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Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 163-168

Predisposing factors of hypoglycemia in patients with type 2 diabetes mellitus presented with symptomatic hypoglycemia in a tertiary hospital of Bangladesh

1 Department of Endocrinology, Mainamoti Medical College, Comilla, Bangladesh
2 Department of Endocrinology, Mymensingh Medical College and Hospital, Mymensingh, Bangladesh

Date of Submission05-Sep-2019
Date of Decision20-Nov-2019
Date of Acceptance28-Nov-2019
Date of Web Publication1-Sep-2020

Correspondence Address:
Dr. A. B.M. Kamrul-Hasan
Department of Endocrinology, Mymensingh Medical College and Hospital, Mymensingh.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JOD.JOD_27_19

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Background: Hypoglycemia is almost inevitable complication of diabetes treatment and the most important barrier in achieving tight glycemic control in diabetes patients. Objective: To describe characteristics of the patients with T2DM presenting with hypoglycemia and identify the predisposing factors of hypoglycemia in them. Materials and Methods: This cross-sectional study was conducted in a tertiary hospital of Bangladesh from January 2017 to March 2018. Venous plasma glucose was measured in all patients with T2DM presented with signs-symptoms of hypoglycemia, patients having biochemically confirmed hypoglycemia (venous plasma glucose <3.9 mmol/L) were finally selected for the study. A semi-structured data collection sheet was used to obtain the demographic and clinical data including hypoglycemic symptoms. Results: One hundred patients with T2DM were included in the study among whom 59% were female, 53% aged ≥60 years, 90% lived in rural and sub-urban areas, 60% had diabetes for ≥10 years, and 88% took insulin. Hypertension was the most common (45%) co-morbid condition followed by ischemic heart disease (28%). Adrenergic symptoms were present in the majority of the subjects and 62% lost consciousness before reaching the hospital. Their mean plasma glucose at presentation was 2.41 mmol/L (±0.48); mean HbA1c was 7.5% (±1.7) and 86% of them had eGFR <60 mL/min/1.73m2. Most of them (92%) received no education on hypoglycemia management and did not perform (95%) self-monitoring of blood glucose (SMBG). More than half had (51%) hypoglycemic episodes in the preceding 6 months and 28% were hospitalized for that. The meal-related factors (missed, inadequate or delayed meals) were the most common precipitating factors followed by drug overdose and excess exercise before hypoglycemia. Conclusion: Diabetes education emphasizing on appropriate lifestyle and dietary habit, and SMBG at recommended frequency are of utmost importance to prevent hypoglycemia.

Keywords: Type 2 diabetes, Hypoglycemia, Insulin, Lifestyle factors, Diabetes education, Bangladesh

How to cite this article:
Paul AK, Kamrul-Hasan AB. Predisposing factors of hypoglycemia in patients with type 2 diabetes mellitus presented with symptomatic hypoglycemia in a tertiary hospital of Bangladesh. J Diabetol 2020;11:163-8

How to cite this URL:
Paul AK, Kamrul-Hasan AB. Predisposing factors of hypoglycemia in patients with type 2 diabetes mellitus presented with symptomatic hypoglycemia in a tertiary hospital of Bangladesh. J Diabetol [serial online] 2020 [cited 2021 May 7];11:163-8. Available from: https://www.journalofdiabetology.org/text.asp?2020/11/3/163/294041

  Introduction Top

The benefits of strict glycemic control have been proved by two milestone studies, Diabetes Control and Complications Trial in patients with type 1 diabetes mellitus (T1DM) and the United Kingdom Prospective Diabetes Study in patients with type 2 diabetes mellitus (T2DM).[1],[2] On the contrary, aggressive glycemic goals are associated with a threefold increase in the risk of hypoglycemia, counterbalancing the benefits conferred by intensive glucose control.[3] Hypoglycemia may be inconvenient or frightening to patients with diabetes and can cause acute harm to the person with diabetes or others. More severe hypoglycemia can progress to loss of consciousness, seizure, coma, or even death.[4] So, hypoglycemia is the major limiting factor in the strict glycemic control in diabetes. Moreover, hypoglycemic episodes, especially severe ones, directly or indirectly increase the costs of medical care.[5] In addition to more stringent glycemic control, other known risk factors for hypoglycemia in diabetes include the use of insulin and insulin secretagogues (sulfonylureas and glinides), nonadherence to recommended diet and exercise, renal and hepatic impairment, longer duration of diabetes, and alcohol ingestion.[4]

Around 70 million adults have diabetes in Bangladesh, and T2DM accounts for more than 95% of them.[6] One study showed 42.49% of patients with diabetes in Bangladesh are using insulin.[7] But we lack data on the characteristics and risk factors of the patients with diabetes experiencing hypoglycemia. These problems were addressed in this study.

  Materials and Methods Top

This observational cross-sectional study was conducted in the inpatient department of endocrinology of a tertiary hospital delivering specialized diabetic care situated in a divisional city of Bangladesh from January 2017 to March 2018. The protocol of the study was approved by the institutional review board of the hospital. All patients with T2DM, aged 20 years or more, admitted in the department with signs and symptoms of hypoglycemia during the study period, were included in the sample. Pregnant women, patients with other critical illness, those with alcohol intoxication, and with nondiabetic hypoglycemia were excluded. Non-probability convenient sampling technique was applied, venous blood glucose and glycated hemoglobin (HbA1c) levels were measured at admission in all of these patients; a venous plasma glucose level <3.9 mmol/L was considered for the threshold for the diagnosis of hypoglycemia.[8],[9] Of 112 patients presenting with hypoglycemic signs and symptoms, 100 patients, who had biochemically confirmed hypoglycemia, were finally selected for the study. Relevant history was taken, physical examination, including anthropometric measurements, was carried out after initial stabilization of the patients; collected data were recorded in a prespecified data collection sheet. Obesity status was determined by body mass index categories applicable to the Asian Indians.[10]

Biochemical analysis: Plasma glucose was estimated by using glucose oxidase–peroxidase method (colorimetric method) on a semiauto analyzer (Screen Master 3000; Biochemical Systems International, Arezzo, Italy), and HbA1c was assayed by immunofluorescence assay on NGSP-certified quantitative immunoassay analyzer Getein 1100 (Getein Biotech, Nanjing, China).

Statistical analysis: The data were statistically analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 23.0 (IBM SPSS Statistics for Windows, IBM, Armonk, New York). The categorical variables were represented as percentages, and measurable variables as mean ± standard deviation.

  Ethical Clearance Top

Ethical approval for this study (CDH/IRB/2017/02) was provided by the Institutional Review Board of Comilla Diabetic Association, Cumilla, Bangladesh, on 01 January 2017.

  Results Top

More than half (53%) of the study subjects were 60 years and older, more than half (59%) were female, and homemaker was the most frequent occupation among the study subjects. More than half (55%) resided in rural areas. The majority were overweight (52%) or obese (44%). Nearabout half (45%) had previous diagnosis of hypertension, 38% had ischemic heart disease, 26% had renal failure, and 9% had previous diagnosis of liver disease [Table 1].
Table 1: Background characteristics of the study subjects (N = 100)

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The common symptoms of hypoglycemia were excess sweating (89%), pounding heart (88%), pale skin (82%), generalized weakness (82%), and dizziness (76%) [Table 2].
Table 2: Hypoglycemic symptoms (N = 100)

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The mean HbA1c level of the study subjects was 7.5% (±1.7), the mean venous plasma glucose concentration was 2.41 ± 0.48 mmol/L. The majority (86%) had estimated glomerular filtration rate (eGFR) <60mL/min/1.73 m2 [Table 3].
Table 3: Biochemical parameters of the study subjects (N = 100)

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More than half (60%) of the study subjects had diabetes for 10 years or longer. Most of them (88%) were insulin treated (68% only insulin and 20% insulin and oral antidiabetic drug [OAD] combinations). More than one-quarter (27.3%) of them took insulin for 10 years or longer. Though the majority received education about diabetes management (80%) and insulin technique (64%), only few (8%) of the study subjects were educated about hypoglycemia recognition and management. Only 28% of them had glucometer but only 5% participants performed self-monitoring of blood glucose (SMBG). More than half (52%) were irregular at the follow-up visits to the physicians [Table 4].
Table 4: Diabetes and related factors (N = 100)

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Higher proportions of the study subjects with eGFR <60mL/min/1.73 m2 were on either insulin or insulin plus OADs in comparison to those with eGFR ≥60mL/min/1.73 m2 [Table 5].
Table 5: Distribution of antidiabetic drugs in subjects with estimated glomerular filtration rate <60 and ≥ 60 (N = 100)

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More than half (51%) of the subjects had a history of hypoglycemia in the preceding 6 months, and 28% were hospitalized for hypoglycemia during that period. Missing meals was the most frequent (68%) precipitating factor of the current hypoglycemic episode, followed by inadequate meal (51%), excess delay to take meal after drug intake (42%), drug overdose (26%), and excess exercise (20%). The mean duration of hospital stay for the current hypoglycemic episode was 4.58 days; 1% of the patients died during this period [Table 6].
Table 6: Hypoglycemia-related factors (N = 100)

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  Discussion Top

This cross-sectional study was conducted among 100 patients with diabetes who got admitted with documented symptomatic hypoglycemia in a tertiary hospital delivering specialized diabetes care in a divisional city of Bangladesh to identify the patient characteristics and factors associated with hypoglycemia. The American Diabetes Association and the European Medicines Agency have defined hypoglycemia as “any abnormally low plasma glucose concentration that exposes the subject to potential harm” with a proposed threshold plasma glucose value <70mg/dL (<3.9 mmol/L).[8],[9] Though hypoglycemia rates are higher in patients with T1DM than in those with T2DM, a very tight glucose target in patients with T2DM may confer a similar risk to those with T1DM. Majority of hypoglycemic episodes experienced by patients with diabetes are related to medications. Approximately 90% of all patients who receive insulin have experienced hypoglycemic episodes and 7%–25% of patients with T2DM using insulin have experienced at least one severe episode annually. Hypoglycemia also is commonly reported in patients with T2DM on OADs.[11],[12] In this study, most (88%) of the patients were taking insulin and 12% were taking only OADs. Hypoglycemia may also result from certain seldom causes such as pancreatic or non-islet cell tumors, autoimmune conditions, organ failure, endocrine disease, inborn errors of metabolism, dietary toxins, alcohol consumption, stress, infections, and miscellaneous conditions (such as sepsis, starvation, and severe excessive exercise). The short- and long-term complications of diabetes-related hypoglycemia include precipitation of acute myocardial infarction, cerebrovascular disease, neurocognitive dysfunction, retinal cell death, and loss of vision in addition to health-related quality of life issues pertaining to sleep, driving, employment, and recreational activities involving exercise and travel.[5]

The elderly patients are at increased risk of hypoglycemia due to deteriorating renal function affecting drug clearance, adverse drug interactions resulting from polypharmacy, which is common in the elderly, and impaired cognitive functioning.[5],[11] In this study, more than half of the patients were aged 60 years or older. More than half of the subjects admitted with hypoglycemia in this study were female. Female gender was identified as a risk factor for hypoglycemia in previous researches.[13] The majority of the study participants resided in rural and suburban areas where availability of health-care services is limited and there may be a considerable delay to avail medical help after the onset of hypoglycemic episodes rendering the patients to more serious complications.

Hypertension and ischemic heart disease were present in 45% and 38% of the study subjects, respectively. As previously discussed, hypoglycemic events are associated with adverse cardiovascular outcomes, including precipitation of myocardial ischemia and sudden cardiac death from arrhythmias, a high proportion of the study subjects are increased risk of them.[5],[11],[12] More than one-quarter of this study subjects had the previous diagnosis of renal failure, and after assessment of renal function, 86% of them were found to have eGFR <60mL/min/1.73 m2. Patients with diabetes who have chronic kidney disease (CKD) have a higher frequency of hypoglycemia than patients with diabetes who do not have CKD. Reasons for this increased risk include reduced insulin requirements because of decreased renal clearance of insulin, decreased degradation of insulin in peripheral tissues, reduced renal gluconeogenesis due to a reduction in renal mass, and prolonged half-life of other drugs in CKD.[14] Furthermore, the majority of our study subjects having eGFR <60 were on insulin (±OADs), which might confer higher risk of hypoglycemia in them. Decreased glucose production, resulting from diminished glycogen storage and impaired gluconeogenesis in liver disease, increases hypoglycemia risk in these patients, and 9% of our patients had liver disease.[13]

T2DM is a progressive disease. The duration of diabetes and progressive insulin deficiency are also found to be associated with an increased risk of hypoglycemia in patients with T2DM, which appears to be amplified in those who have received insulin for more than 10 years.[15],[16] The UK Hypoglycemia Study showed that in patients with type 2 diabetes, the risk of severe hypoglycemia is low in the first few years (7%) and that risk increases to 25% later in the course of diabetes.[17] The duration of diabetes was 10 years or longer in 60% of the subjects of this study, and 24% of the subjects were using insulin for 10 or more years, which undoubtedly increased their risk of hypoglycemia.

Previous studies showed that a prior history of hypoglycemia is one of the strongest predictors of all severe hypoglycemic events. Recurrent hypoglycemia causes defective glucose counterregulation by attenuating the adrenomedullary epinephrine response and hypoglycemia unawareness. Thus hypoglycemia can trigger a vicious cycle of recurrent hypoglycemia.[18] In our study, more than half of the patients had hypoglycemic episode(s) in the preceding 6 months, and 28% got admitted to hospital for hypoglycemia.

Although tight glycemic control contributed to reducing diabetic microvascular complications, it also resulted in an increased risk of hypoglycemia episodes as previously discussed.[1],[2],[13] The mean HbA1c level of this study was lower than the finding of the previous researches conducted in this area.[7],[19] More aggressive glycemic control may be a risk factor of hypoglycemia in these subjects.

Dietary error (missed, inadequate, or delayed meals), excessive physical activity, wrong drug dosage, and wrong time of drug administration are recognized risk factors of hypoglycemia in patients with diabetes.[5] In this study, missing meals was identified as the precipitating factor of hypoglycemia in 68% subjects, whereas inadequate meal and excess delay to take meal after drug intake were the precipitating factors in 51% and 42% subjects, respectively. On the contrary, drug overdose and excess exercise before the hypoglycemic events were identified in 26% and 20% of the study subjects, respectively.

Education at a level appropriate to the patient understanding is the key to diabetes management, including prevention of hypoglycemia. Every patient with diabetes should be educated about early identification of hypoglycemic symptoms, its causes, the various preventive measures, and the available treatment options. It is also important to educate them about the importance of SMBG at the appropriate frequency, good record keeping, and regular follow-up with their physicians.[5],[20] The number of school years of more than three-quarter of our study subjects was 5 or less, which may not be sufficient for the proper understanding of hypoglycemia management. Moreover, most of our patients did not receive education about hypoglycemia management though they were instructed about the insulin technique and other aspects of diabetes management. Their frequency of follow-up visits to the health-care centers was also not regular. Lacking specific education regarding the management of hypoglycemia rendered these patients vulnerable to hypoglycemia.

Concerning symptomatic definitions, hypoglycemia may be self-treated (mild) or severe/major (i.e., requiring the assistance of a third party). Symptoms can be divided into two broad groups: autonomic (e.g., sweating, palpitations, shakiness, dizziness, hunger, pallor, anxiety, irritability, and headache) and neuroglycopenic (e.g., confusion, drowsiness, speech difficulty, odd behavior, incoordination, seizures, and unconsciousness).[11] Most of the subjects of this study had autonomic symptoms, and 62% of them lost consciousness before they were brought to the hospital. The high frequency of unconsciousness may be due to the time needed to avail medical services after reaching the hospital from their rural or suburban residence and not taking any immediate measure for hypoglycemia correction in most instances; these might result in very low plasma glucose (mean 2.41 mmol/L) causing neuroglycopenia at the time of initial assessment of these patients. The mean duration of hospital stay for these subjects was 4.58 days; the mean length of hospital stay was between 6.6 and 9.5 days in previous research.[11] Despite aggressive correction of hypoglycemia, one patient died during hospital stay, the remaining 99 were discharged safely. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial study, the mortality rate among those reporting severe hypoglycemia was 19.5%, compared with 9% for those without severe hypoglycemia.[21]

Our study had several limitations. We only assessed the patients who got admitted to the hospital, all having severe hypoglycemia by definition. Milder forms of hypoglycemia not seeking medical assistance or more severe forms resulting in death before coming to the hospital could not be investigated. The capillary blood glucose level at the early onset of hypoglycemic events was not measured by any of the study subjects, so their symptoms could not be correlated with their blood glucose levels. The time interval between the onset of hypoglycemic symptoms and the measurement of venous plasma glucose level after hospital admission was also not quantified. We did not search for the presence of hypoglycemia unawareness in these patients. The potential cardiovascular, neurogenic, psychological, and socioeconomic adverse effects of hypoglycemia were also beyond the scope of this study.

  Conclusion Top

Hypoglycemia in patients with diabetes is multifactorial. Patient education about hypoglycemia management is the cornerstone for the prevention of such potentially life-threatening complication of diabetes treatment. Individualized glycemic target, judicious use of antidiabetic medications, appropriate lifestyle and dietary habit, and SMBG should be implemented in all patients with diabetes for the avoidance of hypoglycemia.

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  References Top

The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.  Back to cited text no. 1
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.  Back to cited text no. 2
Kim JT, Oh TJ, Lee YA, Bae JH, Kim HJ, Jung HS, et al. Increasing trend in the number of severe hypoglycemia patients in Korea. Diabetes Metab J 2011;35:166-72.  Back to cited text no. 3
American Diabetes Association. 6. Glycemic targets: Standards of medical care in diabetes-2019. Diabetes Care 2019;42:S61-70.  Back to cited text no. 4
Kalra S, Mukherjee JJ, Venkataraman S, Bantwal G, Shaikh S, Saboo B, et al. Hypoglycemia: The neglected complication. Indian J Endocrinol Metab 2013;17:819-34.  Back to cited text no. 5
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Siddiqui NI, Kamrul-Hasan M, Hossain MA, Chanda PK, Bakar MA, Rahman M, et al. Ramadan perspective epidemiology and education in diabetes (RAPEED) study. Mymensingh Med J 2017;26:256-65.  Back to cited text no. 7
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European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus.London, United Kingdom: European Medicines Agency;2012.  Back to cited text no. 9
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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