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The American Journal of Managed Care April 2018
Delivering on the Value Proposition of Precision Medicine: The View From Healthcare Payers
Jane Null Kogan, PhD; Philip Empey, PharmD, PhD; Justin Kanter, MA; Donna J. Keyser, PhD, MBA; and William H. Shrank, MD, MSHS
Care Coordination for Children With Special Needs in Medicaid: Lessons From Medicare
Kate A. Stewart, PhD, MS; Katharine W.V. Bradley, PhD, MBA; Joseph S. Zickafoose, MD, MS; Rachel Hildrich, BS; Henry T. Ireys, PhD; and Randall S. Brown, PhD
Cost Sharing and Branded Antidepressant Initiation Among Patients Treated With Generics
Jason D. Buxbaum, MHSA; Michael E. Chernew, PhD; Machaon Bonafede, PhD; Anna Vlahiotis, MA; Deborah Walter, MPA; Lisa Mucha, PhD; and A. Mark Fendrick, MD
The Well-Being of Long-Term Cancer Survivors
Jeffrey Sullivan, MS; Julia Thornton Snider, PhD; Emma van Eijndhoven, MS, MA; Tony Okoro, PharmD, MPH; Katharine Batt, MD, MSc; and Thomas DeLeire, PhD
A Payer–Provider Partnership for Integrated Care of Patients Receiving Dialysis
Justin Kindy, FSA, MAAA; David Roer, MD; Robert Wanovich, PharmD; and Stephen McMurray, MD
Financial Burden of Healthcare Utilization in Consumer-Directed Health Plans
Xinke Zhang, PhD; Erin Trish, PhD; and Neeraj Sood, PhD
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Progress of Diabetes Severity Associated With Severe Hypoglycemia in Taiwan
Edy Kornelius, MD; Yi-Sun Yang, MD; Shih-Chang Lo, MD; Chiung-Huei Peng, DDS, PhD; Yung-Rung Lai, PharmD; Jeng-Yuan Chiou, PhD; and Chien-Ning Huang, MD, PhD
Limited Distribution Networks Stifle Competition in the Generic and Biosimilar Drug Industries
Laura Karas, MD, MPH; Kenneth M. Shermock, PharmD, PhD; Celia Proctor, PharmD, MBA; Mariana Socal, MD, PhD; and Gerard F. Anderson, PhD
Provider and Patient Burdens of Obtaining Oral Anticancer Medications
Daniel M. Geynisman, MD; Caitlin R. Meeker, MPH; Jamie L. Doyle, MPH; Elizabeth A. Handorf, PhD; Marijo Bilusic, MD, PhD; Elizabeth R. Plimack, MD, MS; and Yu-Ning Wong, MD, MSCE

Progress of Diabetes Severity Associated With Severe Hypoglycemia in Taiwan

Edy Kornelius, MD; Yi-Sun Yang, MD; Shih-Chang Lo, MD; Chiung-Huei Peng, DDS, PhD; Yung-Rung Lai, PharmD; Jeng-Yuan Chiou, PhD; and Chien-Ning Huang, MD, PhD
Rapid progression of diabetes complications was associated with higher risk of severe hypoglycemia.

Objectives: The association between the progression of diabetes severity and risk of severe hypoglycemia is unknown. This study aimed to evaluate the association between the progression of diabetes severity and severe hypoglycemia in patients with diabetes.

Study Design: A 13-year population-based retrospective cohort study of patients with diabetes in Taiwan.

Methods: Diabetes progression was evaluated by the adapted Diabetes Complications Severity Index (aDCSI) score from index date to end of follow-up. The progression of diabetes severity was divided into 3 categories: slow, moderate, and rapid increase in aDSCI score. We further compared those 3 categories and evaluated the risk of first hospitalization due to severe hypoglycemia.

Results: A total of 330,831 patients with diabetes were recruited. The mean age of patients in this study was 56.8 years, and mean follow-up duration was 9.3 years. The mean initial aDCSI score was 0.7, whereas the mean aDCSI score at the event date or end date was 2.9. A rapid increase in aDCSI score was associated with higher risk of severe hypoglycemia compared with a slow increase (hazard ratio, 4.91; 95% CI, 4.65-5.18). The incidence densities of severe hypoglycemia (per 1000 person-years) for slow, moderate, and rapid increase in aDCSI score were 2.3, 2.5, and 11.4, respectively.

Conclusions: This study demonstrated that rapid progression of diabetes complications was associated with higher risk of severe hypoglycemia. It is imperative that treating physicians identify patients with acute worsening of diabetes severity and provide proper hypoglycemia education and prevention care.

Am J Manag Care. 2018;24(4):e99-e106
Takeaway Points
  • Rapid progression of diabetes complications was associated with higher risk of severe hypoglycemia. 
  • Being 45 years or older or having a prescription for insulin or sulfonylureas was associated with increased risk of severe hypoglycemia, whereas having a prescription for biguanides, α-glucosidase inhibitors, thiazolidinediones, or dipeptidyl peptidase-4 inhibitors was associated with a lower risk of hypoglycemia. 
  • Patients with metabolic complications had the highest risk of severe hypoglycemia.
The treatment of diabetes involves striking a delicate balance between attaining good glycemic control and avoiding hypoglycemic events. When ideal glycemic control is achieved, a favorable outcome can be expected due to the decreased frequency of microvascular and cardiovascular complications.1-3 However, overtreatment with insulin or oral antidiabetic drugs (eg, a sulfonylurea)can lead to severe hypoglycemia, which has negative consequences due to its association with increased cardiovascular events,4 cardiac arrhythmia,5 cognitive impairment,6 stress,7 and mortality.8 Although mild hypoglycemia can be easily resolved by consuming carbohydrates, when hypoglycemia occurs rapidly or goes untreated, confusion, seizure, or irreversible cognitive impairment can occur.

Severe hypoglycemia, which is a diabetes emergency, is defined as having low blood glucose that requires the assistance of another person to treat. The frequency of severe hypoglycemia is common. It has been estimated that about 7% to 25% of patients with type 2 diabetes who use insulin experience at least 1 severe episode annually.9 Nevertheless, the distribution of severe hypoglycemia in patients with diabetes is skewed, with a small proportion (5%) of patients accounting for the majority (54%) of severe hypoglycemic events.10 Therefore, it is important to improve the methods by which patients with a high risk of hypoglycemia are identified and managed. Previous study findings have demonstrated several risk factors for severe hypoglycemia in patients with diabetes, including antidiabetic medication prescription,11-13 previous hypoglycemia,13,14 preexisting retinopathy,13 depression,13 vigorous exercise,13 history of chronic kidney disease,15 advanced age,16 and hypoglycemia unawareness.17

Moreover, the timing and progression of diabetes severity might play an important role in the development of severe hypoglycemia. However, few studies in the literature address the association between progression of diabetes severity and risk of severe hypoglycemia. Therefore, we conducted a 13-year population-based cohort study using Taiwan’s National Health Insurance Research Database (NHIRD) to evaluate the association between the progression of diabetes severity and severe hypoglycemia in patients with newly diagnosed diabetes. We hypothesized that a rapid progression of adapted Diabetes Complications Severity Index (aDCSI) score is associated with higher risk of severe hypoglycemia.


Setting and Data Source

This observational retrospective cohort study was conducted using the Longitudinal Cohort of Diabetes Patients database, which was obtained from Taiwan’s National Health Insurance (NHI) program. This program is a compulsory insurance system that is regulated by Taiwan’s government, providing coverage for almost 99% of the population. For data protection and privacy reasons, the NHIRD releases only about 75% of data from the diabetic population for research purposes every year. This data set contains detailed information pertaining to patients’ disease diagnoses, drug prescriptions, medical expenses, hospital admissions, and discharge diagnoses. A detailed description of patient recruitment and sampling procedures is available on the NHIRD website.18 The information on disease diagnoses, drug prescriptions, and hospitalizations contained in the NHIRD is of high quality, and numerous studies have been published based on data obtained from this database.19 The accuracy of diabetes diagnoses in this NHI claims database has been validated with a good positive predictive value.20 All patients’ data in the NHIRD are encrypted and scrambled before being released to the public for academic research. Data for this study were extracted and analyzed by 1 independent reviewer. This study was reviewed and approved by the Institutional Review Board of Chung Shan Medical University Hospital (Taichung, Taiwan).


Patients were enrolled in the study by random selection of 360,000 newly diagnosed patients with diabetes between 1999 and 2001. Diabetes was defined as either an inpatient hospitalization for diabetes diagnosed in accordance with the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 250.x, at least 2 outpatient physician visits with ICD-9-CM code 250.x, or 1 outpatient physician visit with ICD-9-CM code 250.x plus a prescription for an oral antihyperglycemic agent within 365 consecutive days. All patients with diabetes diagnosed during this study period were included except those with gestational diabetes. Patients were tracked from January 1, 1999, to December 31, 2011, with a total follow-up duration of 13 years. Overall, 330,831 patients were included in the retrospective cohort analyses.

Progress of Diabetes Severity and aDCSI Score

The Diabetes Complications Severity Index (DCSI), which was developed by Young et al in 2008, measures the severity of diabetes-related complications and is used to predict the risk of diabetes-related hospitalizations, healthcare utilization,21 and mortality. A DCSI score ranges from 0 to 13 according to the presence of 7 categories of diabetes complications: retinopathy, nephropathy, neuropathy, stroke, cardiovascular disease, peripheral vascular disease, and metabolic complications. Each diabetes complication category is scored on a range of 0 to 2, determined by the presence and severity of complications (0 = not present, 1 = some abnormality, 2 = severe abnormality), except for neuropathy, which is given a score of 0 or 1 (0 = not present, 1 = abnormal). For example, within the cardiovascular category, patients with angina pectoris would be given a score of 1, whereas patients with myocardial infarction would have a score of 2. When multiple complications within the same category exist, the highest score within that category should be used (score of 2). It should be noted that the presence of severe hypoglycemia was identified as a disease event, rather than a DCSI item (eAppendix Figure [eAppendices available at]).

The patients’ original DCSI scores were calculated using a combination of their diagnosis code (ICD-9-CM code) and laboratory data (within nephropathy category). However, a recently modified version of the DCSI developed by Chang et al, known as aDCSI, which omits laboratory data from the nephropathy category, was demonstrated to be as effective as the original DCSI for estimating diabetes severity and predicting hospitalizations.22 The aDCSI was validated in a study that analyzed data from Taiwan’s NHIRD, and the results showed that the performance of the aDCSI in predicting the risk of hospitalization was similar to that of the original DCSI found in the study by Young et al.23

Study Protocol

All patients with diabetes and their complications were identified from the index date, and the patients were followed until the event date (severe hypoglycemia) or the end date of the study (disenrollment, mortality, or December 31, 2011). An observation for each patient was stopped after the first episode of severe hypoglycemia. The highest aDCSI score occurring in the first 6 months after diagnosis of diabetes was used as the initial aDCSI score (Figure). When diabetes complications within the same category appeared multiple times during this study period, they were calculated only once. The progression of diabetes severity was defined as the increase in aDCSI score per year, which was calculated by subtracting the initial aDCSI score from the total aDCSI score during this study period and dividing by the number of observation years. For instance, patient A had retinopathy at the initial diagnosis of diabetes and thus had a DCSI score of 1. In the fifth year, 1 additional diabetes complication developed (diabetic neuropathy with aDCSI score = 1) without the occurrence of severe hypoglycemia. In the seventh year, he experienced severe hypoglycemia, and during that time, he also had a first stroke (aDSCI score = 2), so his total aDCSI score was 4. Thus, the final score of progression of diabetes severity was 0.43 per year, which was obtained by subtracting the initial aDCSI score of 1 from the total aDCSI score of 4 and then dividing by 7, the number of observation years. We further classified the progression of diabetes severity into 3 categories (approximately 110,000 patients in each group): slow (increased scores of <0.1 per year), moderate (increased scores of 0.1-0.3 per year), or rapid increase in aDCSI score (increased scores of >0.3 per year). Thus, in this example, patient A should be categorized in the third group with an increase in aDCSI score of more than 0.3 per year.

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