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Diabetic Emergencies: Hypoglycemia Caused by Insulin Secretagogues, Part 1

Dec 31, 2012

Stavros Liatis, Nikolaos Katsilambros







Sulfonylureas and non-sulfonylurea insulin secretagogues (meglitinides) exert their antidiabetic effects by binding to the sulfonylurea receptor (SUR) on the beta-cell, which regulates the activity of an ATP-dependent potassium channel.1

Binding of insulin secretagogues to the SUR results in closure of the potassium channels and depolarization of the membrane of the beta-cells, with subsequent opening of the calcium channels and stimulation of insulin release.1 In the beta-cell, insulin secretagogues increase insulin secretion in a relatively glucose-dependent fashion, resulting in a reduction of both fasting and postprandial glucose levels. The net effect is a reduction in HbA1c of 1-2%, the exception being nateglinide, which is associated with a 0.5-1.0% reduction as a result of its short half-life and residence time on the SUR.2….

Some characteristics of the insulin secretagogues currently available in many countries are shown in Table 5.1.

The first-generation sulfonylureas (tolbutamide, tolazamide, and chlorpropamide) bind significantly to plasma proteins and have high milligram dosage requirements. Because of the protein binding, they can displace or be displaced by other agents, leading to certain drug interactions. Tolbutamide is rapidly cleared by the liver and must be taken two to three times daily.3,4

Chlorpropamide is slowly cleared by the kidney and accumulates, particularly when renal function declines, and as a result may cause serious hypoglycemia. Chlorpropamide also may cause an Antabuse (disulfiram)-like intolerance to alcohol, or potentiate antidiuretic hormone action leading to water intoxication. Because of these limitations, use of these first-generation agents is uncommon.3,4

The second-and third-generation sulfonylureas (glibenclamide [glyburide], glipizide, and glimepiride) have lower total dosage requirements. They are metabolized mainly by the liver and cleared by the kidneys, except that glimepiride is excreted by both renal and hepatic mechanisms. Glibenclamide (glyburide) has an active metabolite that is excreted by the kidney. Thus, in the setting of renal insufficiency, glibenclamide (glyburide) is associated with greater concern and glimepiride with the least issues from a drug metabolism perspective. Both glibenclamide (glyburide) and glipizide require twice-daily dosage to produce 24-hour coverage. Glipizide and gliclazide are also available in extended-release formulations that, like glimepiride, are effective given once a day.3,4

The newest non-sulfonylurea insulin secretagogues are meglitinides. Their action is mediated through the SUR, and they hold some structural homology to the sulfonylureas but do not contain the actual sulfonylurea moiety. Both repaglinide and nateglinide are rapidly absorbed after oral administration and rapidly cleared by hepatic metabolism. This rapid time-course calls for two or three doses daily with meals. Repaglinide is able to reduce fasting levels of glucose despite its short half-life because of prolonged residence on the SUR complex and thus it is able to reduce HbA1c equivalently to sulfonylureas. Nateglinide on the other hand has a short residence time and does not substantially reduce fasting glucose.



As a result, nateglinide is the secretagogue with the most specific activity in lowering postprandial glucose and the lowest risk of hypoglycemia. However, because of its lack of effect on fasting glucose, its efficacy in lowering HbA1c is modest. 2–4

The main complication of insulin secretagogues is hypoglycemia. Risk factors for hypoglycemia are aging, past history of cardiovascular disease or stroke, impaired renal function, and reduced food intake (Box 5.1). The risk of hypoglycemia is also related to the pharmacological half-life of the medication and to the time it is bound to the SUR. Glibenclamide (glyburide) seems to be associated with the highest risk of hypoglycemia, followed by glimepiride, gliclazide, repaglinide, nateglinide, and sustained release formulations of glipizide. The risk of severe hypoglycemia is low with meglitinides. Patients with modest hyperglycemia should be started with the lowest possible dose in order to avoid hypoglycemia. In addition, certain drug interactions can potentiate the hypoglycemic effects of insulin secretagogues (Box 5.2). The use of multiple medications can also affect appetite and further potentiate hypoglycemia. 5





Regarding drug interactions, antibiotics such as chloramphenicol, sulfonamides and ciproflxacin, cimetidine, coumarin derivatives, and monoamine oxidase inhibitors may decrease hepatic metabolism of insulin secretagogues. Allopurinol, probenecid, and salicylates can decrease renal excretion of the medications and their metabolites. Fibrates, trimethoprim, salicylates, sulfonamides, and coumarin derivatives can displace sulfonylureas from albumin binding sites and increase their bioavailability. Antifungals may increase their plasma concentration. Alcohol inhibits gluconeogenesis and increases the risk of hypoglycemia.5


Prevalence of hypoglycemia caused by insulin secretagogues

Data from the United Kingdom Prospective Diabetes Study have shown that over 10 years the frequency of all hypoglycemic episodes with glibenclamide (glyburide) was 17.0% and with chlorpropramide 11.0%; the frequency of severe hypoglycemia with glibenclamide (glyburide) was 0.6% and with chlorpropramide 0.4%. In the same study, the frequency of hypoglycemia with insulin was 36.5% and that of severe hypoglycemia 2.3% (Figure 5.1).6

A retrospective study in England showed a prevalence of 20% of hypoglycemia in patients treated with sulfonylurea (alone or in combination with metformin) within a period of 6 months.7 A Swedish study reported 19 cases of glipizide-associated severe hypoglycemia over a 7-year period. Eleven cases presented with coma, 3 cases with reduced consciousness, and 5 with other symptoms. It is of note that 5 patients had prolonged or recurrent hypoglycemia for up to 60 hours, while 2 patients died.8 Another study from Switzerland showed that over 12 years the incidence of severe hypoglycemia was 0.224 episodes per 100 patient-years with long-acting sulfonylureas versus 0.075 episodes per 100 patient-years with short-acting sulfonylureas. In addition, the odds ratio for severe hypoglycemia was 3.01 (95% confidence interval 1.35-6.77) for the long-acting versus the short-acting sulfonylureas.9 The Diabetes Outcome Progression Trial (ADOPT) showed that with glibenclamide (glyburide) the overall prevalence of hypoglycemia was 38.7% and that of severe hypoglycemic episodes 0.6%.10

One prospective study examined the prevalence of hypoglycemia in individuals with Type 2 diabetes treated with sulfonylureas. The study showed that over a 12-month period the prevalence of symptomatic hypoglycemia was 7%. However, a higher proportion (about 20%) of asymptomatic hypoglycemic episodes was detected using the continuous glucose monitoring system (CGMS).11

In another study the CGMS was used to detect hypoglycemic events in subjects with Type 2 diabetes treated with sulfonylureas; the frequency of asymptomatic hypoglycemia lasting for at least 15 minutes was 56% over a period of 6 days.12 Although hypoglycemia unawareness is more common in Type 1 diabetes, it may be more frequent in Type 2 diabetes than is appreciated.

Glibenclamide (glyburide) is associated with a greater risk of severe hypoglycemia than gliclazide because active metabolites prolong its hypoglycemic effects for 24 hours.3,13 Glibenclamide (glyburide) may also attenuate the glucagon response to hypoglycemia in patients with Type 2 diabetes.14

Glimepiride is associated with a lower risk of hypoglycemia in comparison with glibenclamide (glyburide). One multicenter European trial showed that glimepiride and the modified release form of gliclazide were associated with similar glycemic control. However, the modified release form of gliclazide was associated with fewer cases (3.7%) of mild or moderate hypoglycemia than glimepiride (8.9%) while no case of severe hypoglycemia was observed in either group.15

The risk of hypoglycemia with meglitinides is low. One head-to-head comparison of repaglinide and nateglinide showed that, over 4 months, the frequency of mild hypoglycemic episodes was 7% in the repaglinide group in comparison with no hypoglycemic episode in the nateglinide group.16 The same study showed slightly better improvement in HbA 1c with repaglinide than nateglinide.


Counter-regulation in hypoglycemia in Type 2 diabetes

People with Type 2 diabetes have greater protection against hypoglycemia because the counter-regulatory responses commence at higher blood glucose levels than in non-diabetic individuals17 (Figure 5.2) and in subjects with Type 1 diabetes.13,18 Previous studies examined the counter-regulatory responses to hypoglycemia in subjects with Type 2 diabetes who had been treated with diet alone or with sulfonylureas, and they were compared with subjects with Type 1 diabetes. These studies showed that the counter-regulatory hormones were released at higher glucose levels than in those with Type 1 diabetes.17-19


The glucagon response to hypoglycemia is preserved in persons with Type 2 diabetes who are adequately controlled with oral antidiabetic medications. However, patients with long-duration Type 2 diabetes who need insulin for treatment and in whom endogenous insulin secretion is low have diminished glucagon secretion in hypoglycemia.19 That is, these patients behave like those with Type 1 diabetes, in whom glucagon secretion is impaired in the early stages of the disease. 

Impaired hypoglycemia awareness has been associated primarily with Type 1 diabetes. However, antecedent hypoglycemia can also cause hypoglycemia unawareness in patients with Type 2 diabetes. An interesting study showed that antecedent hypoglycemia caused by a hypoglycemic insulin clamp diminished the magnitude of the symptomatic and neuroendocrine responses to any subsequent episode of hypoglycemia within the following 24-48 hours in subjects with Type 2 diabetes. 20 

Aging is associated with blunted counter-regulatory responses to hypoglycemia and is itself an important risk factor for hypoglycemia. Thus, although counter-regulation usually begins at higher glucose thresholds in middle-aged patients with Type 2 diabetes, this is not the case for older patients. Although the symptomatic and counter-regulatory hormonal responses (growth hormone, cortisol, glucagon, and epinephrine) to hypoglycemia are modified by advancing age, it is not known at which age these changes become apparent.2 



  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Jennings AM, Wilson RM, Ward JD. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care 1989; 12: 203-8.
  8. Asplund K, Wiholm BE, Lundman B. Severe hypoglycaemia during treatment with glipizide. Diabet Med 1991; 8: 726-31.
  9. 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.
  10. 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.
  11. Chico A, Vidal-R í os P, Subir à 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.
  12. 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.
  13. 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.
  14. Banarer S, McGregor VP, Cryer PE. Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response. Diabetes 2002; 51: 958-65.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes 2002; 51: 724-33.
  21. McAulay V, Frier BM. Hypoglycemia. In: Sinclair AJ, Finucane P (ed), Diabetes in Old Age, 2 nd edn, West Sussex, England: John Wiley & Sons Ltd, 2001: 133-52.
  22. 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.
  23. 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.
Next Excerpt: Hypoglycemia caused by insulin secretagogues-Part 2
Nikolaos Katsilambros, MD, PhD, FACP
SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Athens, Greece

Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Athens, Greece

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
Athens, Greece

Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
Athens, Greece

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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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