https://www.ajmc.com/journals/issue/2018/2018-vol24-n4/progress-of-diabetes-severity-associated-with-severe-hypoglycemia-in-taiwan
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

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.

METHODS AND MATERIALS

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).

Participants

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 ajmc.com]).

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.

Disease Variables

The date of diabetes diagnosis was defined as the index date. Patients were followed until the first event of severe hypoglycemia, which served as the event date, or the end date, which was designated asdisenrollment; mortality; or December 31, 2011. Severe hypoglycemia was defined as a diagnosis of patients who required hospitalization or a visit to an emergency department (ED) for treatment with an ICD-9-CM code of 250.3, 251.0, 251.1, 251.2, or 962.3. Because of the possibility of ambiguity with ICD-9-CM code 250.3 (diabetes with other coma) between diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic syndrome (HHS) with hypoglycemic coma,24 we manually identified and analyzed our data for patients who were diagnosed with ICD-9-CM code 250.3. However, none of the patients in our study population appeared to have DKA/HHS with hypoglycemic coma. Disease comorbidities that potentially increased the risk of severe hypoglycemia, such as hypertension (ICD-9-CM codes 401-405), coronary heart disease (ICD-9-CM codes 414, 429.2), chronic liver disease (ICD-9-CM code 571), chronic kidney disease (ICD-9-CM code 585), heart failure (ICD-9-CM code 428), cancer (ICD-9-CM codes 140-208), depression (ICD-9-CM codes 296.2, 296.3), chronic obstructive pulmonary disease (ICD-9-CM codes 490-492, 494, 496), and stroke (ICD-9-CM codes 430-437), were identified, as were prescriptions for antidiabetic drugs, such as biguanides, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, glinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and insulin. Antidiabetic medication prescription was defined as a prescription with a drug exposure window of at least 180 days during this study period. A cutoff of 180 days was applied to avoid an irregular pattern of drug use, which might be related to patients’ nonadherence or initial antidiabetic drug adverse effects. The primary end point of this study was the first hospitalization due to severe hypoglycemia.

Statistical Analysis

Hazard ratios (HRs) and 95% CIs for the Cox proportional hazards model were used to analyze the data and determine the risk of severe hypoglycemia. One-way analysis of variance was used to compare data among the 3 groups. The Kaplan-Meier method was used to estimate severe hypoglycemia cumulative incidences. A 2-sided value <.05 was considered to be statistically significant. All statistical analyses were performed using the SPSS Statistical Package, version 18 (SPSS; Chicago, Illinois).

RESULTS

Table 1 shows the baseline demographic characteristics of the patients in this study. A total of 330,831 patients were included in this cohort from January 1, 1999, through December 31, 2011. The mean age 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. Patients with rapid increase in aDSCI score per year generally were older, were more likely to be male, and had more disease comorbidities and complications and a shorter follow-up duration.

Table 2 shows that the risks of severe hypoglycemia were associated with progression in aDCSI score. Compared with the patients with diabetes with slow progression of diabetes severity (increase in aDCSI score of <0.1 per year), the HRs of patients with moderate progression (increase of 0.1-0.3) and rapid progression (increase of >0.3) increased in proportion to diabetic progression, with HRs of 1.08 (95% CI, 1.02-1.14) and 4.91 (95% CI, 4.65-5.18), respectively. 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.

Table 3 shows the risk of severe hypoglycemia with different diabetes complications. Before adjustment for potential confounders, all diabetes complications were associated with higher risk of severe hypoglycemia. However, after adjustment for age, gender, and antidiabetic medication, patients with metabolic complications showed the highest risk of severe hypoglycemia (HR, 1.96; 95% CI, 1.87-2.06). Retinopathy (HR, 1.11; 95% CI, 1.07-1.15), nephropathy (HR, 1.33; 95% CI, 1.28-1.37), and stroke (HR, 1.21; 95% CI, 1.17-1.25) were also associated with severe hypoglycemia. Meanwhile, cardiovascular disease (HR, 0.90; 95% CI, 0.87-0.93) was associated with lower risk of severe hypoglycemia.

The eAppendix Figure shows the Kaplan-Meier curves of the cumulative incidence of severe hypoglycemia in the 3 groups of aDCSI score increase per year. The Kaplan-Meier curves showed that the risk of severe hypoglycemia seemed to emerge in the first year, and it can be seen that there was marked divergence of aDCSI score increase among the 3 groups over the 13-year follow-up period.

Table 4 [part A and part Bshows various model adjustments that were performed to evaluate the risk of severe hypoglycemia according to the progression of diabetes complications. Despite adjustment for age, gender, disease comorbidities, and prescriptions for antidiabetic drugs, the progression of diabetes complications still had a significant effect on the risk of developing severe hypoglycemia.

DISCUSSION

This study found that progression of diabetes severity was associated with an increased incidence of severe hypoglycemia. To the best of our knowledge, this is the first study to examine the association between progression of diabetes severity and risk of severe hypoglycemia. An increase in aDCSI score per year was positively related to risk of severe hypoglycemia. Furthermore, we found that being older than 45 years or having a prescription for insulin or a sulfonylurea was associated with increased risk of severe hypoglycemia, whereas having a prescription for biguanides, α-glucosidase inhibitors, thiazolidinediones, or DPP-4 inhibitors was associated with a lower risk of hypoglycemia.

The progression of diabetes complications is difficult to quantify. The severity of diabetes complications increases with time after diabetes onset, and patients with diabetes often exhibit different patterns of progression and complications. Previous study findings have demonstrated that patients with older age,16 previous hypoglycemia,13,14 history of chronic kidney disease,15 retinopathy,13 and antidiabetic drug prescriptions11-13 have a higher risk of hypoglycemia. In this study, we further explored the importance of timing and severity of these complications. We used increase in aDCSI score per year to measure the progression of diabetes complications. Compared with patients with slow progression of diabetes complications, severe hypoglycemia occurred more frequently in patients with complications that progressed rapidly within a short period of time. Furthermore, we demonstrated that severe hypoglycemia risk increased in proportion to the progression of diabetes complications (Table 4).

Surprisingly, patients with metabolic complications, such as DKA or HHS, had the highest risk of developing severe hypoglycemia. In these patients, a high degree of glucose variability might contribute to the mechanism of severe hypoglycemia.25,26 The potential mechanism of hypoglycemia might be characterized by deficient counterregulatory hormone release, especially in older patients, and a diminished autonomic response.27 Regarding antidiabetic medications, our findings showed that sulfonylurea prescription (HR, 2.50; 95% CI, 2.39-2.61) was associated with the highest risk of hypoglycemia, whereas DPP-4 inhibitor prescription was correlated with the lowest risk of hypoglycemia (HR, 0.22; 95% CI, 0.22-0.25). This finding was consistent with results reported in a previous study.11-13

Strengths and Limitations

This study has several strengths, most notably its large sample size and long-term follow-up. Our data are representative of Taiwan’s general population. To minimize the risk of selection bias and overdiagnosis of severe hypoglycemia, we included only patients who required hospitalization or an ED visit with a primary diagnosis of hypoglycemia. 

The potential limitations of this study should also be noted. First, because the NHIRD is primarily maintained for reimbursement purposes, there were no data on patients’ personal information, such as smoking history, body weight, and body mass index; laboratory data, including glucose level, glycated hemoglobin, and lipid profile; and dosage of medications, such as insulin, which may each potentially influence the risk of hypoglycemia. Second, patients with self-reported severe hypoglycemia who did not have an ED visit or hospital admission were not included in this study. Third, the retrospective nature of the study itself may have potentially resulted in selection bias. Finally, this study included only Taiwanese patients, and thus the results might not be generalizable to other populations.

Because the data set used in the present study was derived from the whole population without applying a sampling procedure, potential selection bias related to sampling error was not a concern. Although disease diagnosis might have been misclassified, the likelihood of such an occurrence was low because miscategorized diagnoses influence reimbursement, which would not be tolerated by hospitals and clinics. Taiwan’s NHI program also conducts stringent monitoring of claims and imposes strict penalties to avoid overdiagnosis and prevent financial irregularities.

CONCLUSIONS 

The current guideline of the American Diabetes Association recommends frequent self-monitoring of blood glucose for patients receiving intensive insulin treatment (multiple-dose insulin or insulin pump) to monitor and prevent hypoglycemia. Patients should receive education to increase their awareness of certain situations that might increase the risk of hypoglycemia, such as vigorous exercise, fasting for medical tests or procedures, and during sleep.27

Finally, this study demonstrated that patients with rapid progression of diabetes complications had a higher risk of developing severe hypoglycemia. Therefore, it is important for treating physicians to slow the progression of diabetes complications and identify patients with increases in aDCSI score per year. At-risk patients should be given proper hypoglycemia education, prevention, and treatment. 

Acknowledgments

The authors thank Yu-Hsun Wang of Chung Shan Medical University Hospital for his support and contribution. 

The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, the Ministry of Health and Welfare, or the National Health Research Institutes.
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