Compliance and Persistence With Concomitant Statin and Oral Antihyperglycemic Therapy

Objectives:

To compare compliance and persistence with statin and oral antihyperglycemic therapies in patients with type 2 diabetes who received concomitant therapy.

Study Design:

Retrospective cohort study using a large US commercial claims database.

Methods:

Patients with type 2 diabetes and dispensed prescriptions for both statin and oral antihyperglycemic therapies on the same date in 2006 (index date = first date of such dispensing) were included in the analysis (N = 52,414). Patients were required to have continuous enrollment in the database for 1 year prior to (baseline) and 2 years after (follow-up) index date. The 2-year medication possession ratio (MPR) was compared between statin and oral antihyperglycemic therapy. For the persistence analysis, treatment discontinuation was defined by a gap >30 days between the last date of supply from previous dispensing and subsequent refill. The likelihood of discontinuation of statin versus oral antihyperglycemic therapy was estimated by fitting a robust Cox proportional hazards regression model, adjusted for baseline variables.

Results:

The 2-year MPR was 70% for statin and 78% for oral antihyperglycemic therapy (P <.0001). The proportion of patients with a 2-year MPR >80% was 52% for statin and 63% for oral antihyperglycemic therapy (P <.0001). The median time to discontinuation of statin was significantly shorter compared with oral antihyperglycemic therapy (284 vs 495 days, P <.001). There was a greater risk to discontinue statin than oral antihyperglycemic therapy (adjusted hazard ratio: 1.47 [95% confidence interval 1.45-1.48]).

Conclusions:

Compliance and persistence with statin therapy significantly lagged behind oral antihyperglycemic therapy in patients with type 2 diabetes who were treated concomitantly with both therapies.

(Am J Manag Care. 2011;17(11):746-752)

• In patients with type 2 diabetes who received concomitant treatment with statin therapy and oral antihyperglycemic therapy, compliance and persistence were significantly lower with statin therapy compared with oral antihyperglycemic therapy.

• Integrative approaches to improve compliance and persistence with these agents may reduce cardiovascular risks and improve clinical outcomes in this population.

Patients with type 2 diabetes are at an increased risk for microvascular and macrovascular complications and mortality.^1-3 Statins are recommended for patients with type 2 diabetes, regardless of low-density lipoprotein (LDL)-cholesterol levels, to reduce their elevated cardiovascular risk.^4,5 Improvement in glycemic control, including the use of antihyperglycemic therapies, reduces the risk of microvascular outcomes in patients with type 2 diabetes.^6-8 Despite the clinical benefits of these agents for diabetes related vascular complications, many patients are not at recommended cholesterol and glycemic treatment targets and the use of statins and antihyperglycemic agents is suboptimal.^9-12 Moreover, compliance (or adherence) and persistence are important factors for effective lipid and glycemic control.^13,14 Importantly, nonadherence to statins and antihyperglycemic agents has been shown to be associated with an increased risk for hospitalization and mortality, as well as increased costs, in patients with type 2 diabetes.^15-20

Adherence and persistence with statin and antihyperglycemic treatments ranges from 36% to 93%.^15,21-25 Previous studies on estimates of compliance (or adherence) and persistence mainly focus on individual drug classes across patient cohorts, and estimates have not been published, to date, for concomitant use of statin and antihyperglycemic therapy. Given that statin therapy is recommended for patients with type 2 diabetes, it was of interest to assess the compliance (ie, act of conforming to the recommendations of the provider for the prescribed therapy²⁶) and persistence (ie, act of continuing a treatment for a prescribed duration²⁶) with statin and oral antihyperglycemic agents in patients with type 2 diabetes who received these therapies concomitantly. Therefore, using a large US claims database, the present study compared compliance and persistence with statin and oral antihyperglycemic therapies in patients with type 2 diabetes who received concomitant therapy.

METHODS

Data Source

Data for this analysis are from a large US commercial claims database (Thomson Reuters MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database). The commercial database contains de-identified, personspecific health data including clinical utilization, expenditures, insurance enrollment/plan benefit, inpatient, outpatient, and outpatient prescription information. The data cover more than 20 million individuals annually, and include private sector health data from approximately 100 payers. The data can be linked to track detailed patient information across sites and types of providers, and over time. The supplemental database provides similar data for retirees with Medicare supplemental insurance paid for by large employers.

Study Design and Patient Selection

In a retrospective cohort study, patients with type 2 diabetes and 18 years and older were eligible if they were dispensed prescriptions for both a statin and any oral antihyperglycemic agent on the same date in 2006. The same date was used in order to have a similar starting point for each patient. Patients

with type 2 diabetes were identified by The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9- CM) diagnosis codes (250.x2). The first date in 2006 of such dispensing was considered the index date. Patients needed to have medical records for at least 1 year prior to (baseline) and 2 years after (follow-up) the index date. Patients with type 1 diabetes or secondary diabetes or pregnant women were excluded. Patients on only injectable antihyperglycemic agents were excluded from the analysis. Insulin was not included because comparisons between oral and injectable agents are difficult. Persistency measures may vary substantially with insulin compared with oral antihyperglycemic agents because patients may have severe adverse events if they stop their insulin. Furthermore, insulin prescription refill is variable because of constant dose adjustments to maintain glucose control. Exenatide, a glucagon-like peptide-1 agonist, was relatively new to the diabetes market in 2006 and thus would not have had a meaningful impact on the overall findings.

End Points

Statin and oral antihyperglycemic therapy utilization were assessed as separate entities for each patient. The follow-up period was censored at the end of 2 years. Compliance was estimated as the medication possession ratio (MPR) over 2 years (MPR = total days of supplies of medicine dispensed during the 2-year follow-up/730 days). The proportion of patients with an MPR of at least 80% was calculated.^27,28 A sensitivity analysis was conducted for compliance using a 1-year followup period. To control for different therapy start dates, compliance was also assessed in a subgroup of patients who had their first prescriptions (ie, new to both treatments) for statin and oral antihyperglycemic therapy on the same date in 2006.

For the persistence analysis, treatment discontinuation was defined as a gap of at least 30 days between the last date of supply from previous dispensing and the subsequent refill. A switch in the type of statin or oral antihyperglycemic agent was not considered a nonpersistent event as long as there was not a gap of at least 30 days. Persistence was also assessed using a minimum of 60- and 90-day gaps to define treatment discontinuation because down-titration or dose-splitting may have increased the time between prescription refills.

Statistical Analyses

Overall MPR and the proportion of patients with an MPR of at least 80% were compared between statin and oral antihyperglycemic therapies. Discontinuation and time to discontinuation were estimated and compared between therapies. The likelihood of discontinuation of statin versus oral antihyperglycemic therapy was estimated by fitting a robust Cox proportional hazards regression model, adjusted for patient characteristics and comorbidities at baseline. ICD-9-CM and Current Procedural Terminology (CPT) codes were used to determine comorbid disease conditions.

RESULTS

In total, 52,414 patients with type 2 diabetes met the inclusion criteria. The mean age of the cohort was 62 years, 54% were men, 23% had preexisting cardiovascular conditions, and 14% had preexisting microvascular conditions (Table 1). Based on the study design, there were 4 treatment scenarios in terms of the timing of statin and oral antihyperglycemic therapies on the index date: 1) existing statin existing oral antihyperglycemic agent users (68.3% of entire cohort); 2) new statin new oral antihyperglycemic agent users (9.5%); 3) new statin existing oral antihyperglycemic agent users (15.7%); and 4) existing statin new oral antihyperglycemic agent users (6.5%). The patients in this new new users cohort were generally younger and had fewer preexisting comorbid conditions relative to the overall cohort (data not shown).

Table 2

Overall compliance, assessed using MPR, was significantly lower (P <.0001) with statin therapy compared with oral antihyperglycemic therapy after 2 years of follow-up (). The proportion of patients with MPR of at least 80% after 2 years was significantly lower (P <.0001) with statin than with oral antihyperglycemic therapy (Table 2). In an analysis focused on compliance to concomitant therapy with a statin and oral antihyperglycemic therapy, the proportion of patients with an MPR of at least 80% for both therapies after 2 years was 43%. In sensitivity analyses, the between-treatment difference in MPR results after 1 year was generally consistent with the 2-year results (Table 2).

In an analysis focused on the cohort which initiated both statin and oral antihyperglycemic therapy for the first time on the same date in 2006, MPR values were generally lower compared with the entire cohort, and the difference between statin and oral antihyperglycemic therapy was significant (Table 2). Between-treatment differences were generally consistent after 1 and 2 years of follow-up in this cohort (Table 2).

Figure

The median time to discontinuation for statin therapy was significantly shorter (284 days [95% confidence interval (CI) 280-289] vs 495 days [484-505]; P<.0001) compared with oral antihyperglycemic therapy (). A lower proportion of patients was persistent (ie, no treatment gaps >30 days) with statin therapy (28%) than with oral antihyperglycemic therapy (41%) over the 2-year period. In sensitivity analyses using no treatment gaps of a minimum of 60 or 90 days, the overall trend in persistency for both classes was numerically higher compared with the gap of at least 30 days, but the between-treatment difference remained significant (data not shown).

In a robust Cox proportional hazards regression model controlling for baseline characteristics and comorbid conditions, patients were at a greater risk (hazard ratio [HR] = 1.47 [95% CI 1.45-1.48]) to discontinue statin therapy during follow-up compared with oral antihyperglycemic therapy (Table 3). All subgroups of younger patients had a greater risk to discontinue either therapy relative to patients aged at least 65 years. Patients from urban areas and those with preexisting heart failure were at a greater risk to discontinue either therapy. Males, patients with health maintenance organization and preferred provider organization insurance plans, and those with preexisting microvascular conditions had a lower risk of discontinuing therapy (Table 3). Similar trends were found among patients in 3 of the 4 treatment scenarios, which accounted for 93.5% of the entire study cohort: cohort of new statin new oral antihyperglycemic agent users (HR for statin discontinuation = 1.18; [95% CI 1.14-1.21]), cohort of new statin existing oral antihyperglycemic agent users (HR = 1.89 [1.84-1.94]), and cohort of existing users for both statin and oral antihyperglycemic agent (HR = 1.50 [1.48-1.53]). In contrast, statin therapy was slightly less likely to be discontinued (HR = 0.94 [95% CI 0.90-0.98]) in the cohort of existing statin new oral antihyperglycemic agent users (6.5% of the entire cohort).

DISCUSSION

Type 2 diabetes is a chronic condition that requires longterm lifestyle and pharmacologic interventions. Antihyperglycemic agents and statins are among the recommende therapies to reduce the increased risk of vascular events in patients with type 2 diabetes.^4,5 Clinical outcomes are affected by both adherence and persistence.²⁹

The present retrospective database analysis was the first to estimate compliance and persistence to concomitant therapy with statin therapy and oral antihyperglycemic agents in a large cohort of patients with type 2 diabetes. After 2 years, only 43% of patients were compliant (ie, MPR >80%) with both statin and oral antihyperglycemic treatments. Patients were more compliant with their oral antihyperglycemic treatment than their statin therapy over this time frame. In a multivariate analysis controlling for baseline variables and comorbid conditions, patients had an approximately 50% increase in risk of discontinuing their statin therapy relative to their oral antihyperglycemic agent. Furthermore, persistence over 2 years was greater with oral antihyperglycemic treatment (41%) than with statin therapy (28%), although both rates were low in these patients.

Multiple sensitivity analyses were consistent with the primary findings. Shorter-term follow-up (1 year) and wider treatment gaps (>60 or >90 days) to define discontinuation revealed, as expected, higher rates for compliance or persistence in both treatment classes, but the differences between statin and oral antihyperglycemic therapy were still apparent. To control for different therapy start dates, a cohort of patients who received their first prescriptions for both statin and oral antihyperglycemic therapies on the same date in 2006 was selected. Interestingly, the MPR values for statin and oral antihyperglycemic therapies tended to be lower ithis sub-cohort relative to the entire cohort. Nonetheless, compliance was still greater for the oral antihyperglycemic therapy. In contrast, in the cohort with existing statin new oral antihyperglycemic agent users, patients were less likely to discontinue statin therapy than oral antihyperglycemic therapy. Possible reasons include that this population inherently selected for patients who were compliant to statin therapy may not have experienced any major statin-related side effects or patients who newly initiated oral antihyperglycemic therapy may have experienced side effects (eg, hypoglycemia), both of which may have impacted discontinuation rates. Findings in 3 of the 4 treatment scenarios comprising 93.5% of the entire cohort were consistent with the overall findings.

To date there is limited information on the compliance (or adherence) and persistence of concomitant therapy. In a retrospective cohort analysis, Chapman et al³⁰ found that patients receiving concomitant treatment were more adherent with their antihypertensive agent (58%) than with their statin (43%). In contrast to the present findings, concurrent use of antihyperglycemic therapy did not influence statin adherence in a smaller cohort (12% of 5488 patients had diabetes) from a single health insurance plan.³¹ Estimates for adherence tend to be lower for statins relative to antihyperglycemic agents in most^15,22-25 but not all¹⁷ cross-sectional, retrospective analyses. After 1 year, persistence using a 60-day treatment gap to define discontinuation was higher with oral antihyperglycemic agents (54%) compared with statins (43%).²² Furthermore, a recent meta-analysis observed that a diagnosis of diabetes (and presumably treatment with antihyperglycemic therapy) was associated with better adherence to statin therapy.³² Collectively, these results suggest greater compliance (or adherence) and persistence with antihyperglycemic therapy relative to statins.

There are potential reasons for better compliance with oral antihyperglycemic agents relative to statins. There are symptoms associated with hyperglycemia and hypoglycemia, whereas elevated cholesterol is generally asymptomatic.^4,33 Patients with type 2 diabetes are more likely to discuss management of their diabetes as compared with other cardiovascular risk factors³⁴ and to have their glucose levels assessed more often than lipids at office visits.³⁵ Patients with type 2 diabetes understand that elevated blood glucose is a central feature of their condition and the target for disease management.Patients with type 2 diabetes have greater awareness of diabetes-related microvascular complications (eg, amputations, blindness) than macrovascular-related complications (myocardial infarction).³⁴ Patients may perceive that statins are used only to lower cholesterol and not to reduce cardiovascular risks.¹⁴ However, total cholesterol and LDL-cholesterol levels are generally similar if not lower in patients with type 2 diabetes compared with those without diabetes,³⁶ and thus lipids may not be perceived as an issue for their care. Lastly, a treatment gap may exist where management of diabetes is focused on glucose control (“glucocentric”) to the detriment of other cardiovascular risk factors.^12,34,37

Single-pill formulations or fixed-dose combination therapies have been shown to improve adherence by reducing pill burden, regimen complexity, and costs.^38-41 Recently, patients taking a single-pill formulation of the antihypertensive agent amlodipine and the statin atorvastatin were found to adhere more to their therapy compared with patients adding a statin to their amlodipine regimen.⁴² A similar approach with a single- pill formulation, including a statin and an oral antihyperglycemic agent, could be used to improve statin compliance in patients with type 2 diabetes.

The strengths of this study include the population cohort design, large sample size, length of follow-up period, confirmatory sensitivity analyses, and detailed prescription records. The following limitations need to be considered when interpreting the results. Compliance and persistence were based on pharmacy dispensing claim records and not actual use of the therapies. Continued filling of prescriptions over time could be interpreted as continuous use of the agents; however, from a database study, it cannot be known for certain that patients actually took the medication. Information on adverse experiences, intercurrent illness, and laboratory measurements was not available, and thus discontinuation or disruptions in therapy related to these issues could not be assessed. Physicians may have advised their patients to discontinue or alter the dose of the drugs. This information was not provided in the medical and pharmacy claims data. Patients who discontinued statin therapy may have been switched to another lipid-modifying therapy (eg, fibrates, cholesterol absorption inhibitor). Patients who discontinued oral antihyperglycemic therapy may have been switched to an injectable antihyperglycemic agent (eg, insulin or exenatide). These switches in therapy would lead to an underestimation of compliance and persistence overall. However, statins are the leading therapeutic class for treating dyslipidemia, and oral antihyperglycemic agents are used more frequently than injectable agents for a majority of patients with type 2 diabetes. Therefore, the measurements of compliance and persistence to lipid or antihyperglycemic therapy should be minimally impacted by excluding the use of non-statin lipid therapy or injectable antihyperglycemic therapy in the analyses.

In conclusion, overall compliance and persistence were generally low for both statin and oral antihyperglycemic therapy over 2 years. However, compliance and persistence were significantly lower with statin therapy compared with oral antihyperglycemic therapy in patients with type 2 diabetes who received concomitant treatment with these agents. Integrative approaches to improve compliance (or adherence) and persistence with these agents may reduce vascular risks and improve clinical outcomes in this population.

Acknowledgments

The analysis was sponsored by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ.

Author Affiliations: From Global Health Outcomes (QZ, CZ, LR), Global Medical and Scientific Publications (MJD), Merck Sharp & Dohme Corp, Whitehouse Station, NJ; Clinical Research (TS), Merck Sharp & Dohme Corp, Rahway, NJ.

Funding Source: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ.

Author Disclosures: All authors (QZ, CZ, MJD, LR, TS) are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, manufacturer of cholesterol and diabetes medicines, and all hold stock options in the company.

Authorship Information: Concept and design (QZ, CZ, MJD, LR, TS); acquisition of data (CZ); analysis and interpretation of data (QZ, CZ, MJD, LR, TS); drafting of the manuscript (MJD, QZ); critical revision of the manuscript for important intellectual content (LR, CZ, TS); statistical analysis (CZ); obtaining funding (QZ); and administrative, technical, or logistic support (QZ, LR).

Address correspondence to: Qiaoyi Zhang, MD, PhD, Global Health Outcomes, Merck Sharp & Dohme Corp, WS2E85, 1 Merck Dr, Whitehouse Station, NJ 08889. E-mail: qiaoyi_zhang@merck.com.

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