Diabetes Ther (2018) 9:1185–1199 https://doi.org/10.1007/s13300-018-0431-3 ORIGINAL RESEARCH Factors Inﬂuencing the Prescribing Preferences of Physicians for Drug-Naive Patients with Type 2 Diabetes Mellitus in the Real-World Setting in Japan: Insight from a Web Survey . . Hiroki Murayama Kota Imai Masato Odawara Received: March 14, 2018 / Published online: April 25, 2018 The Author(s) 2018 primary endpoints were the proportions of ABSTRACT physicians who considered particular treatment factors and patient characteristics when select- Introduction: The Japanese guidelines for type ing the appropriate treatment for drug-naive 2 diabetes mellitus (T2DM) emphasize individ- T2DM patients. ualization of treatment based on patient need Results: A total of 491 physicians participated and encourage physicians to select an appro- in the survey. Dipeptidyl peptidase-4 inhibitors priate oral antidiabetes drug (OAD). However, (DPP-4is) were the most-preferred ﬁrst-line limited evidence is available on the factors OADs, followed by metformin, of both special- inﬂuencing the selection by physicians (dia- ists (69% vs. 60%) and nonspecialists (73% vs. betes specialists and nonspecialists) of the ﬁrst- 47%). The most inﬂuential factors when a DPP- line OAD to treat drug-naive patients with 4i was selected were found to be glycated T2DM. A survey was designed to explore the hemoglobin (HbA1c), postprandial glucose treatment factors and patient characteristics (PPG)-lowering effect, and a low risk of hypo- that inﬂuence physicians when they choose an glycemia, which were considered by [ 80% of initial OAD to prescribe to a drug-naive patient physicians, whereas the key factors when met- with T2DM in a real-world setting in Japan. formin was selected were improvement in Methods: The 25-min web-based online survey insulin resistance, low cost, low risk of hypo- consisted of simple and focused multiple-choice glycemia, and PPG- and HbA1c-lowering effects, questions, and was circulated to physicians which were considered by [ 85% of physicians. across eight selected regions in Japan. The Regression analysis revealed that the dominant reason for choosing DPP-4is over metformin Enhanced Digital Features To view enhanced digital was their ease of use in patients with renal features for this article go to https://doi.org/10.6084/ impairment, whereas the dominant reasons for m9.ﬁgshare.6126977. choosing metformin over DPP-4is were improvement in insulin resistance and low cost. H. Murayama (&) K. Imai Medical Division, Novartis Pharma K.K, Toranomon The key patient characteristics driving the Hills, Mori tower, 23-1, Toranomon 1-Chome, choice of DPP-4is or metformin as the ﬁrst-line Minato-ku, Tokyo 105-6333, Japan OAD by physicians were similar to those that e-mail: firstname.lastname@example.org inﬂuenced the treatment intensiﬁcation deci- M. Odawara sion (DPP-4is: PPG and renal function; met- Department of Diabetes, Endocrinology, formin: age, BMI, insulin resistance, and renal Metabolism, and Rheumatology, Tokyo Medical function). University, Tokyo, Japan 1186 Diabetes Ther (2018) 9:1185–1199 Conclusion: In Japan, DPP-4is are the preferred costs (when patients have to pay for the drug), ﬁrst-line OADs, followed by metformin. The key and polypharmacy can pose a challenge to treatment factors and patient characteristics physicians treating T2DM . This could lead to considered when selecting DPP-4is or met- wide variation in the drugs chosen and in formin are similar for both specialists and treatment patterns among the physicians in nonspecialists. These results may prompt fur- Japan . ther discussion of the differences in T2DM Although metformin is the ﬁrst-line thera- treatment between Japan and other counties. peutic option for T2DM in the US and European Funding: Novartis. countries , a considerable number of T2DM patients receive other OADs as their initial therapy [10, 11], which suggests that, apart Keywords: Dipeptidyl peptidase-4 inhibitor; from recommendations, the pathophysiology Diabetes nonspecialist; Diabetes specialist; of the disease and the patient’s condition can Drug-naive; Japan; First line; Metformin; also inﬂuence pharmacotherapy practice . Online survey; Oral antidiabetes drugs; It is therefore vital to understand the factors Treatment choices; Type 2 diabetes mellitus that inﬂuence the selection of treatment for drug-naive T2DM patients by physicians. INTRODUCTION Although there is substantial evidence of the prescription patterns that occur in many coun- In parallel with the steadily increasing burden tries, including Japan [8, 13–15], little or no imposed by diabetes in Japan [1, 2], the global data are available on the process by which spe- landscape of type 2 diabetes mellitus (T2DM) cialists and nonspecialists choose the appropri- management has evolved considerably over the ate treatment for newly diagnosed T2DM last decade, especially in terms of the availabil- patients based on therapeutic regimen and ity of new classes of antihyperglycemic agents patient characteristics. (AHAs). In Japan, nine different classes of AHAs Thus, the aim of the study reported in the are currently approved for the treatment of present paper was to understand physicians’ preferences and to explore the factors inﬂu- T2DM, including oral antidiabetes drugs (OADs) and injectables such as insulin and glucagon- encing their choice of treatment of T2DM in the real-world setting in Japan. like peptide-1 (GLP-1) receptor agonists . Despite the increased accessibility of all types of AHAs in Japan, less than half of all patients with METHODS T2DM reach the optimal glycemic goal of HbA1c \ 7% [4–6]. Study Design The T2DM guidelines in Japan  recom- mend a patient-centered approach in which the This was a noninterventional 25-min web-based physician (a diabetes specialist or nonspecialist) online survey for physicians, which comprised chooses a medication at their discretion, based focused multiple-choice questions. The posting on factors such as the patient’s age, T2DM of free text comments was restricted in order to duration, complications of the patient’s T2DM, make the survey simple and lucid. This study risk of hypoglycemia, and support systems. In did not include data collected from patients and such a scenario where the guidelines emphasize tailored therapy but do not guide the physician hence did not follow a therapy protocol, a diagnostic/therapy procedure, or a visit sched- on the application of a speciﬁc regime to drug- naive patients, the optimal management of ule. The online questionnaire included ques- tions on the physician’s proﬁle, the number of T2DM becomes increasingly challenging and drug-naive patients, and the number of patients complex, especially for physicians who are not treated with each OAD. It also probed the rea- familiar with diabetes treatment. Additionally, sons for selecting OADs for use as a ﬁrst-line factors such as limited time, the expanding therapy and for treatment intensiﬁcation, armamentarium of OADs, comorbidities, drug Diabetes Ther (2018) 9:1185–1199 1187 taking both treatment factors and patient and the patient characteristics that inﬂuenced characteristics into account. Participating the treatment intensiﬁcation decision in drug- physicians were requested to score each OAD naive patients with T2DM. used as ﬁrst-line therapy in order of priority Statistical Analysis (maximum score: 7). The recruitment criteria for the physicians who participated in the sur- A precision-based approach was used to evaluate vey included the following: • The majority (50% or more) of their profes- the sample size, where approximately 40% of the physicians (n = 192) selected their most fre- sional time was spent in direct patient care, quently prescribed drug. The proportion of excluding nonclinical activities such as physicians that considered a particular factor research or teaching when selecting the OAD ranged from 20 to 50%. • They had personally managed/treated at least 150 patients with T2DM in the last The half-width of the 95% conﬁdence interval (CI) was 4.7–5.8%, which provided the range of 6 months Diabetes specialists were deﬁned as being board 10% for the estimate. Categorical variables were presented as a number and proportion, whereas certiﬁed by the Japan Diabetes Society (JDS), whereas nonspecialists were deﬁned as physicians continuous variables were expressed as the mean, standard deviation, 25th percentile, median, 75th who had not been board certiﬁed by the JDS, even if they had treated many patients with T2DM. percentile, and the minimum and maximum values of the distribution as applicable. To elucidate the reasons that the physicians Data Sources chose the OADs, multinomial logistic regression was performed to assess the odds ratio (OR) and to The survey data were collected by M3 Global compare the most and second most popular OADs Research in Japan (Tokyo). As this study pri- used as ﬁrst-line therapy. All analyses were per- marily involved the collection of data from formed using the Statistical Package for the Social physicians, a web-based questionnaire was used Sciences (SPSS) (IBM SPSS Statistics, version 24). as the data source in this study. Ethics and Good Clinical Practice Participants The study was conducted in accordance with the The plan was to include 480 physicians—both ethical guidelines for medical and health research specialists and nonspecialists in a 1:1 ratio— involving human subjects as deﬁned by the Min- from eight different regions across Japan in the istry of Education, Culture, Sports, Science and survey. Physicians who agreed to participate Technology and the Ministry of Health, Labour were sent a link to the survey and were screened and Welfare, Japan. We carried out the study in further by asking them how many T2DM accordance with the code of professional behavior patients they had handled and the professional and relevant privacy principles. All physicians time they spent on patient care. consented to be part of this survey and to have their data reported in this manuscript. The study protocol was reviewed and approved by a central Study Outcomes ethics committee (EC) in Osaka. The primary endpoints were the proportions of RESULTS physicians that considered various treatment factors (such as drug efﬁcacy, tolerability, and Background Characteristics other features) and patient characteristics when of the Participating Physicians selecting the appropriate OAD for drug-naive patients with T2DM. The secondary endpoints included the proportions of physicians who A total of 240 diabetes specialists and 251 non- selected particular OADs as the ﬁrst-line therapy specialists participated in the online survey, 1188 Diabetes Ther (2018) 9:1185–1199 which was conducted from 26 May to 26 June Table 1 Background characteristics of the participating physicians 2017. The geographical distributions of both groups across the eight selected regions in Japan Parameter Specialists Nonspecialists were similar (Table 1). The background charac- (n = 240) (n = 251) teristics of the specialists and nonspecialists dif- Age (years) 47.8 ± 9.6 50.9 ± 9.7 fered with respect to parameters such as age, practice setting, and medical specialty. The mean % of time spent on 89.0 ± 11.0 90.2 ± 9.9 age of the specialists was 47.8 ± 9.6 years, with patient care 16.5 ± 8.7 years of experience in clinical prac- Practice setting tice, whereas the mean age of the nonspecialists was 50.9 ± 9.7 years, and they had more experi- Hospital-based 188 (78.3%) 149 (59.4%) ence in treating patients (21.9 ± 9.4 years). The Ofﬁce-based 52 (21.7%) 102 (40.6%) number of drug-naive T2DM patients treated by the physician in the last six months was similar Medical specialty for the specialists and nonspecialists, as was the PCP/GP 6 (2.5%) 48 (19.1%) percentage of their professional time spent on patient care (see Table 1). Internist 25 (10.4%) 121 (48.2%) Diabetologist 189 (78.8%) 21 (8.4%) Choice of Initial Therapy for Drug-Naive Endocrinologist 16 (6.7%) 9 (3.6%) Patients Cardiologist 4 (1.7%) 52 (20.7%) Among the various OADs available, dipeptidyl Average number of 16.5 ± 8.7 21.9 ± 9.4 peptidase-4 inhibitors (DPP-4is) were used by years spent practicing the largest percentage of physicians, followed by metformin, regardless of whether specialists Region (DPP-4i: 69%; metformin: 60%) or nonspecial- Hokkaido 17 (7.1%) 15 (6.0%) ists (DPP-4i: 73%; metformin: 47%) were con- Tohoku 10 (4.2%) 16 (6.4%) sidered. Other drugs that were prescribed by the physicians included SGLT-2 inhibitors, which Kanto 76 (31.7%) 89 (35.5%) were more popular with nonspecialists (non- Chubu 45 (18.8%) 38 (15.1%) specialists: 14% vs. specialists: 8%), and glin- ides, which were more popular with specialists Kinki 33 (13.8%) 43 (17.1%) (specialists: 6% vs. nonspecialists: 1%) (Fig. 1). Chugoku 13 (5.4%) 8 (3.2%) When the OAD most frequently used by each physician was considered, similar proportions Shikoku 17 (7.1%) 11 (4.4%) of the specialists were found to most frequently Kyushu 29 (12.1%) 31 (12.4%) prescribe DPP-4is (49%) and metformin (45%) to drug-naive patients as the ﬁrst-line treat- Number of drug-naive 35.6 ± 40.7 35.1 ± 63.1 ment, whereas a considerably larger percentage T2DM patients treated (59%) of the nonspecialists most frequently in the last 6 months prescribed DPP-4is as compared to those who The values presented are the mean ± standard deviation most frequently prescribed metformin (34%). or n (%) unless otherwise speciﬁed SGLT-2 inhibitors (specialists: 3% vs. nonspe- cialists: 4%), sulfonylureas (specialists: 2% vs. PCP primary care physician, GP general practitioner, nonspecialists: 1%), alpha-glucosidase inhibi- T2DM type 2 diabetes mellitus tors (1% for both specialists vs. nonspecialists), Since both specialists and nonspecialists and glinides (1% for specialists) were only rarely selected mainly DPP-4is or metformin as the the most frequently prescribed OADs (see ﬁrst-line OAD, we focused on these drugs in Fig. 1). subsequent analyses. Diabetes Ther (2018) 9:1185–1199 1189 Fig. 1 Selection of the initial treatment for drug-naive frequently than any other OADs (the ‘‘Most frequently patients with T2DM. Each value shown in the table is a prescribed OAD (% of physicians)’’ columns). DPP-4 proportion of the total physician population—either the dipeptidyl peptidase-4, GI glucosidase inhibitor, OADs oral proportion who have prescribed a particular OAD (the ‘‘% antidiabetes drugs, SGLT-2 sodium-glucose cotransporter- of physicians who prescribe the OAD’’ columns) or the 2, SU sulfonylurea, T2DM type 2 diabetes mellitus, TZD proportion who prescribe this particular OAD more thiazolidinedione Treatment Factors Affecting the Selection Treatment Factors Affecting the Selection of a DPP-4i or Metformin as the First-Line of the Initial OAD in Drug-Naive Patients: OAD Comparing the Physicians’ Choices DPP-4 Inhibitors There was a considerable difference of [10% The treatment factors most commonly consid- between diabetes specialists and nonspecialists ered by specialists when prescribing DPP-4is in the importance of treatment factors such as a were HbA1c-lowering effect, postprandial glu- low risk of gastrointestinal side effects, cose (PPG)-lowering effect, a low risk of hypo- improvement in insulin resistance, effect on glycemia, fasting plasma glucose (FPG)- glucagon, protection of b-cell function, and lowering effect, and no weight gain (89%, 85%, frequency of administration when DPP-4is were 83%, 69%, and 68%, respectively), whereas the chosen (Fig. 2a, b). corresponding proportions for nonspecialists Treatment factors with a more than 10% were 94%, 86%, 87%, 74%, and 70%, respec- difference in inﬂuence between specialists and tively (Fig. 2a, b). nonspecialists were effect on insulin, effect on glucagon, no weight gain, improvement in insulin resistance, and PPG-lowering effect Metformin when metformin was chosen as the ﬁrst-line Improvement in insulin resistance, low cost, OAD (Fig. 2a, b). low risk of hypoglycemia, and HbA1c- and FPG- lowering effects were treatment factors that commonly inﬂuenced the selection of met- Regression Analysis Comparing DPP-4is formin by specialists (93%, 91%, 89%, 87%, and and Metformin 85%, respectively) and by nonspecialists (80%, 92%, 81%, 86%, and 75%, respectively). Con- The ORs for the effects of various treatment siderable scientiﬁc evidence (81%) and PPG- factors when selecting DPP-4is or metformin as lowering effect (75%) were other factors that the ﬁrst-line OAD are presented in Table 2. signiﬁcantly drove the selection of metformin Among specialists, ease of use in patients with by nonspecialists (Fig. 2a, b). renal impairment (OR 11.7; 95% CI 2.4, 57.3) 1190 Diabetes Ther (2018) 9:1185–1199 Fig. 2 Comparison of the importance of various treat- percentages of physicians. CV cardiovascular, DPP-4i ment factors during the selection of a DPP-4i or dipeptidyl peptidase-4 inhibitor, FPG fasting plasma metformin as the ﬁrst-line OAD by specialists (a) and glucose, GI gastrointestinal, HbA1c glycated hemoglobin, nonspecialists (b). The values shown in the ﬁgure are OAD oral antidiabetes drug, PPG postprandial glucose Diabetes Ther (2018) 9:1185–1199 1191 Table 2 Effects of various treatment factors on the insulin resistance (OR 0.2; 95% CI 0.04, 1.0) and selection of a DPP-4i or metformin as the ﬁrst-line drug of low cost (OR 0.01; 95% CI 0.001, 0.05). choice Patient Characteristics Affecting Drug class Treatment factor OR 95% CI the Selection of DPP-4is or Metformin Lower Upper as First-Line OAD Specialists DPP-4 Inhibitors DPP-4 Easy to use for 11.7 2.4 57.3 The specialists and nonspecialists had similar inhibitors patients with considerations regarding patient characteristics. renal More than 50% of the physicians who pre- impairment scribed a DPP-4i as the ﬁrst-line OAD were most strongly inﬂuenced by PPG-lowering effect, Frequency of 8.6 1.9 38.6 followed by renal function (specialists: 56% and administration 53%; nonspecialists: 51% and 57%, respectively; Metformin Insulin resistance 0.1 0.02 0.6 see Fig. 3a, b). improvement Metformin Low cost 0.02 0.003 0.08 Both specialists and nonspecialists who selected Nonspecialists metformin as the ﬁrst-line OAD considered DPP-4 HbA1c-lowering 63.1 4.4 913.4 similar patient characteristics: age, renal func- inhibitors effect tion, BMI, and insulin resistance (specialists: 81%, 76%, 71%, and 64%; nonspecialists: 59%, Easy to use for 10.7 1.7 67.8 71%, 75%, and 56%, respectively; see Fig. 3a, b). patients with It should be noted, however, that age and renal insulin resistance were considered more by impairment specialists than nonspecialists. The inﬂuence of PPG-lowering effect on Metformin Insulin resistance 0.2 0.04 1.0 diabetes specialists was over 10% greater when improvement DPP-4is were selected rather than metformin, Low cost 0.01 0.001 0.05 whereas they were more strongly inﬂuenced by age, BMI, insulin resistance, and renal function CI conﬁdence interval, DPP-4 dipeptidyl peptidase-4, (difference [ 10%) when metformin was selec- HbA1c glycated hemoglobin, OR odds ratio ted over DPP-4is. A similar trend in the effects of the various patient characteristics was observed and frequency of administration (OR 8.6; 95% for nonspecialists who selected either DPP-4is or CI 1.9, 38.6) were the most inﬂuential factors metformin as the ﬁrst-line OAD. when choosing DPP-4is. Alternatively, improvement in insulin resistance (OR 0.1; 95% Patient Characteristics Affecting CI 0.02, 0.6) and low cost (OR 0.02; 95% CI the Selection of the Initial OAD in Drug- 0.003, 0.08) were the factors driving the selec- Naive Patients: Comparing the Physicians’ tion of metformin. Choices The nonspecialists mainly considered HbA1c-lowering effect (OR 63.1; 95% CI 4.4, 913.4) and ease of use in patients with renal When a DPP-4i was selected as the ﬁrst-line impairment (OR 10.7; 95% CI 1.7, 67.8) as fac- OAD, the average number of patient character- tors when selecting DPP-4is. The treatment istics considered by a specialist was 4.3 ± 2.8, factors that were most important to diabetes whereas the average number considered by a nonspecialists who selected metformin were the nonspecialist was 4.1 ± 2.7) The inﬂuence of same as those of specialists: improvement in BMI was more than 10% stronger among the 1192 Diabetes Ther (2018) 9:1185–1199 Fig. 3 Comparison of the effects of various patient patient characteristics when selecting a DPP-4i or met- characteristics on the selection of DPP-4i or metformin formin as the ﬁrst-line OAD. BMI body mass index, CV as the ﬁrst-line OAD by specialists (a; DPP-4 n = 118, cardiovascular, DPP-4i dipeptidyl peptidase-4 inhibitor, metformin n = 107) and nonspecialists (b; DPP-4 n = FPG fasting plasma glucose, OAD oral antidiabetes drug, 148, metformin n = 85). The values shown in the PPGpostprandial glucose ﬁgure are the percentages of physicians whoconsidered the specialists than the nonspecialists when a DPP- decision were similar to those considered when 4i was chosen as the ﬁrst-line OAD. When diabetes specialists and nonspecialists selected metformin was chosen as the ﬁrst-line OAD, the either DPP-4is or metformin as the ﬁrst-line average number of patient features considered OAD in drug-naive T2DM patients (Figs. 3, 4). was slightly higher for specialists than for non- specialists (5.0 ± 2.8 vs. 4.4 ± 2.3), and the Frequency of Laboratory Tests for T2DM only patient characteristic that inﬂuenced dia- Patients betes specialists over 10% more strongly than nonspecialists was age (Fig. 3a, b). Most specialists and nonspecialists responded that they measured body weight (83.3% and Patient Characteristics Affecting 74.1%) and HbA1c (73.8% and 62.2%) every the Treatment Intensiﬁcation Decision month, but the specialists were more regular with these tests than the diabetes nonspecialists The patient characteristics that were most were (Table 3). PPG, serum creatinine, and liver inﬂuential in the treatment intensiﬁcation function parameters [aspartate transaminase Diabetes Ther (2018) 9:1185–1199 1193 Fig. 4 a, b Comparison of the effects of various patient characteristics during the treatment intensiﬁcation deci- characteristics on the treatment intensiﬁcation decision sion when a DPP-4i or metformin was employed as the made by specialists (a; DPP-4 n = 165, metformin n = ﬁrst-line OAD. BMI body mass index, CVcardiovascular, 144) and nonspecialists (b; DPP-4 n = 183, metformin n DPP-4i dipeptidyl pepditase-4 inhibitor, FPG fasting = 118) for patients receiving DPP-4i or metformin as the plasma glucose, OAD oral antidiabetes drug, PPGpost- ﬁrst-line OAD. The values shown in the ﬁgure are the prandial glucose percentages of physicians whoconsidered the patient (AST), alanine aminotransferase (ALT), and nonspecialists responded that they measured gamma-glutamyl transferase (c-GTP)] were the FPG at least every 2 months. measured at least every 3 months by more than 75% of the physicians. However, the specialists Diabetes Complication Checks for Drug- measured these parameters more frequently Naive T2DM Patients than the nonspecialists did. The ﬁndings from the survey also indicated that around 45.0% of It was found that 91.7% of the specialists con- the specialists measured C-peptide every ducted checks for diabetic retinopathy and 7–12 months, whereas 34.7% of the nonspe- 86.3% conducted checks for neuropathy in cialists performed this test during the same drug-naive patients; the corresponding per- period. Around 22–25% of the specialists and centages of the diabetes nonspecialists were 1194 Diabetes Ther (2018) 9:1185–1199 Table 3 Data on the frequencies that various laboratory tests were ordered for T2DM patients by specialists and nonspecialists Frequency of the tests Body weight HbA1c FPG PPG Serum AST/ALT/c- C-peptide (%) (%) (%) (%) creatinine (%) GTP (%) (%) Specialists Do not perform this 0.4 0.4 13.3 4.2 0.4 1.3 22.1 test (0.0) Every 7–12 months 0.0 0.8 7.1 1.3 1.7 2.5 45.0 (1.5) Every 4–6 months 0.8 0.4 10.4 5.4 11.7 13.8 15.0 (2.5) Every 3 months (4.0) 5.0 5.4 12.5 12.9 19.2 18.3 11.3 Every 2 months (6.0) 10.4 19.2 25.0 27.5 21.7 22.5 3.8 Every month (12.0) 83.3 73.8 31.7 48.8 45.4 41.7 2.9 Nonspecialists Do not perform this 2.0 0.0 13.9 11.2 0.4 2.4 35.1 test (0.0) Every 7–12 months 1.2 0.0 3.6 1.2 2.4 3.6 34.7 (1.5) Every 4–6 months 2.8 2.4 8.8 7.2 21.1 20.7 16.7 (2.5) Every 3 months (4.0) 7.6 12.7 16.7 13.9 24.7 26.3 8.0 Every 2 months (6.0) 12.4 22.7 22.3 24.3 23.9 23.9 5.2 Every month (12.0) 74.1 62.2 34.7 42.2 27.5 23.1 0.4 The values presented are the percentages of the diabetes specialists and nonspecialists who prescribed the tests c-GTP gamma-glutamyl transferase, ALT alanine aminotransferase, AST aspartate transaminase, FPG fasting plasma glu- cose, HbA1c glycated hemoglobin, PPG postprandial glucose 80.1% and 61.0%, respectively. However, It is interesting to note that the numbers of almost all specialists and nonspecialists exam- drug-naive patients with T2DM treated over the ined the patients for renal complications last six months by specialists and nonspecialists (97.5% vs. 96.4%; see Fig. 5). were similar. This can be explained by the fact that the number of specialists for the large Japanese T2DM population of about 7.4 million DISCUSSION in 2017 was approximately 5500 . As the number of people with T2DM is increasing, The present study explored the inﬂuences of there is also an increased demand for specialists, various treatment factors and patient charac- which in turn may be leading to an increasing teristics on physicians (diabetes specialists and number of visits to nonspecialists. nonspecialists) when they select the ﬁrst-line Our questionnaire-based survey of physi- treatment for drug-naive patients with T2DM in cians revealed that the ﬁrst-line OADs most a real-world setting in Japan. Diabetes Ther (2018) 9:1185–1199 1195 effect of metformin compared to that of the DPP-4is. The assignment of higher dosages by specialists may have resulted in similar HbA1c- lowering effects of DPP-4is and metformin, meaning that the frequency of administration was left as a factor by which to select DPP-4is according to regression analysis. The underlying reason for the choice of a DPP-4i as the ﬁrst-line OAD in drug-naive T2DM patients could be the variability in the pathophysiology of T2DM in East Asians, including the Japanese population. It is well Fig. 5 Percentages of the specialists and nonspecialists established that T2DM in East Asians is charac- who performed checks for various diabetes complications. terized by b-cell dysfunction; incretin-based The values shown in the ﬁgure are the percentages of physicians whochecked for the particular diabetes compli- therapies such as DPP-4is most likely exert their cations in drug-naivepatients with T2DM glucose-lowering effects by improving b-cell dysfunction, as they increase the concentra- frequently prescribed by specialists and non- tions of active GLP-1 and glucose-dependent specialists in Japan were DPP-4is, followed by insulinotropic polypeptides (GIP) . The metformin. HbA1c-lowering effect and a low stronger HbA1c-lowering effects of incretin- risk of hypoglycemia were considered to be based therapies such as DPP-4i in East Asians among the most important treatment factors compared with Caucasians may further conﬁrm when a DPP-4i or metformin was selected as the that b-cell dysfunction is a greater inﬂuence on ﬁrst-line OAD. However, the inﬂuences of hyperglycemia in the former group . Addi- treatment factors such as ease of use in patients tionally, the availability of DPP-4is as ﬁrst-line with renal impairment, improvement in insulin monotherapies in Japan based on Japanese resistance, and low cost on the ﬁrst-line OAD guidelines  makes them more attractive selection process depended signiﬁcantly on choices for use as the initial drug therapy in whether a DPP-4i or metformin was chosen. newly diagnosed patients with T2DM. It is also According to multinomial logistic regression important to note that metformin was consid- analysis, the selection of a DPP-4i over met- ered by both specialists and nonspecialists due formin was dependent on the importance to to its ability to improve insulin resistance in specialists of the ease of use of the drug in patients with T2DM and its cost effectiveness. patients with renal impairment and the fre- The ﬁnding that metformin is one of the two quency of administration, or the importance of most prevalent initial prescriptions suggests the HbA1c-lowering effect to nonspecialists. that the recommendations by the American When metformin was preferred, this was due to Diabetes Association (ADA) and The European attributes such as improvement in insulin Association for the Study of Diabetes (EASD)  resistance and cost effectiveness. While factors that metformin should be used as the ﬁrst-line inﬂuencing the selection of DPP-4is or met- OAD are generally followed in Japan. formin were similar for specialists and nonspe- The guidelines in Japan recommend that cialists, the former considered the frequency of treatment objectives should be established on a administration while the latter considered case-by-case basis, considering parameters such HbA1c-lowering effect as a factor when select- as age, duration of disease, complications, risk ing a DPP-4i rather than metformin. Though of hypoglycemia, and support systems [3, 18]. It the reason for this is not clear, it may be related is interesting to note that PPG-lowering effect to the dosage of metformin prescribed by the was considered when the physician selected a nonspecialists; the lower dose of metformin DPP-4i, whereas age, BMI, improvement in (500 mg) prescribed by the nonspecialists may insulin resistance, and renal function were have resulted in a suboptimal HbA1c-lowering considered when metformin was selected as the 1196 Diabetes Ther (2018) 9:1185–1199 initial drug therapy by specialists as well as present in these patients due to a delayed nonspecialists. This accentuates the fact that diagnosis, as it is essential to treat such com- there is agreement between the diabetes spe- plications . In the present survey, although cialists and nonspecialists in the patient char- most of the parameters relating to diabetes and acteristics that should be considered when its complications were monitored by the choosing the ﬁrst-line OAD for newly diagnosed physicians, we observed that kidney-related T2DM patients. Age was less likely to be con- complications were reviewed to similar extents sidered by nonspecialists who chose metformin by both specialists and nonspecialists, indicat- as the ﬁrst-line therapy than if they chose DPP- ing that nephropathy is an important concern 4is, but none of the other patient characteristics among all physicians who treat T2DM patients signiﬁcantly differed in inﬂuence depending on in Japan. whether a DPP-4i or metformin was selected. The limitations of the present study should This observation can be explained by differ- be considered. This study is noninterventional ences in the metformin dosages assigned by in nature and may include information bias, specialists and nonspecialists, as discussed selection bias, and feasibility limitations. For above; if nonspecialists tend to prescribe a lower example, we did not include the timing of dose of metformin, they are unlikely to consider administration but we did include the fre- age as a factor due to the associated GI or lactic quency of administration and the drug dosage. acidosis issues when prescribing metformin. To be noted, participating physicians would However, there is no clear evidence to support respond their prescription preference based on this theory, so further investigations are war- general perception on DPP-4is rather than ranted. In addition, non-specialists tend to focusing on drug-naive patients whose renal consider BMI more than specialists while function are usually not impaired. We must selecting metformin over DPP-4is. This could be therefore be careful when applying these results explained by the ﬁndings of UKPDS 34, a well- in clinical practice because we believe that renal known study even of non-specialists, which function is a critical factor in the decision of indicated that metformin can decrease the risk whether to use a DPP-4i or metformin. Diabetes of diabetes-related complications in overweight complication checks were conducted frequently patients and is associated with weight neutrality by both specialists and nonspecialists. This and fewer hypoglycemic events . observation differs from previous reports , The patient characteristics that tended to probably because no clear deﬁnition on diabetes inﬂuence the treatment intensiﬁcation decision complications, such as microalbuminuria was were similar to those that most strongly inﬂu- set, and therefore physicians could respond as enced the selection of the ﬁrst-line OAD by they usually check diabetic nephropathy when specialists. PPG-lowering effect was considered they measure serum creatinine routinely. The an important factor when a DPP-4i was pre- behavior of physicians according to the current scribed, whereas age, renal function, BMI, and survey results should be checked for validity by improvement in insulin resistance were the comparing the results of this survey with other factors considered when metformin was chosen. data sources such as databases in order to Substantial numbers of specialists and non- examine the consistency and differences specialists responded that they measured HbA1c between the data sources. Despite these limita- monthly and C-peptide at least yearly. These tions, web-based online surveys are considered test frequencies could be speciﬁc to clinical to be a fast and cost-effective method of practice in Japan and may differ in other obtaining feedback from physicians (specialists countries . Such frequencies could depend and nonspecialists) spread across various geo- on whether the health insurance system covers graphical regions. They also facilitate the these laboratory tests in the country of interest. inclusion of both hospital-based and ofﬁce- At the time of the ﬁrst consultation, the based specialists and nonspecialists. Addition- Japanese guidelines advise physicians to test for ally, the present survey length is capped at diabetes-related complications that may be 25 min in order to maximize respondent Diabetes Ther (2018) 9:1185–1199 1197 participation and minimize the dropout rate. Guha Thakurta, Ph.D., of Novartis Healthcare Pvt. Also, we only focused on DPP-4is and met- Ltd, Hyderabad, India for medical writing sup- formin in this survey in order to examine the port, which was funded by Novartis Pharma AG, main factors affecting initial OAD selection for Basel, Switzerland, in accordance with good pub- drug-naive patients, as these were the drugs lication practice (GPP3) guidelines (http://www. predominantly prescribed by the physicians. ismpp.org/gpp3). Further studies are needed to examine other Authorship. All named authors meet the drugs, such as SGLT-2 inhibitors and sulfony- International Committee of Medical Journal lurea, to further probe the factors that affect the Editors (ICMJE) criteria for authorship for this selection of drugs for more sophisticated dia- manuscript, take responsibility for the integrity betes treatments. of the work as a whole, and have given ﬁnal approval to the version to be published. CONCLUSION Disclosures. Hiroki Murayama is an In summary, the ﬁndings from the present employee of Novartis Pharma K.K. Kota Imai is survey show that DPP-4is are the preferred ﬁrst- an employee of Novartis Pharma K.K. Masato line treatment by physicians in Japan due to Odawara has served as an advisory board their ease of use in patients with renal impair- member for Novartis, has received research ment, frequency of administration, and HbA1c- grants with contracts from Novo Nordisk and lowering effect. The next most popular ﬁrst-line Astellas, has received unrestricted research treatment is metformin, due to the resulting grants from Daiichi Sankyo, MSD, Ono, Novar- improvement in insulin resistance and its cost tis, Astellas, Sanwa Kagaku Kenkyusho, Astra- effectiveness. The patient characteristics taken Zeneca, Kyowa Hakko Kirin, Kowa, Takeda, into account when choosing the ﬁrst-line OAD Mitsubishi Tanabe, Eli Lilly, Nippon Boehrin- as well as when deciding upon treatment ger, Sanoﬁ, Novo Nordisk, Sumitomo Dainip- intensiﬁcation were essentially the same pon, and Taisho Toyama, and has received regardless of whether the physician was a dia- lecture fees from Daiichi Sankyo, MSD, Ono, betes specialist or nonspecialist. In this regard, Novartis, Astellas, Sanwa Kagaku Kenkyusho, the information provided by this study should AstraZeneca, Kyowa Hakko Kirin, Kowa, Takeda, prompt discussion of the differences in T2DM Mitsubishi Tanabe, Eli Lilly, Nippon Boehrin- treatment between Japan and other counties. ger, Sanoﬁ, Novo Nordisk, Sumitomo Dainip- pon, and Taisho Toyama. Compliance with Ethics Guidelines. The ACKNOWLEDGEMENTS study was conducted in accordance with the ethical guidelines for medical and health We thank the participants of the study. research involving human subjects deﬁned by the Ministry of Education, Culture, Sports, Sci- Funding. Sponsorship and article processing ence and Technology and the Ministry of charges for this study were funded by Novartis. Health, Labour and Welfare, Japan. The study All authors had full access to all of the data in protocol was reviewed and approved by a cen- this study and take complete responsibility for tral ethics committee (EC). All physicians who the integrity of the data and accuracy of the provided information for this survey consented data analysis. to be part of it and to the inclusion of their survey data in a manuscript to be published in a Medical Writing and/or Editorial Assis- peer-reviewed journal. tance. The authors thank Megha Saraf of Novar- tis Healthcare Pvt. Ltd, Hyderabad, India for her Data Availability. The data sets generated support when conducting the survey reported in during and/or analyzed during the current this manuscript. The authors also thank Ishita 1198 Diabetes Ther (2018) 9:1185–1199 9. Inzucchi SE, Bergenstal RM, Buse JB, et al. Man- study are available from the corresponding agement of hyperglycemia in type 2 diabetes, 2015: author on reasonable request. a patient-centered approach: update to a position statement of the American Diabetes Association Open Access. This article is distributed and The European Association for the Study of under the terms of the Creative Commons Diabetes. Diabetes Care. 2015;38:140–9. Attribution-NonCommercial 4.0 International 10. Rafaniello C, Arcoraci V, Ferrajolo C, et al. 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Published: Apr 25, 2018