Stavros Liatis, Nikolaos Katsilambros
Classification of iatrogenic hypoglycemia
A confirmatory blood glucose test during an episode of hypoglycemia is often unavailable while, in other cases, a discrepancy may be observed between self-measured blood glucose values and clinical presentation of hypoglycemia (usually due to defective counter-regulation).
These situations often create confusion both in clinical practice and in clinical studies. In 2005, an American Diabetes Association (ADA) workgroup on hypoglycemia proposed certain criteria to define and classify hypoglycemic events in patients with diabetes:10
- Severe hypoglycemia: any hypoglycemic episode that the patient is unable to self-treat, requiring the assistance of another person to deal with it. Subdivisions of this category are cases requiring medical assistance and those that lead to seizures or/and coma. A low blood glucose measurement is not necessary, as recovery attributable to the administration of carbohydrates (either orally or parenterally) and/or glucagon is considered sufficient evidence that the event was induced by a low blood glucose concentration.
- Documented symptomatic hypoglycemia: an event with typical symptoms of hypoglycemia, accompanied by a measured plasma glucose concentration ≤ 70 mg/dl (3.9 mmol/L).
- Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dl (3.9 mmol/L). It has been argued by some experts that defining hypoglycemia as any value ≤70 mg/dl (3.9 mmol/L) may lead to overestimation of clinically important events.11 The European Agency for Evaluation of Medicinal Products (EMEA) proposed a respective value of ≤ 54 mg/dl (3.0 mmol/L) when assessing the hypoglycemic risk of different treatment regimens, as this might have the advantage of better clinically detecting significant hypoglycemia.12 This approach, however, could result to an underestimation of true hypoglycemic events.
- Probable symptomatic hypoglycemia: a self-reported event that is not confirmed by a measured low plasma glucose value. This is a common situation in patients who experience frequent hypoglycemic episodes and often neglect to measure their blood glucose, despite typical symptoms, choosing to directly consume carbohydrates in order to treat the event.
- Relative hypoglycemia: a situation "opposite" to the previous one. It refers to a symptomatic event interpreted by the patient as hypoglycemia but accompanied by a plasma glucose value higher than 70 mg/dl (3.9 mmol/L). This situation can be explained by the fact that when glycemic control is poor, symptoms of hypoglycemia may appear at higher plasma glucose levels.
In clinical practice the most important discrimination lies between severe and mild hypoglycemia, the latter including all non-severe hypoglycemic event.
The term "moderate hypoglycemia" is sometimes used to describe a self-treated event which, however, leads to significant "lifestyle disruption." This category is falling out of use due to its unclear definition.
The frequency of iatrogenic hypoglycemia in diabetes
Iatrogenic hypoglycemia is a frequent medical condition associated with the treatment of patients with diabetes. It is more frequent by far in Type 1 than in Type 2 diabetes, although rates rise in Type 2 diabetes in direct relation to the duration of the disease and the severity of insulin deficiency. This can be explained by the fact that in these situations more aggressive therapies are introduced, including exogenous insulin administration.
Patients with Type 1 diabetes often become familiar with hypoglycemia as part of their everyday life. It has been estimated that in patients treated with intensive insulin therapy aimed at optimal glycemic control (recommended for all patients with Type 1 diabetes, since it has been shown to reduce long-term complications), plasma glucose levels may be less than 50-60 mg/dl (2.8-3.3 mmol/L) about 10% of the time.13 A JDRF (Juvenile Diabetes Research Foundation) study using continuous glucose monitoring in 176 intensively treated individuals with Type 1 diabetes showed that hypoglycemic events occurred during 8.5% of nights and the duration of hypoglycemia was ≥ 2 hours on 23% of nights with hypoglycemia.14 In the Diabetes Control and Complications Trial (DCCT), the reported rate of serious hypoglycemic events was 62 per 100 patient-years in the intensively treated arm, while even conventionally treated patients experienced more than one such episode during the 6.5-year duration of the trial.15 In unselected cohorts, the frequency of severe hypoglycemia ranged between 1.0 and 1.7 episodes per patient-year.16
In Type 2 diabetes, the frequency of hypoglycemia is highly variable due to the heterogeneity of the disease and its treatment modalities. Newly-diagnosed patients, or those in the primary stages of the disease who are being treated with diet alone or metformin monotherapy, rarely experience hypoglycemia. On the other hand, when severe insulin deficiency develops and insulin is used in variable treatment regimens, hypoglycemia can become a frequent side effect. In the landmark UKPDS (United Kingdom Prospective Diabetes Study) study, only the severe episodes were reported. As expected, a higher frequency of hypoglycemia was associated with advanced stages of the disease and with intensive, compared with conventional, treatment with either sulfonylureas or insulin.17 In the so-called "megatrials" of Type 2 diabetes (ACCORD, ADVANCE, and VADT 18-20), which examined the effects of very intensive management of hyperglycemia aiming at an HbA1c < 6.5%, the rates of severe hypoglycemia in the intensive arm of the trials were high but varied considerably: 3.2, 0.7, and 9.0 per 100 patient-years respectively. The lowest incidence of hypoglycemia was reported in the ADVANCE trial which had the lowest rate of insulin use (40% at the end) compared to the other two trials (> 75%).
It has to be emphasized, however, that data obtained in clinical trials are not usually representative of the general diabetic population, since participants receive treatment according to strict protocols while reporting of hypoglycemic episodes follows certain defined rules. On the other hand, most observational studies record the frequency of hypoglycemia retrospectively, relying on patient recall of low blood glucose episodes, a practice that is usually inaccurate.
A population survey conducted in a region of Scotland (DARTS-MEMO database) recorded all episodes of severe hypoglycemia requiring emergency medical assistance and reported, over a 12-month period, that 7.3% of insulin-treated patients with Type 2 diabetes suffered at least one episode of severe hypoglycemia, a figure comparable to patients with Type 1 diabetes (7.1%).21 It has been shown, however, that people with insulin-treated Type 2 diabetes who exhibit a severe hypoglycemic episode may be more likely to require emergency assistance than people with Type 1 diabetes, since severe hypoglycemia in the latter group is often treated at home.22 In a 12-month survey of all attendances with a primary diagnosis of diabetes in two hospitals in the UK, 37% were due to hypoglycemia while hyperglycemia, the next most common reason for attendance, was affecting 14.9% of patients.23
Both mild and severe hypoglycemic episodes are much more common in Type 1 diabetes, while in Type 2 diabetes their frequency depends on the type of treatment and the degree of insulin deficiency, approaching, in some cases, that of Type 1 diabetes in intensively insulin-treated patients with advanced disease.
Clinical presentation of hypoglycemia
Symptoms and signs of hypoglycemia (Table 4.1) are non-specific and vary considerably among patients with diabetes as their occurrence depends upon several factors such as degree of hypoglycemia, rapidity of glucose decline, age, level of activity, past experience of the patient, and presence of HAAF. The experience of a hypoglycemic event is somehow unique for each given patient, especially in patients with Type 1 diabetes. However, two main categories of symptoms are clearly recognized: those elicited through the activation of the autonomic nervous system (mainly the sympathoadrenal system), which are usually described as "autonomic symptoms," and those due to brain neuronal glucose deprivation, often described as "neuroglycopenic symptoms" (Table 4.1). Symptoms of hypoglycemia have also been categorized using factor analysis, a multivariate statistical technique that enables a large set of variables to be reduced to a smaller number of latent variables (or factors). This type of analysis has been used in several studies, both in non-diabetic individuals (using a hypoglycemic clamp experiment) and in people with insulin-treated diabetes, to classify the symptoms of acute hypoglycemia into groups.24 A three-factor model (referred to as the Edinburgh Hypoglycemia Scale — Table 4.2) identified11 common symptoms and has been used subsequently by many researchers for the objective assessment of hypoglycemia.25
Symptoms are elicited at different glucose concentrations, depending mainly upon the "quality " of glucose control.3,4 Patients with poorly controlled diabetes and infrequent hypoglycemic events usually experience autonomic symptoms early, at plasma glucose concentrations even higher than those required to elicit symptoms in healthy individuals. On the other hand, patients with frequent hypoglycemic events (usually, but not exclusively, those with decent glycemic control) exhibit mild or no autonomic symptoms, since they often suffer from HAAF and hypoglycemia unawareness. In these patients, hypoglycemia commonly exhibits neuroglycopenic symptoms, typically elicited at lower plasma glucose concentrations, increasing the risk for severe hypoglycemic episodes.
Predisposing factors for hypoglycemia in insulin-treated patients
Iatrogenic hypoglycemia occurs when circulating insulin levels (depending mainly on the amount and the type of injected insulin) exceed actual patient needs at the moment that hypoglycemia occurs. The most common causes of hypoglycemia in insulin-treated patients are a higher than required insulin dose, a missed/delayed meal, or increased, usually non-planned, physical activity.26 Several other factors should be taken into account, however, in the evaluation of a hypoglycemic episode (Box 4.1). Special attention should be paid to identifying the glycemic threshold at which a particular patient recognizes hypoglycemia, since hypoglycemia unawareness is a strong predisposing factor for severe and recurrent hypoglycemic episodes. It is generally recommended that glycemic targets should be individualized and set after careful evaluation of each patient’s history of hypoglycemic events (especially severe ones) and his/her potential risk for such serious episodes.27 As a consequence, for elderly patients with co-morbidities (especially those with renal failure or cardiovascular disease) or patients with a low life expectancy, higher glycemic targets may be more appropriate.27
10. American Diabetes Association (ADA) Workgroup on Hypoglycaemia. Defi ning and reporting hypoglycaemia in diabetes. Diabetes Care 2005; 28: 1245-49.
11. Amiel SA, Dixon T, Mann R, et al. Hypoglycaemia in Type 2 diabetes. Diabet Med 2008; 25: 245-54.
12. European Agency for Evaluation of Medicinal Products (EMEA). Note for guidance on clinical investigation of medicinal products in the treatment of diabetes mellitus. 2006. Available at: http://www.ema.europa. u/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003262.pdf. Last accessed 23 March 2011.
13. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003; 26: 1902-12.
14. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose monitoring in children and adults with Type 1 diabetes. Diabetes Care 2010; 33: 1004-8.
15. 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.
16. Pedersen-Bjergaard U, Pramming S, Heller SR, et al. Severe hypoglycemia in 1076 adult patients with Type 1 diabetes: Infl uence of risk markers and selection. Diabetes Metab Res Rev 2004; 20: 479-86.
17. United Kingdom Prospective Diabetes Study 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: 837-52.
18. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59.
19. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-72.
20. Duckworth W, Abraira C, Moritz T, et al. Intensive glucose control and complications in American veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-39.
21. Leese GP, Wang J, Broomhall J, et al, the DARTS/MEMO Collaboration. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: A population-based study of health service resource use. Diabetes Care 2003; 26: 1176-80.
22. Donnelly LA, Morris AD, Frier BM, et al, the 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: 449-55.
23. Brackenridge A, Wallbank H, Lawrenson RA, et al. Emergency management of diabetes and hypoglycaemia. Emerg Med J 2006; 23: 183-5.
24. McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet Med 2001; 18: 690-705.
25. Deary IJ, Hepburn DA, MacLeod KM, et al. Partitioning the symptoms of hypoglycaemia using multi-sample confi rmatory factor analysis.Diabetologia 1993; 36: 771-7.
26. Liatis S. Treatment of diabetes with insulin. In: Katsilambros N, Diakoumopoulou E, Ioannidis I, Liatis S, Makrilakis K, Tentolouris N, Tsapogas P (ed), Diabetes in Clinical Practice, Questions and Answers from Case Studies, West Sussex, England: John Wiley & Sons Ltd, 2006: 371-408.
27. American Diabetes Association. Clinical practice recommendations 2010. Diabetes Care 2008; 33 (Suppl 1): S11-61.
SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
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