|Year : 2021 | Volume
| Issue : 2 | Page : 157-163
Frequency and predictors of hypoglycemia in Type 2 diabetes: A population-based study
Nesma Ali Ibrahim
Department of Internal Medicine, Endocrinology and Diabetes Unite, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||21-Jun-2020|
|Date of Decision||24-Jul-2020|
|Date of Acceptance||10-Aug-2020|
|Date of Web Publication||31-Mar-2021|
Dr. Nesma Ali Ibrahim
Department of Internal Medicine, Endocrinology and Diabetes Unite, Faculty of Medicine, Ain Shams University, Cairo.
Source of Support: None, Conflict of Interest: None
Background: Hypoglycemia presents a barrier to optimum diabetes management; however, data are limited on the frequency of hypoglycemia incidents outside of clinical trials. Aim: The aim of the present study was to investigate the frequency of self-reported hypoglycemic events in patients with Type 2 diabetes mellitus (T2DM) and to define factors that predict a higher risk of hypoglycemia. Materials and Methods: A sample of 1500 patients with T2DM were recruited in this prospective, observational study, selected at random from a validated community population, attending the outpatient clinic of diabetes, Ain Shams University Specialized Hospital. Eligible patients were followed up for 12 months and were instructed on the use of a diary to record hypoglycemic events. Ordinal logistic regression was performed to identify potential predictors of hypoglycemia. Results: Of a total of 1347 patients with data available for the present analysis, 583(43.28%) had experienced hypoglycemia. The participants experienced a total of 3816 hypoglycemic events during the study period, which amounts to 2.83 events (95% CI 2.74, 2.92) per patient per year. Of those who experienced hypoglycemia, 13(2.23%) recorded severe events and 125(21.44%) had evidence of impaired awareness of hypoglycemia. Patients who had experienced hypoglycemic events were elder and have higher body mass index, longer duration of diabetes, and higher HbA1c than those who had not experienced hypoglycemia, the difference was significant (all P < 0.05). Also, they were on insulin therapy, have diabetes complications, used to have irregular meals, and do not practicing exercise when compared with patients who had not experienced hypoglycemia (all P < 0.05). No significant difference was found based on gender (P = 0.25) between patients who experienced and those had not experienced hypoglycemia. Conclusions: Hypoglycemia is a frequent adverse effect in patients with T2DM, and particular attention is warranted in elder, obese patients with poor control and longer duration of diabetes. The presence of diabetes complications, insulin therapy, and unhealthy life style are also predictors of hypoglycemia.
Keywords: Frequency, hypoglycemia, predictors, type 2 diabetes
|How to cite this article:|
Ibrahim NA. Frequency and predictors of hypoglycemia in Type 2 diabetes: A population-based study. J Diabetol 2021;12:157-63
| Introduction|| |
The goal of diabetes management for people with Type 1 or Type 2 diabetes mellitus (T1DM or T2DM) is to maintain normoglycemia so as to reduce diabetic complications and the risk of mortality; however, the intensification of therapy to achieve this goal may increase the incidence of hypoglycemic episodes. Hypoglycemia is a serious adverse effect while using antidiabetic pharmacotherapy, irrespective of its severity. With many antidiabetic drugs such as sulfonylureas or insulin, intensified blood glucose lowering has been associated with an increase in the rate of hypoglycemia.,,
There can also be substantial consequences for an individual, with an increased risk of mortality and morbidity from severe episodes.,, Even in cases of less severe hypoglycemia, a substantial reduction of cognitive and motor function and also hormonal counter regulation is observed. Hypoglycemia significantly affects individual’s quality of life, their employment, social interactions, and driving.,, Furthermore, hypoglycemia presents a significant barrier to optimum diabetes management, as fear of hypoglycemic events may cause exaggerated avoidance behavior and consequently suboptimum antidiabetic therapy and poor glycemic control.,
Although hypoglycemia is well recognized in the management of T1DM, less is known about the true prevalence of hypoglycemia in patients with T2DM. Individuals with T2DM who experience significant hypoglycemia have more health care visits and higher annual all-cause and diabetes-related health care costs than patients without hypoglycemia. Thus, preventing hypoglycemia has become a major focus of T2DM management, especially in older and/or at-risk T2DM populations.
Although the accurate recording of severe hypoglycemia is usually robust in research studies, it may represent only the “tip of the iceberg” of all acute events. Hypoglycemia rates have been shown to be underreported in randomized controlled trails (RCTs) compared with observational studies. Thus, real-world data are needed to evaluate the true incidence of hypoglycemia in clinical practice.
The aim of the present fieldwork study was to investigate the real-world frequency of self-reported hypoglycemic events and to ascertain the burden of self-reported mild and severe hypoglycemic events, in a group of patients with T2DM who were selected at random from a validated community population, and to define what factors are associated with a higher risk of hypoglycemia.
| Subjects and Methods|| |
Study design and population
This is a prospective, observational study which was conducted on 1500 diabetic patients. Patients with T2DM who aged 18 years or older were invited at random to participate in the study during their attendance at the outpatient clinic of diabetes, Ain Shams University Specialized Hospital, from September 2018 to March 2020.
Those who are not under regular supervision of the healthcare worker team for the duration of the study, those with T1DM, pregnancy, diabetes secondary to malnutrition, infection or surgery, with maturity onset diabetes of the young, known cancer or limited life expectancy, acute emergencies, participation in a clinical trial, patients with further reasons that made impossible or highly problematic to participate and come to the follow-up visits were excluded from participation.
Eligible patients were followed up for 12 months to observe which patients developed episodes of hypoglycemia and to determine patient, disease, or treatment characteristics that predicted the development of hypoglycemia.
Written informed consent was obtained from the participants and the study was approved by the local research ethics committee.
All participants underwent a thorough history taking including age, diabetes duration, diabetes complications, current diabetes therapy, eating habits, and exercises.
They were asked about their eating habits including number of meals, meal timing, and frequency of meals and snacks. Also, they were asked about physical activity and exercise and considered to perform regular exercise if they practice at least 150 min/week of moderate to vigorous aerobic exercise spread out during at least 3 days during the week, with no more than 2 consecutive days between bouts of aerobic activity.
Complete clinical examination was done including anthropometric measures where body weight and height were measured with subjects in light clothes and without shoes using standard apparatus. Body weight was measured to the nearest 0.1 kg using a calibrated manual weighing scale (Seca 709, Les Mureaux, France). Height was measured to the nearest 0.5cm on a standardized wall-mounted height board. Body mass index (BMI) was defined as weight in kilograms divided by height in meters squared (kg/m2).
For measuring HbA1c, a venous whole blood specimen collected in ethylenediaminetetraacetic acid (EDTA) was required. After centrifugation, the supernatant was injected into the high-performance liquid chromatography (HPLC) system. The gradient separation via HPLC at 30°C lasted 5 min. The chromatograms were recorded by an UV detector. The quantification was performed with a delivered blood calibrator and the concentration was calculated via integration of peak heights.
Assessment and documentation
Participating patients were instructed on the use of a diary to record hypoglycemic events, which included the date, time, circumstances, and contemporaneous blood glucose (patients were encouraged to use their own glucose meter to take their recording), together with the nature of the remedial action taken and whether the episode required assistance of a third party (i.e. severe hypoglycemia) for each episode of symptomatic hypoglycemia.
The diary also incorporated the Edinburgh Hypoglycaemia Scale, to record hypoglycemia symptoms and recorded a series of “events” including a symptom record scale identical to the scale included in the initial Hypoglycaemia Awareness Assessment, as a patient’s subjective assessment of their state of awareness is a reliable indicator of the coexistence of impaired awareness of hypoglycemia.
Incident hypoglycemia was collected using the diary that patients were supposed to show at each physician visit, the follow-up visits were monthly.
Hypoglycemia was classified as follows: Level I (mild) hypoglycemia: The range of blood glucose level is 54–70 mg/dL. Symptoms include tremor, palpitations, tachycardia, nervousness, sweating and hunger due to sympathetic nervous system stimulation. Level II (moderate) hypoglycemia: The range of blood glucose level is 40–54 mg/dL. Symptoms include confusion, irritation, inability to concentrate, headache, lightheadedness, memory loss, numbness of the lips and tongue, slurred speech, lack of coordination, emotional changes, drowsiness, and double vision, or any combination of these symptoms due to impaired function of central nervous system. Level III (severe) hypoglycemia: The blood glucose level is less than 40 mg/dL. Central nervous system function is impaired further. Symptoms may include disoriented behavior, seizures, stupor, or loss of consciousness. During this stage patients need help from another as they become unable to function because of physical and mental changes.,
Awareness of hypoglycemia was scored on a scale of 1–7 (1 = always aware, 7 = never aware), in participants who had experienced hypoglycemia. Any subjective change in symptom intensity that had occurred over time was recorded. Participants were asked to assess subjectively whether symptoms of hypoglycemia had increased, decreased, or were unaltered over time. Diminution in symptom intensity and/or a score of 4 out of 7 or more on the awareness scale has been shown previously to correlate with impaired awareness of hypoglycemia.
Statistical Package for Social Science (version 20; SPSS) program was used for the analysis of data. Numerical data were presented as mean ± standard deviation (SD) and categorical data were presented as number and percentage of total. Comparative analysis of numerical data was performed with unpaired Student’s t‑test, and comparative analysis of categorical data was done with Chi‑square test. The significance of the test was determined according to the P-value to be not significant (NS) if P > 0.05 and significant (Sig) if P < 0.05.
| Results|| |
For the present analysis on the incidence of hypoglycemia, a total of 1347 out of 1500 initially enrolled patients were available. Of those patients, 153 were excluded from the analyses because they were either not alive, had no data available on hypoglycemia incidence, or were lost to follow up.
Variables entered into the model were identified from univariate analysis, selected for their potential impact on hypoglycemia and included age, gender, BMI, diabetes duration, diabetes control (HbA1c), diabetes complications, current diabetes therapy, eating habits and exercises.
Demographic characteristics of all included patients are shown in [Table 1].
Of the recruited 1347 patients with data available for the present analysis 583(43.28%) had experienced hypoglycemic events. The participants experienced a total of 3816 hypoglycemic events during the study period, this amounts to 2.83 events (95% CI 2.74, 2.92) per patient per year.
Of those who experienced hypoglycemia, 382 (65.52%) recorded mild events, 287(49.23%) recorded moderate events, 13(2.23%) recorded severe events, and 125(21.44%) had evidence of impaired awareness of hypoglycemia based on historical reports and on evaluation using the hypoglycemia awareness scale.
When comparing patients who had experienced hypoglycemic events with those who had not, we find that patients who had experienced hypoglycemic events are elder, have higher BMI, longer duration of diabetes, and higher HbA1c than those who had not experienced hypoglycemia, the difference was significant (all P < 0.05). Also, they are on insulin therapy, have diabetes complications, used to have irregular meals and do not practicing exercise when compared with patients who had not experienced hypoglycemia (all P < 0.05). While there was no significant difference regarding gender (P = 0.25), as shown in [Table 2].
|Table 2: Comparison between patients who experienced hypoglycemic events and those who did not experience hypoglycemic events|
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| Discussion|| |
Hypoglycemia remains a common and unpredictable side effect of insulin therapy and other antihyperglycemic agents and has a negative physical and emotional impact on people with diabetes. In recent years, the pursuit of strict glycemic control in T2DM has encouraged the earlier introduction of insulin and the use of more intensive regimens, which may increase the risk of hypoglycemia in these patients.
Although data are available for rates of hypoglycemia from RCTs, evidence from real-world clinical practice is limited, meaning that the true frequency of hypoglycemia is difficult to determine. The frequency of mild symptomatic hypoglycemia is difficult to determine with accuracy unless measured prospectively,, and the frequency of asymptomatic (biochemical) hypoglycemia is determined principally by the frequency with which blood glucose is measured.
The present study examined self-reported hypoglycemia in a sample of community-based patients with T2DM, the results revealed that, of the recruited 1347 T2DM, 583(43.28%) experienced hypoglycemic events. Of those who experienced hypoglycemia, 382 (65.52%) recorded mild events, 287(49.23%) recorded moderate events, 13(2.23%) recorded severe events, and 125(21.44%) had evidence of impaired awareness of hypoglycemia based on evaluation using the hypoglycemia awareness scale.
Predictors of hypoglycemia were higher age, BMI, HbA1c, and diabetes duration. The presence of diabetes complications, insulin therapy, and unhealthy life style were also predictors of hypoglycemia.
The results are consistent with those of Henderson et al., when the frequencies of mild (self-treated) and severe (required assistance) hypoglycemia during the preceding year were estimated retrospectively, of the 215 participants, 157(73%) had experienced hypoglycemia since commencing insulin, the frequency of which increased with duration of diabetes and of insulin therapy and was inversely related to current HbA1c (all P < 0.05). Of the 157 people who had experienced hypoglycemia, 13 (8%) had evidence of impaired awareness of hypoglycemia based on historical reports and on evaluation using the hypoglycemia awareness scale. Moreover, they reported an annual prevalence of severe hypoglycemia in insulin-treated T2DM of 15%, directly related to the duration of insulin therapy.
Also, Gehlaut et al. reported that, about half (49.1%) of all of T2DM participants screened in their study experienced at least one episode of hypoglycemia during 5 days of continuous glucose monitoring system (CGMS) with 21% of those experiencing a severe hypoglycemic episode (<50 mg/dL). Hypoglycemia was more significantly frequent in individuals on insulin therapy. The majority (75%) of patients were not aware of their hypoglycemia at all times when detected by CGMS.
And, Donnelly et al. demonstrated that ~45% of the patients with insulin-treated T2DM had a hypoglycemic event and 2% of which were severe; moreover, a history of previous hypoglycemia and duration of insulin treatment were significant predictors.
Lopez et al. reported that, of the participants with T2DM taking antihyperglycemic agents who were knowledgeable of their hypoglycemia history, 55.7% had ever experienced hypoglycemia. Compared with those who never experienced hypoglycemia, those who experienced hypoglycemia tended to be younger; have higher HbA1c levels; have a higher body mass index; have higher Charlson Comorbidity Index scores; be on insulin, sulfonylureas, and/or glucagon-like peptide-1 agonists; and be less adherent to their antihyperglycemic agents.
A systematic review and meta-analysis of population-based studies showed that hypoglycemia is considerably prevalent amongst people with T2DM. That review of 46 studies (n = 532,542) estimated that the prevalence (proportion of people) of hypoglycemia is 45% for mild/moderate and 6% for severe in population-based studies of Type 2 diabetes. Hypoglycemia is particularly prevalent among those on insulin. They reported that severe episodes are a burden on both the individual and healthcare utilization, due to their cost and the significant dangers that can result from an episode,; moreover, that quantity of mild/moderate episodes could substantially impact on work, social life, and driving, as well as potentially decreasing general quality of life and increasing risk of severe events if left untreated.,
Hypoglycemia is associated with significant morbidity and mortality, which further add to the burden for people with T2DM. In a post hoc analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Control Evaluation) trial, severe hypoglycemia was associated with significant increases in the risks of major microvascular and macrovascular events and deaths. In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE trials, patients with a history of severe hypoglycemia events had approximately a 1.4-fold to 3-fold higher risk of mortality, with one-third to one-half of all deaths being cardiovascular in nature. However, it is not known whether severe hypoglycemia contributes to adverse outcomes or whether it is a marker of vulnerability to these events.
Glycemic control is the common factor that determines death and complication from diabetes., The risk of complication in T2DM is directly related to prior glucose control level. HbA1c levels were associated with lower risks of macrovascular events and death down to a cutpoint of 7.0% while microvascular events down to a cutpoint of 6.5%, in patients with T2DM. Hypoglycemia presents a barrier to optimum glycemic control, increasing the risk of diabetic complications and mortality; therefore, discussion during physician consultations and education on the recognition and treatment of hypoglycemic events for people with diabetes are imperative to encourage greater communication with physicians.
The results of the current study highlight an urgent need for raising awareness within everyday clinical practice. When considering treatment options, hypoglycemia risk consideration should be incorporated through the individualization of treatment regimens prescribed. Blood glucose targets should also be individualized and, in some cases, a higher target may be optimal for the patient. Educational programs should be focused on successfully increasing knowledge of hypoglycemia in relation to appropriate self-treatment methods, risk factors, and predisposing symptoms, as this has previously been shown to be low in the T2DM population.,
The reluctance of people with diabetes to discuss their hypoglycemia may be caused by wider factors such as concerns regarding driving privileges, implications for employment, or fear that they may be perceived by their general practitioner/specialist to have poor control of their diabetes. Further research is needed to understand the reasoning behind why people may not actively be reporting their hypoglycemic events. Along with discussions on the frequency of nonsevere hypoglycemic events and severe hypoglycemic events, other important aspects such as impaired hypoglycemia awareness and fear of hypoglycemia, should be addressed, given that these are associated with an increased risk of severe hypoglycemic events and a risk of suboptimum glycemic control,, respectively. An opportunity exists for more standardized measures of these self-reported outcomes, which may also help to improve understanding for people with diabetes, and improve communication levels. While greater education could be expected to improve blood glucose management, there will still be an underlying increase in hypoglycemic complications as insulin treatment regimens are intensified over time.
Research into mild episodes is more challenging than severe episodes in terms of reliability and access to data, with data collection methods limited to constant glucose monitoring, prospective diary recording, and retrospective recall. Constant glucose monitoring is the most reliable, but can be costly and so generally involve small populations and short data collection periods., Retrospective recall is convenient and least costly, although potentially less reliable.
Limitations of the current study include its observational nature and relatively short prospective period. On the other hand, being prospective, the data collected were not subject to recall bias, missing values, and variability in the interpretation of questions. In addition, as hypoglycemia is self-reported, results may be confounded due to the subjective nature of the reporting. However, this also represents strength of the study. Self-reporting of hypoglycemia captures information where patients may have missed or neglected their blood glucose testing or were unaware of the threshold at which blood glucose concentration represents a hypoglycemic event.
| Conclusions|| |
Hypoglycemia is a frequent adverse effect in patients with T2DM, particular attention is warranted in elder, obese patients with poor control, and longer duration of diabetes. The presence of diabetes complications, insulin therapy, and unhealthy life style are also predictors of hypoglycemia.
I wish to express my gratitude to the healthcare worker team of Ain Shams University Specialized Hospital for being abundantly helpful and offering invaluable assistance and support. Great thanks to the Department of Public Health, Ain Shams University, for the invaluable consultations in biostatistical analysis.
Financial support and sponsorship
Conflicts of interest
| References|| |
UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: Effects of treatment modalities and their duration. Diabetologia 2007;50:1140-7.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al
; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al
. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al
. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
Feinkohl I, Aung PP, Keller M, Robertson CM, Morling JR, McLachlan S, et al
; Edinburgh Type 2 Diabetes Study (ET2DS) Investigators. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: The Edinburgh type 2 diabetes study. Diabetes Care 2014;37:507-15.
Bloomfield HE, Greer N, Newman D, MacDonald R, Carlyle M, Fitzgerald P, et al
. Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes—A Systematic Review of the Evidence. Washington (DC): VA Evidence-based Synthesis Program Reports; 2012.
Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al
; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410-8.
Cox D, Gonder-Frederick L, McCall A, Kovatchev B, Clarke W The effects of glucose fluctuation on cognitive function and QOL: The functional costs of hypoglycaemia and hyperglycaemia among adults with type 1 or type 2 diabetes. Int J Clin Pract Suppl 2002;129:20-6.
Stargardt T, Gonder-Frederick L, Krobot KJ, Alexander CM Fear of hypoglycaemia: Defining a minimum clinically important difference in patients with type 2 diabetes. Health Qual Life Outcomes 2009;7:91.
Vexiau P, Mavros P, Krishnarajah G, Lyu R, Yin D Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in france. Diabetes Obes Metab 2008;10(Suppl 1):16-24.
Williams SA, Pollack MF, Dibonaventura M Effects of hypoglycemia on health-related quality of life, treatment satisfaction and healthcare resource utilization in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2011;91:363-70.
Wild D, von Maltzahn R, Brohan E, Christensen T, Clauson P, Gonder-Frederick L A critical review of the literature on fear of hypoglycemia in diabetes: Implications for diabetes management and patient education. Patient Educ Couns 2007;68:10-5.
Leiter LA, Yale JF, Chiasson JL, Harris S, Kleinstiver P, Sauriol L Assessment of the impact of fear of hypoglycemic episodes on glycemic and hypoglycemia management. Can J Diabetes 2005;29:1-7.
Zammitt NN, Frier BM Hypoglycemia in type 2 diabetes: Pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care 2005;28:2948-61.
Bron M, Marynchenko M, Yang H, Yu AP, Wu EQ Hypoglycemia, treatment discontinuation, and costs in patients with type 2 diabetes mellitus on oral antidiabetic drugs. Postgrad Med 2012;124:124-32.
Hex N, Bartlett C, Wright D, Taylor M, Varley D Estimating the current and future costs of type 1 and type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet Med 2012;29:855-62.
Pramming S, Pedersen-Bjergaard U, Heller SR, Wallace T, Rasmussen AK, Jorgensen HV, et al
. Severe hypoglycaemia in unselected patients with type 1 diabetes: A cross-sectional multicentre survey. Diabetologia 2000;43:A194.
Elliott L, Fidler C, Ditchfield A, Stissing T Hypoglycemia event rates: A comparison between real-world data and randomized controlled trial populations in insulin-treated diabetes. Diabetes Ther 2016;7:45-60.
Deary IJ, Hepburn DA, MacLeod KM, Frier BM Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis. Diabetologia 1993;36:771-7.
Gold AE, MacLeod KM, Frier BM Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994;17:697-703.
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care 1995;18:517-22.
International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017;40:155-7.
Ratner RE Hypoglycemia: New definitions and regulatory implications. Diabetes Technol Ther 2018;20(Suppl 2):S2-50–S2-5341.
Henderson JN, Allen KV, Deary IJ, Frier BM Hypoglycaemia in insulin-treated type 2 diabetes: Frequency, symptoms and impaired awareness. Diabet Med 2003;20:1016-21.
Kern W, Holstein A, Moenninghoff C, Kienhöfer J, Riedl M, Kulzer B Self-reported hypoglycaemic events in 2430 patients with insulin-treated diabetes in the german sub-population of the HAT study. Exp Clin Endocrinol Diabetes 2017;125:592-7.
Tattersall RB Frequency, causes and treatment of hypoglycaemia. In: Frier BM, Fisher BM, editors. Hypoglycaemia in Clinical Diabetes. Chichester: John Wiley and Sons; 1999. p. 55-87.
Janssen MM, Snoek FJ, de Jongh RT, Casteleijn S, Devillé W, Heine RJ Biological and behavioural determinants of the frequency of mild, biochemical hypoglycaemia in patients with type 1 diabetes on multiple insulin injection therapy. Diabetes Metab Res Rev 2000;16:157-63.
Gehlaut RR, Dogbey GY, Schwartz FL, Marling CR, Shubrook JH Hypoglycemia in type 2 diabetes–more common than you think: A continuous glucose monitoring study. J Diabetes Sci Technol 2015;9:999-1005.
Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, et al
; DARTS/MEMO Collaboration. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: A population-based study. Diabet Med 2005;22:749-55.
Lopez JM, Annunziata K, Bailey RA, Rupnow MF, Morisky DE Impact of hypoglycemia on patients with type 2 diabetes mellitus and their quality of life, work productivity, and medication adherence. Patient Prefer Adherence 2014;8:683-92.
Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC, Gray LJ, Davies MJ, et al
. Prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: A systematic review and meta-analysis of population based studies. PLoS One 2015;10:e0126427.
Brod M, Christensen T, Thomsen TL, Bushnell DM The impact of non-severe hypoglycemic events on work productivity and diabetes management. Value Health 2011;14:665-71.
Brod M, Pohlman B, Wolden M, Christensen T Non-severe nocturnal hypoglycemic events: Experience and impacts on patient functioning and well-being. Qual Life Res 2013;22:997-1004.
Noh RM, Graveling AJ, Frier BM Medically minimising the impact of hypoglycaemia in type 2 diabetes: A review. Expert Opin Pharmacother 2011;12:2161-75.
Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, 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.
Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, et al
. Obesity and type 2 diabetes: What can be unified and what needs to be individualized? J Clin Endocrinol Metab 2011;96:1654-63.
Hardy OT, Czech MP, Corvera S What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes 2012;19:81-7.
Zoungas S, Chalmers J, Ninomiya T, Li Q, Cooper ME, Colagiuri S, et al
; ADVANCE Collaborative Group. Association of hba1c levels with vascular complications and death in patients with type 2 diabetes: Evidence of glycaemic thresholds. Diabetologia 2012;55:636-43.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al
. Management of hyperglycaemia in type 2 diabetes: A patient-centered approach. Position statement of the american diabetes association (ADA) and the european association for the study of diabetes (EASD). Diabetologia 2012;55:1577-96.
National Collaborating Centre for Chronic Conditions. Type 2 Diabetes: National Clinical Guideline for Management in Primary and Secondary Care (update). London: Royal College of Physicians; 2008.
Crasto W, Jarvis J, Khunti K, Skinner TC, Gray LJ, Brela J, et al
. Multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: The microalbuminuria education and medication optimisation (MEMO) study. Diabetes Res Clin Pract 2011;93:328-36.
Browne DL, Avery L, Turner BC, Kerr D, Cavan DA What do patients with diabetes know about their tablets? Diabet Med 2000;17:528-31.
Lund A, Knop FK Worry vs. Knowledge about treatment-associated hypoglycaemia and weight gain in type 2 diabetic patients on metformin and/or sulphonylurea. Curr Med Res Opin 2012;28:731-6.
Akram K, Pedersen-Bjergaard U, Carstensen B, Borch-Johnsen K, Thorsteinsson B Frequency and risk factors of severe hypoglycaemia in insulin-treated type 2 diabetes: A cross-sectional survey. Diabet Med 2006;23:750-6.
Monnier L, Wojtusciszyn A, Colette C, Owens D The contribution of glucose variability to asymptomatic hypoglycemia in persons with type 2 diabetes. Diabetes Technol Ther 2011;13:813-8.
Chico A, Vidal-Ríos P, Subirà M, Novials A The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. Diabetes Care 2003;26:1153-7.
[Table 1], [Table 2]