Safety and Effectiveness of Mail Order Pharmacy Use in Diabetes

Julie A. Schmittdiel, PhD; Andrew J. Karter, PhD; Wendy T. Dyer, MS; James Chan, PharmD, PhD; and O. Kenrik Duru, MD, MSHS

Mail order pharmacies are widely used to deliver medications in the United States, with up to one-third of chronic illness medications delivered by mail.1,2 Research suggests a positive association between mail order pharmacy use and greater adherence to diabetes and antihypertensive medications,3-6 and with better low-density lipoprotein cholesterol control.7 These   favorable outcomes may reflect improved access to medications with mail order pharmacy use,8 which may be of particular value to patients with disabilities, time constraints, or limited transportation (Figure).3,8 However, there may be unintended consequences to using mail order pharmacies. When medical offices and pharmacies are in the same location, patients who use mail order pharmacies may be less likely to access preventive care services. This may increase the risk of hospitalizations and emergency department (ED) visits that are sensitive to preventive care quality.9,10 Diabetes patients, who often take multiple medications, may be particularly at risk for exposure to contraindicated medications.11,12 Mail order pharmacy users may miss face-to-face consultations with pharmacists and physicians designed to prevent contraindicated medication use. Finally, many medications require laboratory monitoring to reduce the risk of potential adverse drug events,13 and mail order pharmacy use may inadvertently   reduce the likelihood that such tests are ordered by physicians and completed by patients. The purpose of this study was to examine the relationship between mail order pharmacy use and safety and healthcare outcomes in diabetes patients, and whether effects vary by key patient characteristics.


Study Population and Setting

This study was conducted within Kaiser Permanente Northern California (KPNC), an integrated health system providing  comprehensive medical care to more than 3 million members. We selected subjects from the KPNC Diabetes Registry. The registry, established in 1993, is updated annually by adding patients with diabetes identified from automated databases of pharmacy data,laboratory data, hospitalization records, and outpatient diagnoses.3,14 Study subjects were required to be at least 18 years of age by January 1, 2006, and to have been prescribed a new antiglycemic, antihypertensive, or lipid-lowering medication from January 1 through May 31, 2006. We defined having a new medication as having no history of any medication prescription fill within the same therapeutic drug class within the past 24 months. If patients were prescribed multiple new cardiometabolic medications during this period, the earliest prescription was defined as the index medication. We excluded the small proportion (<5%) of  members who lacked KPNC drug benefits during the study period.

KPNC maintains a mail order pharmacy distribution system in coordination with more than 120 local walk-in KPNC pharmacies located within outpatient clinics and hospitals.3,7 The first fill of a medication is typically at a local KPNC pharmacy and includes a pharmacist consultation. Patients may then refill existing prescriptions either by mail or at any KPNC local pharmacy. Mail delivery of medications with free shipping can be requested by phone or online. While KPNC members also have the option of filling prescriptions at non-KPNC pharmacies, the cost of these fills is not covered by the patient’s pharmacy benefit. Pharmacists are available via telephone to answer medicationrelated questions regardless of the mode of delivery. There is no proscribed days of supply of pills required for mail delivery; KPNC typically dispenses 100-day supplies through both mail order and local pharmacies. Some patients have a financial incentive to use mail order in the form of a lower copayment for the same number of days of supply.  For this analysis, patients were defined as local KPNC pharmacy users if they never used the mail order pharmacy to fill the new index medication in the 12 months after initiation, and as mail order pharmacy users if they filled the index medication at least once via mail during that time frame.

Outcome Variables

All-cause hospitalizations, preventable hospitalizations, all-cause ED use, and preventable ED use were defined as no episodes versus 1 or more episodes in the 3 years after the index medication initiation date. Preventable hospitalizations and preventable ED visits were defined using published and validated lists of encounters that are considered sensitive to primary care access and quality (eg, hospitalizations and ED visits for asthma).9,10,15

Among patients whose index medication was an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or diuretic, we examined whether there was an appropriate potassium or serum creatinine lab test within 30 days after the index date.13,16 These tests monitor for the possibility of electrolyte abnormalities or decreased renal function in patients new to these medications.

Potential for serious medication interaction was defined using a published list of contraindicated medications17 and was operationalized as 2 or more occurrences of overlapping days of supply of contraindicated drugs (eg, anticoagulants and thyroid hormones) for 1 or more days in the 15 months after the index date.

Statistical Analysis

We estimated separate logistic regression models to examine the relationship between mail order pharmacy use and each outcome variable. In each analysis we adjusted for age; sex; race/ethnicity; neighborhood deprivation score calculated with geocoded census socioeconomic data18,19; number of comorbidities; smoking status; use of nonformulary medications, antidepressants, or insulin; whether the index medication was generic or brand name; length of therapy with the index medication; days of supply of the first refill; distance from the patient’s home to their nearest local KPNC pharmacy; and the patient’s KPNC primary outpatient medical facility (operationalized as a series of dichotomous variables). Detailed definitions of these variables have been published previously.3 Patients with missing covariates (n = 85) were excluded from the analysis. Models included interaction terms for mail order use with age, race/ethnicity, and deprivation score to assess whether different groups of patients might be more vulnerable to potential safety concerns when using the mail order pharmacy. Since the age interaction was the only interaction term that was significant, we present the results as adjusted percentages from models stratified by age less than 65 years versus age 65 years or older.

Omitted (unmeasured) variable bias may be of particular concern when studying the impact of mail order pharmacy use on patient safety outcomes. It is possible that patients who used the mail order pharmacy were different from those who did not in ways we were unable to measure (eg, patient motivation). As a sensitivity analysis, we examined the potential impact of unmeasured variables on the relationship between mail order pharmacy use and our outcomes using methods that test the robustness of effect sizes in the presence of confounding.20-22

All analyses were performed using Stata release 10.1 (StataCorp, College Station, Texas). The study protocol was approved by the KPNC Institutional Review Board.


A total of 17,217 diabetes patients met study eligibility criteria. Of these, 5890 (34.2%) used the mail order pharmacy at least once to refill their new cardiometabolic medication during the study period (Table 1). Mail order pharmacy users were more likely to be white (56.7% vs 37.1%; P <.001) and to live in census tracts with higher socioeconomic status (P <.001).

Table 2 shows the adjusted predicted percentages of patients experiencing each outcome, stratified by age. After adjustment for demographic, clinical, and census-block characteristics, patients aged less than 65 years using the mail order pharmacy were less likely to have an all-cause ED visit (33.8% vs 40.2%; P <.001); less likely to have a preventable ED visit (7.7% vs 9.6%; P <.01); and less likely to receive a recommended serum creatinine lab test within 30 days if their index medication was an ACE, ARB, or diuretic (41.2% vs 47.2%; P <.01). Among patients aged 65 or more years, those using mail order were less likely to experience a preventable ED visit (13.4% vs 16.3%; P <.05) and slightly more likely to experience 2 or more occurrences of overlap in days of supply of contraindicated medications (1.1% vs 0.7%; P <.01).

Our sensitivity analysis found that our observed effects of mail order use on ED visits, hospitalizations, and overlapping days of supply of contraindicated medications were very robust to the presence of a hypothetical unmeasured confounder; for example, even an unmeasured confounder strongly related to an outcome such as ED use (assuming a relative risk of 2.0) and prevalent in more than 50% of the mail order pharmacy–using population would not change the relationship seen in our findings.20-22


This is the first study to examine the relationship between mail order pharmacy use and patient safety and utilization outcomes. We found that mail order use was not negatively associated with patient safety outcomes overall, suggesting that mail order use does not serve as a barrier to receiving primary and preventive care services for most patients. Patients aged less than 65 years who used the mail order pharmacy did have slightly lower rates of serum creatinine testing with ACE, ARB, or diuretic use (41.4% vs 47.2%; P <.01). While there was no statistically significant difference in potassium laboratory testing in this group, or for any lab testing in patients aged 65 or more years, our findings suggest that inperson pharmacy refills may increase opportunities for monitoring of persistent medications in settings where laboratories and pharmacies are co-located.

Our study also found that patients aged 65 or more years had slightly higher rates of 2 or more occurrences of overlapping days of supply of contraindicated medications. While these rates were extremely low for both mail order and local pharmacy users (1.1% and 0.7%, respectively), our analysis adds to the evidence suggesting that older patients using multiple medications may require additional monitoring for adverse events.12,13 It is important that pharmacies provide increased access to chronic illness medications while also maintaining appropriate systems for preventing contraindicated medication use.

We found mail order pharmacy use was associated with lower overall ED use in patients aged less than 65 years, as well as lower preventable ED use in patients in all age groups. Previous studies have shown mail order use is associated with greater medication adherence3-6 and low-density lipoprotein cholesterol control.7 Since good medication adherence and cardiovascular disease risk factor control are associated with reduced hospitalizations and better outcomes,23-25 mail order use may lead to lower preventable utilization over time.

Mail order pharmacy services, which are provided at the healthcare delivery system level rather than the physician or practice level, can be considered a structural or system-level intervention for improving access to chronic illness medications.3,7 While this study and others3-7 suggest that using mail order pharmacy services may improve outcomes, our study also suggests that certain patients may be more sensitive to any potential negative impact of mail order pharmacy use on healthcare access. System-level efforts to promote mail order use should preserve patient choice in pharmacy services and maintain a patient-centered approach to meeting an individual’s overall healthcare needs. Future research should continue to address the important issue of how to appropriately target and promote mail order pharmacy services while preserving the benefits of in-person interaction with pharmacists and other care providers.

This study has several limitations. Observational studies cannot entirely control for differences between patients who use mail order pharmacy services and those who do not. While our sensitivity analysis demonstrated that the relationship between mail order pharmacy use and our outcomes would still be observed even in the presence of a powerful, prevalent confounder, future research should leverage randomized controlled trial designs to examine the impact of mail order pharmacy use on intermediate outcomes, healthcare utilization, and patient safety.

We were unable to ascertain pharmacy utilization at non-KPNC pharmacies. However, we limited our analyses to members with a drug benefit, which is only recognized at KPNC pharmacies. This under-ascertainment should be minimal, as previous research suggests that diabetes patients with drug benefits report extremely low use of non-KPNC pharmacies.26

This study was conducted in an integrated delivery system where patients access prescription medications differently than in many other settings. Use of “brick and mortar” pharmacies to fill prescriptions is primarily limited to KPNC local pharmacies; KPNC’s mail order and local pharmacies do not differ in the standard days of supply of pills issued; and mail order pharmacy does not require physician enrollment of the prescription. In addition, KPNC local pharmacies are primarily co-located with medical offices and laboratories, which is often not the case in other settings. This co-location may make any relationship between in-person pharmacy use and preventive care services stronger than in cases where patients obtain in-person refills from brick-and-mortar pharmacies that are not integrated with outpatient care. It is therefore possible that the use of mail order pharmacy services in KPNC has a different impact on outcomes than it would have in other settings.


Mail order pharmacy use is not associated with adverse events in most diabetes patients and may be associated with improved health outcomes. System-level interventions to increase mail order pharmacy use may be an important strategy for improving processes and outcomes of care for patients with chronic illness; however, these interventions should use a patient-centered approach that does not increase risk in older patients and others who may be sensitive to primary and preventive care access.
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