Morita2019 Article TreatmentPatternsOfDrug-naiveP
Morita2019 Article TreatmentPatternsOfDrug-naiveP
Morita2019 Article TreatmentPatternsOfDrug-naiveP
Abstract
Background: Guidelines for Type 2 diabetes mellitus (T2DM) management in Japan provide physicians the discre-
tion to select treatment options based on patient pathophysiology of the disease. There exists a wide variation of
preference for initial antidiabetes drugs (AD). The current database analysis aimed to understand the real world treat-
ment patterns in drug-naive patients with T2DM in Japan.
Methods: We analyzed data of patients (≥ 18 years) diagnosed with T2DM between October 2012 and September
2016 from the Medical Data Vision, a Diagnosis Procedure Combination database. The primary objective was to deter-
mine the proportion of T2DM patients receiving each type of treatment as first-line therapy among the drug-naive
cohort.
Results: Of the 436,546 drug-naive patients, 224,761 received their first-line T2DM treatment in the outpatient set-
ting. The mean age of the patient population was 65.6 years at index date. Dipeptidyl peptidase-4 (DPP-4) inhibitor
was the most prescribed (56.8%) outpatient AD monotherapy, followed by metformin (15.4%). DPP-4 inhibitors were
prescribed over metformin in patients with renal disease (odds ratio [OR]: 4.20; p < 0.0001), coronary heart disease and
stroke (OR: 2.22; p < 0.0001). Male (OR: 1.03; p = 0.0026), presence of diabetic complications [retinopathy (OR: 1.33;
p < 0.0001), neuropathy (OR: 1.05; p = 0.0037), nephropathy (OR: 1.08; p < 0.0001)] and a high baseline HbA1c (OR: 1.45;
p < 0.0001) received treatment intensification during 180 days.
Conclusion: DPP-4 inhibitors were the most prevalent first-line T2DM treatment followed by metformin in Japan.
The findings from this retrospective analysis also support the previously published web survey results and can help
understand the real world utilization of T2DM treatment.
Trial registration Retrospectively registered
Keywords: Database analysis, Dipeptidyl peptidase-4 inhibitor, Drug-naive, Japan, Metformin, Real world, Treatment
intensification, Type 2 diabetes mellitus
*Correspondence: yohei.morita@novartis.com
1
Medical Division, Novartis Pharma K.K, Toranomon Hills, Mori Tower 23‑1,
Toranomon 1‑Chome, Minato‑ku, Tokyo 105‑6333, Japan
Full list of author information is available at the end of the article
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Morita et al. Diabetol Metab Syndr (2019) 11:90 Page 2 of 10
Background index date, while the post-index period was 180 days after
Type 2 diabetes mellitus (T2DM) is a major health con- the index date. The study schema is depicted in Fig. 1.
cern that imposes a significant socio-economic bur-
den worldwide. In Japan, the prevalence of T2DM was Study objectives
about 7.7% in adults aged 20–79 years in 2017, and it was The primary objective of the analysis was to determine
among the 10 ten countries in the world with the highest the proportion of patients receiving each type of T2DM
expenditure on diabetes [1]. Despite the availability and therapy (AD or insulin) as first-line treatment. The sec-
advancement of several therapeutic options for the treat- ondary objectives were to determine: (1) the features
ment of T2DM [2], less than half of all patients in Japan of drug-naive patients treated with the first and second
reach the optimal glycemic goal of glycated hemoglobin most frequently used outpatient AD monotherapy, (2)
(HbA1c) < 7% [3, 4]. the proportion of patients with T2DM requiring addi-
Guidelines for T2DM management in Japan provide tional treatment within 180 days after initiation of the
physicians the discretion to select treatment options first-line treatment in outpatient settings, and (3) patient
based on patient needs and pathophysiology of the dis- characteristics associated with this additional treatment.
ease [2]; this could result in a wide variation in the pre- In addition, the exploratory objective was to determine
scription of antidiabetes drugs (AD) and treatment the proportion of patients with T2DM undergoing one
patterns in clinical practice [5]. Thus, there is a need to or more examinations for diabetic complications of inter-
understand the factors that drive these preferences in est—neuropathy, retinopathy, and nephropathy.
prescriptions.
Furthermore, treatment intensification during the Data sources and sample size
course of the disease is crucial to achieve good glycemic The MDV database used in this study is a DPC adminis-
control to prevent diabetes-related complications [6, 7]. trative database. As of 2015, the MDV database included
In some instances, patients may require an additional records of > 11 million patients from > 200 acute phase
oral antidiabetes drug (OAD) in the short term (less than Japanese institutions. Data for elderly patients (> 65 years
6 months) after starting the first OAD. However, there is of age) are included, along with patients’ characteris-
limited evidence on the characteristics of patients who tics (e.g. age, sex, concomitant disease) and treatment
require additional treatment, and there are no data on information (name and dosage of the prescribed drugs).
physicians’ preferences of the OAD as an add-on therapy. However, the availability of HbA1c data was limited to
Our earlier results based on an online survey of phy- approximately 25% of the sampled patients. The cod-
sicians highlighted the factors influencing the prescrib- ing of diagnoses and disease names was standardized
ing patterns for drug-naive T2DM patients in Japan [8]. using the International Classification of Diseases, tenth
In the present analysis, we used data from The Medical revision (ICD-10) and the disease codes of the Medical
Data Vision (MDV) database, a Diagnosis Procedure Information System Development Center (MEDIS-DC),
Combination (DPC) administrative database containing respectively [11].
extensive data from across Japan [9, 10], to help us under-
stand the treatment patterns and factors driving these Statistical analysis
preferences in the real world setting. Findings from this Categorical variables were presented as numbers and
analysis will provide better understanding of initial treat- proportions; continuous variables were expressed as
ment patterns and treatment intensification, and factors mean, standard deviation, interquartile range, and range.
associated with these prescribing patterns, in drug-naive Univariate logistic regression was used to assess the
patients with T2DM in Japan. odds ratio (OR) and 95% confidence interval (CI) for the
most vs second most frequently prescribed first-line AD
Methods with each patient demographic and clinical characteris-
Study design and population tic of interest. Similar analyses were performed examin-
This was a retrospective cohort, non interventional study ing patients requiring vs not requiring additional T2DM
involving secondary use of data collected from the MDV treatment within 180 days after the index date. The fre-
database during 01 October 2012 to 30 September 2016 quency and percentage of missing data were calculated
in Japan. Patients aged ≥ 18 years and on the first record for each variable.
with a confirmed diagnosis of T2DM in outpatient set-
tings were included in the analysis. The index date was Ethical considerations
defined as the date of the first record with a code for This study was conducted in accordance with the Ethi-
T2DM treatment (AD or insulin) on or after the diag- cal Guidelines for Medical and Health Research Involv-
nosis date. The pre-index period was 180 days before the ing Human Subjects (The Ministry of Education,
Morita et al. Diabetol Metab Syndr (2019) 11:90 Page 3 of 10
Fig. 1 Study schema. *Proportion of patients receiving each type of T2DM therapy (AD or insulin) as first-line treatment. ^Features of drug-naive
patients treated with the first and second most frequently used outpatient AD monotherapy. #Proportion of patients with T2DM undergoing one
or more examinations for diabetic complications of interest. AD antidiabetes, HbA1c glycated hemoglobin, MDV Medical Data Vision, T2DM type 2
diabetes mellitus
Culture, Sports, Science and Technology and the Min- proportion of patients diagnosed with coronary heart
istry of Health, Labour and Welfare, Japan). A central disease and stroke was the highest at 30.9% followed by
ethics committee of the Clinical Research Promotion liver disease at 21.9%; renal disease was the least diag-
Network reviewed and approved the study protocol since nosed comorbidity at 9.0%. The mean HbA1c level was
no personally identifiable data was included in the data- 8.0% in the 16,429 (7.3%) patients with available data on
base extraction for the study. HbA1c levels.
Additionally, 2.7% of the outpatients were classified
Results as having diabetes with intensified therapy and HbA1c
Participants levels ≥ 8.0%. A total of 91,554 (40.7%) outpatients had
A total of 662,678 patients in the MDV database with at least one clinic visit during 180 days pre-index date,
a diagnosis of T2DM during the study period were with a mean of 3.8 total visits.
retrieved for the analysis, of which 436,546 (65.9%)
patients were adults with T2DM treatment on or after
the diagnosis date. The number of patients with an out- Selection of first‑line AD therapy for drug‑naive patients
patient record for first-line T2DM treatment was 224,761 with T2DM
(33.9%). Figure 2 is a flowchart depicting the summary of Overall
patient selection for the analysis. Among 436,546 patients included in the drug-naive
cohort, 224,761 (51.5%) received their first-line T2DM
Baseline demographics and clinical characteristics treatment in the outpatient setting. Of these, 81.2%
Details of the baseline demographics and clinical char- received AD therapy, 9.3% insulin therapy and 9.5%
acteristics of the outpatient cohort are presented in insulin and AD combination therapy as first-line
Table 1. The mean age of the patients was 65.6 years T2DM treatment at index date. The total proportion
at the index date and 61.2% were male. The mean of patients who received AD intracombination (35.0%),
body mass index (BMI) was 24.6 kg/m2 in the 12,839 insulin and AD combination (9.3%) or insulin (9.5%)
(5.7%) patients where data on BMI was available. The was 53.8% (Fig. 3). More outpatients received AD intra
combination therapy (43.1%) than monotherapy.
Morita et al. Diabetol Metab Syndr (2019) 11:90 Page 4 of 10
Fig. 2 Flow chart of patient selection from the MDV database. AD antidiabetes drugs, MDV Medical Data Vision, T2DM type 2 diabetes mellitus
Fig. 3 Selection of first-line AD therapy for drug-naive patients with T2DM in the outpatient setting. AD antidiabetes drugs, DPP-4 dipeptidyl
peptidase-4, GI glucosidase inhibitor, GLP-1 RA glucagon like peptide-1 receptor agonist, SGLT-2 sodium glucose co-transporter-2, SU sulfonylurea,
T2DM type 2 diabetes mellitus, TZD thiazolidinediones
Table 2 Univariate logistic regression analysis of DPP-4 inhibitors vs metformin as first-line outpatient AD therapy
with patient characteristics and comorbidities
Prescribed drug class Treatment factors OR 95% CI
Lower limit Upper limit
to the findings from the previous web-based survey [8], in Japan. To optimize the usage of metformin, there is a
indicating a gap between the physicians’ intentions and need to discuss and overcome the barriers, which may
the actual prescription pattern in the real-world setting lead to hesitation among physicians to prescribe it.
Morita et al. Diabetol Metab Syndr (2019) 11:90 Page 7 of 10
Table 3 Patient characteristics associated with additional plausible reason could be that data from DPC hospitals
treatment during 180 days post-index date also included patients aged > 65 years possibly with mul-
Patient characteristics OR 95% CI tiple moderate-to-severe comorbidities [19, 20] which
could have resulted in higher proportion of patients with
Lower limit Upper limit
coronary heart disease/stroke or liver diseases.
HbA1c level %a 1.45* 1.42 1.48 It was observed that elderly patients and patients
Diabetic retinopathya 1.33* 1.29 1.37 with renal disease were associated with a prescription
Patient total visitsa 1.18* 1.14 1.22 of DPP-4 inhibitors as the index treatment. This may
Diabetic nephropathya 1.08* 1.04 1.11 be partly due to the use of metformin being avoided in
Diabetic neuropathya 1.05§ 1.02 1.09 patients at risk for lactic acidosis, such as older individ-
Gender (male vs femaleb) 1.03^ 1.01 1.06 uals and those with advanced renal insufficiency [21].
BMIa 1.00# 0.99 1.01 Thus, DPP-4 inhibitors may be perceived as the safer
Age at index date 0.98* 0.98 0.98 treatment option in such cases. Furthermore, BMI was
Renal diseasea 0.94ψ 0.91 0.98 associated with the prescription of metformin as the
Liver disease a
0.88* 0.85 0.90 index T2DM treatment vs DPP-4 inhibitors, confirming
Coronary heart disease and strokea 0.73* 0.72 0.75 the results of the web-based survey [8]. This may be sup-
An OR > 1 indicates a positive association with receiving additional treatment
ported by the findings from the UKPDS 34 study, where
BMI body mass index, CI confidence interval, HbA1c glycated haemoglobin, ns
metformin was shown to decrease the risk of diabetes-
non significant, OR odds ratio related complications in overweight patients and was
* p < 0.0001, §p = 0.0037, ^p = 0.0026, ψp = 0.0014, #p = 0.721 (ns). Patient’s total associated with weight neutrality and fewer hypoglyce-
visits > sample median total visits vs patient’s total visits ≤ sample median total
mic events [22]. However, there are studies such as the
visits
a
Assessed within the 180 days before the index date
Melbin observational research (MORE) study in Japanese
b
Female were the referent group for male vs female
patients which demonstrated that the HbA1c reduction
was comparable (0.9 ± 1.2% vs 1.0 ± 1.4%) in patients
with BMI ≥ or < 25 kg/m2 indicating that regardless of
Overall, the proportion of patients diagnosed with body weight, metformin may have the same effect in
coronary heart disease/stroke was comparatively higher patients with T2DM [23].
as compared to those with other comorbidities in the The current results showed that a diagnosis of mac-
drug-naive cohort at baseline. One of the factors could rovascular disease and renal disease were associated
be considerable proportion of patients with hyperten- with prescription of DPP-4 inhibitors rather than met-
sion and dyslipidemia, which are established risk factors formin, while diagnosis of a microvascular complication
for cardiovascular and liver diseases [17, 18]. Another was associated with the prescription of metformin over
DPP-4 inhibitors as the index T2DM treatment. This important being the inability to follow the clinical record
may indicate that metformin was considered more use- if the patient moves from one hospital to another. Hence,
ful for patients diagnosed with microvascular disease there is a possibility that patients were misclassified as
based on the findings from the UKPDS study [22]. How- drug-naive since we could not, from this database, dif-
ever, the reasons for the use of DPP-4 inhibitors over ferentiate real drug-naive patients and patients referred
metformin in patients with coronary heart disease and from clinics who have already been treated with AD. Fur-
stroke remains unclear. Additionally, at that time of the ther, the analysis was not adjusted for key confounding
database analysis, DPP-4 inhibitors were considered to factors such as age, gender, duration of diabetes, and thus
increase hypoglycemia, as indicated in several reports of future studies including multivariate logistic regression
hypoglycemia with DPP-4 inhibitors in combination with models to simultaneously control multiple potential con-
SUs [24]. As low glycemia is one of the causes of retin- founders are warranted. Additionally, patients included
opathy, metformin may have been preferred over DPP-4 in the analysis were a convenience sample from hospitals
inhibitors in patients with microvascular disease. Find- contributing data to the database rather than a random
ings from earlier studies suggest that about 1 in 3 patients sample of patients in order to meet the selection criteria.
with T2DM will develop retinopathy, 1 in 4 will develop Although we cannot be sure that our convenience sample
nephropathy, and 1 in 2 will develop neuropathy [25–27] is representative of the general T2DM patient population
due to suboptimal glycemic control. However, with opti- in Japan, the MDV database includes extensive patient
mal glycemic control, these microvascular complications specific data from over 100 acute phase hospitals in Japan
may be delayed or prevented [28, 29]. [9, 10].
The present database analysis showed that high base-
line HbA1c was the key driving factor influencing phy-
sicians to choose add-on treatment, while BMI did not Conclusions
affect the decision of treatment intensification. The pro- The present database analysis confirms that the most
portion of patients diagnosed with macrovascular disease prevalent first-line outpatient T2DM monotherapy is
requiring additional T2DM treatment during 180 days DPP-4 inhibitors in Japan, followed by metformin. The
post-index date was markedly low while the proportion dominant patient characteristic associated with receiv-
of patients diagnosed with microvascular disease requir- ing a prescription of a DPP-4 inhibitor over metformin
ing additional treatment was comparatively high. This was a diagnosis of renal impairment. Male compared to
may be attributed to the insights from the ACCORD female, patients with diabetic complications and high
study, which showed that intensive glucose lowering baseline HbA1c, were more likely to receive treatment
therapy does not have an effect on the prevention of intensification. Although these analyses did not adjust for
death for those who already have macrovascular disease key confounders, they may offer some early evidence to
[30]. In such a condition, the physician’s concern might assist physicians with understanding patient character-
be more towards avoiding low blood glucose than in low- istics associated with the initiation of T2DM treatment
ering HbA1c. On the other hand, studies have demon- and additional therapy. The findings from the web survey
strated that intensive glucose-lowering therapy reduces and database analysis revealed similarities as well as dif-
or delays the onset and progression of diabetic retinopa- ferences between physicians’ intentions and the actual
thy, neuropathy and nephropathy [28, 29, 31]. prescription of drugs among drug-naive T2DM patients
In the present database analysis, patients received more in Japan. Overall, these findings may help physicians
examinations for diabetic retinopathy and nephropathy understand real world utilization of T2DM treatment
compared to diabetic neuropathy. The clinical evalua- among Japanese adults and further help refine treatment
tion and investigations of diabetic neuropathy involve algorithms.
challenges and its diagnosis can be difficult due to the
co occurrence of other similar symptoms, thus only a Abbreviations
small proportion of patients are extensively evaluated AD: antidiabetes drugs; ADA: American Diabetes Association; Alpha-GI:
for this condition [32]. As most of these examinations alpha-glucosidase inhibitor; BMI: body mass index; DPC: Diagnosis Procedure
Combination; DPP-4: dipeptidyl peptidase-4; EASD: European Association for
should have been conducted before treatment initiation, the Study of Diabetes; ICD-10: International Classification of Diseases, tenth
it is possible that several patients included in the cur- revision; MDV: Medical Data Vision; MEDIS-DC: Medical Information System
rent analysis may have been introduced from another Development Center; MORE: Melbin observational research; OAD: oral antidia-
betes drug; SGLT2i: sodium glucose co-transporter-2 inhibitor; SU: sulfonylu-
hospital. rea; T2DM: type 2 diabetes mellitus.
Certain limitations of this study are inherent to all stud-
ies using secondary data [33] and must be acknowledged. Acknowledgements
The authors also thank Ishita Guha Thakurta, PhD, CMPP of Novartis Healthcare
The MDV database has several limitations, the most Pvt. Ltd, Hyderabad, India for medical writing support, funded by Novartis
Morita et al. Diabetol Metab Syndr (2019) 11:90 Page 9 of 10
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Funding 8. Murayama H, Imai K, Odawara M. Factors influencing the prescribing
Sponsorship and article processing charges for this study were funded by preferences of physicians for drug-naive patients with type 2 diabetes
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Competing interests claims-based cohort study. BMJ Open. 2019;9(3):e025806.
Yohei Morita is employee of Novartis Pharma K.K. Masato Odawara has served 14. Oishi M, Yamazaki K, Okuguchi F, et al. Changes in oral antidiabetic pre-
as an advisory board member for Novartis; has received research grants with scriptions and improved glycemic control during the years 2002–2011 in
contracts from Novo Nordisk and Astellas; has received unrestricted research Japan (JDDM32). J Diabetes Investig. 2014;5:581–7.
grants from Daiichi Sankyo, MSD, Ono, Novartis, Astellas, Sanwa Kagaku 15. American Diabetes Association. Prevention or delay of type 2 diabetes.
Kenkyusho, AstraZeneca, Kyowa Hakko Kirin, Kowa, Takeda, Mitsubishi Tanabe, Sec. 5. In Standards of Medical Care in Diabetes-2017. Diabetes Care.
Eli Lilly, Nippon Boehringer, Sanofi, Novo Nordisk, Sumitomo Dainippon, and 2017;40(Suppl. 1):S44–7.
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