Real-world Effectiveness of Liraglutide vs. Sitagliptin Among Older Patients with Type 2 Diabetes Enrolled in a Medicare Advantage Prescription Drug Plan: A Retrospective Observational Study

Type 2 diabetes (T2D) is a rising health concern in the USA, particularly within an aging population. In 2015, 9.4% of the total US population was estimated to have diabetes; this number increased to 17.0% when this analysis was restricted to adults aged 45–64 years only and to 25.2% among adults aged 65 years or older [1]. This number is expected to continue to rise due to the aging US population and increased life expectancy of people with diabetes. Older diabetic patients have a higher risk for diabetes-related complications, including microvascular and macrovascular damage and hypoglycemia, and therefore present significant challenges in achieving strict glycemic control and constitute a growing burden on the US healthcare system [2‐4].

Despite the importance of effectively managing T2D in older adults, this patient population has often been excluded from randomized clinical trials, and limited data exist on this older population regarding real-world outcomes related to different glucose-lowering therapies [4]. The class of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP-4) inhibitors, may allow for improved control of hyperglycemia and offers important advantages to an older population (i.e., minimal risk for hypoglycemia, weight loss, and lower risk for cardiovascular disease associated with GLP-1 RAs) [5]. Previous studies have found that the GLP-1 analogue liraglutide provides sustained glycosylated hemoglobin (HbA1_c) reduction, achievement of specific HbA1_c goals, and weight loss when compared to the DPP-4 inhibitor sitagliptin [6‐12]. Additionally, retrospective observational studies have demonstrated the cost-effectiveness of liraglutide when compared within and between antidiabetic drug classes; however, cost-effectiveness has not been specifically explored in a T2D population aged 65 years and older [11, 13‐16].

The aim of the current study was to compare liraglutide with sitagliptin in achieving glycemic control among older people with T2D enrolled in a Medicare Advantage Prescription Drug (MAPD) plan. This was accomplished by evaluating mean change in HbA1_c, mean reduction in HbA1_c of ≥ 1%, and the percentage of patients achieving the treatment goals of HbA1_c < 7% and HbA1_c < 8% over a 1-year period. The analysis also compared all-cause healthcare costs (pharmacy and medical combined) in this population. This information may be important when considering real-world treatment in the growing older population with T2D in the USA.

Overall, 3056 patients met the criteria of persistence on index treatment and had HbA1_c results available within the baseline period and 1 year later (Fig. 2). Within this study population, 218 (7.1%) patients were treated with liraglutide and 2838 (92.9%) patients were treated with sitagliptin.

After adjusting for baseline characteristics, the results of this study suggest that in an older population, improved glycemic control (greater mean decrease in HbA1_c and increased likelihood of achieving glycemic treatment goals [HbA1_c < 7%, HbA1_c reduction of ≥ 1%]) was associated more with the use of liraglutide than with the use of sitagliptin. All-cause healthcare costs related to achieving an HbA1_c < 7% were slightly higher in the liraglutide group compared to the sitagliptin group, but this difference did not reach statistical significance. This lack of significant difference could be the result of the small sample size.

Although no significant difference was detected between the liraglutide and sitagliptin treatment groups in rates of achieving an HbA1_c level of < 8%, most patients in both groups (i.e., > 75%) achieved this less stringent endpoint. Additionally, the majority of patients in each treatment group had a baseline HbA1_c level of < 8.0%, suggesting that a lower treatment goal (e.g., 7.0%) may have been considered the most appropriate for many of the study participants. According to T2D treatment guidelines established by the American Diabetes Association, a reasonable HbA1_c goal for many adults without an increased risk for hypoglycemia or other adverse effects of treatment is < 7%, even in an older T2D patient population who are otherwise healthy and should have low glycemic goals [19]. The relatively small prevalence of comorbidities observed in the liraglutide patient population therefore supports the relevance of a lower HbA1_c goal and our focus on outcomes associated with achievement of an HbA1_c < 7.0% treatment goal.

GLP-1 RAs and DPP-4 inhibitors are recommended as components of diabetes therapy [20], with GLP-1 RAs reported to have superior glycemic efficacy, pharmacokinetics, and physiologic activity [21]. Compared to the DDP-4 sitagliptin, the GLP1-RA liraglutide may also provide improved cardiovascular safety risk and a reduction in body weight in an older population [2, 22]. In a clinical trial, compared to a placebo, liraglutide significantly reduced cardiovascular risk factors, including weight, blood pressure, and heart rate. In addition, patients taking liraglutide had a lower risk of nonfatal myocardial infarction, nonfatal stroke, and first occurrence of cardiovascular death compared to the placebo group [22]. In our analysis, the proportion of patients with cardiovascular disease was higher in the sitagliptin group than in the liraglutide group. Consideration of these factors may therefore be of key importance to clinicians, patients, and decision-makers interested in improving outcomes and managing costs associated with T2D.

These data are also supported by similar studies demonstrating superior efficacy and cost-effectiveness of liraglutide versus sitagliptin in the general adult population with T2D [6, 7, 12]. Specifically, the NN2211-1860 (-LIRA-DPP-4) trial comparing the efficacy and safety of liraglutide versus sitagliptin demonstrated a greater lowering of HbA1_c after 26 weeks and 52 weeks of treatment with liraglutide [6, 7]. Additionally, multiple observational studies have confirmed greater reductions in HbA1_c and a higher likelihood of achieving glycemic endpoints with liraglutide versus sitagliptin during a 6-month assessment [8‐11]. A recent real-world study has also highlighted the long-term effectiveness of liraglutide in this population [12]. A meta-analysis also demonstrated the efficacy and safety of liraglutide compared with sitagliptin when combined with metformin [23]. Furthermore, various studies sourcing data from clinical trials and claims data demonstrated better cost-effectiveness of liraglutide compared with sitagliptin, with any increases in pharmacy costs associated with liraglutide being offset by decreases in other diabetes-related medical expenses [13‐16].

This analysis may be limited by the inconsistency in data collection processes inherent in claims data, including the absence of available disease severity information, an important prognostic factor in determining treatment outcomes. However, IPTW methodology was incorporated as a strategy of mitigating unmeasured confounding. The IPTW methodology may have increased standardized bias; additional sensitivity analysis could quantify any potential residual confounding. Results may also have been influenced by the exclusion of patients with baseline use of insulin, which may have resulted in the selection of individuals with less severe disease and may not be reflective of what is experienced in the real-world clinical setting. The analysis cohort sample size was also limited by the requirement of HbA1_c results and persistence on index therapy; however, these data were considered essential in comparing the effects of liraglutide and sitagliptin treatments. Excluding patients that did not have HbA1c values at 1-year post-baseline could have introduced selection bias. Of note, previous clinical studies comparing the efficacy of liraglutide versus sitagliptin included stratification of liraglutide doses, with a higher dose demonstrating greater efficacy [6, 7]; however, assigning the liraglutide dose using claims data would be subject to a lack of patient information, and dosing information was therefore not included in the current analysis. The detection of hypoglycemic events using claims data was also limited and potentially restricted to severe events requiring medical intervention, despite the importance of hypoglycemic risk in treating older people with diabetes. This lack of hypoglycemic event data precluded our ability to include ‘no hypoglycemia’ in composite outcomes. Finally, whereas the study was sufficiently powered for the main outcome, any inference on secondary outcomes (i.e., cost) may not have sufficient sample size and may be subject to type II error. Results reported on secondary outcomes should be used to inform additional research.

These real-world data add to a body of evidence that suggests liraglutide is associated with a greater HbA1_c reduction compared to sitagliptin, and this association is maintained in an older population. Older people with T2D who initiate liraglutide treatment may be more likely to achieve treatment goals of HbA1_c < 7% and an HbA1_c reduction of ≥ 1% after 1 year of therapy compared with those who initiate treatment with sitagliptin. Additionally, cost data offer preliminary evidence that glycemic benefits of liraglutide are not associated with a significant increase in all-cause health care costs compared to sitagliptin, although further longer-term evaluation is warranted.