Effects of Once-Daily and Twice-Daily Dosing on Adherence with prescribed Glipizide Oral Therapy for Type 2 Diabetes.

ABSTRACT

Background. We evaluated differences in adherence and persistence with prescribed therapy of once-daily (OD) dosing compared with twice-daily (BID) dosing of glipizide in patients with type 2 diabetes.

Methods. The study cohort was derived from a pharmacy benefit manager claims database. Patients new to extended-release gastrointestinal therapeutic system (GITS) and immediate-release glipizide therapy were identified and followed for 1 year. Adherence indices (AIs) were calculated and persistence curves were constructed.

Results. Adherence indices rates were 60.5% in the GITS OD cohort and 52.0% in the BID cohort. Rates of persistence at 12 months were 44.4% in the GITS OD cohort vs 35.8% in the BID cohort.

Conclusion. Initiation of OD pharmacotherapy results in better adherence and persistence compared with a BID regimen, despite a greater daily pill burden in the OD cohort. These data suggest that dosing frequency exerts a greater impact on patient adherence and persistence than number of tablets per dose.

NONADHERENCE to prescribed therapy continues to be a major challenge to the health care system. In the United States, the economic consequences are estimated at $100 billion per year, 30% of which is indirect medical costs. (1) Studies suggest that regimen complexity is an important determinant of nonadherence. (2) Complicated dosing regimens hamper adherence, especially if multiple dosing of multiple drugs is involved? (3) Previous studies, with intervals ranging from 12 weeks to 5 months, have indicated an adherence benefit over the short term of once-daily (OD) dosing versus twice-daily (BID), three-times-daily, and four-times-daily dosing. (4,5) Cramer et al (4) examined a total of 15 patients in the OD and BID categories, and Detry et al (5) examined 104 patients overall. Pullar et al (6) found greater adherence on an OD regimen (n = 52) but not much better than BID (n = 54); however, these patients with diabetes were followed for 28 days using phenobarbital as a pharmacologic indicator of compliance. An interesting review of adherence among health care professionals by Corda et al (7) revealed a statistically significant advantage achieved through OD dosing (88% adherence) compared with BID (74% adherence) in both the short term and the long term. This may indicate the upper limit of adherence, given the nature of the participants and the use of a self-administered survey for data collection. In a recent Scottish study of 2,920 patients receiving oral hypoglycemic drugs for type 2 diabetes, Morris et al (8) established a highly significant and independent association of an improved adherence index (AI) with OD sulfonylurea dosing and an observed decrease in adherence of 22% for each increase in the frequency of the daily dose over 12 months.

Our research sought to examine the relationship between patient adherence and persistence with therapy patterns using an OD oral antidiabetic extended-release formulation glipizide gastrointestinal therapeutic system (GITS) and a BID oral antidiabetic immediate-release formulation glipizide, and examine whether the dosage frequency or number of tablets per dose influenced the adherence patterns. The goal of the study is to quantify the impact of regimen complexity on adherence in cohorts with type 2 diabetes.

METHODS

This retrospective database analysis used claims from a national pharmacy benefit manager organization. Members included in the analysis were naive to glipizide or glipizide GITS therapy during the period between July 1997 and March 2000, and they were continuously enrolled during the 12-month review period. A 6-month washout period before the review period was used to identify naive patients, thus requiring a minimum eligibility period of 18 months. The date of the first glipizide or glipizide GITS prescription was the index date, from which each patient was followed for 360 days.

Outcome measures evaluated in this study included AI and persistence with therapy. The AI, designed not to exceed 100%, was defined as the cumulative number of days for which the drug was supplied divided by the number of days in the observation period (8); for example, patients with a 180-day drug supply lasting for 360 days would have an Al of 50%. Patients were identified as persistent as long as they refilled the prescription within 60 days of the end of the supply of the previous prescription and were followed for 1 year; however, they were only given credit for the actual number of days of supply from the last prescription when determining the end of persistent therapy. Constructed curves indicating the percentage of patients remaining on therapy each month introduced chronology into the adherence assessment. (9) We defined BID as more than 15 mg (99.6% on 20 mg dosing) and two pills per day for all glipizide prescriptions. By limiting the patient cohort to those receiving more than the 15 mg dose, we a ssume a BID regimen as recommended by the labeling approved by the Food and Drug Administration. (10) The same dosage requirement (more than 15 mg) was set for the glipizide GITS OD cohort and the mean starting number of pills was determined. A random sample of 1,000 glipizide GITS OD patients and 304 glipizide BID patients were identified for inclusion into the study. Patients who were recognized as switching to glyburide, an alternative sulfonylurea, were excluded from the analysis. This yielded sample sizes of 746 for the OD cohort and 246 for the BID cohort. Proportions were compared using the Z statistic to determine the statistical significance of the differences observed. The Student's t test was used to compare the differences in age.

RESULTS

Study Population Characteristics

The demographic characteristics of all 992 patients who met the eligibility criteria are shown in Table 1. The twice-daily group was older and had a significantly greater propordon of male subjects relative to the OD group.

Outcome Measures

The AI for the OD cohort was an absolute 8.5% higher (P = .027) (17% relative difference) than the BID cohort (Table 2), despite the GD cohort exhibiting a greater number of mean pills per day (P < .001). Patients on the OD regimen also exhibited a higher degree of persistence with therapy at 12 months. The persistence rate (those remaining on therapy within the set parameters) of the OD group at 12 months was an absolute 8.7% higher (24% relative difference) than that of the BID cohort (Figure). There were no significant differences in overall adherence by sex, with Ms of 56.3% for males and 52.4% for females (P= .218).

To determine if patient age influenced adherence, patients were stratified into three age groups: less than 40, 40 to 60, and more than 60 years old. Patients over age 60 had significantly (P = .03) higher Ms compared with those under age 40, and the group age 40 to 60 also had significantly (P = .005) higher Ms compared with the group less than 40 years old (Table 3). Stratifying by age and sex (Table 4) revealed tendencies toward higher Ms for the OD cohort compared with the BID cohort in every stratum.

DISCUSSION

Corda et al (7) showed a benefit in adherence comparing a long-term BID regimen (76% adherence) to an OD regimen (88% adherence) among health care professionals. While these rates are likely an upper limit, the key distinction is the variance between the two groups. In a previous study, we found adherence benefits in the 20% range for OD venlafaxine extended-release versus BID venlafaxine as well as OD glipizide GITS versus BID glipizide but did not account for dosing as was done in this study. (11) Gur data appear to be consistent with those from Corda et al, (7) suggesting that an increased dosage frequency is associated with poorer adherence. Older age was associated with better adherence. Sex, though not significant, suggested a trend toward better adherence rates in males. It is understood that outside of this observation, there may be little evidence supporting a predictable association between patient characteristics and regimen adherence in chronic illness. (12)

We recognize the inherent limitations of claims-based analysis, especially the assumption that a filled prescription results in ingestion of a full supply of the drug. It would be reasonable to assume, however, that continued refilling of prescriptions is consistent with a willingness to adhere to the prescribed regimen. (9) In the absence of diagnosis information, a prescription for glipizide was presumed to represent a diagnosis of type 2 diabetes (for which it is indicated). Reported differences in Ms and persistence may be conservative estimates in that the BID cohort contains older patients (who exhibited higher degrees of adherence) and have a higher proportion of males (who tend to have higher AIs in this analysis, though the trend was not statistically significant). These results suggest that regimen simplification of an OD (more than 2 pills) regimen compared with a BID (2 pills) regimen yields significant increases in adherence and persistence with therapy. These increases were evidenced despite th e OD cohort exhibiting a greater number of mean pills per day versus the BID cohort. These data suggest that OD versus BID dosing frequency has a greater impact on patient adherence and persistence than number of tablets per dose.

References

(1.) Shorter H: Noncompliance with Medications: An Economic Tragedy with Important Implications for Health Care Reform. Task Force for Compliance Report, 1993

(2.) Gottlieb H: Medication nonadherence: finding solutions to a costly medical problem. Drug Benefit Trends 2000; 12:57-62

(3.) Dezii CM: Medication noncompliance: what is the problem? Managed Care 2000; 9(suppl):7-12

(4.) Cramer JA, Mattson RH, Prevey ML, et al: How often is medication taken as prescribed? JAMA 1989; 261:3273-3277

(5.) Detry J-MR, Block P, DeBacker G, et al: Patient compliance and therapeutic coverage: amlodipine vs nifedipine (slow release) in the treatment of angina pectoris. J Int Med Res 1994; 22:278-286

(6.) Pullar T, Birtwell AJ, Wiles PG, et al: Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily. Clin Pharmacol Ther 1988; 44:540-545

(7.) Corda RS, Burke HB, Horowitz HW: Adherence to prescription medications among medical professionals. South Med J 2000; 93:585-589

(8.) Morris AD, Brennan GM, MacDonald TM, et al: Population based adherence to prescribed medication in type 2 diabetes: a cause for concern (Abstract). Diabetes 2000; 49(suppl 1):307

(9.) Dezii CM: Persistence with drug therapy: a practical approach using administrative claims data. Managed Care 2001; 110:42-45

(10.) Physicians' Desk Reference. Montvale, NJ, Medical Economics Co Inc, 54th Ed, 2000, pp 2345-2347

(11.) Dezii CM, Kawabata H, Tran M: Compliance and persistency benefits achieved by utilizing a once daily extended-release medication vs a twice daily regimen. Value in Health 2000; 13:110

(12.) Christensen AJ: Patient-by-treatment context interaction in chronic disease: a conceptual framework for the study of patient adherence. Psychosom Med 2000; 62:435-443

[Graph omitted]

TABLE 1.

Cohort Demographics

                  Glipizide GITS OD    Glipizide BID        P Value

No.               746                  246
Mean age (years)  54.2 [+ or -] 12.42  56.1 [+ or -] 13.00  .0433
Sex (male)        49%                  57%                  .03
TABLE 2.

Mean Adherence Index (Al)

                Glipizide GITS OD   Glipizide BID   P Value

Mean AI                      60.5%           52.0%     .027
Mean pills/day               2.25            2.00     <.001
TABLE 3.

Adherence Index by Age Stratification

                No.  Adherence Index  P Value

<40 years       107      42.80%        .005
40 to 60 years  575      57.60%
<40 years       107      42.80%        .03
>60 years       310      65.10%
TABLE 4.

Adherence Index by Age Stratification and Sex

                                           Age (years)
                            <40            40 to 60     >60

Glipizide GITS OD male      46.9% (43)     62.9% (219)  69.4% (103)
Glipizide GITS OD female    42.2% (42)     58.0% (219)  64.3% (120)
Glipizide GITS OD overall   44.6% (85)     60.5% (438)  66.7% (223)
Glipizide BID male          39.6% (15)     49.7% (69)   61.9% (58)
Glipizide BID female        28.6% (7)      46.9% (68)   59.9% (29)
Glipizide BID overall       36.1% (22)     48.6% (137)  61.2% (87)
Data are given as AI (No.)


                            Overall Adherence

Glipizide GITS OD male      62.9% (365)
Glipizide GITS OD female    58.3% (381)
Glipizide GITS OD overall   60.5% (746)
Glipizide BID male          53.6% (142)
Glipizide BID female        49.3% (104)
Glipizide BID overall       52.0% (246)
Data are given as AI (No.)

RELATED ARTICLE: KEY POINTS

* Once-daily pharmacotherapy results in higher adherence and persistence with therapy compared with a twice-daily regimen.

* Improved adherence rates may be achieved with a once-daily regimen despite a higher pill burden.

* Methods such as drug regimen simplification should be aggressively sought to improve adherence.