Nikolaos Tentolouris, Nikolaos Katsilambros
Symptoms and signs of hypoglycemia in Type 2 diabetes
The symptoms of hypoglycemia do not differ between people with Type 1 and Type 2 diabetes.
In addition, the agent inducing hypoglycemia (sulfonylurea or insulin) induces identical symptoms in patients with Type 2 diabetes whenever blood glucose is lowered in the same individual to the same level. 22,23 However, in elderly people who have diabetes, symptoms of hypoglycemia may differ from those observed in younger individuals.24 Generalized malaise, hypothermia, and a group of neurological symptoms including unsteadiness, sleepiness, poor coordination, blurred and/or double vision, slurred speech, and other focal neurological deficits have been identified in patients with Type 2 diabetes.13,24 These neurological symptoms and signs may be confused with other conditions such as stroke or vaso-vagal syncope. In addition, elderly people usually report lower symptom scores of hypoglycemia and limited perception of symptoms than younger individuals, with autonomic and neuroglycopenic symptoms being affecting equally.3 Two studies suggested that the attenuation in symptom intensity is a feature of increasing age, independent of any effects of diabetes. 25,26
Thus, in older people with diabetes, differences in symptoms, lower symptom intensity, and altered glycemic thresholds can predispose to severe hypoglycemia.
In general, it is a good rule to regard all insulin secretagogues as having the potential to cause hypoglycemia and to inform patients and their families accordingly. The best way to prevent hypoglycemia is by frequent self-monitoring of blood glucose after initiation of a new therapy with insulin secretagogues and during periods of illness and reduced food intake. In case of doubt at home, it is always better for the patient to be treated for hypoglycemia than to ignore the possibility.
In elderly people and in those living alone, alternative treatment modalities should be considered such as dipeptidyl-peptidase inhibitors, glucagon-like 1 agonists, or insulin secretagogues with a low risk of hypoglycemia, instead of long-lasting sulfonylureas. 29 Particular attention should be paid to the concomitant medications the patients receive. Health care professionals should keep in mind that patients treated with sulfonylureas may not present with the classic symptoms of hypoglycemia and that concomitant treatments may mask symptoms.
Mild hypoglycemic episodes due to sulfonylureas may be treated with simple carbohydrates, as described in Chapter 4, and a meal if it is close to that time, but the patient/carers should be aware of the possibility of repeated hypoglycemia over the next hours. Frequent self-monitoring of blood glucose is the key to treatment (Figure 5.4 ).
Hypoglycemic coma caused by insulin secretagogues is not uncommon. Virtually every unconscious diabetic patient should be considered to be hypoglycemic until immediate estimation of the blood glucose levels has ruled it out. 5,22
When hypoglycemia occurs due to the use of sulfonylureas it can be potentially prolonged and require hospitalization. Intravenous bolus administration of 20-50 ml of 50% glucose solution or 50 ml of 35% glucose solution followed by infusion of 10-20% glucose solution should begin immediately and continued uninterrupted for one or more days. Blood glucose levels should be monitored frequently (see Figure 5.4 ). In the case of refractory hypoglycemia, addition of glucagon, hydrocortisone sodium, or diazoxide may be needed until the effects of the sulfonylurea have worn off. The duration of hospitalization depends on the sulfonylurea used and its duration of action. Thus, hospitalization and frequent glucose monitoring for 24-72 hours may be needed. 22
Data from the ACCORD trial showed that patients with Type 2 diabetes who experience symptomatic, severe hypoglycemia are at increased risk of death, regardless of the intensity of glucose control. 30 Thus, hypoglycemia may be an important cause or contributing factor for death in 3-6% of patients with diabetes. The cause of death during hypoglycemia may be related to development of arrhythmia (frequent supraventricular and ventricular ectopic beats, prolongation of the QT interval and development of ventricular tachycardia, atrial fibrillation), silent myocardial ischemia, myocardial infarction, cerebral damage from glucopenia, and cerebral ischemia from acute thrombotic occlusion of the cerebral arteries. 21 In one series, among 102 patients hospitalized for hypoglycemic coma, 92 patients had Type 2 diabetes and 50 of these patients had been treated with glibenclamide (glyburide) alone, 15 with the combination of glibenclamide (glyburide) and insulin, and 10 with glibenclamide (glyburide) and metformin.31 Sixty-two patients responded to treatment with intravenous glucose infusion during the first 12 hours, while 40 patients had protracted hypoglycemia of 12-72 hours’ duration. Of note, severe head trauma and bone fractures were found in 8 patients, while transient asymptomatic myocardial ischemia was noticed in 2 patients; death occurred in 5 patients. 30 Because of increasing physical frailty and osteoporosis, elderly patients are more susceptible to physical injury during hypoglycemia, and bone fractures, joint dislocations, soft tissue injuries, and head injuries are not uncommon. 21
- Bolen S, Feldman L, Vassy J, et al. Systematic review: Comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007; 147: 386-99.
- DeFronzo RA, Stonehouse AH, Han J, Wintle ME. Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: A meta-analysis of randomized clinical trials. Diabet Med 2010; 27: 309-17.
- Wallace TM, Matthews DR. The drug treatment of type 2 diabetes. In: Pickup JC, Williams G (ed), Textbook of Diabetes Mellitus, 3rd edn, Oxford, UK: Blackwell Publishing, 2003: 45.1-45.18.
- Tsapogas P. Treatment with pills 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: 341-69.
- Gloser B, Leibowitz G. Hypoglycemia. In: Kahn R, King GL, Moses AC, Weir GC, Jacobson AM, Smith RJ (ed), Joslin’s Diabetes Mellitus, 14th edn, Philadelphia, USA: Lippincott Williams & Wilkins, 2005: 1147-75.
- 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.
- Jennings AM, Wilson RM, Ward JD. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care 1989; 12: 203-8.
- Asplund K, Wiholm BE, Lundman B. Severe hypoglycaemia during treatment with glipizide. Diabet Med 1991; 8: 726-31.
- Stahl M, Berger W. Higher incidence of severe hypoglycaemia leading to hospital admission in Type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. Diabet Med 1999; 16: 586-90.
- Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43.
- 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.
- Hay LC, Wilmshurst EG, Fulcher G. Unrecognized hypo-and hyperglycemia in well-controlled patients with type 2 diabetes mellitus: The results of continuous glucose monitoring. Diabetes Technol Ther 2003; 5: 19-26.
- Zammitt NN, Frier BM. Hypoglycaemia in Type 2 diabetes and in elderly people. In: Friers B, Fisher M (ed), Hypoglycaemia in Clinica Diabetes, 2nd edn, West Sussex, England: John Wiley & Sons, 2007: 239-64.
- Banarer S, McGregor VP, Cryer PE. Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response. Diabetes 2002; 51: 958-65.
- Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest 2004; 34: 535-42.
- Rosenstock J, Hassman DR, Madder RD, et al. Repaglinide Versus Nateglinide Comparison Study Group. Repaglinide versus nateglinide monotherapy: A randomized, multicenter study. Diabetes Care 2004; 27: 1265-70.
- Spyer G, Hattersley AT, MacDonald IA, Amiel S, MacLeod KM Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes. Lancet 2000; 356: 1970-4.
- Korzon-Burakowska A, Hopkins D, Matyka K, et al. Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes. Diabetes Care 1998; 21: 283-90.
- Israelian Z, Gosmanov NR, Szoke E, et al. Increasing the decrement in insulin secretion improves glucagon responses to hypoglycemia in advanced type 2 diabetes. Diabetes Care 2005; 28: 2691-6.
- Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes 2002; 51: 724-33.
- McAulay V, Frier BM. Hypoglycemia. In: Sinclair AJ, Finucane P (ed), Diabetes in Old Age, 2nd edn, West Sussex, England: John Wiley & Sons Ltd, 2001: 133-52.
- Ioannidis I. Hypoglycaemia. In: Katsilabros 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: 71-80.
- 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.
- Cooppan R, Beaser R, Shetty GK. Acute complications. In: Joslin Diabetes Center (ed), Joslin’s Diabetes Desktop, 2 nd edn., Boston: Wolters Kluwer, Lippincott Williams & Wilkins, 2007: 403-27.
- Meneilly GS, Cheung E, Tuokko H. Altered responses to hypoglycemia of healthy elderly people. J Clin Endocrinol Metab 1994; 78: 1341-8.
- Meneilly GS, Cheung E, Tuokko H. Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes. Diabetes 1994; 43: 403-10.
- Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 79: 777-81
- Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991; 260: E67-74.
- Vaidya HB, Goyal RK. Glucagon like peptides-1 modulators as newer target for diabetes. Curr Drug Targets 2008; 9: 911-20.
- Bonds DE, Miller ME, Bergenstal RM, 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.
- Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y. Drug-induced hypoglycemic coma in 102 diabetic patients. Arch Intern Med 1999; 159: 281-4.
- UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes:UKPDS 38. BMJ 1998, 317: 703-13.
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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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.
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