Patient factors associated with hemoglobin a1c change with pioglitazone as adjunctive therapy in type 2 diabetes mellitus.

Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. Original Research
Patient factors associated with hemoglobin A1C
change with pioglitazone as adjunctive therapy
in type 2 Diabetes Mellitus
Mongthuong T. TRAN, Thomas DELATE, Shakti BACHMANN. ABSTRACT*
VARIABLES ASOCIADAS A CAMBIOS EN
Objective: To identify patient factors associated with LA HEMOGLOBINA A1C EN PACIENTES
change in hemoglobin A1C (A1C) with adjunct COM PIOGLITAZONA COMO
pioglitazone therapy in routine clinical practice. COADJUVANTE EN DIABETES MELLITUS
Methods: This was a retrospective analysis of adult type 2 diabetes mellitus patients in a health maintenance organization setting who were newly- initiated on pioglitazone between January 2002 and December 2005. Eligible patients were receiving at Objetivo: Identificar las variables asociadas a least one other oral antihyperglycemic medication cambios en hemoglobina A1C en pacientes con prior to initiating pioglitazone and maintained a pioglitazona como tratamiento coadyuvante en la stable dose of pioglitazone for 90 days. Data on eligible patients’ characteristics, pharmacy Métodos: Fue un análisis retrospectivo de pacientes purchases, comorbidities, and A1C measurement con diabetes tipo 2 entre enero 2002 y diciembre 90 days prior to the pioglitazone purchase date 2005 en una organización sanitaria donde se (baseline) and 90 days after achieving a stable dose acababa de iniciar la pioglitazona. Los pacientes (follow-up) were obtained from electronic records. elegibles estaban recibiendo al menos otro Multivariate regression modeling was used to antidiabético oral antes de comenzar la pioglitazona assess factors independently associated with: 1) y mantuvieron una dosis estable de pioglitazona absolute change in A1C, 2) achieving a ≥1 durante 90 días. Se obtuvieron los datos a partir de percentage point decrease in A1C, and 3) achieving los registros electrónicos de las características de Results: Baseline and follow-up A1Cs were comorbilidades, y medidas de A1C 90 días antes de available for 128 patients. At baseline, mean age la compra de la pioglitazona (basal) y 90 días was 65 years, 38% were female, mean A1C was 8.4%, and 74% had an A1C>8%. At follow-up, the (seguimiento). Se utilizó un modelo de regresión mean A1C change was -1.2 percentage points multivariada para evaluar las variables asociadas (interquartile range= -0.4, -2.1), 59% achieved a ≥1 independientemente con: 1) el cambio absoluto en unit decrease in A1C, and 44% achieved an A1C, 2) el alcanzar una disminución de ≥1% en la A1C<7%. Independent predictors in all models were baseline A1C and time (in days) between baseline Resultados: Se dispuso de A1C basales y de and follow-up A1C measurements (p<0.05). seguimiento de 128 pacientes. Al inicio, la media Conclusions: Adjunct pioglitazone therapy in routine de edad era de 65 años, 38% eran mujeres, la media clinical practice was associated with clinically de A1C era de 8,4% y el 74% tenían una A1C >8%. meaningful reductions in A1C levels. Patients with En el seguimiento, la media de A1C era -1,2% higher baseline A1C achieved the greatest absolute menor (rango intercuartil -0,4; -2,1%), el 59% reduction in A1C but were less likely to achieve redujo ≥1% la A1C, y el 44% alcanzó una A1C <7%. Los predictores independientes en todos los modelos fueron la A1C basal y el tiempo (en días) entre el inicio y las medidas de seguimiento de Keywords: Diabetes Mellitus, Type 2.
Thiazolidinediones. Regression Analysis. United
pioglitazona se asoció en la práctica clínica con reducciones significativas de los niveles de A1C. Los pacientes con niveles iniciales de A1C más altos alcanzaron la mayor reducción en valor absoluto de A1C, pero eran los menos probables de *Mongthuong T. TRAN. PharmD, BCPS, CDE, Clinical Pharmacy Specialist in Endocrinology, Kaiser Permanente Colorado Pharmacy Department; Clinical Assistant Palabras clave: Diabetes Mellitus, Tipo 2.
Professor, School of Pharmacy, University of Colorado Tiazolidindionas. Análisis de regression. Estados Health Sciences Center. Denver, CO (USA). Thomas DELATE. PhD, MS; Clinical Pharmacy Research Scientist, Kaiser Permanente Colorado Pharmacy Department. Denver, CO (USA). Shakti BACHMANN. PharmD, Clinical Pharmacy Call Center Pharmacist, Kaiser Permanente Colorado Pharmacy Department. Denver, CO (USA). www.pharmacypractice.org
Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. and provide additional data regarding the patient characteristics associated with changes in A1C after the addition of pioglitazone to existing oral antihyperglycemic therapy in a diverse, real-world INTRODUCTION
population of patients managed in routine clinical practice. Two landmark trials, the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), emphasize the significance of glycemic control in patients with diabetes mellitus.1-3 These studies Setting and Design
reported that maintaining glycemic control (i.e., This was a naturalistic, retrospective, pre-to-post hemoglobin A1C [A1C]<7.0%) is necessary to analysis conducted at Kaiser Permanente Colorado, reduce the risk of microvascular and macrovascular a group model, not-for-profit, health maintenance complications, including nephropathy, neuropathy, organization with approximately 450,000 members retinopathy, and cardiovascular events, such as in the Denver/Boulder metropolitan area, operating myocardial infarction or stroke.1-3 An 18 regional medical offices. All phases of the study epidemiological review of the UKPDS revealed that were approved by the Kaiser Permanente Colorado a reduction in A1C of 1 percentage point resulted in a 35% reduction in the microvascular complications (i.e., retinopathy, nephropathy, and neuropathy) of Patient Population
diabetes mellitus type 2 (DM 2).1,2 Based largely on Active Kaiser Permanente Colorado patients 18 the results of these two trials, the American years of age and older who had newly initiated Diabetes Association recommends a target A1C pioglitazone therapy to existing other oral goal of <7% for most patients with diabetes and antihyperglycemic medication therapy between maintains that glycemic control is fundamental to January 1, 2002 and December 31, 2005 were reducing the microvascular complications of the eligible for inclusion (Figure 1). A newly-initiated disease.4 In fact, a recent hyperglycemia regimen was identified as a pioglitazone management consensus algorithm advocates that prescription purchased from a Kaiser Permanente an A1C≥7 serves as a call to action to optimize Colorado pharmacy during the study period with no other pioglitazone prescription purchased in the Thiazolidinedione (TZD) agents, selective agonist of prior 180 days (to ensure that 90- and 180-day the peroxisome proliferator-activated receptor- supply mail order prescription purchases were gamma subtype (PPARγ), are oral accounted for in this assessment). The first antihyperglycemic agents approved by the Food purchase date of the newly-initiated pioglitazone and Drug Administration (FDA) for use in DM2 as therapy was set as the study index date. Patients monotherapy or in combination with sulfonylureas, were included if they had continuous coverage for a metformin, or insulin.6,7 While TZDs have Kaiser Permanente Colorado pharmacy benefit for demonstrated efficacy in the reduction of A1C the 180 days prior to the index date (to ensure values when used in combination with other oral comprehensive prescription purchase history) and antihyperglycemic agents in clinical trials,8-11 limited remained on a single dose of pioglitazone for at real-world effectiveness data are available.12-16 In least 90 days after initiation of therapy. The study addition, few studies have reported on factors stable date was defined as the date when a patient associated with change in A1C in clinical had remained on a single dose of pioglitazone for practice.12,13,17,18 Importantly, knowledge of 90 days. In addition, patients that had purchased characteristics of patients who respond to adjunct insulin therapy at any time in the 180 days prior to pioglitazone is narrow. The intent of this study was the index date and 180 days after the stable date to evaluate pre-to-post the effectiveness of adjunctive pioglitazone therapy in patients with DM2 2) No Insulin -or-Pioglitazone Purchases3) Chronic Disease Score Calculated4) Medical DiagnosesAssessed5) Other Medication Use Assessed www.pharmacypractice.org
Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. Baseline patient characteristics and study outcomes Data Collection
were reported as means and standard deviations for Data were extracted from integrated electronic interval- and ratio-level variables (e.g., age, time) medical, pharmacy, and laboratory record and proportions for nominal- and ordinal-level data databases. Patients’ data were linked across (e.g., gender, use of other oral antihyperglycemic databases by their Kaiser Permanente Colorado medications). Interval- and ratio-level variables were unique nine digit health record number. Validity of assessed for the normality of their distributions. these data sources has been described Times were log transformed to normalize their previously.19 Pharmacy records were queried using distribution. The paired-sample t-test23 was used to Generic Product Identifier numbers20 to assess evaluate the change from baseline in A1C. medication prescription purchases and purchase Independent sample t-tests and chi-square tests of dates during the 180 days prior to the index date association23 were used to compare means and (these data were required to assess inclusion proportions between sub-groups (i.e., those that did criteria and calculate a chronic disease score21). and did not achieve a 1 percentage point decrease Patient demographics were extracted from their in A1C and a <7% A1C). To identify predictors of pharmacy records. Medical records were queried change in A1C, multivariate linear and logistic with International Classification of Diseases, Ninth regression modeling23 were utilized. Age, gender, Revision (ICD-9) codes to identify a medical office daily stable pioglitazone dose (15 mg, 30 mg, and diagnosis for coronary artery disease, chronic 45 mg), time between index date and follow-up A1C kidney disease, gastroparesis, previous myocardial measurements, baseline metformin, glipizide, infarction, neuropathy, retinopathy, and/or previous glyburide, antihyperlipidemic and antihypertensive stroke in the 180 days prior to the index date. Age medications use, chronic disease score, persistence was calculated as of the index date. The strength of with pioglitazone, retinopathy and neuropathy the dose of pioglitazone at the stable date was diagnoses, and baseline A1C measurement were recorded (stable dose). Electronic laboratory entered into all models. Diagnoses for coronary records data were queried to identify the most proximal A1C in the 90 days prior to the index date gastroparesis, and previous myocardial infarction, for the baseline measurement and between 90 and stroke and baseline sulfonylurea use were not 180 days after the stable date for the follow-up entered in the models due to their very low and high measurement (Figure 1). Patients without both a prevalence rates, respectively. The baseline A1C baseline and follow-up A1C measurement were values were assessed as a continuous and excluded. Baseline weight was identified from categorized (i.e., ≤8% vs. >8%) variable. integrated medical records; however, as data were missing in 22% of the included patients, analysis In total, 128 patients were included in the analysis Outcomes
(Figure 2). The mean age was 65 years, 38% were The primary outcome was to quantify from baseline female, 41% were receiving a stable dose of 15 mg to follow-up the absolute change in A1C values after pioglitazone, mean A1C was 8.4%, 74% had an initiation of pioglitazone. Secondary analyses were A1C>8% at the time of pioglitazone initiation, and performed to quantify the proportions of patients mean chronic disease score was 7 (indicating, on achieving a ≥1 percentage point decrease in A1C average, a clinical y significant chronic disease and an A1C<7% during the follow-up. Additionally, burden21) (Table 1). The mean absolute A1C factors (predictors) independently associated with reduction was 1.2 percentage points (interquartile absolute A1C change, achieving a ≥1 percentage range= -0.4, -2.1 percentage points, p<0.001), 59% point decrease in A1C, and achieving an A1C<7% achieved a ≥1 percentage point decrease in A1C, Analysis
In bivariate analysis, patients who achieved a ≥1 percentage point decrease in A1C had a higher Time (in days) between index date and follow-up mean baseline A1C (p<0.001) and were less likely A1C measurement was calculated. A chronic to have had a baseline A1C ≤8% (p<0.001) than disease score,21,22 a risk adjustor for baseline health patients who did not achieve a ≥1 percentage point status, was calculated for all patients using decrease in A1C. All patients were persistent with pharmacy purchase data for the 180 days prior to their baseline metformin, glyburide, glipizide, and/or the index date. Chronic disease scores can range sulfonylurea antihyperglycemic prescription from 0 to 35 with increasing scores indicating an medications at the time of their follow-up A1C increasing count of chronic diseases under measurement (p>0.05, data not shown). There were treatment. Use of the chronic disease score allows no other differences in clinical and demographic for the accounting of each patient’s chronic disease characteristics (p>0.05) between the groups of burden at the time of his/her initiation of patients who were or were not able to achieve an pioglitazone. Persistence with oral A1C<7%. antihyperglycemic agents at the time of the follow-up A1C was determined based on the medication Multivariate linear regression analysis revealed two sold date, days supplied, and quantity dispensed predictors of absolute change in A1C: baseline A1C resulting in a day’s supply of medication within +/- level (beta-coefficient= -0.831; p<0.001) and time two weeks of the follow-up A1C measurement date. between the index date and follow-up A1C measurement date (beta-coefficient=0.528; www.pharmacypractice.org
Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. p=0.003) (adjusted R2=0.55) (Table 2). The beta- measurement date will have a less favorable coefficients indicate that when comparing two response to pioglitazone. When categorizing patients with all other characteristics being equal, baseline A1C at ≤8% and >8%, patients with an the patient with the higher baseline A1C wil have a A1C≤8% (beta-coefficient=1.220; p<0.001) were more favorable response to pioglitazone. predicted to have a less favorable response to Conversely, the patient with a greater number of days between the index date and follow-up A1C 1022 patients with a pioglitazone purchase during 01/01/02-12/31/05 223 excluded for not having a stable dose of pioglitazone 91 excluded for prior use of pioglitazone 125 excluded for not having continuous membership 145 excluded for not having a baseline and follow-up A1C measurement Figure 2: Reasons for and Numbers of Patients Excluded, Included, and Utilized in Analysis Table 1: Baseline Patient Characteristics Overall and by A1C Decrease* Cohort * Achievement occurred during 90 to 180 days after date of initiation of stable dose 1 – Between cohorts 2 – At time of pioglitazone initiation 3 – As assessed by a purchase for the medication in the 90 days prior to pioglitazone initiation 4 – At the time of the follow-up A1C measurement 5 - As assessed by a medical office diagnosis for the indication in the 180 days prior to pioglitazone initiation www.pharmacypractice.org
Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. Table 2. Predictors of Absolute Change in A1C 1 – Adjusted R-Square = 0.55 2 – Adjusted R-Square = 0.28 Multivariate logistic regression analysis revealed Multivariate logistic analysis revealed two predictors two predictors of achieving a ≥1 percentage point of achieving an A1C<7%: baseline A1C level decrease in A1C: baseline A1C level (odds ratio (OR=0.64; p=0.038), and time between the index [OR]=12.84; p<0.001) and time between the index (OR=0.14; p=0.002) (c-statistic=0.78) (Table 4). (OR=0.19; p=0.032) (c-statistic=0.92) (Table 3). When categorizing baseline A1C at ≤8% and >8%, When categorizing baseline A1C at ≤8% and >8%, patients with an A1C ≤8% (OR=4.27; p<0.001) were patients with an A1C ≤8% (OR=0.04; p<0.001) were predicted to be more likely to achieve an A1C<7% predicted to be less likely to achieve a ≥1 (c-statistic=0.80). In total, these models indicate percentage point decrease in A1C (c-statistic=0.88). that, while patients with higher baseline A1C levels These odds ratios support the previous model achieve greater absolute decreases in A1C, these whereby patients with higher baseline A1Cs and patients are less likely to reach an A1C goal of longer times between initiation of pioglitazone and follow-up A1C measurements had more and less favorable, respectively, response to pioglitazone. www.pharmacypractice.org
Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. Table 3. Predictors of Achieving a ≥1 Percentage Point Decrease in A1C 1 – c-statistic = 0.92; 2 – c-statistic = 0.88. CI – Confidence Interval
DISCUSSION
of 0.8 to 1.7 percentage points from baseline were obtained when pioglitazone was used in This study provides additional information about the combination with a sulfonylurea or metformin for 24 real-world effectiveness of pioglitazone use as weeks.7 Other studies have revealed mean adjunctive therapy to other oral antihyperglycemic reductions in A1C of 0.8 to 1.9 percentage points agents. We found that adding pioglitazone to with pioglitazone use.8-13 Specifically, we identified a regimens of other oral antihyperglycemic comparable mean A1C reduction over a similar medication(s) for patients with inadequate glycemic follow-up time to that reported by Riedel and control resulted in clinical y significant reductions in colleagues (-1.2 percentage points) for patients A1C but less than half of the patients achieved an receiving combination TZD-metformin.13 Our A1C<7% after 90 days of pioglitazone use at a observed reduction in A1C was also clinically significant given the results of the UKPDS, which Pioglitazone has a distinct mechanism of action that reported that for every 1% reduction in A1C, the risk can provide additional glucose reduction when of developing microvascular complications added to a sulfonylurea and/or metformin.24 According to its package insert, reductions in A1C www.pharmacypractice.org
Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. Table 4. Predictors of Achieving an A1C<7% 1 – c-statistic = 0.78 2 – c-statistic = 0.80 We found that higher baseline A1C levels were A1C>8%. An additional caveat to consider is that associated with greater change in A1C. Our finding triple oral therapy has not demonstrated cost- suggests that patients with higher baseline A1C effectiveness compared to a regimen of insulin and measurements may experience improved glycemic control from the addition of pioglitazone. Conversely, patients with worse glycemic control at We found that the greater number of days between baseline were less likely to achieve a goal A1C of the index date and follow-up A1C was associated <7%; which is the definitive target in diabetes with a less favorable response to pioglitazone. This management, more so than is the magnitude of suggests that the A1C-lowering ability of A1C change. Riedel and colleagues similarly pioglitazone may degenerate over time. This is identified a higher baseline A1C as a predictor of contrary to the results of a recent clinical trial where not achieving A1C goal.13 Based on this13 and our the antihyperglycemic effect of pioglitazone was results, adjunct therapy with pioglitazone appears to sustained over 2 years when used in combination lack effectiveness in achieving glycemic control with other oral antihyperglycemic agents such as targets, particularly in patients with a baseline gliclazide (a sulfonylurea not available in the United www.pharmacypractice.org
Tran MT, Delate T, Bachmann S. Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus. Pharmacy Practice 2008 Apr-Jun;6(2):79-87. States) or metformin.26 Our results may have varied be associated with clinical y significant differences due to the difference in study settings (e.g., clinical trials incorporate techniques to enhance adherence) goals.12,13 However, the reported adjusted R2 and c- and patient populations (e.g., patients were statistics of our models suggest that a substantial excluded from clinical trials because they had other proportion of the variance in A1C change and goal achievement was accounted for by our models. Several aspects of our investigation warrant comment. The retrospective nature of our CONCLUSIONS
evaluation and lack of a pioglitazone-naïve control group prevented us from assessing causality and In this retrospective, naturalistic, pre-to-post regression to the mean; however, we feel that this evaluation, we found that adjunct pioglitazone information is the best available data to describe therapy was associated with a clinical y significant what occurs in a real-world population of patients reduction in A1C, particularly in patients with higher with DM2. As this was a naturalistic investigation, baseline A1C measurements, and also an increase we investigated patients started on pioglitazone in the proportion of patients achieving A1C<7% in therapy who received the usual course of care those patients with a lower baseline A1C. These which included the use of other oral findings provide real-world evidence that antihyperglycemic agents. However, since our pioglitazone as adjunct therapy may be associated findings mirrored those reported in other studies,6,8- with improved glycemic control; however, they also 13 we hypothesize that incorporation of a control group in our investigation would have yielded similar hyperglycemic control (as shown by higher baseline results. Nevertheless, future studies of pioglitazone A1C levels) are less likely to reach treatment efficacy should include an adequate control group. targets, thus casting doubt on the clinical utility of pioglitazone therapy in combination with other oral Our data are derived from a limited sample size, agents. Future naturalistic studies utilizing adequate and this was attributable to the stringent inclusion control groups are needed to confirm the criteria we employed to provide a more rigorous effectiveness of pioglitazone in A1C reduction and assessment of the independent role pioglitazone played in achievement of the outcomes. Such stringent criteria may potentially introduce selection bias (e.g., patients who failed to respond to ACKNOWLEDGEMENTS
pioglitazone therapy during the 90 days after This study was funded entirely by the Kaiser initiation were not included) that limits the Permanente Colorado Pharmacy Department. The generalizability of our findings. Inclusion of patients authors of this manuscript would like to thank John who failed to respond to pioglitazone therapy likely Merenich, MD in the Endocrinology Department at would have provided additional information about Kaiser Permanente Colorado for his contributions to the patient population that was prone to fail to the study design and methods. As part of a clinical achieve an A1C<7% but likely would not have illuminated the patient population that was prone to presentation of some of this material was made at the Western States Conference for Pharmacy The suboptimal dosing of adjunct pioglitazone Residents, Fellows, and Preceptors in Pacific detected in this real-world examination exposes the need for additional reinforcement for prescribers to optimize therapy should they choose to add CONFLICT OF INTEREST
pioglitazone to existing oral therapy. Additionally, This study was supported and funded in whole by we included a limited amount of variables in the multivariate analysis. Potentially important factors Department. None of the authors have any known not found in the integrated databases (e.g., race/ethnicity, nutritional assessment, socioeconomic status, health behaviors) may also References

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