Email updates

Keep up to date with the latest news and content from Diabetology & Metabolic Syndrome and BioMed Central.

Open Access Research

Incidence and predictors of hypoglycemia in Japanese patients with type 2 diabetes treated by insulin glargine and oral antidiabetic drugs in real-life: ALOHA post-marketing surveillance study sub-analysis

Masato Odawara1*, Takashi Kadowaki2 and Yusuke Naito3

Author Affiliations

1 Department of Diabetology, Metabolism, and Endocrinology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

2 Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

3 Sanofi K.K, 3-20-2 Nishi-Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

For all author emails, please log on.

Diabetology & Metabolic Syndrome 2014, 6:20  doi:10.1186/1758-5996-6-20


The electronic version of this article is the complete one and can be found online at: http://www.dmsjournal.com/content/6/1/20


Received:10 September 2013
Accepted:8 February 2014
Published:15 February 2014

© 2014 Odawara et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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.

Abstract

Background

Add-on Lantus® to Oral Hypoglycemic Agents (ALOHA), an observational, non-interventional, 24-week post-marketing surveillance study in Japanese patients with type 2 diabetes (T2DM) having uncontrolled glycemic control, demonstrated that basal supported oral therapy (BOT) with insulin glargine was an effective and safe treatment in real-life clinical practice. We performed subgroup analysis to identify incidence and predictors associated with risk of hypoglycemia.

Methods

Among 4219 patients with T2DM, 3732 patients were insulin-naïve and 487 patients were insulin non-naïve who switched from other insulin to insulin glargine. All hypoglycemic episodes were counted by physicians’ documentation based on patients’ reports. Relationships between baseline patient characteristics and glargine-related hypoglycemic episodes were examined by univariate and multivariate analysis.

Results

Among 4219 patients, 44 (1.0%) patients experienced hypoglycemic episodes (41 insulin-naïve patients; 3 insulin non-naïve patients), with a rate of incidence 0.035 episodes/patient-years. Majority of patients with hypoglycemia (37 of 44) had just one hypoglycemic episode during study period. Among insulin-naïve patients, incidence of hypoglycemia differed significantly depending on age, diabetic complications, estimated glomerular filtration rate (eGFR), and postprandial plasma glucose (P <0.05). In a multivariate adjusted model, poor renal function (eGFR <60 mL/min/1.73 m2) was a statistically significant risk factor (P < 0.05).

Conclusion

Our results suggest that BOT using insulin glargine is an option of insulin therapy with 1% risk of hypoglycemia in patients with T2DM with inadequate glycemic control. Patients with low renal function might need a careful follow-up.

Keywords:
Hypoglycemia; Insulin glargine; Insulin-naïve; Oral antidiabetic drugs; Type 2 diabetes; Relative risk

Background

High prevalence of type 2 diabetes mellitus (T2DM) in Japan is associated with a significant economic burden, which increases with increasing number of diabetic complications [1]. Intensive glycemic control by multiple insulin therapy has shown to delay onset and progression of diabetic complications in Japanese patients with T2DM [2]. However, intensive glucose-lowering treatments used to achieve and maintain strict glycemic control are associated with increased risk of hypoglycemia [3-6]. Hypoglycemia impacts morbidity, mortality and quality of life of these patients [4,7-9], and also leads to higher medical expenditure [10]. Thus, it can pose a hindrance in the management of T2DM and can be major barrier in initiating and intensifying insulin treatment.

One way to ensure effective diabetes management is by opting for therapies proven to be associated with low rate of hypoglycemia. Previous data demonstrate that basal long-acting insulin analogue, insulin glargine, results in a reduced risk of nocturnal and severe hypoglycemic events compared with conventional insulin therapies [11]. Basal supported oral therapy (BOT) using insulin glargine is known to be more simple, safe and effective, as compared to neutral protamine Hagedorn (NPH) [12-15], insulin lispro [16] and premixed insulin [17,18]. Earlier studies in Japan also demonstrated that BOT with insulin glargine was effective, without causing serious hypoglycemia [19,20]. Another way to prevent or limit the incidence of hypoglycemia is to understand the underlying contributing factors. Earlier studies demonstrated that factors like old age, long disease duration, poor renal function, peripheral neuropathy, low body mass index (BMI), ≥2glucose-lowering drugs, long duration of insulin treatment, etc. are significant independent predictors of hypoglycemia [3,21,22].

The Add-on Lantus® to Oral Hypoglycemic Agents (ALOHA) study analyzed a large cohort of Japanese T2DM patients with inadequate glycemic control and demonstrated that BOT with insulin glargine was safe and effective [23]. It demonstrated that diabetic retinopathy, medical history, history of allergy and adverse events (AEs), and concomitant use of insulin resistance reducing agents and drugs other than OADs, were contributing factors to the occurrence of AEs. The ALOHA database yielded further sub-analysis on various aspects including dosing of insulin glargine and baseline predictive factors for achieving glycemic control that have been published [24-26].

To the best of our knowledge, there is no evidence on incidence and predictors of hypoglycemia in Japanese patients with T2DM. To address this need, we conducted a sub-analysis of the data from the ALOHA study to assess incidence of hypoglycemia and association of patient characteristics with risk of hypoglycemia in Japanese patients with T2DM. In the present sub-analysis, we stratified the ALOHA safety analysis cohort in insulin-naïve and insulin non-naive sub-groups. The present results further add to our understanding on incidence and predictors of hypoglycemia in insulin-naïve patients.

Methods

Study design

Between 2007 and 2009, this observational, non-interventional, 24-week follow-up, post-marketing surveillance study recruited 5223 patients from 987 centers across Japan. The detailed design and methodology of the ALOHA study is published elsewhere [23,25,26]. In the current study, Japanese patients having T2DM and inadequate glycemic control, were followed for 24 weeks to determine the incidence of hypoglycemia and any patient characteristics which predicted occurrence of hypoglycemia.

This study was endorsed by the Health Authority in Japan and was conducted as a post-marketing surveillance in accordance with the Good Post-marketing Study Practice (GPSP) [27], and Good Vigilance Practice [28] in Japan.

Patients

Patients having T2DM who were to start BOT with insulin glargine, but who were naïve to treatment with insulin glargine, were eligible for participating in the ALOHA study. The study included patients having T2DM who satisfied the following criteria within 4 weeks screening period before initiation of insulin glargine: 1) received treatment with OADs for ≥12 weeks, 2) had HbA1c (National Glycohemoglobin Standardization Program [NGSP]*) values ≥7.9% and <12.4%, and 3) had BMI < 30 kg/m2.

*The NGSP values were selected based on the JDS values (≥7.5% and <12.0%, respectively). HbA1c data were collected as JDS values and then converted to NGSP values by the following conversion formula: HbA1c (NGSP) = 1.02 × HbA1c (JDS) + 0.25% with rounding off to the first decimal place [29].

Treatment

Initiation of insulin treatment and adjusting insulin doses were determined by attending physicians. Concomitant OADs were also selected by the physicians, as part of routine clinical care.

Patients who required additional insulin, for example, bolus insulin, were terminated to follow-up due to no longer fulfilling the inclusion criteria.

Data collection

All eligible patients’ data were collected via paper-based case report forms (CRFs). Data collected included background characteristics (gender, age, duration of diabetes, hospitalization or outpatients, disease history, complications, type and dose of prior drug therapy, etc.), treatment details, patient compliance, laboratory tests, and AEs.

Study assessment

Safety and effectiveness data were collected over 24 weeks. Effectiveness parameters included HbA1c, fasting plasma glucose (FPG), postprandial glucose (PPG), and weight. Safety was determined by documenting all AEs and accompanying symptoms of hypoglycemia as reported by the attending physicians during the observational period. For serious AEs its seriousness, intervention, outcome and causal relationship to glargine were evaluated. Hypoglycemic episodes were counted by physicians’ documentation (any hypoglycemic episodes and any symptoms derived from hypoglycemia), based on patients’ reports. Severe hypoglycemia included hypoglycemic episodes satisfying any of the following serious AEs criteria; 1) resulted in death, 2) life-threatening, 3) required or prolonged inpatient hospitalization, 4) persistently or significantly disabling/ incapacitating, 5) a congenital anomaly, and/or 6) medically important.

Statistical analysis

We used Fisher exact test to determine the difference between patients with or without hypoglycemia, according to patient characteristics. After calculating differences in hypoglycemia incidence and its 95% confidence intervals (CI) among subgroups, we calculated number needed to harm (NNH) by the inverse of incidence difference between subgroups. Among subgroups having statistically significant differences, we calculated multivariate adjusted relative risk estimates and 95% CI by using negative binomial regression model. All statistical tests were two-sided at α = 0.05. All statistical calculations were performed using SAS system software, version 9.1.3 (SAS Institute Inc., Cary, NC, USA) and R 2.15.2.

Results

Patient disposition and baseline characteristics

Of 5223 patients enrolled in the study, 5181 patients completed CRFs. Of these, 4219 patients were included in the safety analysis set (Figure 1). This set is further divided into 2 sub-groups: 1) Insulin-naïve group: patients treated with OADs (n = 3732), and 2) Insulin non-naïve group: patients treated with OADs + insulin other than insulin glargine, and switching to OADs + insulin glargine (n = 487).

thumbnailFigure 1. Patient disposition.

Baseline characteristics of total and sub-group patients are presented in Table 1. Majority of patients in both groups had duration of T2DM >5 years. In insulin-naïve group receiving only OADs, majority of patients were prescribed combination of 2 or 3 OADs, while in insulin non-naïve group receiving insulin + OADs, patients commonly received 1 or 2 OADs. There were differences in the types of OADs used in insulin-naïve group (sulfonylurea [SU] – 88.9%, biguanides [BG] – 47.7%, and alpha-glucosidase inhibitors [α-GI] – 46%) and insulin non-naïve group (SU – 55.6%, α-GI – 52.2%, and BG – 42.9%). The prevalence of diabetic complications was similar in both groups.

Table 1. Baseline characteristics in total and sub-group patients

The HbA1c value at baseline in the naïve population was 9.53 ± 1.19% (n = 3732). In the non-naïve population the baseline HbA1c value was 9.08 ± 1.11% (n = 487). The HbA1c values at the end of the study were 8.07 ± 1.21% (n = 3337) and 8.46 ± 1.39% (n = 424) in the naïve and non-naïve populations, respectively.

Hypoglycemia

The data on incidence of hypoglycemia in total as well as subgroup patients have been presented in Table 2. In total patients, incidence of hypoglycemia was 1.0% (0.035 episodes/patient-years). Incidence of hypoglycemia in insulin-naïve group (1.1% [0.036 episodes/patient-years]) and insulin non-naïve group (0.6% [0.029 episodes/patient-years]) was similar to the overall incidence. The difference in the incidence of hypoglycemia between naïve and non-naïve groups was not statistically significant; p-value was 0.4752 by fisher exact test. Among total 4219 patients, 4 (0.1%) patients had severe hypoglycemia (0.002 episodes/patient-years). At the end of the 24-weeks study period, cumulative incidence of hypoglycemia was 1.0% (Figure 2a), and cumulative incidence rate of hypoglycemia was 0.016 episodes/patient (Figure 2b).

Table 2. Cumulative incidence and rate of hypoglycemia in overall and sub-group patients

thumbnailFigure 2. a) Cumulative incidence and b) cumulative incidence rate (episodes/patient) of hypoglycemia.

Altogether, 44 patients reported 63 hypoglycemic episodes: 37 (0.88%) patients had 1 episode, 3 (0.07%) had 2 episodes, 2 (0.05%) had 4 episodes, and 1 (0.02%) patient each had 5 and 7 episodes. The details of the 63 hypoglycemic episodes were as follows: 20 episodes with convincing symptoms, 31 episodes in patients with morning injection, 24 episodes in patients with bedtime injection, 4 episodes identified by self-monitored blood glucose measurement (2 patients), and 2 episodes in the night (1 in evening and 1 with bedtime injection).

Hypoglycemia incidence and rate according to patient characteristics in insulin-naïve group: univariate analysis

When we assessed incidence of hypoglycemia and its rate with various patient characteristics in insulin-naïve patients, there was no statistically significant difference in sub-groups such as sex, BMI, duration of diabetes, renal disorder not due to diabetes, baseline HbA1c, FPG, OADs prescribed prior to and during study, and compliance to diet and exercise (data not shown). There was a statistically significant difference in hypoglycemic incidence in insulin-naïve patients in subgroups according to age, diabetic complications, estimated glomerular filtration rate (eGFR), and PPG levels (Table 3). Among the diabetic complications, the NNH was low for retinopathy and/or nephropathy. Also, for eGFR <60 mL/min/1.73 m2, the NNH was lower than eGFR levels of >60 mL/min/1.73 m2.

Table 3. Cumulative incidence and rate of hypoglycemia in insulin-naïve group (N = 3732), according to patient characteristics

Since, there were only 6 episodes of hypoglycemia in 3 patients in insulin non-naïve group, we did not assess them in the univariate analysis.

Predictors of hypoglycemia in insulin-naïve group: multivariate analysis

All factors having a statistically significant difference in the univariate analysis (Table 3), were examined by multivariate analysis. PPG was excluded because of missing data. Due to a very few hypoglycemic episodes, diabetic complication category was forced to be contracted into dichotomous unlike all combinations of complications presented in Table 3. Multivariate adjusted negative binomial regression model revealed that among the parameters studied, poor renal function defined as eGFR <60 mL/min/1.73 m2 was the only statistically significant risk factor of hypoglycemic events (relative risk [RR] 5.34, 95% confidence interval [CI] 1.48-22.85, P <0.05).

Discussion

This observational, non-interventional, 24-week post-marketing surveillance study in Japan provides detailed real-life information on incidence of hypoglycemia in T2DM patients using BOT with insulin glargine. The overall incidence of hypoglycemia was 1.0%, with majority of patients experienced hypoglycemia only once during 24-week follow-up period. The study also demonstrated, for the first time, that among insulin-naïve T2DM Japanese patients, hypoglycemia is associated with poor renal function.

The prospective, observational registry in Germany demonstrated that hypoglycemia is a frequent AE in insulin-naïve T2DM patients having insufficient glycemic control on OADs, and receiving intensified antidiabetic treatment [30]. The rate of hypoglycemia in this study, over a 12-month follow-up period, was mild: 13.0%, moderate: 0.7%, and severe: 0.5%. The results of this study indicated that the risk of hypoglycemia might be substantially reduced by carefully selecting antidiabetic pharmacotherapy [31]. Earlier randomized trials using BOT with insulin glargine reported high incidence of hypoglycemia. In the HOE 901/3002 study, 33% of insulin-naïve patients receiving insulin glargine experienced at least one episode of symptomatic hypoglycemia, and 9.9% patients experienced nocturnal hypoglycemia [12]. In the HOE 901/2004 study, among T2DM patients having inadequate glycemic control on OADs, 22.1% and 7.3% of patients receiving insulin glargine experienced symptomatic hypoglycemia and nocturnal hypoglycemia, respectively [13]. Other studies reported the hypoglycemia incidence rate in the range of 0.7 to 5.2 episodes per patient-year [14,16,17,32]. Outside the clinical setting, an earlier observational study reported 0.1% prevalence of hypoglycemia [33]. In the current study, rate of hypoglycemia in insulin-naïve patients was 1.1%, which is higher than that reported in the earlier observational study. The difference in the rate of hypoglycemia can be due to heterogeneity of the study populations and different definitions of hypoglycemia used in these studies. The higher hypoglycemia rate in clinical trials could be due to intensive antidiabetic treatments used to achieve glycemic targets, as opposed to the observational studies.

The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) guidelines [34] and the Japan Diabetes Society (JDS) treatment guide [35] recommend intervention at the time of diagnosis, with OADs in combination with lifestyle changes in diet and exercise. In patients who do not meet glycemic goals by taking only OADs, the guidelines recommend timely augmentation of this therapy with additional agents and early addition of insulin therapy. However, there exist patient barriers such as fear of hypoglycemia, injections and weight gain, as well as physicians’ concerns such as reluctance to prescribe insulin, result in non-adherence to initiation and intensification of insulin treatment, leading to delayed use of effective therapy [36,37]. Early initiation of insulin therapy might help patients with T2DM achieve long-term glycemic control and improve quality of life. It has been demonstrated that first insulinization with basal insulin is effective and safe with reduced AEs including hypoglycemia, in clinical trial [38], as well as real-world setting [15]. However, in the current study, majority of patients had T2DM for more than 5 years and still were prescribed only one and/or two OADs (61.5%) and were insulin-naïve (81%). Thus, physician and patient education is necessary to overcome barriers to insulin use and ensure its appropriate and optimal use.

In the present study, we demonstrated association of hypoglycemia with older age (relative risk [RR] 1.58, 95% CI: 0.74, 3.44). Advanced age has been a contributing factor to severe hypoglycemia in previous population-based studies [39,40]. Earlier ACCORD [41] and ADVANCE [9] trials reported significant associations between older age and risk of severe hypoglycemia. In an earlier study in insulin-naïve T2DM patients, age <65 years was an independent predictor of reduced incidence of hypoglycemia (OR 0.76; 95% CI 0.59-0.96) [31]. The DAWN Japan study demonstrated that old age was one of the top three concerns for physicians to delay insulin initiation [42]. Hence, future studies to address appropriate strategies to overcome these physician barriers are warranted.

In ADVANCE study, history of microvascular disease was associated with twofold increase in risk of severe hypoglycemia (hazards ratio 2.1, 95% CI 1.5 to 3.) [9]. Diabetic complications such as coronary artery disease and peripheral neuropathy are also known as risk factors for hypoglycemia [22,43]. In line with the earlier evidence, in the current study also, hypoglycemia was associated with presence of diabetic complication (s) (RR 1.36, 95% CI: 0.66, 2.83). Many earlier studies reported poor renal function diagnosed by low eGFR as a significant predictor of first of recurrent hypoglycemia [22,43]. Our results confirm this by showing significant association of hypoglycemia and poor renal function i.e. eGFR <60 mL/min/1.73 m2 (RR 5.34, 95% CI: 1.48, 22.85). However, the risk difference was very low and not clinically relevant.

One of the inclusion criteria of the current study is BMI <30 kg/m2. Accordingly, the mean BMI of the patients in safety analysis set was 23.8 kg/m2. Earlier studies demonstrated that low BMI was an independent risk factor of severe hypoglycemia [9,41]. However, these studies recruited global population of T2DM patients. In the current study, the incidence of severe hypoglycemia was 0.1%. This can be due to the lower cut-off levels of BMI for overweight and obesity in Asian population as compared to the Western population [44].

The results of the present observational study explore the incidence and predictors of hypoglycemia in real-life clinical practice in insulin-naïve diabetic patients in Japan having inadequate glycemic control and who are starting with BOT with insulin glargine. However, this population might not represent general T2DM patient population who initiate insulin glargine. Also, unlike a treat-to-target trial, the present observational study has no interventional target of glycemic control. Another limitation of the study is that because of the observational nature of the study, it is likely that incidence of hypoglycemia might have been under-reported. The data on hypoglycemia in patients receiving insulin other than glargine and switching to insulin glargine will be further elaborated in subsequent publication, which would include comprehensive results of effectiveness and safety in this cohort.

Conclusions

In conclusion, our results suggest that BOT using insulin glargine is an option of insulin therapy with a 1% risk of hypoglycemia in insulin-naïve patients with T2DM with inadequate glycemic control. Age, presence of diabetic complications, and poor renal function were the predictors of hypoglycemia in insulin-naïve patients. Patients with low renal function might need a careful follow-up.

Abbreviations

α-GI: Alpha-glucosidase inhibitors; ADA: American diabetes association; AE: Adverse event; EASD: European association for the study of diabetes; BG: Biguanide; BMI: Body mass index; BOT: Basal supported oral therapy; CI: Confidence interval; CRF: Case report form; GPSP: Good Post-marketing Study Practice; eGFR: Estimated glomerular filtration rate; FPG: Fasting plasma glucose; HbA1c: Glycosylated hemoglobin; JDS: Japan diabetes society; NNH: Number needed to harm; NPH: Neutral protamine Hagedorn; OAD: Oral antidiabetic drug, PPG, prandial plasma glucose; RR: Relative risk; SU: Sulfonylurea; T2DM: Type 2 diabetes mellitus; TZD: Thiazolidinedione.

Competing interests

MO received advisory board fees, lecture fees, honoraria for manuscripts, and scholarship grants fees from Sanofi K.K. TK received advisory board fees, lecture fees and scholarship grants fees from Sanofi K.K.YN is an employee of Sanofi K.K.

Authors’ contributions

Sanofi was responsible to design and conduct this study. YN was responsible for the statistical analysis. MO and TK made significant suggestions to the analysis and interpretation of data. YN drafted the manuscript, MO and TK reviewed and revised the draft manuscript. All authors have reviewed and approved the final version of this manuscript.

Acknowledgments

The authors would like to thank all physicians from 987 hospitals and clinics who participated in the ALOHA study.

This study was funded and conducted by Sanofi K.K.

Editorial assistance in preparing this manuscript was provided by Dr. (Ms.) Jai Tilak-Jain and Anahita Gouri from Sanofi, India.

References

  1. Neville SE, Boye KS, Montgomery WS, Iwamoto K, Okamura M, Hayes RP: Diabetes in Japan: a review of disease burden and approaches to treatment.

    Diabetes Metab Res Rev 2009, 25(8):705-716. PubMed Abstract | Publisher Full Text OpenURL

  2. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.

    Diabetes Res Clin Pract 1995, 28(2):103-117. PubMed Abstract | Publisher Full Text OpenURL

  3. Amiel SA, Dixon T, Mann R, Jameson K: Hypoglycaemia in Type 2 diabetes.

    Diabet Med 2008, 25(3):245-254. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  4. Barnett AH, Cradock S, Fisher M, Hall G, Hughes E, Middleton A: Key considerations around the risks and consequences of hypoglycaemia in people with type 2 diabetes.

    Int J Clin Pract 2010, 64(8):1121-1129. PubMed Abstract | Publisher Full Text OpenURL

  5. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergeonneau C, Kassai B, Erpeldinger S, Wright JM, Gueyffier F, Cornu C: Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials.

    BMJ 2011, 343:d4169. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  6. Okawa M, Kunimoto F, Kanamoto M, Narahara H, Hinohara H, Tobe M, Yanagisawa A, Saito S: Effect of different blood glucose target levels on the incidence of hypoglycemia during insulin therapy in the intensive care unit ().

    J Diabetes 2013, 5(1):51-56. PubMed Abstract | Publisher Full Text OpenURL

  7. Sheu WH, Ji LN, Nitiyanant W, Baik SH, Yin D, Mavros P, Chan SP: Hypoglycemia is associated with increased worry and lower quality of life among patients with type 2 diabetes treated with oral antihyperglycemic agents in the Asia-Pacific region.

    Diabetes Res Clin Pract 2012, 96(2):141-148. PubMed Abstract | Publisher Full Text OpenURL

  8. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, Dudl RJ, Ismail-Beigi F, Kimel AR, Hoogwerf B, et al.: The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.

    BMJ 2010, 340:b4909. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  9. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, Woodward M, Ninomiya T, Neal B, MacMahon S, et al.: Severe hypoglycemia and risks of vascular events and death.

    N Engl J Med 2010, 363(15):1410-1418. PubMed Abstract | Publisher Full Text OpenURL

  10. Lundkvist J, Berne C, Bolinder B, Jonsson L: The economic and quality of life impact of hypoglycemia.

    Eur J Health Econ 2005, 6(3):197-202. PubMed Abstract | Publisher Full Text OpenURL

  11. Dailey G, Strange P: Lower Severe Hypoglycemia Risk: Insulin Glargine Versus NPH Insulin in Type 2 Diabetes.

    Am J Manag Care 2008, 14:25-30. PubMed Abstract | Publisher Full Text OpenURL

  12. Yki-Jarvinen H, Dressler A, Ziemen M, Group HOEsS: Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group.

    Diabetes Care 2000, 23(8):1130-1136. PubMed Abstract | Publisher Full Text OpenURL

  13. H. O. E. Study Investigators Group: Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients.

    Diabet Med 2003, 20(7):545-551. PubMed Abstract | Publisher Full Text OpenURL

  14. Riddle MC, Rosenstock J, Gerich J: The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients.

    Diabetes Care 2003, 26(11):3080-3086. PubMed Abstract | Publisher Full Text OpenURL

  15. Tsai ST, Pathan F, Ji L, Yeung VT, Chadha M, Suastika K, Son HS, Tan KE, Benjasuratwong Y, Nguyen TK, et al.: First insulinization with basal insulin in patients with Type 2 diabetes in a real-world setting in Asia.

    J Diabetes 2011, 3(3):208-216. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  16. Bretzel RG, Nuber U, Landgraf W, Owens DR, Bradley C, Linn T: Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial.

    Lancet 2008, 371(9618):1073-1084. PubMed Abstract | Publisher Full Text OpenURL

  17. Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Jarvinen H: Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes.

    Diabetes Care 2005, 28(2):254-259. PubMed Abstract | Publisher Full Text OpenURL

  18. Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Ceriello A, Esposito K: Efficacy of insulin analogs in achieving the hemoglobin A1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials.

    Diabetes Care 2011, 34(2):510-517. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  19. Suzuki D, Umezono T, Miyauchi M, Kimura M, Yamamoto N, Tanaka E, Kuriyama Y, Sato H, Miyatake H, Kondo M, et al.: Effectiveness of basal-supported oral therapy (BOT) using insulin glargine in patients with poorly controlled type 2 diabetes.

    Tokai J Exp Clin Med 2012, 37(2):41-46. PubMed Abstract | Publisher Full Text OpenURL

  20. Kawamori R, Iwamoto Y, Kadowaki T, Iwasaki M: Efficacy and safety of insulin glargine in concurrent use with oral hypoglycemic agents for the treatment of type 2 diabetic patients.

    Rinsho Iyaku 2003, 19(5):445-464. OpenURL

  21. Luddeke HJ, Sreenan S, Aczel S, Maxeiner S, Yenigun M, Kozlovski P, Gydesen H, Dornhorst A, Group PS: PREDICTIVE- a global, prospective observational study to evaluate insulin detemir treatment in types 1 and 2 diabetes: baseline characteristics and predictors of hypoglycaemia from the European cohort.

    Diabetes Obes Metab 2007, 9(3):428-434. PubMed Abstract | Publisher Full Text OpenURL

  22. Davis TM, Brown SG, Jacobs IG, Bulsara M, Bruce DG, Davis WA: Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.

    J Clin Endocrinol Metab 2010, 95(5):2240-2247. PubMed Abstract | Publisher Full Text OpenURL

  23. Ohtani T, Ito T: Safety and effectiveness of BOT (Basal supported Oral Therapy) using insulin glargine in Japanese patients with type 2 diabetes—results from postmarketing surveillance of insulin glargine (ALOHA study).

    Shinyaku to Rinsho (J New Rem Clin) 2011, 60:458-475. OpenURL

  24. Kadowaki T, Ohtani T, Odawara M: Potential Formula for the Calculation of Starting and Incremental Insulin Glargine Doses: ALOHA Subanalysis.

    PLoS One 2012, 7(8):e41358. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  25. Odawara M, Ohtani T, Kadowaki T: Dosing of Insulin Glargine to Achieve the Treatment Target in Japanese Type 2 Diabetes on a Basal Supported Oral Therapy Regimen in Real Life: ALOHA Study Subanalysis.

    Diabetes Technol Ther 2012, 14(7):635-643. PubMed Abstract | Publisher Full Text OpenURL

  26. Kadowaki T, Ohtani T, Odawara M: Baseline predictive factors for glycemic control in Japanese type 2 diabetes patients treated with insulin glargine plus oral antidiabetic drugs: ALOHA study subanalysis.

    Diabetol Int 2013, 4(1):16-22. Publisher Full Text OpenURL

  27. Kumano S: GPSP: good post-marketing study practice.

    Nihon Yakurigaku Zasshi 2012, 140(2):81-84. PubMed Abstract | Publisher Full Text OpenURL

  28. Good Pharmacovigilance Practices. European Medicines Agency http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp webcite Last Assessed Mar 11, 2013

  29. Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, Ito C, Inagaki N, Iwamoto Y, The Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus, et al.: Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus.

    J Diabetes Invest 2010, 1:212-228. OpenURL

  30. Tschope D, Bramlage P, Binz C, Krekler M, Deeg E, Gitt AK: Incidence and predictors of hypoglycaemia in type 2 diabetes - an analysis of the prospective DiaRegis registry.

    BMC Endocr Disord 2012, 12(1):23. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  31. Tschope D, Bramlage P, Binz C, Krekler M, Plate T, Deeg E, Gitt AK: Antidiabetic pharmacotherapy and anamnestic hypoglycemia in a large cohort of type 2 diabetic patients–an analysis of the DiaRegis registry.

    Cardiovasc Diabetol 2011, 10:66. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  32. Raskin P, Allen E, Hollander P, Lewin A, Gabbay RA, Hu P, Bode B, Garber A, Group IS: Initiating insulin therapy in type 2 Diabetes: a comparison of biphasic and basal insulin analogs.

    Diabetes Care 2005, 28(2):260-265. PubMed Abstract | Publisher Full Text OpenURL

  33. Schreiber SA, Haak T: Insulin glargine benefits patients with type 2 diabetes inadequately controlled on oral antidiabetic treatment: an observational study of everyday practice in 12,216 patients.

    Diabetes Obes Metab 2007, 9(1):31-38. PubMed Abstract | Publisher Full Text OpenURL

  34. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, American Diabetes A, European Association for Study of D: 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  35. Japan Diabetes Society: Treatment guide for diabetes. Tokyo: Bunkodo; 2007.

  36. Ross SA, Tildesley HD, Ashkenas J: Barriers to effective insulin treatment: the persistence of poor glycemic control in type 2 diabetes.

    Curr Med Res Opin 2011, 27(Suppl 3):13-20. OpenURL

  37. Skovlund S, Peyrot M, on behalf of the DAWN International Advisory Panel: The Diabetes Attitudes, Wishes, and Needs (DAWN) Program: A New Approach to Improving Outcomes of Diabetes Care.

    Diabetes Spectrum 2005, 18(3):136-142. Publisher Full Text OpenURL

  38. Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK, Group TS: Three-year efficacy of complex insulin regimens in type 2 diabetes.

    N Engl J Med 2009, 361(18):1736-1747. PubMed Abstract | Publisher Full Text OpenURL

  39. Shorr R, Ray W, JR D, Griffin M: Incidence and risk factors for serious hypoglycemia in older patients using insulin or sulfonylureas.

    Arch Intern Med 1997, 157:1681-1686. PubMed Abstract | Publisher Full Text OpenURL

  40. Holstein A, Plaschke A, Egberts EH: Clinical characterisation of severe hypoglycaemia–a prospective population-based study.

    Exp Clin Endocrinol Diabetes 2003, 111(6):364-369. PubMed Abstract | Publisher Full Text OpenURL

  41. Miller ME, Bonds DE, Gerstein HC, Seaquist ER, Bergenstal RM, Calles-Escandon J, Childress RD, Craven TE, Cuddihy RM, Dailey G, et al.: The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study.

    BMJ 2010, 340:b5444. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  42. Ishii H, Iwamoto Y, Tajima N: An Exploration of Barriers to Insulin Initiation for Physicians in Japan: Findings from the Diabetes Attitudes, Wishes and Needs (DAWN) JAPAN Study.

    PLoS One 2012, 7(6):e36361.

    doi:36310.31371/journal.pone.0036361

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  43. Lin YY, Hsu CW, Sheu WH, Chu SJ, Wu CP, Tsai SH: Risk factors for recurrent hypoglycemia in hospitalized diabetic patients admitted for severe hypoglycemia.

    Yonsei Med J 2010, 51(3):367-374. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  44. World Health Organization Expert Consultation: Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies.

    Lancet 2004, 363(9403):157-163. PubMed Abstract | Publisher Full Text OpenURL