Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases. Patients are generally advised lifestyle changes with antihyperglycemic agents prescribed. The major drawback of prescribing antihyperglycemic agents is the risk of hypoglycemia which subsequently impacts on health-related quality of life (HRQoL). This study is aimed at examining association between previous history of hypoglycemia and HRQoL. The study was a multicenter cross-sectional study, conducted from February 2013 to March 2015 at 5 tertiary care hospitals in Thailand (Srinagarind, Phramongkutklao, Ramathibodi, King Chulalongkorn Memorial, and Siriraj hospitals). The study population were males or females diagnosed with type 2 DM according to ADA criteria, 30 years of age or older, who had been treated with sulfonylurea (SU) monotherapy or SU and metformin combination for at least 6 months. Prespecified medical factors were extracted from medical records 12 months prior to patients’ enrolment. The experience of hypoglycemia questionnaire was used to collect and measure severity of hypoglycemia experienced during the previous 6 months. HRQoL was assessed using the 3-level version of EuroQol-5-dimension (EQ-5D-3L) and visual analogue scale (EQ-VAS) questionnaires. Of 659 eligible patients surveyed, 202 patients (30.65%) had experienced symptoms of hypoglycemia. HRQoL was significantly lower among patients reporting at least one of hypoglycemic symptoms, measured by EQ-VAS scores (
Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease with serious long-term micro- and macrovascular complications [
This study was a multicenter cross-sectional study conducted in patients who have been treated with sulfonylurea (SU) monotherapy or SU and metformin combination therapy (SU+MET) for at least 6 months prior to the study enrolment in 5 tertiary care hospitals in Thailand (i.e., Srinagarind, Phramongkutklao, Ramathibodi, King Chulalongkorn Memorial, and Siriraj hospitals). The study was conducted from February 2013 to March 2015. This study was approved by the Ethics Committee of each hospital. The potential patient medical charts were retrospectively reviewed to check if they meet inclusion and exclusion criteria. The patients satisfying the selection criteria were enrolled in the study after providing written informed consent to participate in the study.
The patients who were diagnosed with T2DM according to American Diabetes Association (ADA) criteria [
A standardized data collection form was developed to record data of clinical and laboratory assessment of patients from medical records that were completed by physicians or personnel who had been trained. Prespecified medical data from charts were extracted for the 12-month period prior to the patient enrolment date. On the day of enrolment, participating patients were subjected to a standard blood draw after overnight fasting for measurements of HbA1c, fasting plasma glucose, serum creatinine, total cholesterol, triglycerides, HDL-cholesterol, and LDL-cholesterol. In addition, each patient’s body weight, blood pressure, and waist circumference were measured and recorded. Alcohol consumption and regular physical activity were also assessed.
Experience of hypoglycemia during the previous 6 months was assessed with the questionnaire that was developed by Merck Sharp & Dohme (MSD) (see the Experience of Low Blood Sugar (Hypoglycemia) questionnaire in Supplementary Material
HRQoL was assessed by using the Thai language 3-level version of EuroQol 5-dimension (EQ-5D-3L) questionnaire which is a standardized instrument for measuring the general health outcome and is a recommended utility method because it has acceptable feasibility and validity in Thailand [
The treatment satisfaction was evaluated by using the 14-item treatment satisfaction questionnaire for medication (TSQM, version 1.4) [
We estimated the sample size in order to conduct our survey of HRQoL in hypoglycemia patients using the following formula [
Descriptive statistics were used to report demographic characteristics of patients and clinical characteristics, including patient sociodemographic, clinical, and laboratory test results. The Shapiro-Wilk test was used for checking normality of the continuous data. If the data distribution is normal, the data will be presented by the mean (±SD). If the data significantly deviate from a normal distribution (
One-way analysis of variance (one-way ANOVA) was conducted to evaluate differences in EQ-VAS scores by severity of hypoglycemia episodes and evaluated differences in EQ-5D-3L index scores by episode severity of hypoglycemia. Multivariate linear regression, adjusting for potential confounders, was used to estimate the effect of hypoglycemia on HRQoL (EQ-VAS and EQ-5D-index scores). The technique for selecting the covariates in the multivariate regression analyses was that based on the directed acyclic graph (DAG). Multivariate relationships were conceptualized using directed acyclic graphs and minimum sets of adjustment variables to obtain unbiased estimates of total and direct effects of various exposure variables on occurrence of hypoglycemia, treatment compliance, treatment satisfaction, quality of life, worry about hypoglycemia, and fear of weight gain compatible with the conceptual graph identified.
Directed acyclic graphs were constructed using DAGitty software (version 2.3) [
Participant flow is shown in Figure
Participant flow.
Compared to those who did not experience symptoms of hypoglycemia, patients who did experience symptoms of hypoglycemia were significantly younger (
There were no significant differences in waist circumference, systolic and diastolic blood pressure, micro-/macrovascular complications, and hypoglycemic agents used between the patients with hypoglycemia and without hypoglycemia. In addition, there were no significant differences in marital status, education, or having parents with diabetes mellitus (data not shown). There were no significant differences between patients taking SU versus patients taking SU+MET in terms of hypoglycemia symptoms experienced. The patient demographics by occurrence of hypoglycemia in the previous 6 months are shown in Table
Patient demographics by occurrence of hypoglycemia in previous 6 months.
Variables | No hypoglycemia ( |
Hypoglycemia ( |
|
---|---|---|---|
Male, |
228 (50.8) | 93 (46.0) | 0.272a |
Age (years) | 66.20 (9.59) | 63.94 (10.65) | 0.008b† |
Duration of DM (years), median (IQR) | 10 (5, 15) | 10 (6, 15) | 0.531c |
Height (cms) | 160.5 (8.4) | 160.3 (9.3) | 0.746b |
Body weight (kgs) | 66.5 (12.9) | 65.2 (14.5) | 0.134b |
Did not take physical regular activity, |
156 (34.3) | 86 (42.8) | 0.038a† |
Alcohol consumption, | |||
Never | 318 (69.6) | 149 (74.5) | 0.030a† |
Occasionally | 116 (25.4) | 45 (22.5) | |
Daily | 1 (0.2) | 3 (1.5) | |
Unknown | 22 (4.8) | 3 (1.5) | |
Low-sugar diet, |
214 (47.6) | 116 (57.7) | 0.018a† |
Weight change in previous 12 months | |||
No change | 87 (19.3) | 42 (21.1) | 0.798a, |
Gained | 158 (35.0) | 65 (32.7) | |
Lost | 192 (42.5) | 85 (42.7) | |
Unknown | 15 (3.3) | 7 (3.5) | |
Waist circumference (cm) | 92.4 (10.1) | 91.0 (11.7) | 0.119b |
SBP (mmHg) | 135.7 (17.1) | 133.5 (17.6) | 0.128b |
DBP (mmHg) | 74.5 (10.2) | 73.4 (9.8) | 0.186b |
Hypoglycemic agents, | |||
Sulfonylurea (SU) | 93 (20.3) | 45 (22.3) | 0.604a |
Combination of SU and metformin | 364 (79.7) | 157 (77.7) | |
Macro- and/or microvascular complications, |
99 (21.7) | 38 (18.8) | 0.407a |
aChi-squared test or Fisher exact test as appropriate; bindependent sample
Laboratory test results at enrolment by occurrence of hypoglycemia in the previous 6 months.
Variables | No hypoglycemia ( |
Hypoglycemia ( |
|
---|---|---|---|
HbA1c (%) | 7.29 (1.28) | 7.17 (1.31) | 0.247a |
FPG (mg/dL) | 145.6 (44.6) | 139.4 (39.7) | 0.086a |
Serum creatinine (mg/dL) | 1.26 (1.08) | 1.23 (0.89) | 0.767a |
Total cholesterol (mg/dL) | 167.8 (38.5) | 170.3 (36.1) | 0.581a |
HDL-cholesterol (mg/dL) | 50.4 (20.4) | 51.1 (15.0) | 0.784a |
LDL-cholesterol (mg/dL) | 97.7 (33.9) | 98.1 (32.4) | 0.912a |
Triglycerides (mg/dL), median (IQR) | 133 (92, 179) | 132.5 (91.5, 180) | 0.632b |
Urinary albumen (mg/g), median (IQR) | 10.8 (4.7, 30.3) | 7.3 (2.3, 46.4) | 0.573b |
aIndependent sample
HRQoL was significantly lower among patients reporting at least one of hypoglycemic symptoms either mild, moderate, or severe/very severe symptoms, as measured by EQ-VAS scores (
Patient EQ-5D-VAS and EQ-5D-index scores according to severity of hypoglycemia.
HRQoL | Maximum severity of hypoglycemic episodes experienced | Mean (SD) | 95% CI | |
---|---|---|---|---|
EQ-5D-VAS score | None | 77.01 (13.02) | 75.77, 78.22 | 0.006 |
Mild | 73.66 (13.18) | 71.27, 76.06 | ||
Moderate | 73.56 (15.10) | 70.37, 76.45 | ||
Severe/very severe | 68.93 (14.76) | 62.18, 75.68 | ||
EQ-5D index score | None | 0.79 (0.31) | 0.76, 0.82 | <0.001 |
Mild | 0.62 (0.47) | 0.56, 0.69 | ||
Moderate | 0.68 (0.38) | 0.60, 0.76 | ||
Severe/very severe | 0.58 (0.51) | 0.40, 0.75 |
There was significant association between quality of life in each domain and severity of hypoglycemic episodes experienced as shown in Table
Patient EQ-5D-3L levels by maximum severity of hypoglycemic episodes.
Domain | Maximum severity of hypoglycemic episodes | Level of perceived problem, |
||||
---|---|---|---|---|---|---|
No problem | Some problem | Extreme problems | ||||
Mobility | None | 457 | 297 (65.0) | 140 (30.6) | 20 (4.4) | 0.002† |
Mild | 119 | 52 (43.7) | 55 (46.2) | 12 (10.1) | ||
Moderate | 67 | 35 (52.2) | 28 (41.8) | 4 (6.0) | ||
Severe/very severe | 15 | 9 (60.0) | 5 (33.3) | 1 (6.7) | ||
Self-care | None | 457 | 383 (83.8) | 71 (15.5) | 3 (0.7) | 0.001† |
Mild | 119 | 80 (67.2) | 35 (29.4) | 4 (3.4) | ||
Moderate | 67 | 54 (80.6) | 12 (17.9) | 1 (1.5) | ||
Severe/very severe | 15 | 10 (66.7) | 4 (26.7) | 1 (6.7) | ||
Usual activities | None | 457 | 368 (80.5) | 80 (17.5) | 9 (2.0) | 0.001† |
Mild | 119 | 76 (63.9) | 39 (32.8) | 4 (3.4) | ||
Moderate | 67 | 48 (71.6) | 16 (23.9) | 3 (4.5) | ||
Severe/very severe | 15 | 9 (60.0) | 4 (26.7) | 2 (13.3) | ||
Pain/discomfort | None | 457 | 265 (58.1) | 166 (36.4) | 25 (5.5) | 0.008† |
Mild | 119 | 50 (42.4) | 54 (45.8) | 14 (11.9) | ||
Moderate | 67 | 28 (41.8) | 32 (47.8) | 7 (10.4) | ||
Severe/very severe | 15 | 6 (40.0) | 7 (46.7) | 2 (13.3) | ||
Anxiety/depression | None | 457 | 341 (75.1) | 102 (22.5) | 11 (2.4) | <0.001† |
Mild | 119 | 64 (54.2) | 42 (35.6) | 12 (10.2) | ||
Moderate | 67 | 35 (52.2) | 26 (38.8) | 6 (9.0) | ||
Severe/very severe | 15 | 7 (46.7) | 4 (26.7) | 4 (26.7) |
The results show that higher severity of hypoglycemic episodes experienced, use of SU+MET, higher worry about hypoglycemia scores, weight changes (either lost or gained), and higher fear of weight gain scores were significant factors lowering EQ-5D-3L index score while being male significantly increased the score. The patients with higher severity of hypoglycemic symptoms were negatively associated with HRQoL as measured by EQ-5D-3L index score than those who did not have hypoglycemia (adjusted mean difference; for mild: -0.156 (95% CI: -0.225, -0.087), moderate: -0.096 (CI: -0.183, -0.008), and severe/very severe: -0.198 (CI: -0.373, -0.023) when compared to those who have not experienced hypoglycemia).
For HRQoL, as measured by EQ-VAS scores, higher severity of hypoglycemic episodes experienced and higher worry about hypoglycemia were significant factors lowering EQ-VAS score while higher overall satisfaction was related with a higher EQ-VAS score. The patients with higher severity of hypoglycemic episodes experienced symptoms also demonstrated significantly higher impairment for EQ-VAS score with adjusted mean difference of -2.92 (95% CI: -5.61, -0.23), -3.17 (95% CI: -6.59, 0.25), and -7.89 (95% CI: -14.71, -1.07) for mild, moderate, and severe/very severe hypoglycemia symptoms when compared to those who have not experienced hypoglycemia. Table
Factors associated with health-related quality of life measured by EQ-5D-3L index and EQ-VAS scores from multivariate regression analyses.
Variables |
Adjusted mean difference (95% CI) of EQ-5D-3L index score | Adjusted mean difference (95% CI) of EQ-5D-3L VAS score | ||
---|---|---|---|---|
Hypoglycemia | ||||
None | Reference | <0.001† | Reference | 0.013† |
Mild | -0.156 (-0.225, -0.087) | -2.92 (-5.61, -0.23) | ||
Moderate | -0.096 (-0.183, -0.008) | -3.17 (-6.59, -0.25) | ||
Severe/very severe | -0.198 (-0.373, -0.023) | -7.89 (-14.71, -1.07) | ||
-0.057 (-0.118, 0.003) | 0.064 | -0.32 (-2.63, 1.99) | 0.784 | |
Male | 0.108 (0.054, 0.161) | <0.001† | 1.48 (-0.57, 3.53) | 0.156 |
Vascular complication | -0.020 (-0.046, 0.087) | 0.547 | -2.24 (-4.77, 0.29) | 0.082 |
Treatment | ||||
SU alone | Reference | 0.049† | Reference | 0.127 |
SU+MET | -0.067 (-0.133, 0.000) | 1.97 (-0.56, 4.51) | ||
Weight change | ||||
None | Reference | 0.003† | Reference | 0.809 |
Gain | -0.116 (-0.189, -0.042) | 0.83 (-2.05, 3.71) | ||
Loss | -0.119 (-0.190, -0.048) | 0.88 (-1.92, 3.67) | ||
Adherence to medication | -0.018 (-0.071, 0.034) | 0.490 | -0.45 (-2.49, 1.60) | 0.668 |
Worry about hypoglycemia/unit score (0 to 4) | -0.059 (-0.103, -0.015) | 0.009† | -3.14 (-4.83, -1.46) | <0.001† |
Fear of weight gain/unit score (0 to 4) | -0.070 (-0.099, -0.041) | <0.001† | -0.73 (-1.85, 0.39) | 0.203 |
Overall satisfaction/unit score (0 to 100) | 0.0016 (-0.0008, 0.0039) | 0.184 | 0.103 (0.014, 0.193) | 0.024† |
In this study of Thai patients with T2DM treated with SU alone or SU+MET, symptoms of hypoglycemia were reported by approximately 30.65% of patients and only 6.59% reported severe or very severe events. The proportion of patients reporting hypoglycemic symptoms reported by United State (US) patients (63% during 6 months [
Our results demonstrated that patients with hypoglycemic symptoms reported a decrease in EQ-5D index and EQ-5 VAS scores relative to patients who did not, even after adjusting for a number of confounders. This is similar to the results published in Marrett et al. [
The current results should be considered within the context of several limitations. Hypoglycemia was determined by a patient-reported low plasma glucose questionnaire, cross-sectional survey. The hypoglycemia data were not verified against clinician diagnoses or chart reviews nor were reports of low blood sugar confirmed by blood glucose monitoring. The future studies of quality of life at the time or immediately after the hypoglycemia symptom confirmation or when the hypoglycemia is confirmed by blood sugar monitoring are needed. In addition, this study is limited by its cross-sectional design. Future studies with more rigorous designs, such as prospective cohort studies, are also needed to confirm the impact of hypoglycemia and to compare within the individual patients.
Additional consideration is that EQ-5D index scores were calculated using the coefficient from the “Social tariff for EuroQol” [
In this survey of Thai patients with T2DM who were treated with SU alone or SU+MET, approximately one-thirds reported experiencing hypoglycemic symptoms. The results from the study showed significant decrement of HRQoL as determined by the EQ-5D index scores and the EQ-VAS in the patient-reported symptoms of hypoglycemia compared with patients who did not report those symptoms, relative to severity of hypoglycemia. Even after adjusting for a number of variables, patients who experienced hypoglycemic symptoms still continued to report a decrease in the HRQoL.
The patient-level data used to support the findings of this study have not been made publicly or shared with the third parties due to the institutes/hospitals’ Human Research Ethics Committee regulations.
The authors declare that there is no conflict of interest regarding the publication of this paper. Although MSD (Thailand) Ltd. supported the study funding, the study was conducted and the study results were interpreted without the influence of the pharmaceutical company.
All authors contributed equally to the study conduct. TP mainly drafted the article. All other authors reviewed the literatures and revised it critically. All authors read and approved the manuscript and met the criteria for authorship.
The authors gratefully acknowledge the contributions of the participating patients and general practitioners. They would like to thank Alan Geater and Walailuk Jitpiboon, Epidemiology Unit, Faculty of Medicine, Prince of Songkhla University, for statistical analysis. Merck Sharp and Dohme (Thailand) Ltd. supported for the study funding (e.g., cost of materials, data management, data analysis, and cost of publication).
The study questionnaires (i.e., Experience of Low Blood Sugar, Worry Scale of HFS II, TSQM, version 1.4) were translated from English to Thai by the Psychology Department, Faculty of Liberal Arts, Thammasat University. The translations were done by forth and back translation. Content validity was checked using double-blind fashion. The questionnaires were tested by 15 diabetic patients, and the average duration to complete the questionnaire was 41.25 minutes.