FormalPara Key Summary Points

Current evidence indicates that rivaroxaban may be a safe and effective alternative to warfarin among patients with nonvalvular atrial fibrillation (NVAF) and obesity, although the added impact of polypharmacy in this population warrants further investigation

The present real-world study hypothesized that rivaroxaban would be an effective and safe treatment option compared to warfarin among NVAF patients with obesity and polypharmacy use (≥ 5 medications)

In this retrospective study of NVAF patients with obesity and polypharmacy in the US, rivaroxaban was associated with a significantly lower risk of stroke/systemic embolism and a similar risk of major bleeding compared to warfarin over a 36-month follow-up period

This pattern of results remained consistent in the subgroup analyses of patients with 5–9 and ≥ 10 medications

The present findings support our initial hypothesis that rivaroxaban is a viable treatment option with long-term incremental benefits compared to warfarin among complex NVAF patients with obesity and polypharmacy in a commercially-insured US population

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Introduction

Obesity is a major risk factor for developing atrial fibrillation (AF) [1, 2], which in turn confers an elevated risk of stroke and systemic embolism (SE) [3, 4]. Although AF is predominantly a disease of the elderly (mean age ≥ 70 years) [5,6,7,8], obesity has been associated with a higher risk of incident AF in younger individuals [9,10,11,12,13], even in the absence of additional predisposing risk factors [11]. Nonvalvular AF (NVAF) is the most common type of AF in the US, accounting for > 15% of all strokes [14]. Direct-acting oral anticoagulants (DOAC) [15,16,17] such as rivaroxaban are being increasingly preferred over vitamin K antagonists (VKA) such as warfarin for the treatment of NVAF [18, 19] because of their limited drug and food interactions without the need for routine laboratory monitoring and dosage adjustments [20, 21]. Current evidence indicates that the pharmacokinetic profile of rivaroxaban is not significantly impacted by body weight [22,23,24]. Rivaroxaban may also be considered a safe and effective alternative to warfarin among NVAF patients with obesity based on analyses of clinical trial data [25,26,27] and the findings of recent observational studies [28,29,30,31,32].

Despite this accumulating evidence that rivaroxaban is safe and effective among NVAF patients with obesity [25,26,27,28,29,30,31,32], the added impact of polypharmacy use among this population warrants further investigation. Polypharmacy, commonly defined as the concurrent use of ≥ 5 medications [33,34,35], has become increasingly prevalent in the US [36]. In particular, NVAF is associated with multiple comorbidities requiring concomitant medication use, resulting in an estimated polypharmacy rate of > 50% [37]. Obesity is also associated with frequent complications and comorbidities, which is likely to contribute to increasing dependence on polypharmacy [36, 38, 39]. Polypharmacy is linked to poor clinical outcomes and reduced anticoagulation control, which may reflect drug-drug interactions and the negative impact of multiple medication use on adherence [34, 40,41,42,43,44]. Warfarin-treated patients with polypharmacy may be especially prone to drug-drug interactions, which are associated with increased risk of bleeding complications [42, 45].

To date, several studies have examined the impact of polypharmacy on the performance of anticoagulants such as rivaroxaban and warfarin among patients irrespective of body weight or body mass index (BMI) [37, 44, 46]. These prior studies suggest that rivaroxaban is safe and effective across complex patients with polypharmacy. In an analysis of the ROCKET AF trial population, Piccini et al. [44] examined the risk of stroke and bleeding events between rivaroxaban and warfarin according to number of concurrent baseline medications (i.e., 0–4, 5–9, and ≥ 10). Overall, there was no difference in outcomes between rivaroxaban and warfarin-treated patients with increasing number of medications. In more recent retrospective claims-based studies of polypharmacy users, rivaroxaban has been associated with a risk of stroke/SE that is similar or reduced compared to warfarin, with no difference in the risk of major bleeding [37, 46].

Studies investigating the impact of polypharmacy on the clinical outcomes among anticoagulant users with obesity are currently scarce in the literature. To address this knowledge gap, the present study compared the effectiveness and safety of rivaroxaban and warfarin in a nationally representative commercially-insured population of NVAF patients with obesity and polypharmacy in the US. We hypothesized that rivaroxaban would be an effective and safe treatment option for NVAF patients with obesity and polypharmacy compared to warfarin.

Methods

Data Source

The IQVIA PharMetrics® Plus data spanning from January 1, 2010, to September 30, 2019, were used to meet the study objectives. The IQVIA PharMetrics® Plus data used for the study offered a diverse representation of enrollees and are representative across geographic zones in the US. They contained around 40 million patients with both medical and pharmacy benefits in any given recent year, with an average length of health plan enrollment of approximately 39 months. The enrollee population in the IQVIA PharMetrics® Plus data is generally representative of the < 65 years of age, commercially-insured population in the US with respect to both age and gender. All database records were statistically de-identified and certified as fully compliant with US patient confidentiality requirements outlined in the Health Insurance Portability and Accountability Act. Permission to access these records for the current study was granted by IQVIA PharMetrics® Plus data. Because the current study relied exclusively on de-identified patient records and did not involve the collection, use, or dissemination of individually identifiable data, institutional review board approval was not necessary.

Study Design and Population

A retrospective weighted-cohort design was used to evaluate outcomes among NVAF patients with obesity and polypharmacy initiated on rivaroxaban or warfarin. Eligible patients were those with ≥ 1 dispensing for rivaroxaban or warfarin between November 4, 2011, and September 30, 2019 (identification period), with the first dispensing defined as the index date. The baseline period was defined as the 12 months prior to the index date. Although rivaroxaban was approved in November 2011, only patients with an index date on or after January 1, 2013, were included in the study population as it may take a certain amount of time for recently approved medications to be prescribed and early adopters may differ in their characteristics. Patients in the overall polypharmacy cohort were defined as having ≥ 5 concurrent outpatient pharmacy dispensings for any medications on the index date (including rivaroxaban or warfarin); concurrent use was defined based on the number of dispensing with days of supplies overlapping with the index date [34]. At the index date, patients in the overall polypharmacy cohort were further stratified based on categories used in the analysis of the ROCKET AF trial population by Piccini et al. [44], with patients having either 5–9 medications or ≥ 10 medications.

Patients were required to meet the following additional inclusion criteria: ≥ 1 medical claim with a diagnosis of AF (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 427.31 or International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM]: I48.0–148.2x, 148.91) during the baseline period or on the index date, ≥ 1 medical claim with a diagnosis code for obesity or BMI ≥ 30 kg/m2 (see Table S1 for a list of ICD-9-CM and ICD-10-CM codes used to define obesity/BMI ≥ 30 kg/m2) during the baseline period or on the index date, ≥ 12 months of continuous health plan enrollment before the index date (i.e., baseline period), and ≥ 18 years of age in the index year. A prior study has validated the use of diagnosis codes for identifying obesity among NVAF patients with high positive predictive value (PPV; 89.8%) and high specificity (95.2%) [47]. Patients were excluded from the analysis if they had pharmacy claims for > 1 oral anticoagulant (i.e., rivaroxaban, warfarin, apixaban, edoxaban, betrixaban, or dabigatran) at the index date or if they met any of the following exclusion criteria during the baseline period: ≥ 1 pharmacy claim for an oral anticoagulant, ≥ 1 medical claim for VTE or knee or hip replacement surgery, ≥ 1 medical claim with a diagnosis of mitral-stenosis, or ≥ 1 medical claim for a mechanical heart valve procedure.

Patients’ demographics and clinical characteristics were evaluated during the baseline period and outcomes were evaluated at follow-up. Clinical effectiveness outcomes were assessed using an intention-to-treatment (ITT) approach, which spanned from the index date until the earliest of 36 months, health plan disenrollment, or end of data availability. The safety outcome was assessed using an on-treatment approach that was censored upon the earliest date of switch to or addition of another anticoagulant (so that patients were continuously treated with the index anticoagulant), anticoagulant discontinuation, 36 months, health plan disenrollment, or end of data availability. Anticoagulant discontinuation was defined as a gap of ≥ 60 days of supply between the end of an anticoagulant dispensing and the next medication refill or end of data availability. In a sensitivity analysis, outcomes were also assessed using an on-treatment approach.

Study Outcomes

Effectiveness and safety outcomes were assessed over a 36-month follow-up period. The primary effectiveness outcome was the composite of stroke (ischemic or hemorrhagic) or SE (stroke/SE), which was defined as a primary diagnosis of stroke or SE documented in a hospitalization or emergency room visit (see Table S2 for the list of diagnosis codes used to identify stroke/SE). The effectiveness outcomes were also assessed separately (i.e., stroke, ischemic stroke, hemorrhagic stroke, and SE). The safety outcome was the occurrence of a major bleeding event, which was identified using hospitalizations with diagnoses and procedures indicating an episode of bleeding (i.e., Cunningham algorithm) [48]. Of note, hemorrhagic stroke was also included in the definition of a major bleeding event.

Statistical Analysis

Inverse probability of treatment weighting (IPTW) based on the propensity score (PS) was used to balance the rivaroxaban and warfarin cohorts, with PS defined as the conditional probability of receiving rivaroxaban based on observable covariates [49]. The IPTW approach uses weights derived from the PS to create a pseudo-population, so that the distribution of covariates in the population is independent of treatment assignment. Patients’ weight in each cohort was equal to the inverse of their probability of receiving treatment with rivaroxaban (i.e., 1/PS for the rivaroxaban cohort and 1/[1 – PS] for the warfarin cohort). Variables used in the PS calculation included age, sex, year of index date, region, type of insurance plan, obesity type, baseline stroke/SE, baseline major bleeding, cardiovascular-related medications, cardiovascular procedures, use of non-oral anticoagulants, prior history of cancer diagnosis and cancer treatment, baseline HRU and healthcare costs, and baseline risk factors for stroke and bleeding events (with ≥ 5% prevalence in either cohorts).

Patient characteristics by treatment cohort were evaluated using descriptive statistics including mean, standard deviation (SD), and median values for the continuous variables and relative frequencies and proportions for the categorical variables. Differences in baseline characteristics between patients in the cohorts were assessed using standardized differences. A standardized difference < 10% was considered a negligible imbalance [50].

Time to stroke/SE and time to major bleeding events were assessed with weighted Kaplan-Meier (KM) survival analysis. Cumulative KM rates were reported at 12, 24, and 36 months following the index date. Study outcomes were also assessed and compared between cohorts using weighted Cox proportional hazards regression models, with corresponding hazard ratios (HR), 95% confidence intervals (CI), and p values.

Results

NVAF patients with obesity and polypharmacy included a total of 7000 patients initiated on rivaroxaban and 3920 patients initiated on warfarin. The subgroup with 5–9 medications comprised 5339 rivaroxaban-treated patients and 2574 warfarin-treated patients and the subgroup with ≥ 10 comprised 1661 rivaroxaban-treated patients and 1346 warfarin-treated patients (Fig. 1).

Fig. 1
figure 1

Source: IQVIA PharMetrics® Plus data, consisting of AF patients with obesity, from January 1, 2010, to September 30, 2019. AF atrial fibrillation, BMI body mass index, GPI generic product identifier, ICD International Classification of Disease, NVAF nonvalvular atrial fibrillation, VTE venous thromboembolism. Notes: (1) A total of 326 rivaroxaban patients with > 1 oral anticoagulant medication on the index date were excluded. (2) A total of 379 warfarin patients with > 1 oral anticoagulant medication on the index date were excluded. (3) Continuous eligibility was defined as continuous health plan enrollment with medical and pharmacy coverage. (4) Baseline period was defined as the 12 months prior to the index date. (5) AF was identified with the following ICD-9-CM: 427.31 and ICD-10-CM: I48.0–148.2x, 148.91. (6) See Table S1 for obesity diagnosis codes. (7) Patients with concurrent pharmacy dispensing for ≥ 5 different medications based on the date of the pharmacy claim and days’ supply on the index date. Chen et al. [34]

Patient disposition: NVAF polypharmacy population. Data

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Baseline Demographics and Clinical Characteristics

Among the overall polypharmacy cohort, the weighted rivaroxaban and warfarin cohorts were well balanced (i.e., std. diff. < 10%) with respect to baseline demographic and clinical characteristics (Table 1) and baseline comorbidities (Table 2). In the rivaroxaban and warfarin cohorts, the mean age was 60 years, 31% of the patients were female. Patients in the weighted rivaroxaban and warfarin cohorts had comparable values for the Quan-Charlson comorbidity index (CCI) score (mean: 2.06 and 2.02, respectively), CHA2DS2-VASc score (mean: 2.96 and 3.00, respectively), and HAS-BLED score (mean: 1.99 and 1.98, respectively; Table 2). In the rivaroxaban cohort, 90% of patients had dispensings for the label standard dose of 20 mg for NVAF. Among the 15 most frequently dispensed drug classes at the index date in NVAF patients with obesity and polypharmacy (≥ 5 medications), those with the highest proportion of dispensing were beta-blockers, antihypertensives, and antihyperlipidemics (Table S3). For polypharmacy patients with 5–9 and ≥ 10 medications, the weighted rivaroxaban and warfarin cohorts were well balanced with respect to baseline characteristics and comorbidities (i.e., std. diff. < 10%; see Table S4 and Table S5).

Table 1 Baseline demographic and clinical characteristics of NVAF patients with obesity and polypharmacy (≥ 5 medications)—rivaroxaban and warfarin cohorts
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Table 2 Baseline comorbidities of NVAF patients with obesity and polypharmacy (≥ 5 medications)—rivaroxaban and warfarin cohorts
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Risk of Stroke and Systemic Embolism

In the overall polypharmacy cohort, patients treated with rivaroxaban had a significantly lower risk of stroke/SE at all time points post-index (Fig. 2). At 36 months of follow-up, rivaroxaban was associated with a 29% lower risk of stroke/SE compared to warfarin (HR 0.71, 95% CI 0.57, 0.90, p = 0.004; Fig. 2). Moreover, the risk of stroke (i.e., ischemic stroke and hemorrhagic stroke) and hemorrhagic stroke were significantly lower with rivaroxaban compared to warfarin at all time points post-index (Table S6). The risk of ischemic stroke was significantly lower with rivaroxaban compared to warfarin at 24 months of follow-up (HR 0.75, 95% CI 0.57, 0.99, p = 0.044; Table S6).

Fig. 2
figure 2

Kaplan-Meier rates of stroke/SE1: NVAF patients with obesity and polypharmacy (≥ 5 medications)—rivaroxaban vs. warfarin (intention-to-treat analysis). CI confidence interval, SE systemic embolism. Notes: (1) Defined as a primary diagnosis of ischemic stroke, hemorrhagic stroke, or SE during a hospitalization or emergency. (2) Number of patients still observed at the specific point in time

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Results of an on-treatment sensitivity analysis were consistent with the ITT findings. In particular, patients treated with rivaroxaban had a significantly lower risk of stroke/SE compared to those treated with warfarin at 12 months (HR 0.58, 95% CI 0.42, 0.80, p < 0.001), 24 months (HR 0.59, 95% CI 0.44, 0.80, p < 0.001), and 36 months (HR: 0.63, 95% CI 0.48, 0.84, p = 0.002).

Risk of Major Bleeding

In the overall polypharmacy cohort, risk of major bleeding was numerically but not significantly lower among rivaroxaban- compared to warfarin-treated patients at 36 months of follow-up (HR 0.85, 95% CI 0.70, 1.03, p = 0.089; Fig. 3). Similarly, there was no significant difference in the risk of major bleeding among rivaroxaban- compared to warfarin-treated patients at 12 months (HR 0.95, 95% CI 0.76, 1.18, p = 0.623) and 24 months (HR 0.89, 95% CI 0.73, 1.03, p = 0.259).

Fig. 3
figure 3

Kaplan-Meier rates of major bleeding: NVAF patients with obesity and polypharmacy (≥ 5 medications)—rivaroxaban vs. warfarin (on-treatment analysis). CI confidence interval. Notes: (1) Major bleeding was defined using the Cunningham algorithm, which identifies hospitalizations with diagnoses and procedures indicating an episode of bleeding (excluding bleeding due to major trauma). (2) Number of patients still observed at the specific point in time

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Polypharmacy with 5–9 Medications and 10 + Medications

In the subgroup analysis of patients with 5–9 medications, rivaroxaban was associated with a significantly lower risk of stroke/SE compared to warfarin at all time points post-index (Table 3). At 36 months of follow-up, patients with 5–9 medications initiated on rivaroxaban had a 31% lower risk of stroke/SE compared to those initiated on warfarin at 36 months (HR 0.69, 95% CI 0.52, 0.92, p = 0.011), Table 3). In the subgroup analysis of patients with ≥ 10 medications, the risk of stroke/SE was numerically in favor of rivaroxaban- compared to warfarin-treated patients at all time points post-index; however, these differences did not attain statistical significance, which may reflect a lack of power due to low sample sizes (Table 3). Stroke (i.e., ischemic stroke and hemorrhagic stroke) and hemorrhagic stroke outcomes are reported in Table S7.

Table 3 Time to first stroke/SE: NVAF patients with obesity and polypharmacy stratified by polypharmacy subgroup—rivaroxaban vs. warfarin (intention-to-treat analysis)
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In the subgroup with 5–9 medications, the risk of major bleeding was significantly lower among rivaroxaban-treated patients at 36 months of follow-up (HR 0.75, 95% CI 0.58, 0.96, p = 0.023). Risk of major bleeding was numerically but not significantly lower in rivaroxaban- compared to warfarin-treated patients at 12 months (HR 0.82, 95% CI 0.62, 1.10, p = 0.184) and 24 months (HR 0.78, 95% CI 0.60, 1.01, p = 0.062; Table 4). In the subgroup with ≥ 10 medications, the risk of major bleeding was comparable between rivaroxaban- and warfarin-treated patients (Table 4).

Table 4 Time to first major bleeding: NVAF patients with obesity and polypharmacy stratified by polypharmacy subgroup—rivaroxaban vs. warfarin (on-treatment analysis)
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Discussion

This retrospective weighted-cohort study evaluated the comparative effectiveness and safety of rivaroxaban and warfarin among NVAF patients with obesity and polypharmacy in the US population. Rivaroxaban was associated with a significantly lower risk of stroke/SE in this population at 36 months of follow-up, whereas risk of major bleeding was numerically but not significantly lower compared to warfarin. Subgroup analyses stratified by polypharmacy level (5–9 or ≥ 10 medications) yielded results that were largely consistent with the overall polypharmacy analysis. The present findings support our initial hypothesis that rivaroxaban is a viable treatment option among complex NVAF patients with obesity and polypharmacy and shows long-term incremental benefits when compared to warfarin. A further strength of the present study is its focus on a commercially-insured cohort of younger patients who are distinct from the general AF population but significantly impacted by obesity as a risk factor [13].

The current study expands upon previous research regarding the impact of anticoagulants among NVAF patients with obesity. Prior evidence has suggested that rivaroxaban and warfarin have comparable safety and effectiveness among NVAF patients with obesity [25, 27, 29, 31]. However, more recent findings indicate that rivaroxaban may be more effective compared to warfarin in this population [28, 30]. In a study by the present authors evaluating patients with NVAF and obesity [30], rivaroxaban was associated with a 26% lower risk of stroke/SE (HR 0.74, 95% CI 0.60, 0.91) with no significant difference in the risk of major bleeding compared to warfarin (HR 0.85, 95% CI 0.71, 1.02). The current study corroborates these findings, suggesting that rivaroxaban remains safe and effective in this population despite the use of multiple concurrent medications. Costa et al.[28] analyzed electronic health record data of NVAF patients with obesity and found that rivaroxaban-treated patients had a 17% and 18% lower risk of stroke/SE (HR 0.83, 95% CI 0.73, 0.94) and major bleeding (HR 0.82, 95% CI 0.75, 0.89) compared with warfarin-treated patients, respectively. Consistent with this, rivaroxaban was associated with a significantly lower risk of stroke/SE and major bleeding in the subgroup with 5–9 medications in the present study.

The present findings also add to a growing body of evidence showing that rivaroxaban is safe and effective across complex patients with polypharmacy, irrespective of body weight [37, 44, 46]. In an analysis of the ROCKET AF clinical trial population by Piccini et al. [44], there was no difference in stroke and bleeding outcomes between rivaroxaban- and warfarin-treated patients according to the number of concurrent medications, particularly among those with higher polypharmacy use (i.e., 5–9 and ≥ 10 medications). In the superiority analysis of the ROCKET AF trial population by Patel et al. [27], rivaroxaban had a similar efficacy profile in reducing stroke/SE with a lower risk of intracranial hemorrhage compared to warfarin, whereas the present study observed lower rates of stroke/SE and comparable rates of major bleeding with rivaroxaban. In the present study, hemorrhagic stroke was included in the definition of a major bleeding event and also comprised intracranial hemorrhage. The results of our analysis show that risk of hemorrhagic stroke was significantly reduced among patients treated with rivaroxaban compared to those treated with warfarin. Differences between the present study findings and those obtained in the ROCKET AF trial population may partly reflect distinct patient characteristics, since the latter population was of older age (median 73 years) with normal BMI (median ~ 28 kg/m2) [27, 44]. While the present study included patients with a broad range of risk for stroke/SE, the ROCKET AF trial selected for patients with moderate-to-high risk of stroke, 90% of whom were required to have had a previous ischemic stroke, transient ischemic attack, or SE and two or more risk factors [27, 44].

Subsequent observational studies, including the present study, further suggest that rivaroxaban is a safe and effective option among patients with polypharmacy [37, 46]. In a recent retrospective study by Mentias et al. [46], the comparative effectiveness and safety of oral anticoagulants was evaluated in Medicare patients aged ≥ 65 with low, moderate, or high polypharmacy (i.e., ≤ 3, 4–8, or ≥ 9 other prescription medications, respectively). Overall, the risk of ischemic stroke and bleeding was similar for rivaroxaban compared to warfarin across polypharmacy levels [46]. A retrospective study by Martinez et al.[37] evaluated the safety and effectiveness of rivaroxaban and warfarin among polypharmacy users (≥ 5 or ≥ 10 medications) based on a data source encompassing a mix of commercial, Medicare, and Medicaid insurance plans. Consistent with the present study, rivaroxaban was associated with a significantly lower risk of stroke/SE among patients with ≥ 5 medications, while the difference did not attain statistical significance for patients with ≥ 10 medications. Rivaroxaban and warfarin were associated with a similar risk of major bleeding in both polypharmacy subgroups in this study [37].

The present study findings are clinically relevant for several reasons. First, the high polypharmacy burden associated with NVAF may translate into poor clinical outcomes [51], including an increased risk of major bleeding [34, 44]. Second, the most common multi-drug combinations in the US are for comorbidities and complications related to obesity, including cardiometablic syndrome [36, 38]. Taken together, NVAF patients with obesity and polypharmacy represent a population with a particularly high unmet need for safe and effective treatments. In the present study, the use of multiple medications did not appear to compromise the safety and effectiveness of rivaroxaban in this population. Given the challenges associated with managing complex patients with multimorbidity and polypharmacy [51], these findings may help to inform future treatment decisions. Although polypharmacy is highly prevalent among elderly patients with AF [34], recent evidence suggests that it may increase the risk of adverse clinical outcomes independent of age [52]. Nonetheless, the majority of prior studies evaluating clinical outcomes among rivaroxaban and warfarin users with polypharmacy relied on data from older populations (i.e., median ≥ 70 years) [37, 44, 46]. The present study thus builds on these previous findings by documenting the benefits of rivaroxaban in relatively young patients with commercial insurance plans.

The present study should be viewed in the context of certain limitations. Obesity was classified based on ICD diagnosis codes for high BMI and not a patient’s actual BMI value. Since height and weight are not available in claims data, it is possible that some patients with obesity were not captured in this analysis. Previous validation studies have shown that diagnostic obesity codes may underestimate the true prevalence of obesity. However, given the high specificity and modest to high PPV, obese patients can be identified using diagnosis codes [47, 53,54,55]. The present study may have been subject to additional limitations commonly associated with retrospective claims analyses, including coding inaccuracies that may lead to misidentification and the lack of availability of certain prescription-related information (i.e., medications administered in inpatient settings and over-the-counter medications). Despite the use of IPTW, the present study results may have also been influenced by unmeasured confounders not available in claims databases. Finally, the present study population was broadly representative of patients with commercial insurance in the US; therefore, the results may not be generalizable to other populations.

Conclusion

In this real-world study of NVAF patients with obesity and polypharmacy in the US, rivaroxaban was associated with a significantly lower risk of stroke/SE and a similar risk of major bleeding compared to warfarin over a 36-month follow-up period. This pattern of results remained consistent in the subgroup analyses of patients with 5–9 and ≥ 10 medications. Overall, the present findings suggest that rivaroxaban is a safe and effective treatment with long-term benefits compared to warfarin among complex NVAF patients with obesity and polypharmacy in a commercially-insured US population.