Real-World Clinical Effectiveness and Cost Savings of Liraglutide Versus Sitagliptin in Treating Type 2 Diabetes for 1 and 2 Years

Diabetes is an emerging global epidemic—this chronic metabolic condition affected 1 in every 11 adults worldwide in 2017 and 9.4% of the US population in 2015 [1, 2]. Diabetes can lead to many micro- and macrovascular complications [3] and accounted for 10.7% of global all-cause mortality among people 20–79 years old [2]. Diabetes was estimated to cost $727 billion (US dollars; USD) in 2017, responsible for 6–16.6% of total healthcare expenditures worldwide [2]. About half of the global diabetes budget is spent in the US, where patients with diagnosed diabetes on average spend about $13700 on medical services annually, which is about 2.3 times higher than that spent by people without diabetes [1].

Type 2 diabetes mellitus (T2DM), characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency, accounts for approximately 90% of all diabetes cases [4]. Due to the progressive nature of diabetes, the initiation of pharmacologic agents is recommended at the time of diagnosis of T2DM, along with lifestyle modifications such as diet and exercise to achieve glycemic control [5‐7]. With metformin as the preferred 1st-line therapy, additional anti-diabetic drugs are often considered and, as recommended by the American Diabetes Association (ADA), patient’s history of atherosclerotic cardiovascular (CV) disease plays a key role in the selection of the add-on therapy [5].

Liraglutide, which belongs to the class of glucagon-like peptide-1 (GLP-1) receptor agonists, is a commonly used anti-diabetic therapy. It was shown to reduce the risk of major adverse CV events in a recent clinical trial [8], and it is currently the only agent in its class that has been approved to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal MI or nonfatal stroke) in adults with T2DM and established cardiovascular disease [5].

The efficacy and safety of liraglutide for the treatment of T2DM has been extensively studied in clinical trials. Liraglutide demonstrated superior glycemic control, greater weight loss, and better treatment satisfaction after 52 weeks as an add-on to metformin compared with another incretin-based therapy, sitagliptin [a dipeptidyl peptidase-4 (DPP-4) inhibitor] [9]. The findings were consistent with those observed at a shorter follow-up period [10‐12], while gastrointestinal problems were common adverse reactions to liraglutide [13]. Based on data from the clinical trials, the annual mean cost per patient was estimated to be $5103–$6523 (2012 USD) lower with liraglutide than with sitagliptin to reach glycated hemoglobin (HbA1c) < 7.0% with no hypoglycemia or weight gain, and liraglutide was shown to be more cost-effective than sitagliptin after 5 years of use [14, 15].

Many studies have investigated the effectiveness of liraglutide outside the controlled settings of clinical trials, with recent attention paid to the long-term use of the therapy [16]. A 2-year prospective study of routine clinical practice in France found liraglutide to be as effective as observed in clinical trials [17]. However, the effectiveness of liraglutide and sitagliptin has usually been compared in a 6-month treatment period [18‐21]. Effectiveness for a longer duration has only been examined in a 1-year survey conducted in the UK from 2009 to 2011 [22].

Data on the long-term effectiveness of liraglutide are needed to provide healthcare providers and patients with additional information to support T2DM treatment and management decisions. This study investigated the clinical and cost-effectiveness of liraglutide compared with sitagliptin in the US in a real-world setting for 1 and 2 years of treatment.

The study sample included 3113 patients (493 in the liraglutide cohort and 2620 in the sitagliptin cohort) who had persistently used the index therapy for at least 12 months after applying inclusion/exclusion criteria (Fig. 1). The characteristics of patients in the liraglutide cohort differed from those in the sitagliptin cohort in many aspects (Table 1). Liraglutide users were younger [mean age (standard deviation, SD): 53 (8.5) years vs. 56 (9.7) years], less likely to be male (48.3% vs. 62.3%), more likely to live in the South, and more likely to be enrolled in health plans covering out-of-network services (all p < 0.05). In addition, liraglutide users were more likely to visit endocrinologists, use insulin, and have a diagnosis of obesity or hypertension during the baseline period (all p < 0.05). Baseline HbA1c was similar between the cohorts [8.1 (1.7) % vs. 8.2 (1.7) %; p ≥ 0.05]. The mean HbA1c reduction among liraglutide users during follow-up ranged from 1.2 (%-point) in quarter 1 to 0.9 in quarter 8; reductions ranged from 0.9 to 0.4 among sitagliptin users (Table 2). Baseline pharmacy costs were higher in the liraglutide group than the sitagliptin group before starting index therapy (Table 1). Medical costs were also higher at baseline for the liraglutide group; however, differences were not statistically significant.

After adjustment for covariates, use of liraglutide was associated with a higher reduction in HbA1c from baseline in all quarters during the 1st year of follow-up, as reflected by the positive coefficients (all p < 0.05; Table 3). Specifically, the larger reduction in HbA1c associated with the use of liraglutide versus sitagliptin was estimated to range from 0.34 (%-point) [95% confidence interval (CI) 0.23, 0.45] in quarter 1 to 0.21 (95% CI 0.07, 0.35) in quarter 4. The use of liraglutide was also associated with a higher likelihood of obtaining an HbA1c reduction of ≥ 1%-points [ORs ranging from 1.47 to 2.37] and reductions of ≥ 2%-points (ORs ranging from 1.67 to 2.04; all p < 0.05). Lastly, the use of liraglutide was associated with a higher likelihood of attaining HbA1c goals: with ORs around 2 of achieving HbA1c < 6.5% and around 1.6 of achieving HbA1c < 7% in all quarters (all p < 0.05). Among the patients with at least 2 years of persistent use of the index therapy, the use of liraglutide was associated with a higher reduction in HbA1c in all quarters during the 2nd year of follow-up as well as with a higher chance of an HbA1c reduction of ≥ 1%-points (except for quarter 6), of achieving HbA1c < 6.5% (except for quarter 6), and of achieving HbA1c < 7% (in quarter 5) (all p < 0.05). The small sample size was insufficient to estimate the association between HbA1c reduction ≥ 2%-point and persistent use of index therapy during the 2nd year of follow-up.

Adjusted outcomes and the marginal effects of liraglutide versus sitagliptin were calculated (Figs. 2, 3). The marginal effects on HbA1c reductions from baseline were the same as the regression coefficients due to the model specification. For the other endpoints, 13.4% more patients (48.1% vs. 34.7%, p < 0.05) would obtain HbA1c reduction ≥ 1%-point and 4.4% more (21.9% vs. 17.5%, p < 0.05) would obtain HbA1c reduction ≥ 2%-point in quarter 1 if they used liraglutide rather than sitagliptin, and 10.4% more (34.5% vs. 24.1%, p < 0.05) or 10.5% more (57.4% vs. 46.9%, p < 0.05) patients would reach an HbA1c goal of < 6.5% or < 7.0% in quarter 1, respectively (all p < 0.05). The marginal effects were stable across all quarters during the 1st year of persistent medication use, while more variation was observed during the 2nd year of persistent medication use.

The unadjusted and adjusted predicted costs for each cohort, along with the cost ratios, for the 1st and 2nd years of persistent treatment are presented in Table 4. The adjusted total and medical costs in each cohort and year of follow-up are also illustrated in Fig. 4. In the 1st year, there was no difference in medical costs between persistent users of liraglutide and sitagliptin. The liraglutide cohort had higher total costs (both all cause and diabetes related) than the sitagliptin cohort due to the higher pharmacy costs (p < 0.05). During the 2nd year of persistent drug use, all-cause medical costs were 33% lower for liraglutide patients than sitagliptin patients (adjusted cost ratio 0.67, 95% CI 0.50, 0.89), resulting in a savings of $2674 per patient (adjusted costs: $5410 vs. $8084, p < 0.05). This saving offset the higher pharmacy costs observed in the liraglutide group in the 2nd year and resulted in $602 lower all-cause total costs than in the sitagliptin group (not statistically significant). No significant differences between the cohorts were found for the diabetes-related medical costs and total costs during the 2nd-year follow-up.

This study extends previous studies by providing integrated evidence on the long-term clinical and cost-effectiveness of treatment with liraglutide versus sitagliptin in real-world clinical practice in the US. Even after adjusting for baseline patient characteristics and the use of antidiabetic medications during follow-up, we found that patients persistently using liraglutide for 1 or 2 years experienced improved glycemic control (in terms of higher reduction of HbA1c from baseline, higher likelihood to reach high reduction in HbA1c, and higher likelihood to reach HbA1c target levels) compared with those using sitagliptin. Patients in both cohorts incurred similar medical costs during the 1st year of medication use, while during the 2nd year, liraglutide users had significantly lower all-cause medical costs, which offset their higher pharmacy costs than sitagliptin users.

The 6-month clinical effectiveness of liraglutide in this study is similar to previously published data. Compared with sitagliptin, use of liraglutide has been found to be associated with 0.31–0.41 (%-point) greater reduction of HbA1c from baseline, an 8–15% greater chance to reach HbA1c < 7%, and an 11% greater chance to reach A1C ≤ 6.5% after 6 months since treatment initiation [18, 19], and these were reflected by $994 (2013 US dollar) lower diabetes-related medical costs during the 6 months of follow-up (all p < 0.05) [19].

Trends of clinical effectiveness over 2 years of medication use continued to be favorable for liraglutide versus sitagliptin, as found in our study. Specifically, the difference in HbA1c reduction between the two treatments was highest after 3 months of medication use and then stabilized for the remainder of the year; no obvious trend was observed in the effectiveness in terms of likelihood to obtain high HbA1c reduction or reach HbA1c goals in the 1st year of follow-up. During the 2nd year of medication use, there was much more variation over time in the clinical effectiveness of liraglutide versus sitagliptin, possibly because of the small sample size (liraglutide cohort: N = 113; sitagliptin cohort: N = 798); nevertheless, the clinical effectiveness of liraglutide remained stable.

The improved glycemic control associated with liraglutide relative to sitagliptin led to cost savings, especially for patients treated for longer than 1 year. The findings on the costs during the 2nd year of persistent treatment may be obscured because of the small sample size and large variation in healthcare costs. Thus, a post hoc analysis was conducted on annual costs after the 1st year of persistent use of the index therapy among patients who did not necessarily have persistent use of index therapy during the 2nd year after treatment initiation. The results from the post hoc analysis showed that after 1 year of persistent treatment, medical costs (both diabetes related and all cause) were significantly lower in the liraglutide cohort (Supplementary Appendix Table 6). Further, no difference between the cohorts was found in the annual costs for diabetes-related healthcare, and the annual all-cause healthcare costs were significantly lower for the liraglutide cohort.

The summary statistics of healthcare resource utilization (see Supplementary Appendix Table 5 for results) showed lower use of inpatient and emergency room services when taking liraglutide. Specifically, patients treated with liraglutide had a shorter length of hospital stay during the 1st year [all-cause, mean days (SD): 0.2 (1) vs. 0.4 (2.3); diabetes-related, 0.2 (0.8) vs. 0.3 (1.9); all p < 0.05] and 2nd year [all cause: 0.1 (0.6) vs. 0.4 (2.3); diabetes related, 0.1 (0.6) vs. 0.3 (2.0); all p < 0.01] of persistent treatment than sitagliptin users. Liraglutide users also had fewer visits to the emergency department during the 2nd year of persistent treatment. No differences between treatment groups were observed in other healthcare resource utilization. These findings suggest that hospitalization and emergency room visits may be the main drivers of cost savings associated with liraglutide, and further research is warranted to investigate this hypothesis.

The lower medical costs in the liraglutide cohort compared with sitagliptin during the 2nd year of persistent treatment were statistically significant for all-cause healthcare services, but not for diabetes-related services. This may reflect the nonglycemic benefits of liraglutide (including weight loss and reduced risks of CV events), while sitagliptin had neutral effects [5]. The finding also suggests that better glycemic control can improve a patient’s overall health.

The results of this study should be interpreted with consideration of the limitations associated with studies based on administrative claims data. First, due to the nonexperimental nature of the data and the study design, this study does not allow for causal inferences; unmeasured confounders such as prescription bias may influence the results. Our study considered a wide range of covariates, including socio-demographic and clinical measures, to reduce the residual confounding. Second, although clinical trials determined the efficacy of liraglutide 1.2 mg separately from 1.8 mg, our study considered the overall use of liraglutide. It is challenging to calculate the dose of liraglutide used in clinical practice from claims data since the National Drug Codes may not completely capture the clinical practice of dosing and titration, which may also vary over the considered follow-up period. Third, HbA1c measurements were available for only a subset of T2DM patients; the availability of HbA1c is not expected to be related with patient characteristics and thus should not lead to bias in our findings. Finally, patients 65 years or older are under-represented since the MarketScan databases used in this study contain only Medicare enrollees who purchased supplemental commercial health insurance. However, MarketScan is one of the largest commercial healthcare claims databases in the US, and our findings can be interpreted in a population with commercial health insurance.

In real-world clinical practice in the US, long-term use of liraglutide for 1 or 2 years was associated with better glycemic control compared with sitagliptin. The medical costs were similar between liraglutide users and sitagliptin users during the 1st year of persistent treatment, but savings in medical costs were realized for liraglutide users during the 2nd year of persistent treatment, which offsets differences in pharmacy costs.