Review Article

Dose-Response Relationships of Sulfonylureas: Will Doubling the Dose Double the Response?

Authors: Virendra Rambiritch, PhD, Poobalan Naidoo, BPharm, MMedSc, Neil Butkow, PhD


type 2 diabetes mellitus is currently a global health problem. Although the armamentarium of oral hypoglycemic agents is continuously expanding, sulfonylureas (SUs) are still extensively used for the management of type 2 diabetes mellitus. However, despite decades of use, there is controversy as to the dosing of SUs. Despite many dose-response relationship studies indicating that SUs should be prescribed at lower doses, their dose recommendations remain unchanged. Moreover, studies have demonstrated that high doses of SUs may result in a deterioration of glycemic control and increased frequency of protracted hypoglycemic episodes. In view of the controversial dose-response relationship of SUs, it is suggested that the dose of SUs be titrated against glycemic parameters of blood glucose and glycated hemoglobin.

Key Points

* There is much controversy regarding the dosing of sulfonylureas (SUs).

* There is considerable evidence suggesting that SUs have maximal blood glucose-lowering effects at doses lower than the manufacturer’s maximum recommended dose.

* High-dose SUs may impair glycemic control and are associated with an increased risk of hypoglycemic episodes.

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1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care2006;29:S43–S48.
2. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes and its complications. part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med1998;15:539–553.
3. DCCT Research Group. The effects of intensive treatment on the development and progression of long-term complications in IDDM. N Engl J Med 1993;329:977–986.
4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.
5. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs2005;65:385–411.
6. Chehade JM, Mooradian AD. A rational approach to drug therapy of type 2 diabetes mellitus. Drugs2000;60:95–113.
7. Charbonnel BH, Matthews DR, Schern-Thaner G, et al. A long-term comparison of pioglitazone and gliclazide in patients with type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial. Diabet Med 2005;22:399–405.
8. Duncan GG, Levin R. Symposium of clinical and experimental effects of sulfonylureas in diabetes mellitus. Metabolism 1956;5:721–726.
9. Kahn CR, Shechter Y. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: A Rall TW Nies AS Taylor P eds. Goodman Gilman, Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. 8th edition. McGraw-Hill, Inc, 1991.
10. Palmer KJ, Brogden RN. Gliclazide: an update of its pharmacological properties and therapeutic efficacy in non-insulin dependent diabetes mellitus. Drugs 1993;46:92–125.
11. Muller G, Satoh Y, Geisen K. Extrapancreatic effects of sulfonylureas-a comparison between glimepiride and conventional sulfonylureas. Diabetes Res Clin Pract 1995;28:115–37.
12. Leahy JL, Bonner-Weir S, Weir GC. Beta-cell dysfunction induced by chronic hyperglycaemia: current ideas on mechanism of impaired glucose-induced insulin secretion. Diabetes Care 1992;15:442–455.
13. Lebovitz H, Melander A. Sulfonylureas: basic aspects and clinical uses. In: Alberti KGMM, Zimmet, P DeFronzo RA, eds. International Textbook of Diabetes Mellitus. 2nd edition. Chichester, Wiley and Sons Ltd, 1997, pp 817–840.
14. Heerdink ER, Erquhart J, Leufkens HG. Changes in prescribed drug doses after market introduction.Pharmacoepidemiol Drug Saf 2002;11:447–453.
15. Wahlin-Boll E, Almer L-O, Melander A. Bioavailability, kinetics and effects of glipizide in type 2 diabetics. Clin Pharmacokinet 1982;7:363–372.
16. Shaw KM, Wheeley MS, Campbell DB, Ward JD. Home blood glucose monitoring in non-insulin-dependent diabetics: the effect of gliclazide on blood glucose and weight control, a multicentre trial.Diabet Med 1985;2:484–490.
17. Jackson L, Robertson L. Sulphonyureas (specifically glibenclamide) and their correct dosage. S Afr Med J 1989;76:286–289.
18. Stenman S, Melander A, Groop P-H, et al. What is the benefit of increasing the sulfonylurea dose?Ann Intern Med 1993;118:169–172.
19. Simonson DC, Kourides IA, Feinglos M, et al. for the glipizide gastrointestinal therapeutic system study group: efficacy, safety, and dose response characteristics of glipizide gastrointestinal therapeutic system on glycaemic control and insulin secretion in NIDDM: results of two multicenter, randomized, placebo-controlled clinical trials. Diabetes Care 1997;20:597–606.
20. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281–303.
21. Jonsson A, Hallengren B, Rydberg T, Melander A. Effects and serum levels of glibenclamide and its active metabolites in patients with type 2 diabetes. Diabetes Obes Metab 2001;3:403–409.
22. Melander A. Kinetics-effect relations of insulin-releasing drugs in patients with type 2 diabetes: brief overview. Diabetes 2004;53:151–155.
23. Rambiritch V. The pharmacokinetics and pharmacodynamics of glibenclamide in type 2 diabetics.Dissertation. University of KwaZulu-Natal, South Africa. 2004.
24. Bell DS. Practical considerations and guidelines for dosing sulfonylureas as monotherapy or combination therapy. Clin Ther 2004;26:1714–1727.
25. Groop LC, Groop PH, Stenman S, et al. Comparison of pharmacokinetics, metabolic effects and mechanisms of action of glyburide and glipizide during long-term treatment. Diabetes Care 1987;10:71–78.
26. Groop LC, Barzilai N, Ratheiser K, et al. Dose-dependent effects of glyburide on insulin secretion and glucose uptake in humans. Diabetes Care 1991;14:724–727.
27. Herman WH, Fajans SS, Oritz FJ, et al. Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree. Diabetes 1994;43:40–46.
28. Naidoo P, Virendra R, Layla M. Effects of gliclazide dose escalation on postprandial hyperglycemia in type 2 diabetes mellitus: A prospective, open-label, case-controlled, dose-escalation study. Curr Ther Res 2006;67:81–102.
29. Ceriello A. The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications. Diabetologia 2003;46:M9–16.
30. Avignon A, Radauceanu A, Monnier L. Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. Diabetes Care 1997;20:1822–1826.
31. American Diabetes Association. Clinical practice recommendations 2003. Diabetes Care2003;26:S1–S156.
32. American College of Endocrinology, American Association of Clinical Endocrinologists. American Diabetes Association: American College of Endocrinology consensus statement on guidelines for glycemic control. Endocr Pract 2002;8:S5–S11.
33. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf 1994;11:223–241.
34. Jonsson A, Rydberg T, Ekberg G, et al. Slow elimination of glyburide in NIDDM subjects. Diabetes Care 1994;17:142–145.
35. Rydberg T, Jonsson A, Roder M, Melander A. Hypoglycemic activity of glyburide (glibenclamide) metabolites in humans. Diabetes Care 1994;17:1026–1030.
36. Huizar JF, Gonzalez LA, Alderman J, Smith HS. Sulfonylureas attenuate electrocardiographic ST-segment elevation during an acute myocardial infarction in diabetes. J Am Coll Cardiol 2003;42:1017–1021.
37. Quast U, Stephan D, Bieger S, Russ U. The impact of ATP-sensitive K+ channel subtypeselectivity of insulin secretagogues for the coronary vasculature and the myocardium. Diabetes 2004;53:S156–S164.