Medication adherence and the associated health-economic impact among patients with type 2 diabetes mellitus converting to insulin pen therapy: an analysis of third-party managed care claims data

OBJECTIVE: This study evaluated the impact on adherence, hypoglycemic events, resource utilization, and the associated health care costs of converting from administration of insulin therapy by a vial/syringe to an insulin analogue pen device in patients with type 2 diabetes mellitus. METHODS: This pre-post analysis used an integrated medical and pharmacy claims database containing information for >40 million covered lives from 57 managed care health plans in the United States. Adults with a diagnosis of type 2 diabetes whose treatment was converted from conventional human or analogue insulin injection (vial/syringe) to a prefilled insulin analogue pen from July 2001 through December 2002, with no use of an insulin analogue pen device in the preceding 6 months, were identified and analyzed retrospectively. The primary end points were adherence (as measured by a medication possession ratio [MPR] > or =80%); the odds ratio (OR) for hypoglycemic events requiring health care resource utilization and resulting in a claim; the association between adherence and hypoglycemic events; and all-cause, hypoglycemia-attributable (HA), and diabetes-attributable (DA) health care costs. RESULTS: A total of 1156 subjects were identified and analyzed (mean [SD] age, 45.4 [13.7] years; 53.8% male; previous insulin vial use: 595 [51.5%] human, 561 [48.5%] analogue). Medication adherence was significantly improved after conversion to the insulin pen device (from 62% to 69%; P < 0.01). The proportion of subjects considered adherent was significantly higher in the period after the conversion compared with before the conversion (54.6% vs 36.1%, respectively; P < 0.01). The likelihood of experiencing a hypoglycemic event was significantly reduced after conversion (OR = 0.50; 95% CI, 0.37-0.68; P < 0.05), and the incidence of hypoglycemia in subjects with an MPR > or =80% decreased by nearly two thirds (incident rate ratio = 0.35; 95% CI, 0.11-0.81; P < 0.05). There were significant decreases in HA emergency department visits (OR = 0.44; 95% CI, 0.21-0.92; P < 0.05) and physician visits (OR = 0.39; 95% CI, 0.24-0.64; P < 0.05), whereas HA-related hospitalizations and outpatient visits remained similar after conversion. Total mean all-cause annual treatment costs were reduced by $1590 per patient (from $16,359 to $14,769; P < 0.01). Annual HA costs were reduced by $788 per patient (from $1415 to $627; P < 0.01), predominantly as a result of decreased hospitalization costs (from $857 to $288; P < 0.01). Annual DA costs were reduced by $600 per patient (from $8827 to $8227; P < 0.01). CONCLUSIONS: Among these patients with type 2 diabetes treated in a managed care setting, a switch from administration of insulin therapy by vial/syringe to a prefilled insulin analogue pen device was associated with improved medication adherence, fewer claims for hypoglycemic events, reduced emergency department and physician visits, and lower annual treatment costs.     

A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus

BACKGROUND: The accuracy and convenience of pen devices for insulin injection have improved quality of life for patients with insulin-treated diabetes mellitus (DM). Prefilled, disposable pens have the advantage of simplicity, with minimal training and attention required and no installation of new cartridges necessary. OBJECTIVE: The aim of this study was to assess patient preference, efficacy, and safety profiles of a prefilled, disposable pen (FlexPen) and conventional vial/syringe injection method for insulin injection therapy among patients with DM. METHODS: In a multicenter, randomized, open-label, crossover study, patients with type 1 or 2 DM were transferred from previous QD or BID conventional insulin therapy to a mixture of 70% insulin aspart protamine suspension and 30% insulin aspart injection (NovoLog Mix 7030) for 4 weeks of dose optimization using their usual type of syringe. Patients were then randomly assigned to use either vial/syringe or a prefilled, disposable pen to inject the biphasic insulin aspart 7030 mixture for the next 4 weeks, followed by 4 weeks of use of the other injection device. Efficacy, safety profiles, and patient preference for the delivery systems were compared. RESULTS: A total of 121 patients (mean [SD] age, 57.0 [12.4] years; age range, 28-81 years; mean [SD] body mass index, 31 [5.5] kg/m(2)) were enrolled. One hundred three patients completed the study. Seventy-four percent of patients (78105) indicated a preference for the pen over the vial/syringe method (95% CI, 71%-87%), compared with 20% (21105) who preferred the vial/syringe. Eighty-five percent (88104) considered the pen more discreet for use in public (compared with 9% [9104] for the vial/syringe), 74% (77104) considered it easier to use overall (compared with 21% [22104] for the vial/syringe), and 85% (89105) found the insulin dose scale on the pen easier to read (compared with 10% [10105] for the vial/syringe). Patients had statistically significant improvement in glycosylated hemoglobin values during the study (P < 0.05). No statistically significant differences in fasting plasma glucose, mean 4-point blood glucose profiles, or serum fructosamine values were found between groups. Overall, the safety profiles during treatment periods with the pen were comparable to those with the vial/syringe. CONCLUSIONS: In this trial, differences in efficacy and safety profiles between the vial/syringe and prefilled, disposable pen appeared negligible. However, more patients expressed a preference to continue use of the pen.     

Needle-Free Jet Injection of Rapid-Acting Insulin Improves Early Postprandial Glucose Control in Patients With Diabetes

OBJECTIVE

Clamp studies have shown that the absorption and action of rapid-acting insulin are faster with injection by a jet injector than with administration by conventional pen. To determine whether these pharmacokinetic changes also exist in patients with diabetes and benefit postprandial glucose control, we compared the pharmacologic profiles of insulin administration by jet injection versus conventional insulin pen after a standardized meal in patients with type 1 or type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a randomized, double-blind, double-dummy crossover study, 12 patients with type 1 diabetes and 12 patients with type 2 diabetes received insulin aspart either by jet injection or by conventional pen, in both cases followed by a standardized meal. Blood was sampled for 6 h for determination of glucose and insulin levels to calculate pharmacologic profiles.

RESULTS

Insulin administration by jet injection resulted in shorter time until peak plasma insulin level (51.3 ± 6.4 vs. 91.9 ± 10.2 min; P = 0.003) and reduced hyperglycemic burden during the first hour (154.3 ± 20.8 vs. 196.3 ± 18.4 mmol · min · L⁻¹; P = 0.041) compared with conventional administration. Jet injection did not, however, significantly reduce the hyperglycemic burden during the 5-h period thereafter. There was no indication that the jet injector performed differently in patients with type 1 and type 2 diabetes.

CONCLUSIONS

The considerably more rapid insulin absorption after administration by jet injector translated to a significant if modest decrease in postprandial hyperglycemia in patients with type 1 and type 2 diabetes. The improved early postprandial glucose control may specifically benefit patients who have difficulty in limiting postprandial glucose excursions.The pharmacologic profile of rapid-acting insulin analogs, although considerably faster than regular insulin, is still relatively slow compared with the profile of endogenous insulin release. As a consequence, patients with type 1 diabetes or insulin-requiring type 2 diabetes who use these analogs still face the risk of immediate postprandial hyperglycemia and late postprandial hypoglycemia. In particular, postprandial hyperglycemia has been recognized as an important contributor to suboptimal glucose control (1), which may explain why the introduction of rapid-acting analogs has had little effect on HbA_1c in people with diabetes (2). Some have therefore suggested that these analogs should be injected at least 15 min before meals (3); however, this seems impractical to implement in daily practice.Poor adherence to insulin therapy because of injection-related anxiety may be another, often neglected, reason for failure to reach glycemic targets with current rapid- and long-acting insulin analogs (4). A sizable proportion of insulin users admit to at least occasionally skipping insulin injections or restricting the number of daily injections (4). Although true needle phobia is rare, many patients with diabetes perceive insulin injections as painful or experience some form of anxiety with injections (5,6), the presence of which is strongly associated with nonadherence and poorer glycemic control (7).Jet injectors for insulin administration provide a needle-free alternative to the use of pens or syringes and were originally developed for patients with needle phobia. Administration by jet injection significantly accelerates absorption of rapid-acting insulin from the subcutaneous area into the systemic circulation (8). Jet injectors deliver insulin at a high velocity (typically >100 m/s) directly across the skin in the subcutaneous tissue and dispense the insulin over a larger area than does injection by syringe (9). With the euglycemic clamp technique, we recently showed in healthy volunteers that administration of insulin aspart by jet injection reduced both the time until peak plasma insulin levels and the time to maximal glucose-lowering effect by approximately 50% when compared with insulin administered by conventional insulin pen (10).Although the euglycemic clamp technique is a reliable method to investigate the pharmacodynamics of therapeutic insulin, it cannot be used to predict the glucose-lowering effect of insulin when injected before a meal, particularly in patients with diabetes. The aim of the current study was therefore to investigate the pharmacology of insulin injected by jet injector before a standardized meal in patients with type 1 diabetes and insulin-requiring type 2 diabetes. We also wanted to investigate whether patients would perceive insulin administration with the current jet injector device as more or less painful as insulin injection by pen.     

Hypoglycemia Unawareness Is Associated With Reduced Adherence to Therapeutic Decisions in Patients With Type 1 Diabetes: Evidence from a clinical audit

OBJECTIVE

Hypoglycemia unawareness increases severe hypoglycemia risk. Hypoglycemia avoidance restores awareness, but it is difficult to sustain. We compared adherence to treatment changes by awareness status.

RESEARCH DESIGN AND METHODS

Case notes of 90 type 1 diabetic patients were analyzed retrospectively, identifying awareness status and insulin regimens over four visits. The proportion of patients adhering to advice and percent advice taken were calculated.

RESULTS

A total of 31 patients with hypoglycemia awareness and 19 patients with hypoglycemia unawareness were identified, with insulin regimens available in 23 and 13, respectively. Patients with hypoglycemia unawareness were older (P = 0.001) and had longer diabetes duration (P = 0.002) and lower A1C (P = 0.007). More patients with hypoglycemia unawareness reported severe hypoglycemia (P = 0.002) and fewer were adherent (53.8 vs. 87.0%, P = 0.046), with lower adherence scores (42.5 ± 24.7 vs. 75.3 ± 27.5%, P = 0.001).

CONCLUSIONS

Reduced adherence to changes in insulin regimen in hypoglycemia unawareness is compatible with habituation to hypoglycemic stress. Therapies aimed at reversing repetitive harmful behaviors may be useful to restore hypoglycemia awareness and protection from severe hypoglycemia.Hypoglycemia unawareness in type 1 diabetes increases risk of severe hypoglycemia more than fivefold (1). Hypoglycemia awareness can be restored by hypoglycemia avoidance (2–4), which can be difficult. We hypothesized that hypoglycemia unawareness may translate into resistance to changing insulin regimens targeting hypoglycemia avoidance.     

Mixing Insulin Aspart With Detemir Does Not Affect Glucose Excursion in Children With Type 1 Diabetes

OBJECTIVE

We hypothesized that insulin detemir mixed with aspart had equivalent effects on blood glucose as if being given as separate injections in pediatric type 1 diabetes patients.

RESEARCH DESIGN AND METHODS

Fourteen children with type 1 diabetes were randomly assigned to either Study A (mixed insulins) or Study B (separate insulins) for the first 10 days and crossed over for the last 10 days. Each subject underwent continuous glucose monitoring on the last 72 h of each study.

RESULTS

The 48-h area under the curve (mmol/hour/l), M-value, and mean amplitude of glucose excursion (mmol/l) for Study A versus Study B were 457 ± 70 versus 469 ± 112 (P = 0.58), 39.67 ± 15.37 versus 39.75 ± 9.69 (P = 0.98), and 6.35 ± 1.92 versus 5.98 ± 0.92 (P = 0.42), respectively.

CONCLUSIONS

Insulin detemir mixed with aspart had equivalent effects on blood glucose versus giving them as separate injections in children with type 1 diabetes.One of the barriers to good glycemic control in children with type 1 diabetes is multiple daily insulin injections (1,2). Mixing rapid-acting and slow-acting insulins in the same syringe would decrease the number of injections and may improve adherence (3,4). Although there are concerns that mixing the insulins would change the glucose excursion (5), mixing rapid-acting insulin (aspart or lispro) with slow-acting insulin glargine in the same syringe immediately before use did not change the glucose excursion and rates of hypoglycemia (3,4). We hypothesized that slow-acting insulin detemir mixed with aspart would have equivalent effects on blood glucose versus giving them as separate injections in children with type 1 diabetes.     

Is Patient Support Program Participation Associated with Longer Persistence and Improved Adherence Among New Users of Adalimumab? A Retrospective Cohort Study

Introduction

Adalimumab (ADA) is a medication used in the treatment of several autoimmune diseases. Despite the beneficial effects of ADA, its adherence and persistence rates are low. Patients treated with ADA from Clalit Health Services (CHS) can enroll in AbbVie’s patient support program (PSP), which aims to improve ADA adherence and persistence. Therefore, we examine whether PSP participation is associated with a longer persistence and/or an improved adherence to ADA.

Methods

A real-world retrospective cohort study of all new ADA users from CHS, comparing those enrolled in the offered PSP to those not enrolled. The data regarding PSP users can be tracked using CHS’s data warehouse. The index date was defined as the date of the patients’ first purchase of ADA occurring between August 1, 2012 and December 31, 2014. The follow-up data were collected at 12, 24, and 36 months. Persistence was assessed using survival analyses of time until discontinuation, and adherence was assessed using medication possession ratio (MPR).

Results

There were 1520 patients in the study, 755 (49.7%) of whom were PSP users. PSP users were 54.3% female vs. 51.9% among non-PSP users (p?=?0.355) and they were significantly younger than non-PSP users (mean age 42.3 vs. 45.0 years, p?=?0.002) The PSP and non-PSP users’ persistence was 673 and 574 days, respectively (p?<?0.001). Further, the PSP users were more likely than the non-PSP users to be persistently taking medication at the 12-month follow-up (57.5% vs. 45.6%, p?<?0.001). The 12-month mean adherence rate among those with at least 12 months of persistence was significantly improved for the PSP users compared to the non-PSP users (94.1% vs. 92.9%, p?=?0.026).

Conclusion

The AbbVie PSP provided to CHS patients was associated with a longer persistence among new users of ADA. It was also associated with significantly higher adherence rate within the first 12 months.

Funding

AbbVie Inc.

     

A randomized controlled trial comparing a computer-assisted insulin infusion protocol with a strict and a conventional protocol for glucose control in critically ill patients

Purpose

The objective of this study is to evaluate blood glucose (BG) control efficacy and safety of 3 insulin protocols in medical intensive care unit (MICU) patients.

Methods

This was a multicenter randomized controlled trial involving 167 MICU patients with at least one BG measurement ≥150 mg/dL and one or more of the following: mechanical ventilation, systemic inflammatory response syndrome, trauma, or burns. The interventions were computer-assisted insulin protocol (CAIP), with insulin infusion maintaining BG between 100 and 130 mg/dL; Leuven protocol, with insulin maintaining BG between 80 and 110 mg/dL; or conventional treatment—subcutaneous insulin if glucose >150 mg/dL. The main efficacy outcome was the mean of patients' median BG, and the safety outcome was the incidence of hypoglycemia (≤40 mg/dL).

Results

The mean of patients' median BG was 125.0, 127.1, and 158.5 mg/dL for CAIP, Leuven, and conventional treatment, respectively (P = .34, CAIP vs Leuven; P < .001, CAIP vs conventional). In CAIP, 12 patients (21.4%) had at least one episode of hypoglycemia vs 24 (41.4%) in Leuven and 2 (3.8%) in conventional treatment (P = .02, CAIP vs Leuven; P = .006, CAIP vs conventional).

Conclusions

The CAIP is safer than and as effective as the standard strict protocol for controlling glucose in MICU patients. Hypoglycemia was rare under conventional treatment. However, BG levels were higher than with IV insulin protocols.     

Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology

OBJECTIVE

Insulin administered by jet injectors is dispensed over a larger subcutaneous area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study compared the pharmacologic profile of administration of insulin aspart by jet injection to that by conventional insulin pen.

RESEARCH DESIGN AND METHODS

Euglycemic glucose clamp tests were performed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of aspart, either administered by jet injection or by conventional pen, using a randomized, double-blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from plasma insulin levels, respectively.

RESULTS

The time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ∼40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices.

CONCLUSIONS

Administration of insulin aspart by jet injection enhances insulin absorption and reduces the duration of glucose-lowering action. This profile resembles more closely the pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and correction of postprandial glucose excursions.Administration of insulin by jet injection is a needle-free alternative to conventional insulin administration with syringes or insulin pens. Jet injectors deliver insulin at a high velocity (typically >100 m/s) across the skin in the subcutaneous tissue and may dispense the insulin over a larger area than insulin injected with a syringe (1). This may enhance the efficiency with which insulin is absorbed from the subcutaneous compartment into the circulation so that the insulin peak can be advanced and the duration of (glucose-lowering) action reduced. Studies on jet injection technology for insulin administration date back to the 1960s (2). Most have suggested faster absorption of regular and NPH insulin when injected with a jet injector rather than with a syringe (3–8). Data on the use of jet injectors for the administration of rapid-acting insulin analogs are limited to one open-label study. In that study, peak insulin levels were reached in about half the time when lispro insulin was injected with a jet injector instead of a syringe. However, the glucose-lowering time-action profiles were not significantly different, the number of subjects examined was low (n = 4), and the dose of insulin tested was relatively high (30 units for all) (9).Although rapid-acting insulin analogs have clearly advanced glycemic treatment of type 1 and insulin-requiring type 2 diabetes, their pharmacological profile is still far from mimicking the profile of endogenous insulin release. Indeed, the time until insulin’s maximal glucose-lowering effect generally amounts to >90 min, and the duration of significant hyperinsulinemia often exceeds 3 hours (10–12). As a consequence, risks of (immediate) postprandial hyperglycemia and (late) postprandial hypoglycemia remain relatively high in many patients treated with rapid-acting insulin analogs. Faster absorption of insulin may reduce these risks and may provide a more physiological meal-time substitution of insulin. The aim of this study was therefore to compare the pharmacodynamic and pharmacokinetic profile of subcutaneous administration of the rapid-acting insulin analog aspart by jet injection to that of administration by conventional insulin pen in healthy individuals using the euglycemic glucose clamp technique (13). We chose to use an insulin pen as comparator because insulin pens may be more accurate than syringes (14) and are currently used by the vast majority of insulin-treated patients with diabetes in western Europe (15).     

Correlates of Insulin Injection Omission

OBJECTIVE

The purpose of this study was to assess factors associated with patient frequency of intentionally skipping insulin injections.

RESEARCH DESIGN AND METHODS

Data were obtained through an Internet survey of 502 U.S. adults self-identified as taking insulin by injection to treat type 1 or type 2 diabetes. Multiple regression analysis assessed independent associations of various demographic, disease, and injection-specific factors with insulin omission.

RESULTS

Intentional insulin omission was reported by more than half of respondents; regular omission was reported by 20%. Significant independent risk factors for insulin omission were younger age, lower income and higher education, type 2 diabetes, not following a healthy diet, taking more daily injections, interference of injections with daily activities, and injection pain and embarrassment. Risk factors differed between type 1 and type 2 diabetic patients, with diet nonadherence more prominent in type 1 diabetes and age, education, income, pain, and embarrassment more prominent in type 2 diabetes.

CONCLUSIONS

Whereas most patients did not report regular intentional omission of insulin injections, a substantial number did. Our findings suggest that it is important to identify patients who intentionally omit insulin and be aware of the potential risk factors identified here. For patients who report injection-related problems (interference with daily activities, injection pain, and embarrassment), providers should consider recommending strategies and tools for addressing these problems to increase adherence to prescribed insulin regimens. This could improve clinical outcomes.More than 25% of people with diabetes take insulin (1). The American Diabetes Association and the European Association for the Study of Diabetes recently issued a consensus algorithm for management of type 2 diabetes identifying insulin as the most effective glucose-lowering agent (2). Lower compliance with insulin regimens is associated with higher A1C levels (3,4) and with higher rates of hospital admissions for diabetes-related complications (3).Despite the importance of adhering to prescribed insulin regimens, little is known about the degree to which patients are adherent or about factors associated with adherence. In a study using a Department of Veterans Affairs database, insulin use was 77% of prescribed amounts (3). In this population, two-thirds of whom were ≥65 years of age, age did not predict insulin regimen adherence, and adherence was nearly identical for men and women, but non-Hispanic white patients were more adherent than patients who were African American or Hispanic. In another study of patients who switched from using a syringe to deliver insulin to using a pen, 36% of the patients had medication possession rates of >80% while using a syringe, but this rose to 55% after switching to a pen (5).A recent review identified factors associated with adherence to any diabetes medication (6). These factors include medication costs, regimen complexity, the patient''s emotional well-being, and the patient''s perceptions of medication side effects and medication-related intrusions on activities of daily living.Medication costs can affect adherence. In a U.S. survey of adults with type 2 diabetes using glucose-lowering agents, 11% reported that they had cut back on their medication in the past year (7). Adherence rates are also affected by regimen complexity. Rates of adherence for oral diabetes medication decline with the number of times each day the medication should be taken (8), but we could find no report on the association between insulin injection frequency and insulin omission. Depression also has been associated with diabetes medication nonadherence (9) and with insulin omission among adolescent females (10).Several researchers have developed questionnaires to assess patient perceptions of insulin therapy that could affect regimen adherence (11–16). These questionnaires assess factors such as 1) interference with eating, exercise, and activities of daily living; 2) dissatisfaction with the amount of time required to administer insulin and with injection-related pain, bruising, and embarrassment; 3) worries about insulin-related side effects such as hypoglycemia; and 4) negative affect associated with administering insulin. Unfortunately, none of these studies formally assessed the association between any of these factors and intentional insulin omission. However, a recent publication did find that insulin adherence is lower among young women who are concerned about their weight (17).The current study is designed to address questions about intentional insulin omission, including the frequency of this behavior and factors hypothesized to be associated with this behavior, in a large sample of patients weighted to be representative of all adult diabetic patients in the U.S. who take insulin. In a previous report, we found that most insulin-treated patients wanted to reduce the number of insulin injections they take each day, and some reported that injection-related problems affect the number of injections they are willing to take (18). Here we formally assess the impact of a broad range of factors that might be expected to influence intentional insulin omission, including demographic and disease factors, as well as perceived burden of insulin therapy (i.e., interference with activities of daily living), the injection experience (e.g., pain and embarrassment), and negative emotions (e.g., dread) associated with insulin injections.