, is institutional review board exempt. All authors are employees of Prime Therapeutics, a pharmacy benefits manager. Prime Therapeutics adjudicates and pays pharmacy claims storing all data according to the Health Insurance Portability and Accountability Act (HIPAA) of 1996 regulations from which a limited dataset was created to answer the study objectives.
This retrospective study identified members newly initiating GLP-1 therapy between January 1, 2021, and December 31, 2021 (Identification Period) for the following GLP-1 products: semaglutide (Ozempic), semaglutide (Rybelsus), dulaglutide (Trulicity), liraglutide (Saxenda), semaglutide (Wegovy), and liraglutide (Victoza). Exenatide (Bydureon) was excluded because of low product use and no lixisenatide (Adlyxin) use was found. Date of first GLP-1 pharmacy claim in the identification period was labeled as the index date from which members were required to be continuously enrolled 1-year before (preperiod) and after (postperiod) the index date. A 1-year washout period was used to identify the index GLP-1 fill. During the preperiod, members were required to have a medical claim with diagnosis indicating obesity, defined as International Classification of Disease, Tenth Edition, Clinical Modification (ICD-10-CM) codes beginning E660 through E669, except for E663, or ICD-10-CM codes beginning Z683 through Z684.18 To reduce the possibility of GLP-1 use for diabetes, members were excluded if they had a medical claim with a diabetes diagnosis (T1DM, T2DM, gestational diabetes, diabetes because of underlying condition, chemical-induced diabetes, and other specified diabetes) or a pharmacy claim for an antidiabetic medication during the 365-day preperiod. Members with diagnoses for HIV/AIDS, hemophilia, sickle cell disease, malignant cancer, or end-stage renal disease as identified by diagnosis codes in medical claims during the 365 days before study index date were also excluded. The Clinical Classifications Software Refined for ICD-10-CM diagnoses was used to specify diabetes and other clinical conditions.19
The study primary outcome of GLP-1 persistence and secondary outcomes of adherence and GLP-1 switching were reported by index date GLP-1 product. Switching GLP-1 products was allowed. All persistency and adherence measurements were conducted at the GLP-1 product level. Members were considered persistent if they did not have a 60-day gap in therapy and were censored at the end of the 365-day period.20,21 The last day of supply before gap was defined as the member’s discontinuation date for those who were nonpersistent. Median time-to-GLP-1 discontinuation between products was assessed, and the Kaplan-Meier method was used to compare differences in persistence across index GLP-1 products with significance obtained from the log-rank test.22 Sensitivity analyses using 45 and 90-day gaps for persistence were conducted. Pairwise comparisons in odds of nonpersistence were made between each GLP-1 product using a generalized linear model with a logit link and binomial distribution, and Tukey’s Honest Significant Difference test was used to account for inflated type 1 error rate.
Adherence was measured using the proportion of days covered (PDC) method endorsed by the Pharmacy Quality Alliance and used by Centers for Medicare and Medicaid Services in their Part C & D Star Ratings, with 3 differences: (1) all members were naive to GLP-1 therapy with no GLP-1 claim history in the prior 365 days, (2) a single GLP-1 claim allowed a member to be included in the adherence measurement, whereas Centers for Medicare and Medicaid Services requires 2 claims, and (3) all members were continuously enrolled.23,24 Members with a PDC of greater than or equal to 80% were considered adherent and those with a PDC of less than 80% defined as nonadherent. The same statistical modeling approach for the 365-day persistence outcome was used for the adherence outcome, with a generalized linear model assessing the log odds of achieving adherence over the postperiod.
Switches between GLP-1 products were defined as a change between GLP-1 products from one claim to the next for a given member. For example, if a member initiated Ozempic and switched to Wegovy, that would count as 1 switch, even though both are semaglutide products. If the member then switched from Wegovy back to Ozempic, that would count as another switch, even though the member had prior exposure to Ozempic. The count of member-level product switches was divided into 4 categories (0, 1, 2, 3+), and the difference in switch rate across product was assessed using a chi-square test.
Descriptive statistics compared member demographic and clinical characteristics between index GLP-1 products, as well as for the overall study cohort. The following characteristics were used for this analysis: sex, age, health status, preperiod medial claim identified presence of CVD using the Symmetry Episode Treatment Groups,25 and presence of prediabetes using ICD-10 code R7309. Member sex and age were ascertained at beginning of preperiod using plan enrollment data. Health status was estimated using the Charlson Comorbidity Index (CCI),26 calculated from medical claims during the preperiod. Generalized linear models and chi-square tests were used to evaluate differences in demographic and clinical characteristics across products. All analyses were performed using SAS/STAT software v9.4 (SAS Institute).
Results
A total of 4,066 commercially insured obese adults without diabetes who newly initiated GLP-1 therapy during calendar year 2021 met the requisite inclusion and exclusion criteria requirements (Supplementary Figure 1 (308.4KB, pdf) , available in online article). As shown in Table 1, across the full study population, 81.1% were female with a mean age of 46.4 (SD = 10.1) years and a mean CCI score of 0.6 (SD = 1.5). A history of CVD was observed in 5.5% of members; this did not differ significantly by product (P = 0.566). Prediabetes prevalence was present in 16.1% and varied by product with dulaglutide (Trulicity) having the highest (29.0%) and liraglutide (Saxenda) having the lowest (9.7%) (P < 0.001). The 3 most common index GLP-1 drugs by share of total analyzed members were liraglutide (Saxenda) (39.4%), semaglutide (Ozempic) (34.4%), and semaglutide (Wegovy) (10.3%).
TABLE 1.
Demographics, Clinical Characteristics, and Outcomes by GLP-1 Agonist Index Product
| All membersa N = 4,066 (100%) | Liraglutide (Saxenda)b n = 1,603 (39.4%) | Semaglutide (Ozempic)c n = 1,399 (34.4%) | Semaglutide (Wegovy)b n = 419 (10.3%) | Semaglutide (Rybelsus)c n = 285 (7.0%) | Liraglutide (Victoza)c n = 184 (4.5%) | Dulaglutide (Trulicity)c n = 176 (4.3%) | P valued | ||
|---|---|---|---|---|---|---|---|---|---|
| Characteristice | |||||||||
| Female, n (%) | 3,299 (81.1) | 1,346 (84.0) | 1,116 (79.8) | 328 (78.3) | 224 (78.6) | 152 (82.6) | 133 (75.6) | 0.004 | |
| Male, n (%) | 767 (18.9) | 257 (16.0) | 283 (20.2) | 91 (21.7) | 61 (21.4) | 32 (17.4) | 43 (24.4) | ||
| Age, mean (SD), years | 46.4 (10.1) | 46.0 (10.0) | 46.8 (10.2) | 46.1 (9.6) | 46.1 (10.4) | 46.4 (10.1) | 47.5 (9.5) | 0.204 | |
| Charlson Comorbidity Index,26 mean (SD) | 0.6 (1.5) | 0.7(1.6) | 0.6 (1.4) | 0.5 (1.3) | 0.5 (1.3) | 0.5 (1.2) | 0.8 (1.8) | 0.063 | |
| CVD, n (%) | 223 (5.5) | 76 (4.7) | 88 (6.3) | 24 (5.7) | 14 (4.9) | 10 (5.4) | 11 (6.3) | 0.566 | |
| Prediabetes, n (%) | 653 (16.1) | 155 (9.7) | 314 (22.4) | 46 (11.0) | 54 (18.9) | 33 (17.9) | 51 (29.0) | <0.001 | |
| GLP-1 outcomef | |||||||||
| Persistent without 60-day gap, n (%) | 1,313 (32.3) | 307 (19.2) | 659 (47.1) | 151 (36.0) | 70 (24.6) | 49 (26.6) | 77 (43.8) | <0.001 | |
| Adherence (PDC), mean (SD) | 51.0 (31.9) | 40.8 (28.5) | 63.1 (30.8) | 52.5 (33.3) | 44.5 (31.3) | 46.5 (30.6) | 60.7 (33.4) | <0.001 | |
| Adherent (PDC ≥80%), n (%) | 1,106 (27.2) | 241 (15.0) | 561 (40.1) | 132 (31.5) | 56 (19.6) | 43 (23.4) | 73 (41.5) | <0.001 | |
| Number of switches,g n (%) | |||||||||
| 0 | 3,615 (88.9) | 1,386 (86.5) | 1,319 (94.3) | 357 (85.2) | 246 (86.3) | 148 (80.4) | 159 (90.3) | <0.001 | |
| 1 | 386 (9.5) | 197 (12.3) | 59 (4.2) | 48 (11.5) | 36 (12.6) | 32 (17.4) | 14 (8.0) | ||
| 2 | 50 (1.2) | 15 (0.9) | 14 (1.0) | 14 (3.3) | 1 (0.4) | 4(2.2) | 2 (1.1) | ||
| 3+ | 15 (0.4) | 5 (0.3) | 7 (0.5) | 0 (0) | 2 (0.7) | 0 (0) | 1 (0.6) | ||
aCommercially insured adults without diabetes newly initiating a GLP-1 during calendar year 2021 and with a diagnosis indicating obesity medical claim.
bFDA approved for weight loss treatment.
cFDA approved for diabetes treatment only.
dP values for continuous variables is the F-test resulting from generalized linear model; P values for categorical variables are derived from the chi-square test.
eClinical characteristics measured in 365-day period prior to GLP-1 initiation (preperiod). Age and sex ascertained at first day of member’s preperiod.
fMeasured in 365-day post GLP-1 initiation (postperiod).
gCount of member-level product switches.
CVD = cardiovascular disease; FDA = US Food and Drug Administration; GLP-1 = glucagon-like peptide-1; PDC = proportion of day covered.
The primary study outcome, 1-year GLP-1 persistence measured using a 60-day gap definition, ranged from 19.2% in the liraglutide (Saxenda) cohort to 47.1% in the semaglutide (Ozempic) cohort (Table 1 and Figure 1). During the 1-year follow up, median time-to-GLP-1 discontinuation was significantly different (P < 0.001) across the GLP-1 products assessed. Median time to discontinuation ranged from 279 days (95% CI = 255-336) in the semaglutide (Ozempic) cohort to 120 days (95% CI = 111-125) in the liraglutide (Saxenda) cohort. Persistence sensitivity analysis showed consistent trends across the full study population (Table 1 and Supplementary Figure 2 (308.4KB, pdf) ). Pairwise comparisons across products found that semaglutide (Ozempic) and dulaglutide (Trulicity) persistence was significantly higher than all other products (Supplementary Table 1 (308.4KB, pdf) ).
FIGURE 1.
GLP-1 Agonists: Kaplan-Meier 1 Year Therapy Persistence (n = 4,066)
As shown in Table 1, mean 1-year PDC was lowest in the liraglutide (Saxenda) cohort (40.8% [SD = 28.5]) and highest in the semaglutide (Ozempic) cohort (63.1% [SD = 30.8]). Overall, 27.2% (range = 15.0%-41.5%) of members were adherent to GLP-1 during follow up. Adherence rates varied by product, with members significantly more adherent to semaglutide (Ozempic) and dulaglutide (Trulicity) than to other products. (Supplementary Table 2 (308.4KB, pdf) ). Overall, 11.1% of members had at least 1 GLP-1 switch during the 1-year assessment. The number of GLP-1 switches varied by GLP-1 product, and less than 20% of members across products had a switch during study follow-up.
Discussion
This study found less than one-third of the commercially insured obese adults without diabetes newly initiating GLP-1 weight loss treatment in 2021 remained persistent on GLP-1 therapy a year later. This 1-year persistence rate is substantially lower than the more than 85% persistence rate reported in many weight loss GLP-1 treatment RCTs7,13,27-29 and the real-world diabetes treatment GLP-1 studies with around 50% persistent.15,16 The persistence sensitivity analysis found minimal differences with the most lenient persistence definition of absence of 90-day therapy gap resulting in only 4 in 10 individuals persistent at 1 year. A recent health care electronic health record–based retrospective cohort study found similar rates of GLP-1 obesity treatment persistence with 40.0% (161/402) and 17.2% (40/233) remaining persistent to semaglutide and liraglutide therapy, respectively, at 12 months after initiation.30 This cohort study included both on-label and off-label utilizers of these products and defined persistence at 12 months as a cumulative supply gap of less than 90 days through the 1-year study period.
GLP-1 product switching during the first year of therapy occurred among 1 in 9 individuals included in this study, emphasizing the need to allow for switching when assessing GLP-1 weight loss treatment adherence and persistency. It is unknown why individuals switched products; product shortages, particularly for semaglutide products, may have influenced switching.
We found persistence varied significantly among the GLP-1 products with once weekly injectable semaglutide (Ozempic) having the highest median persistency at 9 months followed by weekly injectable dulaglutide (Trulicity) at 8 months with daily injectable liraglutide (Saxenda and Victoza) products having the lowest median persistence at 4 months. These findings are consistent with a previous RCT evaluating persistence to GLP-1 products used for weight loss, which observed greater persistence with less frequent injections.29 Other potential reasons for the differences in persistency among GLP-1 products include the lower weight loss achieved with liraglutide and oral semaglutide compared with injectable semaglutide, more prevalent gastrointestinal adverse events for the oral semaglutide formulation and with the higher dose semaglutide (Wegovy).30,31
The GLP-1 medication adherence rate was also poor, at 27.2% adherent during their first year of therapy. Adherence also varied by product, with the highest adherence observed for the weekly injectable products and the lowest adherence observed for the daily injectable products and the oral semaglutide formulation. Product shortages may have contributed to the low persistency and adherence, yet GLP-1 product switching was allowed and occurred in 1 in 9 individuals. Furthermore, semaglutide (Ozempic and Wegovy) shortages continue with an unknown resolution date, making these findings relevant to current treatment patterns.32 In addition to dosing frequency and formulation-related factors that contribute to relative differences in persistence and adherence, member cost sharing, members’ perceived benefit from therapy, and medication burden may all have contributed to the persistence and adherence study findings.9,14,20 These findings are important, as most individuals discontinuing their GLP-1 for weight loss, after a year of therapy, regain their weight.27
LIMITATIONS
This study has several notable limitations. First, results are limited by product shortages that may have impacted persistence and adherence. Although the chosen design reduces this impact by allowing for product switching when measuring persistence and adherence, the presence of shortages, particularly for semaglutide products, reduces the generalizability findings once the shortages resolve, although this is not anticipated until 2025.32 Individuals switching to compounded GLP-1 therapy or paying out of pocket for their GLP-1 product may have reduced observed persistence and adherence, as this use was not recorded in insurance claims data. Similarly, those without coverage inclusive of these products would be excluded from the analysis. Also, the use of medical and pharmacy claims to exclude individuals without diabetes diagnosis or by diabetes drug therapy and to identify those with obesity may misclassify cohort members. However, ICD-10 medical claim BMI presence (when defined at BMI ≥30) has been shown to accurately identify patients with obesity.33 Tirzepatide products were not included as an index GLP-1 in this analysis, as they were not available in 2021, although members could have switched to these products and remained persistent and adherent according to this study’s design.
The reason for choosing a particular GLP-1 is unknown and could be due to patient preference, adverse effect potential, product access, and member cost sharing. Some members may have had their GLP-1 appropriately discontinued because of lack of weight loss, and this study did not have BMI follow-up data to assess if individuals had a lack of response. During the dates of the study, evidence demonstrating the weight regain after GLP-1 discontinuation was just being published so providers may have discontinued GLP-1 therapy once the weight loss goal had been met. Our study examined a commercially insured membership and therefore are not generalizable to Medicare or Medicaid populations or individuals paying out of pocket.
The impact of adverse effects, an individual’s cost sharing, other diagnoses, social determinants of health, or other member characteristics are outside the scope of this analysis and are worthy of future consideration. Lastly, some individuals may have successfully made behavioral changes, discontinued their GLP-1 as directed by their health care provider, and successfully maintained their weight loss.
Conclusions
Obesity in the United States is a health crisis, and GLP-1 medications are efficacious when used in the clinical trial setting. This real-world study finds that persistence and adherence to these products is substantially lower than what has been reported in clinical trials. These real-world findings create GLP-1 obesity treatment effectiveness concerns because of the substantial portion of individuals apparently discontinuing therapy within the first year. Additionally, the FDA-approved GLP-1 chronic obesity treatment medications are more than $12,000 a year, creating a substantial societal financial burden to treat obesity.7,34 Value from these products may be obtained through reductions in obesity complications, such as developing diabetes, cardiovascular events, and sleep apnea, but this value is not likely to be realized if a product is discontinued during the first year and weight loss is not achieved or maintained. Understanding real-world persistence and adherence to current GLP-1 products when used for weight loss will aid in assessing products cost-effectiveness, understanding obesity care management program needs, forecasting future GLP-1 use and cost trends, and negotiating GLP-1 pharmaceutical manufacturer value-based purchasing agreements.
Funding Statement
The study was funded by Prime Therapeutics, LLC.
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