Postgraduate Medicine
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Management of Patients Using Combination Therapy With Pioglitazone and a Dipeptidyl Peptidase-4 Inhibitor: An Analysis of Initial Versus Sequential Combination Therapy Morgan Bron PhD, Rajeev Ayyagari PhD, Hari Sharma MS, Kristina Chen PhD, Ana Bozas PhD & Eric Wu PhD To cite this article: Morgan Bron PhD, Rajeev Ayyagari PhD, Hari Sharma MS, Kristina Chen PhD, Ana Bozas PhD & Eric Wu PhD (2014) Management of Patients Using Combination Therapy With Pioglitazone and a Dipeptidyl Peptidase-4 Inhibitor: An Analysis of Initial Versus Sequential Combination Therapy, Postgraduate Medicine, 126:3, 47-55 To link to this article: http://dx.doi.org/10.3810/pgm.2014.05.2755
Published online: 13 Mar 2015.
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C L I N I C A L F O C U S : D I A B E T E S A N D C O N C O M I TA N T D I S O R D E R S
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Management of Patients Using Combination Therapy With Pioglitazone and a Dipeptidyl Peptidase-4 Inhibitor: An Analysis of Initial Versus Sequential Combination Therapy
DOI: 10.3810/pgm.2014.05.2755
Morgan Bron, PhD 1 Rajeev Ayyagari, PhD 2 Hari Sharma, MS 2 Kristina Chen, PhD 2 Ana Bozas, PhD 2 Eric Wu, PhD 2 1 Takeda Pharmaceuticals International, Inc., Deerfield, IL; 2Analysis Group, Inc., Boston, MA
Abstract: Current type 2 diabetes mellitus (T2DM) treatment involves progressive interventions from lifestyle changes to pharmacological therapies. Previous studies found that combination therapy with a dipeptidyl peptidase-4 inhibitor (DPP-4i) and pioglitazone (PIO) is more effective than monotherapies in treating poorly controlled T2DM, but there is no consensus on whether these drugs should be initiated at the same time (initial combination therapy) or sequentially. We aimed to assess glycemic control with initial versus sequential combination therapy with PIO and a DPP-4i in patients with glycosylated hemoglobin (HbA1c) levels $ 7%. A retrospective chart review was conducted on T2DM patients from diverse geographic sites in the United States initiating therapies from March 2, 2010 to February 28, 2011. Patients were selected for initial combination therapy, if starting PIO and a DPP-4i within 30 days of each other, or sequential combination therapy, if first taking PIO alone for $ 60 days before adding a DPP-4i within 1 year of PIO initiation. The HbA1c level reduction from baseline was compared between cohorts using linear regression models adjusting for demographics, baseline HbA1c, T2DM duration, comorbidities, and various medications. There were 250 patients in the initial and 211 in the sequential combination therapy cohorts; 57.3% were male, 65.3% were Caucasian, and the mean age was 54.3 years. Patients receiving initial combination therapy had a significantly higher mean baseline HbA1c level (8.6% vs 8.0%, P , 0.0001), a higher prevalence of coronary artery disease (11.6% vs 6.2%, P = 0.0430), and a lower prevalence of hyperlipidemia (56.4% vs 67.8%, P = 0.0120) and of hypertension (62.4% vs 72.0%, P = 0.0290), compared with the sequential therapy cohort. In adjusted analyses, initial combination therapy was associated with a significantly greater reduction in HbA1c levels than sequential combination therapy at months 12, 16, and 20 (−0.977 vs −0.819, P = 0.034; −1.453 vs −1.242, P = 0.048; and −1.182 vs −0.810, P = 0.013, respectively). Our findings suggest initial combination therapy may be the preferred option in choosing combination therapies. Keywords: type 2 diabetes mellitus; pioglitazone; dipeptidyl-peptidase IV inhibitors; gliptins; hemoglobin A1c protein; combination drug therapy
Correspondence: Rajeev Ayyagari, PhD, 111 Huntington Ave, 10th Floor, Boston, MA 02199. Tel: 617-425-8422 Fax: 617-425-8001 E-mail: [email protected]
Introduction
Increasingly larger numbers of individuals in the United States suffer from diabetes: from 23.6 million affected people (7.8% of the total population) in 20071 to 25.8 million people (8.3% of the total population) in 2011.2 Although the overall disease growth is slowing with time, most likely due to better diagnostic and prevention methods,
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Bron et al
the economic costs of diabetes are escalating, growing from an estimated $174 billion in 2007—or $202 billion when adjusted for inflation as of 2012—to $245 billion in 2012.3 Almost 90% of diabetic individuals have type 2 diabetes mellitus (T2DM),4 a chronic, progressive disease, characterized by deterioration of β-cell function over time, resulting in impaired insulin action, decreased insulin secretion, and increased hepatic glucose production.4–6 The subsequent increased circulating levels of glucose in the blood slowly bind to hemoglobin (over a period of 1–3 months) and result in increased levels of glycosylated hemoglobin (HbA1c).7 The HbA1c level is an indication of a patient’s overall glycemic control; it accurately predicts a patient’s diabetic potential,8–10 and has been shown to be correlated with improved patient health profiles and diabetes-related costs.11–14 Current American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) recommendations for the treatment of diabetes suggest patients aim to reach and maintain HbA1c blood levels , 6.5% (AACE) or , 7% (ADA)15–17 through progressive interventions—from lifestyle changes to various prescribed medication combinations.15,16 Approximately 40% of patients cannot safely achieve this goal on a single drug therapy without an increased risk of hypoglycemia (abnormally low blood glucose levels, typically , 70 mg/dL; hypoglycemia is a particular concern in patients treated with insulin or sulfonylureas)18,19 or adverse effects.20–22 Combination therapies have been explored in various clinical trials23–26 and are currently recommended by ADA and AACE for such patients.27 The pairing of thiazolidinedione (TZD) with a dipeptidyl peptidase-4 inhibitor (DPP-4i) is a common and successful combination of medications with complementary mechanisms of action, addressing the insulin secretion and sensitivity aspects of diabetes, as well as adipose tissue management.15 Pioglitazone (PIO) is the primary TZD used in current clinical practice. It works by binding the peroxisome proliferator-activated γ receptors (PPARγ) in the nuclei of fat cells, which, in turn, induces multiple signaling cascades, resulting in increased expression of glucose transporters, increased sensitivity of fat and β-cells to insulin, adipocyte remodeling, and improved β-cell function, among other effects.28–30 Ultimately, PIO use results in decreased insulin resistance and hepatic glucose production, while correcting the lipotoxicity, inflammation, and oxidative stress associated with free fatty acid overproduction.28–30 On the other hand, a DPP-4i works mainly through the incretin hormone system, by blocking fast-acting incretin peptide degradation enzymes 48
in the blood, thereby leading to mildly increased insulin secretion and suppressed glucagon release.31,32 Administered as initial monotherapy, or given after failed monotherapies, along with metformin or insulin, TZDs and a DPP-4i’s typically reduce HbA1c levels by 0.6% to 1.0%.23,33,34 When added to an existing therapy, these drugs can achieve an additional HbA1c reduction of approximately 1%.26,31 Although previous studies combining PIO with a DPP-4i indicate that a marked improvement in glycemic control is seen in patients treated with a combination of both drugs,35–42 there is no consensus on whether DPP-4i and PIO treatments should be initiated simultaneously (initial combination therapy) or whether patients with T2DM should start with PIO and then receive a DPP-4i at a later date (sequential combination therapy). Additionally, most combination therapy studies have only examined glycemic control achieved over a short period of time, typically 24 or 26 weeks; no long-term studies reliably address the issue of preferred combination therapy. To address this knowledge gap, we conducted a chart review study assessing the long-term, real-world effectiveness of reducing HbA1c blood levels through the use of initial and sequential combination therapies with PIO and a DPP-4i (sitagliptin, saxagliptin, or linagliptin) in patients with poor glycemic control (HbA1c level $ 7%).
Research Design and Methods Study Design
This retrospective physician-administered medical chart review study collected data on patients diagnosed with T2DM who received combination therapy with PIO and a DPP-4i. Physicians were invited to participate in this study through a vendor specializing in online surveys. The physicians were selected from an existing physician panel of medical professionals from diverse geographic sites in the United States, including both urban and rural areas, as well as private and academic practice settings. A total of 133 primary care physicians, endocrinologists, and internists participated in this study. Each physician was asked to select up to 5 eligible patients. To avoid any systematic selection bias, physicians were directed to choose patients whose last name started with a random computer-generated letter. If no last names started with that letter, patients were chosen from names matching the next closest letter in the alphabet. The participating physicians then selected patient information through an online chart abstraction form. The selected patients were distributed into 2 study cohorts: initial combination therapy and sequential combination
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Initial Versus Sequential Combination Therapy
therapy. The initial combination therapy group consisted of patients initiating PIO and a DPP-4i (sitagliptin, saxagliptin, or linagliptin) within 30 days of each other, without prior use of PIO or a DPP-4i. Patients were selected for the sequential combination therapy group only if they were first treated with PIO monotherapy for $ 60 days, and added a DPP-4i to the original therapy within 12 months. The date of initiation of the DPP-4i was called the initiation date for both cohorts. The baseline period was defined as the 1 month preceding the initiation date for both therapy groups. Additionally, to be considered eligible for this study, patients were required to (1) be aged $ 18 years as of therapy initiation date; (2) have a diagnosis of T2DM; (3) undergo treatment with either initial or sequential combination therapy initiated between March 2, 2010 and February 28, 2011; (4) continue T2DM treatment in the physician’s office for $ 1 year after initiation of drug therapy; (5) have $ 1 HbA1c laboratory measurement from the baseline period recorded in their charts (baseline HbA1c value); (6) have a baseline HbA1c level $ 7%; and (7) have $ 1 recorded HbA1c laboratory measurement during the follow-up period after therapy initiation. Patients who received insulin prior to the initiation date of the combination therapy were excluded from the study. Figure 1 summarizes the sample selection criteria. The initial data collected for each patient included demographics (age, sex, race, ethnicity), disease duration, comorbidities, and prior oral antidiabetic, antihyperlipidemic, Figure 1. Sample selection criteria.
and antihypertensive drug treatment profiles prior to the initiation of therapy. The HbA1c values were recorded at 4, 8, 12, 16, and 20 months following the therapy initiation date, if available. Physicians were also asked to provide information on treatment discontinuation, such as which drug was discontinued and at which time point in the follow-up period. Reasons for discontinuations were not provided. Figure 2 illustrates study design details. All abstracted data were de-identified and comply with the patient confidentiality requirements of the Health Insurance Portability and Accountability Act (HIPAA).
Statistical Analysis
Patient characteristics at baseline, including demographics, comorbidities, medications, baseline HbA1c level, and duration of diabetes, were compared between the initial and sequential combination therapy cohorts using Wilcoxon rank sum tests for continuous variables and Χ 2 tests for categorical variables. Descriptive analyses of measured HbA 1c values at months 4, 8, 12, 16, and 20 were performed for the initial and sequential combination therapies; unpaired t tests were used to compare HbA1c values. The rates of discontinuation of either drug during the follow-up period were compared between the cohorts using Χ 2 tests. Multivariate linear regression analysis was used to compare HbA1c level reduction from baseline values between the 2 combination therapies. Linear regression models adjusting for demographic variables, baseline HbA1c level, diabetes duration, comorbidities, and antidiabetic, antihypertensive, or antihyperlipidemic medications were fit to the data and used to obtain adjusted mean HbA1c level reductions from baseline during the studied time points (4, 8, 12, 16, and 20 months). The adjusted HbA1c values were compared between the initial and sequential combination therapy cohorts using Wald tests. A 2-sided α-level of 0.05 was used in determining statistical significance. All analyses used SAS version 9.3 software.
Results
Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
A total of 461 patients—250 patients from the initial combination therapy cohort and 211 from the sequential combination therapy cohort—satisfied the study selection criteria (Figure 1). Among physicians who participated in the survey, endocrinologists (40.4%) had a somewhat higher representation than primary care physicians (27.3%) and internists (32.3%). The majority of physicians (84.2%) were from private practice, with the remainder from mixed (9.5%),
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Figure 2. Study design.
Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
academic (4.3%), and other (2%) settings. The physicians’ specialties and practice settings did not differ significantly between the initial versus sequential combination therapy cohorts (Table 1). The most commonly used index DPP-4i was sitagliptin (taken by 75.7% of patients), followed by saxagliptin and linagliptin (taken by 22.6% and 1.7% of patients, respectively). The median gap between the initiation times of the 2 treatments was 0 days for initial combination therapy, indicating that the majority of patients initiated PIO and the DPP-4i simultaneously. The 75th percentile was 17 days. In the sequential combination therapy cohort, the median gap between initiations of the 2 treatments was 94 days. The majority of patients were Caucasians (65.3%), male (57.3%), and middle-aged (mean age was 54.3 ± 9.1 years), with mean T2DM duration of 2.1 years. Among the 461 patients, the most common reported comorbidities were hyperlipidemia (66.8%) and hypertension (61.6%), and 44.9% of patients were obese (body mass index $ 30 kg/m2). Prior to initiation of PIO or the index DPP-4i, most patients (77.9%) received metformin, many (43.2%) were treated with sulfonylureas, and a small proportion (2.2%) had not received any oral antidiabetic medications. Angiotensinconverting enzyme inhibitors (taken by 35.6% of patients) were the most common antihypertensive medication prior to initiation of PIO or the index DPP-4i, followed by angiotensin II receptor blockers (16.3%). Patients in the 2 cohorts generally had similar demographics, disease duration, and comorbidity profiles (Table 1). Some baseline characteristics differed between the 2 study 50
groups: the initial combination therapy cohort had a significantly higher mean baseline HbA1c level (8.6% vs 8.0%, P , 0.0001), a higher proportion of patients with HbA1c levels . 9% (21.6% vs 3.8%, P , 0.0001), and a higher prevalence of coronary artery disease (11.6% vs 6.2%, P = 0.043). Initial combination therapy patients had a lower prevalence of hyperlipidemia (56.4% vs 67.8%, P = 0.012) and of hypertension (62.4% vs 72.0%, P = 0.029) when compared with patients receiving sequential combination therapy. After initiation of combination therapy, discontinuation rates for either PIO or the index DPP-4i were low (14.1% of all patients), with the majority of discontinuations (7.8%) occurring for PIO, followed by discontinuations of both drugs (3.5%). Only 2.8% of patients discontinued the index DPP-4i without discontinuing PIO. There was no significant difference in the proportions of patients discontinuing combination therapy between the 2 cohorts (14.8% vs 13.3%, P = 0.638). In unadjusted analyses, both patient cohorts showed a similar trend of HbA1c values decreasing steadily from baseline over time. The HbA1c values decreased from 8.6% and 8.0% at baseline for the initial versus sequential combination therapy, to 7.0% and 7.1% at 20 months, respectively. The differences in the HbA1c values at month 20 were not statistically significant (Figure 3). The figure represents average HbA1c levels and the standard errors for the 2 cohorts. There was a significant difference in HbA1c levels between the 2 cohorts at months 0, 4, 8, and 12, but not at months 16 and 20. The greatest reduction in HbA1c levels was seen
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Initial Versus Sequential Combination Therapy
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Table 1. Baseline Demographic and Clinical Characteristics Characteristics
All Patients
Initial1 Combination Therapy [A]
Sequential1 Combination Therapy [B]
P value [A] vs [B]
(n = 461)
(n = 250)
(n = 211)
54.3 ± 9.1 264 (57.3%)
53.5 ± 9.3 145 (58.0%)
301 (65.3%) 76 (16.5%) 67 (14.5%) 16 (3.5%) 1 (0.2%) 126 (27.3%) 186 (40.4%) 149 (32.3%) 388 (84.2%) 20 (4.3%) 44 (9.5%) 9 (2.0%) 24 (5.2%) 2 (0.4%) 19 (4.1%) 42 (9.1%) 27 (5.9%) 9 (2.0%) 27 (5.9%) 144 (31.2%) 284 (61.6%) 308 (66.8%) 36 (7.8%) 207 (44.9%) 11 (2.4%) 1 (0.2%) 11 (2.4%)
154 (61.6%) 50 (20.0%) 34 (13.6%) 11 (4.4%) 1 (0.4%) 74 (29.6%) 91 (36.4%) 85 (34.0%) 205 (82.0%) 14 (5.6%) 25 (10.0%) 6 (2.4%) 14 (5.6%) 1 (0.4%) 12 (4.8%) 29 (11.6%) 14 (5.6%) 7 (2.8%) 16 (6.4%) 86 (34.4%) 141 (56.4%) 156 (62.4%) 19 (7.6%) 108 (43.2%) 5 (2.0%) 0 (0.0%) 8 (3.2%)
55.2 ± 8.8 119 (56.4%) 147 (69.7%) 26 (12.3%) 33 (15.6%) 5 (2.4%) 0 (0.0%) 52 (24.6%) 95 (45.0%) 64 (30.3%)
10 (4.7%) 1 (0.5%) 7 (3.3%) 13 (6.2%) 13 (6.2%) 2 (1.0%) 11 (5.2%) 58 (27.5%) 143 (67.8%) 152 (72.0%) 17 (8.1%) 99 (46.9%) 6 (2.8%) 1 (0.5%) 3 (1.4%)
0.052 0.729 0.101 0.164 0.394 0.679 0.904 0.425 0.043 0.798 0.152 0.589 0.111 0.012 0.029 0.855 0.424 0.554 0.276 0.213
359 (77.9%) 199 (43.2%) 7 (1.5%) 10 (2.2%)
180 (72.0%) 114 (45.6%) 3 (1.2%) 9 (3.6%)
179 (84.8%) 85 (40.3%) 4 (1.9%) 1 (0.5%)
0.001 0.251 0.543 0.022
164 (35.6%) 75 (16.3%) 45 (9.8%) 156 (33.8%) 349 (75.7%) 104 (22.6%) 8 (1.7%) 65 (14.1%) 36 (7.8%) 13 (2.8%) 16 (3.5%)
91 (36.4%) 35 (14.0%) 23 (9.2%) 79 (31.6%) 187 (74.8%) 57 (22.8%) 6 (2.4%) 37 (14.8%) 16 (6.4%) 10 (4.0%) 11 (4.4%)
73 (34.6%) 40 (19.0%) 22 (10.4%) 77 (36.5%) 162 (76.8%) 47 (22.3%) 2 (1.0%) 28 (13.3%) 20 (9.5%) 3 (1.4%) 5 (2.4%)
0.687 0.151 0.658 0.269 0.481 0.622 0.893 0.234 0.638 0.220 0.096 0.235
Demographic Age as of the index date (y; mean ± SD) Male (n, %) Race (n, %) White Black Hispanic Asian Others Physician specialty (n, %) General practice/primary care/family medicine Endocrinology Internal medicine Physician practice setting (n, %) Private Academic Mixed Others Comorbidities (n, %) Arteriosclerosis Cerebral ischemia Chronic renal disease/nephropathy Coronary artery disease Diabetic retinopathy History of heart failure History of hypoglycemia History of smoking Hyperlipidemia Hypertension Neuropathy Obesity (BMI $ 30 kg/m2) Peripheral vascular disease Ulceration or diabetic bone changes Others Medications (n, %) Oral antidiabetic medications Metformin Sulfonylureas Other oral antidiabetic medications No oral antidiabetic medications Other medications ACEi ARBs Other antihypertensives Antihyperlipidemics Index DPP-4i type Sitagliptin Saxagliptin Linagliptin Index therapy discontinuation PIO only DPP-4i only Both PIO and DPP-4i
183 (86.7%) 6 (2.8%) 19 (9.0%) 3 (1.4%)
(Continued) © Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 51 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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Table 1. (Continued) Characteristics
All Patients
Initial1 Combination Therapy [A]
Sequential1 Combination Therapy [B]
P value [A] vs [B]
(n = 461)
(n = 250)
(n = 211)
History of diabetes (y; mean ± SD)2 Baseline HbA1c level (mean ± SD) High severity (HbA1c . 9; n, %) Low severity (HbA1c # 9; n, %)
2.1 ± 3.3 8.3 ± 0.8 62 (13.5%) 399 (86.6%)
1.9 ± 2.8 8.6 ± 0.9 54 (21.6%) 196 (78.4%)
2.4 ± 3.9 8.0 ± 0.6 8 (3.8%) 203 (96.2%)
0.061 , 0.001 , 0.001 , 0.001
Patients are grouped into initial combination therapy cohort if they used both PIO and a DPP-4i within 30 days of each other. If patients used a DPP-4i after 60 days of PIO initiation but within 1 year, they are grouped into the sequential combination therapy cohort. For patients with no diabetes history information, the average of all the other patients within the specific cohort was used. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone; SD, standard deviation. 1
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2
in patients with higher HbA1c values at baseline. In linear regression analyses controlling for baseline characteristics (including baseline HbA1c level), patients treated with initial combination therapy with PIO and DPP-4i medications experienced a significantly greater reduction in HbA1c level than did sequential combination therapy patients at month 12 (−0.977 vs −0.819, P = 0.034), month 16 (−1.453 vs −1.242, P = 0.048), and month 20 (−1.182 vs −0.810, P = 0.013; Figure 4). The figure represents average HbA1c level reduction (± standard error) from baseline and the standard errors for the 2 cohorts. There was a significant difference in HbA1c levels between the 2 cohorts at months 12, 16, and 18, but not at months 4 and 8 (Table 2).
Discussion
Current ADA16 and AACE15 standards recommend that patients with T2DM experiencing poor glycemic control with
oral antidiabetic monotherapies (such as metformin, sulfonylureas, and others) should be treated with more aggressive therapies, combining $ 2 oral agents (such as PIO, a DPP-4i, incretin mimetics, α-glucosidase inhibitors, and others). In all proposed algorithms, TZD, a DPP-4i, or both are suggested as good second-tier add-on therapies, as various clinical trials have demonstrated their superior efficacy in combination with other drugs.17 The combination of PIO and a DPP-4i is considered suitable because these drugs are associated with a low risk of hypoglycemia.33 However, there is no consensus among clinicians and researchers about which therapy combinations should be administered to these patients and in what order.17,27,43,44 The use of fixed-dose combinations is believed to improve medication adherence and HbA1c level response to antihyperglycemic agents45; hence, use of PIO and a DPP-4i in a fixed-dose combination may reduce the discontinuation rates and further reduce blood sugar concentrations.
Figure 3. Mean (± standard error) HbA1c levels during 20-week initial or sequential combination therapy with PIO and DPP-4i. Figure 4. Change in mean (± standard error) HbA1c from baseline.
*P , 0.001. Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
52
*P , 0.05. Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
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Initial Versus Sequential Combination Therapy
Table 2. Average HbA1c Reduction in the Post-initiation Period by Therapy Status Observation Period1
Month 4 Month 8 Month 12 Month 16 Month 20
Initial Combination Therapy [A]
Sequential Combination Therapy [B]
P value [A] vs [B]
N
Unadjusted Reduction
Adjusted Reduction2
N
Unadjusted Reduction
Adjusted Reduction2
Unadjusted Reduction
Adjusted Reduction
235 213 217 118 85
-0.744 -1.058 -1.259 -1.366 -1.528
-0.648 -0.771 -0.977 -1.453 -1.182
200 171 186 83 53
-0.530 -0.712 -0.827 -0.914 -0.913
-0.624 -0.739 -0.819 -1.242 -0.810
0.011
0.695 0.634 0.034 0.048 0.013
, 0.001 , 0.001 , 0.001 , 0.001
HbA1c reduction is measured compared to baseline HbA1c level. Only the patients with HbA1c measurements during the period are included in the analysis. Generalized linear regression models were used to obtain the reduction in HbA1c level. The models adjust for physician specialty, practice setting, race, age, baseline HbA1c levels, history of diabetes, comorbidities, and medications. Abbreviation: HbA1c, glycosylated hemoglobin. 1
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2
In this comparative evaluation of initial compared with sequential combination therapy, we included PIO as the representative TZD, and sitagliptin, saxagliptin, or linagliptin as the DPP-4i, as these were the only drugs in their respective classes that were in widespread use in the United States at the time of the chart review.17,33 Previous clinical trials and studies involving the use of combination therapy with PIO and a DPP-4i demonstrated improved glycemic control in T2DM patients who have failed monotherapies,35,37–42 but did not address the question of whether administering the combination of drugs early, as an initial treatment, or adding one of the drugs later, sequentially, is of greater benefit to the patient. This study compared the effect of initial combination therapy with PIO and a DPP-4i compared with sequential combination therapy in the reduction of HbA1c values during an extended period of time (20 months). Only 2 previous studies have recorded HbA1c values past the typical 24- to 26-week study end point: Yoon et al42 performed a 54-week study of initial combination therapy with PIO and sitagliptin, whereas Gomis et al38 conducted a 78-week open-label extension study of sequential combination therapy with PIO and linagliptin. As there are significant differences in study design (including DPP-4i agents and cohort design) and patient baseline characteristics (including diabetes duration and HbA1c values at indexing) between these studies and our chart review, it is hard to draw a direct comparison between the conclusions of these studies and ours. To our best knowledge, this study is the first to explore the long-term effects of combination therapy of PIO and a DPP-4i in a naturalistic, real-world setting. The findings of this study indicate a possible benefit of initial combination therapy when compared with sequential combination therapy in the reduction of blood sugar.
Patients in the initial combination therapy cohort achieved a baseline-adjusted HbA1c value reduction of −1.182 at 20 months compared with a reduction of −0.812 (P = 0.013) for the sequential combination therapy group, both above the change of 0.5% identified as clinically significant by ADA/ European Association for the Study of Diabetes and the National Institute for Health and Clinical Excellence.46 The difference in reduction, together with findings from other studies demonstrating that HbA1c value reduction is associated with a reduced risk of diabetes-related complications (for example, the Diabetes Control and Complications Trial statistical methodology for patients with T2DM suggests a 21% reduction in deaths due to diabetes for every 1% decrease in HbA1c level),13 indicate that initial combination therapy could potentially result in greater improvements in patients’ morbidity compared with sequential combination therapy. The reduction in HbA1c level was greater for the initial combination therapy group throughout the followup period (though not significantly different between the 2 cohorts at the earliest time points of 4 and 8 months). The discontinuation rates observed in our study, of 14.8% in the case of initial combination therapy and of 13.3% in the case of sequential combination therapy, are relatively low and are in line with previously reported observations for retrospective studies and clinical trials.38,39,47 However, these results should be interpreted with some caution due to the previously noted differences in baseline HbA1c values between the 2 therapy regimens.
Limitations
Although physician-administered medical chart review data are suitable for examining real-world efficacies of various therapies, they are subject to limitations inherent to any retrospective observational study.
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First, the generalizability of the findings may be limited if the patient sample selected by the surveyed physicians is not representative of the general patient population diagnosed with T2DM. However, the physician panel used in this study was chosen to be representative of real-world practice in the United States. An effort was also made to encourage random selection of patients. Second, potential physician reporting errors and inaccuracy of physician recording of medical history information may have occurred, especially among physicians without electronic medical records systems. No information was collected on whether the patient information was accessed through an electronic medical records system. Nevertheless, this factor was expected to affect both cohorts to a similar extent and was thus unlikely to bias the conclusions. Third, the current study did not evaluate combination therapy outcomes stratified by the dosage of each drug component, nor did we limit it to patients who had no changes in dosage over the period of the study. Both PIO and the gliptins are administered in a range of dosages, as per the recommendations. Although this may limit the interpretability of our findings regarding a dose-related effect of each combination therapy component, prior studies have indicated that, with respect to PIO dosages, any such effect is minimal in combination therapies in terms of more effectively lowering HbA1c levels.40,48 Further studies are warranted to investigate dosage-stratified effects of the gliptins and pioglitazone in combination therapies, and with respect to real-world practices, in particular. Finally, patients were not randomized to initial compared with sequential combination therapies. Thus, the comparison between cohorts could be biased by unmeasured confounding. For example, patients may have been started on initial combination therapy if they presented a more severe disease profile, thus resulting in different baseline profiles for the 2 therapy groups. Every effort was made to collect patient characteristics that may have affected the physician’s decision to initiate combination therapy, and these factors were adjusted for in multivariable regressions. However, this study did not collect information on treatment after discontinuation or data prior to initiation of PIO in the sequential therapy arm, and hence it was not possible to adjust for these factors. Nevertheless, further research may be warranted on groups with similar baseline HbA1c levels and with randomization to these therapy regimens, in order to determine the comparable effect of the 2 combination therapy regimens on HbA1c value reduction.
54
Conclusions
This study found that the initial combination therapy of PIO with a DPP-4i led to a greater long-term reduction in blood glucose, as measured by HbA1c level, than sequential combination therapy with the same drugs for the treatment of T2DM. Comparative information pertaining to real-world treatment efficacies in the use of combination therapies may provide clinicians and health care professionals with valuable data to develop strategies for managing patients with poorly controlled T2DM.
Conflict of Interest Statement
This study was funded by Takeda Pharmaceuticals International, Inc., Deerfield, IL. Morgan Bron, PhD, is employed by Takeda Pharmaceuticals International. Eric Wu, PhD, Rajeev Ayyagari, PhD, Kristina Chen, PhD, Hari Sharma, MS, and Ana Bozas, PhD, are current or former employees of Analysis Group, Inc., which has received consultancy fees from Takeda Pharmaceuticals International. Although the sponsor was involved in the design, collection, and analysis of the information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication were made by the authors independently.
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Initial Versus Sequential Combination Therapy 11. Menzin J, Korn JR, Cohen J, et al. Relationship between glycemic control and diabetes-related hospital costs in patients with type 1 or type 2 diabetes mellitus. J Manag Care Pharm. 2010;16(4):264–275. 12. Oglesby AK, Secnik K, Barron J, Al-Zakwani I, Lage MJ. The association between diabetes related medical costs and glycemic control: a retrospective analysis. Cost Eff Resour Alloc. 2006;4(1):1. 13. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–412. 14. Shetty S, Secnik K, Oglesby AK. Relationship of glycemic control to total diabetes-related costs for managed care health plan members with type 2 diabetes. J Manag Care Pharm. 2005;11(7):559–564. 15. Rodbard HW, Jellinger PS, Davidson JA, et al. AACE/ACE Consensus Statement by an American Association of Clinical Endocrinologists/ American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):541–559. 16. Eizirik DL, Nathan DM, Buse JB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203. 17. Colagiuri S. Optimal management of type 2 diabetes: the evidence. Diabetes Obes Metab. 2012;14(Suppl 1):3–8. 18. Schwartz SS. Optimizing glycemic control and minimizing the risk of hypoglycemia in patients with type 2 diabetes. Drugs Context. 2013;2013:212255. 19. Bruderer SG, Bodmer M, Jick SS, Bader G, Schlienger RG, Meier CR. Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK—a nested case-control analysis. Diabetes Obes Metab. 2014. doi:10.1111/dom.12282. 20. Cheung BMY, Ong KL, Cherny SS, Sham PC, Tso AWK, Lam KSL. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122(5):443–453. 21. Fowler GC, Vasudevan DA. Type 2 diabetes mellitus: managing hemoglobin A(1c) and beyond. South Med J. 2010;103(9):911–916. 22. Stolar MW. Defining and achieving treatment success in patients with type 2 diabetes mellitus. Mayo Clin Proc. 2010;85 (12 Suppl):S50–S59. 23. Waugh N, Cummins E, Royle P, et al. Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation. Health Technol Assess. 2010;14(36):1–248. 24. Eskesen S, Kelsberg G, Hitchcock K, Lo V. Clinical inquiries. What is the role of combination therapy (insulin plus oral medication) in type 2 diabetes? J Fam Pract. 2006;55(11):1001–1003. 25. Poolsup N, Suksomboon N, Setwiwattanakul W. Efficacy of various antidiabetic agents as add-on treatments to metformin in type 2 diabetes mellitus: systematic review and meta-analysis. ISRN Endocrinol. 2012;2012:798146. 26. Mikhail N. Combination therapy with DPP-4 inhibitors and pioglitazone in type 2 diabetes: theoretical consideration and therapeutic potential. Vasc Health Risk Manag. 2008;4(6):1221–1227. 27. Aguilar RB. Evaluating treatment algorithms for the management of patients with type 2 diabetes mellitus: a perspective on the definition of treatment success. Clin Ther. 2011;33(4):408–424. 28. Gross B, Staels B. PPAR agonists: multimodal drugs for the treatment of type-2 diabetes. Best Pract Res Clin Endocrinol Metab. 2007;21(4):687–710. 29. Norris AW, Sigmund CD. A second chance for a PPARγ targeted therapy? Circ Res. 2012;110(1):8–11. 30. PPAR Research Journal. http://www.hindawi.com/journals/ppar/. Accessed March 13, 2013. 31. Derosa G, Maffioli P. Dipeptidyl peptidase-4 inhibitors: 3 years of experience. Diabetes Technol Ther. 2012;14(4):350–364. 32. Drab SR. Incretin-based therapies for type 2 diabetes mellitus: current status and future prospects. Pharmacotherapy. 2010;30(6):609–624.
33. Guthrie RM. Evolving therapeutic options for type 2 diabetes mellitus: an overview. Postgrad Med. 2012;124(6):82–89. 34. McIntosh B, Cameron C, Singh SR, et al. Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis. Open Med. 2011;5(1):e35–48. 35. Fonseca V, Staels B, Morgan JD, et al. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications. 2013;27(2):177–183. 36. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9(2):166–174. 37. Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13(7):653–661. 38. Gomis R, Owens DR, Taskinen MR, et al. Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucoselowering agents in 2121 subjects with type 2 diabetes: up to 2 years exposure in 24-week phase III trials followed by a 78-week open-label extension. Int J Clin Pract. 2012;66(8):731–740. 39. Pratley RE, Reusch JEB, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 2009;25(10):2361–2371. 40. Rosenstock J, Kim SW, Baron MA, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9(2):175–185. 41. Yoon KH, Shockey GR, Teng R, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of β-cell function in patients with type 2 diabetes. Int J Clin Pract. 2011;65(2):154–164. 42. Yoon KH, Steinberg H, Teng R, et al. Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54-week study. Diabetes Obes Metab. 2012;14(8):745–752. 43. Schernthaner G, Barnett A H, Betteridge DJ, et al. Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis. Diabetologia. 2010;53(7):1258–1269. 44. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154(9):602–613. 45. Han S, Iglay K, Davies MJ, Zhang Q, Radican L. Glycemic effectiveness and medication adherence with fixed-dose combination or coadministered dual therapy of antihyperglycemic regimens: a meta-analysis. Curr Med Res Opin. 2012;28(6):969–977. 46. National Institute for Health and Clinical Excellence. NICE Short Clinical Guideline 87—Type 2 Diabetes: Newer Agents for Blood Glucose Control in Type 2 Diabetes. London, UK: National Institute for Health and Clinical Excellence; 2009:1–102. http://www.nice.org.uk/nicemedia/ live/12165/44318/44318.pdf. Accessed March 13, 2013. 47. Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–1289. 48. Henry RR, Staels B, Fonseca VA, et al. Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone—a factorial study. Diabetes Obes Metab. 2014;16(3):223–230.
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Management of Patients Using Combination Therapy With Pioglitazone and a Dipeptidyl Peptidase-4 Inhibitor: An Analysis of Initial Versus Sequential Combination Therapy Morgan Bron PhD, Rajeev Ayyagari PhD, Hari Sharma MS, Kristina Chen PhD, Ana Bozas PhD & Eric Wu PhD To cite this article: Morgan Bron PhD, Rajeev Ayyagari PhD, Hari Sharma MS, Kristina Chen PhD, Ana Bozas PhD & Eric Wu PhD (2014) Management of Patients Using Combination Therapy With Pioglitazone and a Dipeptidyl Peptidase-4 Inhibitor: An Analysis of Initial Versus Sequential Combination Therapy, Postgraduate Medicine, 126:3, 47-55 To link to this article: http://dx.doi.org/10.3810/pgm.2014.05.2755
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Management of Patients Using Combination Therapy With Pioglitazone and a Dipeptidyl Peptidase-4 Inhibitor: An Analysis of Initial Versus Sequential Combination Therapy
DOI: 10.3810/pgm.2014.05.2755
Morgan Bron, PhD 1 Rajeev Ayyagari, PhD 2 Hari Sharma, MS 2 Kristina Chen, PhD 2 Ana Bozas, PhD 2 Eric Wu, PhD 2 1 Takeda Pharmaceuticals International, Inc., Deerfield, IL; 2Analysis Group, Inc., Boston, MA
Abstract: Current type 2 diabetes mellitus (T2DM) treatment involves progressive interventions from lifestyle changes to pharmacological therapies. Previous studies found that combination therapy with a dipeptidyl peptidase-4 inhibitor (DPP-4i) and pioglitazone (PIO) is more effective than monotherapies in treating poorly controlled T2DM, but there is no consensus on whether these drugs should be initiated at the same time (initial combination therapy) or sequentially. We aimed to assess glycemic control with initial versus sequential combination therapy with PIO and a DPP-4i in patients with glycosylated hemoglobin (HbA1c) levels $ 7%. A retrospective chart review was conducted on T2DM patients from diverse geographic sites in the United States initiating therapies from March 2, 2010 to February 28, 2011. Patients were selected for initial combination therapy, if starting PIO and a DPP-4i within 30 days of each other, or sequential combination therapy, if first taking PIO alone for $ 60 days before adding a DPP-4i within 1 year of PIO initiation. The HbA1c level reduction from baseline was compared between cohorts using linear regression models adjusting for demographics, baseline HbA1c, T2DM duration, comorbidities, and various medications. There were 250 patients in the initial and 211 in the sequential combination therapy cohorts; 57.3% were male, 65.3% were Caucasian, and the mean age was 54.3 years. Patients receiving initial combination therapy had a significantly higher mean baseline HbA1c level (8.6% vs 8.0%, P , 0.0001), a higher prevalence of coronary artery disease (11.6% vs 6.2%, P = 0.0430), and a lower prevalence of hyperlipidemia (56.4% vs 67.8%, P = 0.0120) and of hypertension (62.4% vs 72.0%, P = 0.0290), compared with the sequential therapy cohort. In adjusted analyses, initial combination therapy was associated with a significantly greater reduction in HbA1c levels than sequential combination therapy at months 12, 16, and 20 (−0.977 vs −0.819, P = 0.034; −1.453 vs −1.242, P = 0.048; and −1.182 vs −0.810, P = 0.013, respectively). Our findings suggest initial combination therapy may be the preferred option in choosing combination therapies. Keywords: type 2 diabetes mellitus; pioglitazone; dipeptidyl-peptidase IV inhibitors; gliptins; hemoglobin A1c protein; combination drug therapy
Correspondence: Rajeev Ayyagari, PhD, 111 Huntington Ave, 10th Floor, Boston, MA 02199. Tel: 617-425-8422 Fax: 617-425-8001 E-mail: [email protected]
Introduction
Increasingly larger numbers of individuals in the United States suffer from diabetes: from 23.6 million affected people (7.8% of the total population) in 20071 to 25.8 million people (8.3% of the total population) in 2011.2 Although the overall disease growth is slowing with time, most likely due to better diagnostic and prevention methods,
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Bron et al
the economic costs of diabetes are escalating, growing from an estimated $174 billion in 2007—or $202 billion when adjusted for inflation as of 2012—to $245 billion in 2012.3 Almost 90% of diabetic individuals have type 2 diabetes mellitus (T2DM),4 a chronic, progressive disease, characterized by deterioration of β-cell function over time, resulting in impaired insulin action, decreased insulin secretion, and increased hepatic glucose production.4–6 The subsequent increased circulating levels of glucose in the blood slowly bind to hemoglobin (over a period of 1–3 months) and result in increased levels of glycosylated hemoglobin (HbA1c).7 The HbA1c level is an indication of a patient’s overall glycemic control; it accurately predicts a patient’s diabetic potential,8–10 and has been shown to be correlated with improved patient health profiles and diabetes-related costs.11–14 Current American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) recommendations for the treatment of diabetes suggest patients aim to reach and maintain HbA1c blood levels , 6.5% (AACE) or , 7% (ADA)15–17 through progressive interventions—from lifestyle changes to various prescribed medication combinations.15,16 Approximately 40% of patients cannot safely achieve this goal on a single drug therapy without an increased risk of hypoglycemia (abnormally low blood glucose levels, typically , 70 mg/dL; hypoglycemia is a particular concern in patients treated with insulin or sulfonylureas)18,19 or adverse effects.20–22 Combination therapies have been explored in various clinical trials23–26 and are currently recommended by ADA and AACE for such patients.27 The pairing of thiazolidinedione (TZD) with a dipeptidyl peptidase-4 inhibitor (DPP-4i) is a common and successful combination of medications with complementary mechanisms of action, addressing the insulin secretion and sensitivity aspects of diabetes, as well as adipose tissue management.15 Pioglitazone (PIO) is the primary TZD used in current clinical practice. It works by binding the peroxisome proliferator-activated γ receptors (PPARγ) in the nuclei of fat cells, which, in turn, induces multiple signaling cascades, resulting in increased expression of glucose transporters, increased sensitivity of fat and β-cells to insulin, adipocyte remodeling, and improved β-cell function, among other effects.28–30 Ultimately, PIO use results in decreased insulin resistance and hepatic glucose production, while correcting the lipotoxicity, inflammation, and oxidative stress associated with free fatty acid overproduction.28–30 On the other hand, a DPP-4i works mainly through the incretin hormone system, by blocking fast-acting incretin peptide degradation enzymes 48
in the blood, thereby leading to mildly increased insulin secretion and suppressed glucagon release.31,32 Administered as initial monotherapy, or given after failed monotherapies, along with metformin or insulin, TZDs and a DPP-4i’s typically reduce HbA1c levels by 0.6% to 1.0%.23,33,34 When added to an existing therapy, these drugs can achieve an additional HbA1c reduction of approximately 1%.26,31 Although previous studies combining PIO with a DPP-4i indicate that a marked improvement in glycemic control is seen in patients treated with a combination of both drugs,35–42 there is no consensus on whether DPP-4i and PIO treatments should be initiated simultaneously (initial combination therapy) or whether patients with T2DM should start with PIO and then receive a DPP-4i at a later date (sequential combination therapy). Additionally, most combination therapy studies have only examined glycemic control achieved over a short period of time, typically 24 or 26 weeks; no long-term studies reliably address the issue of preferred combination therapy. To address this knowledge gap, we conducted a chart review study assessing the long-term, real-world effectiveness of reducing HbA1c blood levels through the use of initial and sequential combination therapies with PIO and a DPP-4i (sitagliptin, saxagliptin, or linagliptin) in patients with poor glycemic control (HbA1c level $ 7%).
Research Design and Methods Study Design
This retrospective physician-administered medical chart review study collected data on patients diagnosed with T2DM who received combination therapy with PIO and a DPP-4i. Physicians were invited to participate in this study through a vendor specializing in online surveys. The physicians were selected from an existing physician panel of medical professionals from diverse geographic sites in the United States, including both urban and rural areas, as well as private and academic practice settings. A total of 133 primary care physicians, endocrinologists, and internists participated in this study. Each physician was asked to select up to 5 eligible patients. To avoid any systematic selection bias, physicians were directed to choose patients whose last name started with a random computer-generated letter. If no last names started with that letter, patients were chosen from names matching the next closest letter in the alphabet. The participating physicians then selected patient information through an online chart abstraction form. The selected patients were distributed into 2 study cohorts: initial combination therapy and sequential combination
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Initial Versus Sequential Combination Therapy
therapy. The initial combination therapy group consisted of patients initiating PIO and a DPP-4i (sitagliptin, saxagliptin, or linagliptin) within 30 days of each other, without prior use of PIO or a DPP-4i. Patients were selected for the sequential combination therapy group only if they were first treated with PIO monotherapy for $ 60 days, and added a DPP-4i to the original therapy within 12 months. The date of initiation of the DPP-4i was called the initiation date for both cohorts. The baseline period was defined as the 1 month preceding the initiation date for both therapy groups. Additionally, to be considered eligible for this study, patients were required to (1) be aged $ 18 years as of therapy initiation date; (2) have a diagnosis of T2DM; (3) undergo treatment with either initial or sequential combination therapy initiated between March 2, 2010 and February 28, 2011; (4) continue T2DM treatment in the physician’s office for $ 1 year after initiation of drug therapy; (5) have $ 1 HbA1c laboratory measurement from the baseline period recorded in their charts (baseline HbA1c value); (6) have a baseline HbA1c level $ 7%; and (7) have $ 1 recorded HbA1c laboratory measurement during the follow-up period after therapy initiation. Patients who received insulin prior to the initiation date of the combination therapy were excluded from the study. Figure 1 summarizes the sample selection criteria. The initial data collected for each patient included demographics (age, sex, race, ethnicity), disease duration, comorbidities, and prior oral antidiabetic, antihyperlipidemic, Figure 1. Sample selection criteria.
and antihypertensive drug treatment profiles prior to the initiation of therapy. The HbA1c values were recorded at 4, 8, 12, 16, and 20 months following the therapy initiation date, if available. Physicians were also asked to provide information on treatment discontinuation, such as which drug was discontinued and at which time point in the follow-up period. Reasons for discontinuations were not provided. Figure 2 illustrates study design details. All abstracted data were de-identified and comply with the patient confidentiality requirements of the Health Insurance Portability and Accountability Act (HIPAA).
Statistical Analysis
Patient characteristics at baseline, including demographics, comorbidities, medications, baseline HbA1c level, and duration of diabetes, were compared between the initial and sequential combination therapy cohorts using Wilcoxon rank sum tests for continuous variables and Χ 2 tests for categorical variables. Descriptive analyses of measured HbA 1c values at months 4, 8, 12, 16, and 20 were performed for the initial and sequential combination therapies; unpaired t tests were used to compare HbA1c values. The rates of discontinuation of either drug during the follow-up period were compared between the cohorts using Χ 2 tests. Multivariate linear regression analysis was used to compare HbA1c level reduction from baseline values between the 2 combination therapies. Linear regression models adjusting for demographic variables, baseline HbA1c level, diabetes duration, comorbidities, and antidiabetic, antihypertensive, or antihyperlipidemic medications were fit to the data and used to obtain adjusted mean HbA1c level reductions from baseline during the studied time points (4, 8, 12, 16, and 20 months). The adjusted HbA1c values were compared between the initial and sequential combination therapy cohorts using Wald tests. A 2-sided α-level of 0.05 was used in determining statistical significance. All analyses used SAS version 9.3 software.
Results
Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
A total of 461 patients—250 patients from the initial combination therapy cohort and 211 from the sequential combination therapy cohort—satisfied the study selection criteria (Figure 1). Among physicians who participated in the survey, endocrinologists (40.4%) had a somewhat higher representation than primary care physicians (27.3%) and internists (32.3%). The majority of physicians (84.2%) were from private practice, with the remainder from mixed (9.5%),
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Figure 2. Study design.
Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
academic (4.3%), and other (2%) settings. The physicians’ specialties and practice settings did not differ significantly between the initial versus sequential combination therapy cohorts (Table 1). The most commonly used index DPP-4i was sitagliptin (taken by 75.7% of patients), followed by saxagliptin and linagliptin (taken by 22.6% and 1.7% of patients, respectively). The median gap between the initiation times of the 2 treatments was 0 days for initial combination therapy, indicating that the majority of patients initiated PIO and the DPP-4i simultaneously. The 75th percentile was 17 days. In the sequential combination therapy cohort, the median gap between initiations of the 2 treatments was 94 days. The majority of patients were Caucasians (65.3%), male (57.3%), and middle-aged (mean age was 54.3 ± 9.1 years), with mean T2DM duration of 2.1 years. Among the 461 patients, the most common reported comorbidities were hyperlipidemia (66.8%) and hypertension (61.6%), and 44.9% of patients were obese (body mass index $ 30 kg/m2). Prior to initiation of PIO or the index DPP-4i, most patients (77.9%) received metformin, many (43.2%) were treated with sulfonylureas, and a small proportion (2.2%) had not received any oral antidiabetic medications. Angiotensinconverting enzyme inhibitors (taken by 35.6% of patients) were the most common antihypertensive medication prior to initiation of PIO or the index DPP-4i, followed by angiotensin II receptor blockers (16.3%). Patients in the 2 cohorts generally had similar demographics, disease duration, and comorbidity profiles (Table 1). Some baseline characteristics differed between the 2 study 50
groups: the initial combination therapy cohort had a significantly higher mean baseline HbA1c level (8.6% vs 8.0%, P , 0.0001), a higher proportion of patients with HbA1c levels . 9% (21.6% vs 3.8%, P , 0.0001), and a higher prevalence of coronary artery disease (11.6% vs 6.2%, P = 0.043). Initial combination therapy patients had a lower prevalence of hyperlipidemia (56.4% vs 67.8%, P = 0.012) and of hypertension (62.4% vs 72.0%, P = 0.029) when compared with patients receiving sequential combination therapy. After initiation of combination therapy, discontinuation rates for either PIO or the index DPP-4i were low (14.1% of all patients), with the majority of discontinuations (7.8%) occurring for PIO, followed by discontinuations of both drugs (3.5%). Only 2.8% of patients discontinued the index DPP-4i without discontinuing PIO. There was no significant difference in the proportions of patients discontinuing combination therapy between the 2 cohorts (14.8% vs 13.3%, P = 0.638). In unadjusted analyses, both patient cohorts showed a similar trend of HbA1c values decreasing steadily from baseline over time. The HbA1c values decreased from 8.6% and 8.0% at baseline for the initial versus sequential combination therapy, to 7.0% and 7.1% at 20 months, respectively. The differences in the HbA1c values at month 20 were not statistically significant (Figure 3). The figure represents average HbA1c levels and the standard errors for the 2 cohorts. There was a significant difference in HbA1c levels between the 2 cohorts at months 0, 4, 8, and 12, but not at months 16 and 20. The greatest reduction in HbA1c levels was seen
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Initial Versus Sequential Combination Therapy
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Table 1. Baseline Demographic and Clinical Characteristics Characteristics
All Patients
Initial1 Combination Therapy [A]
Sequential1 Combination Therapy [B]
P value [A] vs [B]
(n = 461)
(n = 250)
(n = 211)
54.3 ± 9.1 264 (57.3%)
53.5 ± 9.3 145 (58.0%)
301 (65.3%) 76 (16.5%) 67 (14.5%) 16 (3.5%) 1 (0.2%) 126 (27.3%) 186 (40.4%) 149 (32.3%) 388 (84.2%) 20 (4.3%) 44 (9.5%) 9 (2.0%) 24 (5.2%) 2 (0.4%) 19 (4.1%) 42 (9.1%) 27 (5.9%) 9 (2.0%) 27 (5.9%) 144 (31.2%) 284 (61.6%) 308 (66.8%) 36 (7.8%) 207 (44.9%) 11 (2.4%) 1 (0.2%) 11 (2.4%)
154 (61.6%) 50 (20.0%) 34 (13.6%) 11 (4.4%) 1 (0.4%) 74 (29.6%) 91 (36.4%) 85 (34.0%) 205 (82.0%) 14 (5.6%) 25 (10.0%) 6 (2.4%) 14 (5.6%) 1 (0.4%) 12 (4.8%) 29 (11.6%) 14 (5.6%) 7 (2.8%) 16 (6.4%) 86 (34.4%) 141 (56.4%) 156 (62.4%) 19 (7.6%) 108 (43.2%) 5 (2.0%) 0 (0.0%) 8 (3.2%)
55.2 ± 8.8 119 (56.4%) 147 (69.7%) 26 (12.3%) 33 (15.6%) 5 (2.4%) 0 (0.0%) 52 (24.6%) 95 (45.0%) 64 (30.3%)
10 (4.7%) 1 (0.5%) 7 (3.3%) 13 (6.2%) 13 (6.2%) 2 (1.0%) 11 (5.2%) 58 (27.5%) 143 (67.8%) 152 (72.0%) 17 (8.1%) 99 (46.9%) 6 (2.8%) 1 (0.5%) 3 (1.4%)
0.052 0.729 0.101 0.164 0.394 0.679 0.904 0.425 0.043 0.798 0.152 0.589 0.111 0.012 0.029 0.855 0.424 0.554 0.276 0.213
359 (77.9%) 199 (43.2%) 7 (1.5%) 10 (2.2%)
180 (72.0%) 114 (45.6%) 3 (1.2%) 9 (3.6%)
179 (84.8%) 85 (40.3%) 4 (1.9%) 1 (0.5%)
0.001 0.251 0.543 0.022
164 (35.6%) 75 (16.3%) 45 (9.8%) 156 (33.8%) 349 (75.7%) 104 (22.6%) 8 (1.7%) 65 (14.1%) 36 (7.8%) 13 (2.8%) 16 (3.5%)
91 (36.4%) 35 (14.0%) 23 (9.2%) 79 (31.6%) 187 (74.8%) 57 (22.8%) 6 (2.4%) 37 (14.8%) 16 (6.4%) 10 (4.0%) 11 (4.4%)
73 (34.6%) 40 (19.0%) 22 (10.4%) 77 (36.5%) 162 (76.8%) 47 (22.3%) 2 (1.0%) 28 (13.3%) 20 (9.5%) 3 (1.4%) 5 (2.4%)
0.687 0.151 0.658 0.269 0.481 0.622 0.893 0.234 0.638 0.220 0.096 0.235
Demographic Age as of the index date (y; mean ± SD) Male (n, %) Race (n, %) White Black Hispanic Asian Others Physician specialty (n, %) General practice/primary care/family medicine Endocrinology Internal medicine Physician practice setting (n, %) Private Academic Mixed Others Comorbidities (n, %) Arteriosclerosis Cerebral ischemia Chronic renal disease/nephropathy Coronary artery disease Diabetic retinopathy History of heart failure History of hypoglycemia History of smoking Hyperlipidemia Hypertension Neuropathy Obesity (BMI $ 30 kg/m2) Peripheral vascular disease Ulceration or diabetic bone changes Others Medications (n, %) Oral antidiabetic medications Metformin Sulfonylureas Other oral antidiabetic medications No oral antidiabetic medications Other medications ACEi ARBs Other antihypertensives Antihyperlipidemics Index DPP-4i type Sitagliptin Saxagliptin Linagliptin Index therapy discontinuation PIO only DPP-4i only Both PIO and DPP-4i
183 (86.7%) 6 (2.8%) 19 (9.0%) 3 (1.4%)
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Bron et al
Table 1. (Continued) Characteristics
All Patients
Initial1 Combination Therapy [A]
Sequential1 Combination Therapy [B]
P value [A] vs [B]
(n = 461)
(n = 250)
(n = 211)
History of diabetes (y; mean ± SD)2 Baseline HbA1c level (mean ± SD) High severity (HbA1c . 9; n, %) Low severity (HbA1c # 9; n, %)
2.1 ± 3.3 8.3 ± 0.8 62 (13.5%) 399 (86.6%)
1.9 ± 2.8 8.6 ± 0.9 54 (21.6%) 196 (78.4%)
2.4 ± 3.9 8.0 ± 0.6 8 (3.8%) 203 (96.2%)
0.061 , 0.001 , 0.001 , 0.001
Patients are grouped into initial combination therapy cohort if they used both PIO and a DPP-4i within 30 days of each other. If patients used a DPP-4i after 60 days of PIO initiation but within 1 year, they are grouped into the sequential combination therapy cohort. For patients with no diabetes history information, the average of all the other patients within the specific cohort was used. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone; SD, standard deviation. 1
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2
in patients with higher HbA1c values at baseline. In linear regression analyses controlling for baseline characteristics (including baseline HbA1c level), patients treated with initial combination therapy with PIO and DPP-4i medications experienced a significantly greater reduction in HbA1c level than did sequential combination therapy patients at month 12 (−0.977 vs −0.819, P = 0.034), month 16 (−1.453 vs −1.242, P = 0.048), and month 20 (−1.182 vs −0.810, P = 0.013; Figure 4). The figure represents average HbA1c level reduction (± standard error) from baseline and the standard errors for the 2 cohorts. There was a significant difference in HbA1c levels between the 2 cohorts at months 12, 16, and 18, but not at months 4 and 8 (Table 2).
Discussion
Current ADA16 and AACE15 standards recommend that patients with T2DM experiencing poor glycemic control with
oral antidiabetic monotherapies (such as metformin, sulfonylureas, and others) should be treated with more aggressive therapies, combining $ 2 oral agents (such as PIO, a DPP-4i, incretin mimetics, α-glucosidase inhibitors, and others). In all proposed algorithms, TZD, a DPP-4i, or both are suggested as good second-tier add-on therapies, as various clinical trials have demonstrated their superior efficacy in combination with other drugs.17 The combination of PIO and a DPP-4i is considered suitable because these drugs are associated with a low risk of hypoglycemia.33 However, there is no consensus among clinicians and researchers about which therapy combinations should be administered to these patients and in what order.17,27,43,44 The use of fixed-dose combinations is believed to improve medication adherence and HbA1c level response to antihyperglycemic agents45; hence, use of PIO and a DPP-4i in a fixed-dose combination may reduce the discontinuation rates and further reduce blood sugar concentrations.
Figure 3. Mean (± standard error) HbA1c levels during 20-week initial or sequential combination therapy with PIO and DPP-4i. Figure 4. Change in mean (± standard error) HbA1c from baseline.
*P , 0.001. Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
52
*P , 0.05. Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycosylated hemoglobin; PIO, pioglitazone.
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Initial Versus Sequential Combination Therapy
Table 2. Average HbA1c Reduction in the Post-initiation Period by Therapy Status Observation Period1
Month 4 Month 8 Month 12 Month 16 Month 20
Initial Combination Therapy [A]
Sequential Combination Therapy [B]
P value [A] vs [B]
N
Unadjusted Reduction
Adjusted Reduction2
N
Unadjusted Reduction
Adjusted Reduction2
Unadjusted Reduction
Adjusted Reduction
235 213 217 118 85
-0.744 -1.058 -1.259 -1.366 -1.528
-0.648 -0.771 -0.977 -1.453 -1.182
200 171 186 83 53
-0.530 -0.712 -0.827 -0.914 -0.913
-0.624 -0.739 -0.819 -1.242 -0.810
0.011
0.695 0.634 0.034 0.048 0.013
, 0.001 , 0.001 , 0.001 , 0.001
HbA1c reduction is measured compared to baseline HbA1c level. Only the patients with HbA1c measurements during the period are included in the analysis. Generalized linear regression models were used to obtain the reduction in HbA1c level. The models adjust for physician specialty, practice setting, race, age, baseline HbA1c levels, history of diabetes, comorbidities, and medications. Abbreviation: HbA1c, glycosylated hemoglobin. 1
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2
In this comparative evaluation of initial compared with sequential combination therapy, we included PIO as the representative TZD, and sitagliptin, saxagliptin, or linagliptin as the DPP-4i, as these were the only drugs in their respective classes that were in widespread use in the United States at the time of the chart review.17,33 Previous clinical trials and studies involving the use of combination therapy with PIO and a DPP-4i demonstrated improved glycemic control in T2DM patients who have failed monotherapies,35,37–42 but did not address the question of whether administering the combination of drugs early, as an initial treatment, or adding one of the drugs later, sequentially, is of greater benefit to the patient. This study compared the effect of initial combination therapy with PIO and a DPP-4i compared with sequential combination therapy in the reduction of HbA1c values during an extended period of time (20 months). Only 2 previous studies have recorded HbA1c values past the typical 24- to 26-week study end point: Yoon et al42 performed a 54-week study of initial combination therapy with PIO and sitagliptin, whereas Gomis et al38 conducted a 78-week open-label extension study of sequential combination therapy with PIO and linagliptin. As there are significant differences in study design (including DPP-4i agents and cohort design) and patient baseline characteristics (including diabetes duration and HbA1c values at indexing) between these studies and our chart review, it is hard to draw a direct comparison between the conclusions of these studies and ours. To our best knowledge, this study is the first to explore the long-term effects of combination therapy of PIO and a DPP-4i in a naturalistic, real-world setting. The findings of this study indicate a possible benefit of initial combination therapy when compared with sequential combination therapy in the reduction of blood sugar.
Patients in the initial combination therapy cohort achieved a baseline-adjusted HbA1c value reduction of −1.182 at 20 months compared with a reduction of −0.812 (P = 0.013) for the sequential combination therapy group, both above the change of 0.5% identified as clinically significant by ADA/ European Association for the Study of Diabetes and the National Institute for Health and Clinical Excellence.46 The difference in reduction, together with findings from other studies demonstrating that HbA1c value reduction is associated with a reduced risk of diabetes-related complications (for example, the Diabetes Control and Complications Trial statistical methodology for patients with T2DM suggests a 21% reduction in deaths due to diabetes for every 1% decrease in HbA1c level),13 indicate that initial combination therapy could potentially result in greater improvements in patients’ morbidity compared with sequential combination therapy. The reduction in HbA1c level was greater for the initial combination therapy group throughout the followup period (though not significantly different between the 2 cohorts at the earliest time points of 4 and 8 months). The discontinuation rates observed in our study, of 14.8% in the case of initial combination therapy and of 13.3% in the case of sequential combination therapy, are relatively low and are in line with previously reported observations for retrospective studies and clinical trials.38,39,47 However, these results should be interpreted with some caution due to the previously noted differences in baseline HbA1c values between the 2 therapy regimens.
Limitations
Although physician-administered medical chart review data are suitable for examining real-world efficacies of various therapies, they are subject to limitations inherent to any retrospective observational study.
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Bron et al
First, the generalizability of the findings may be limited if the patient sample selected by the surveyed physicians is not representative of the general patient population diagnosed with T2DM. However, the physician panel used in this study was chosen to be representative of real-world practice in the United States. An effort was also made to encourage random selection of patients. Second, potential physician reporting errors and inaccuracy of physician recording of medical history information may have occurred, especially among physicians without electronic medical records systems. No information was collected on whether the patient information was accessed through an electronic medical records system. Nevertheless, this factor was expected to affect both cohorts to a similar extent and was thus unlikely to bias the conclusions. Third, the current study did not evaluate combination therapy outcomes stratified by the dosage of each drug component, nor did we limit it to patients who had no changes in dosage over the period of the study. Both PIO and the gliptins are administered in a range of dosages, as per the recommendations. Although this may limit the interpretability of our findings regarding a dose-related effect of each combination therapy component, prior studies have indicated that, with respect to PIO dosages, any such effect is minimal in combination therapies in terms of more effectively lowering HbA1c levels.40,48 Further studies are warranted to investigate dosage-stratified effects of the gliptins and pioglitazone in combination therapies, and with respect to real-world practices, in particular. Finally, patients were not randomized to initial compared with sequential combination therapies. Thus, the comparison between cohorts could be biased by unmeasured confounding. For example, patients may have been started on initial combination therapy if they presented a more severe disease profile, thus resulting in different baseline profiles for the 2 therapy groups. Every effort was made to collect patient characteristics that may have affected the physician’s decision to initiate combination therapy, and these factors were adjusted for in multivariable regressions. However, this study did not collect information on treatment after discontinuation or data prior to initiation of PIO in the sequential therapy arm, and hence it was not possible to adjust for these factors. Nevertheless, further research may be warranted on groups with similar baseline HbA1c levels and with randomization to these therapy regimens, in order to determine the comparable effect of the 2 combination therapy regimens on HbA1c value reduction.
54
Conclusions
This study found that the initial combination therapy of PIO with a DPP-4i led to a greater long-term reduction in blood glucose, as measured by HbA1c level, than sequential combination therapy with the same drugs for the treatment of T2DM. Comparative information pertaining to real-world treatment efficacies in the use of combination therapies may provide clinicians and health care professionals with valuable data to develop strategies for managing patients with poorly controlled T2DM.
Conflict of Interest Statement
This study was funded by Takeda Pharmaceuticals International, Inc., Deerfield, IL. Morgan Bron, PhD, is employed by Takeda Pharmaceuticals International. Eric Wu, PhD, Rajeev Ayyagari, PhD, Kristina Chen, PhD, Hari Sharma, MS, and Ana Bozas, PhD, are current or former employees of Analysis Group, Inc., which has received consultancy fees from Takeda Pharmaceuticals International. Although the sponsor was involved in the design, collection, and analysis of the information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication were made by the authors independently.
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