Abstract
Oral repaglinide (GlucoNorm®; NovoNorm®; Prandin®; Surepost®) is a rapid-acting insulin secretagogue that lowers postprandial glucose (PPG) excursions by targeting early-phase insulin release, with reductions in PPG considered to be important in reducing long-term cardiovascular complications of diabetes mellitus. Repaglinide, a carbamoylbenzoic acid derivative, is chemically related to the meglitinide class of insulin secretagogues, but unrelated to the sulfonylurea insulin secretagogues. Meglitinides, including repaglinide, have a distinct binding site at the β-cell membrane, which differs from that of sulfonylureas, and corresponds to greater insulinotropic effects with repaglinide than with glibenclamide and/or glimepiride and a more rapid onset of action in in vitro and in vivo studies. This article reviews the clinical efficacy and tolerability of oral repaglinide in the treatment of patients with type 2 diabetes and provides an overview of its pharmacological properties.
In well designed clinical trials of up to 52 weeks’ duration and in the clinical practice setting, recommended dosages of repaglinide (0.5–4mg three times daily up to 30 minutes prior to a meal) provided effective glycaemic control and were generally well tolerated in treatment-naive or -experienced adult patients with type 2 diabetes, including elderly patients and those with renal impairment. Furthermore, as monotherapy or in combination with other oral antihyperglycaemic drugs, repaglinide was at least as effective as other oral antihyperglycaemic drugs at improving or maintaining glycaemic control, with a tolerability profile that was generally similar to that of sulfonylurea drugs and nateglinide. Thus, repaglinide remains an effective option for the management of patients with type 2 diabetes.
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References
International Diabetes Federation. Types of diabetes [online]. Available from URL: http://www.idf.org/types-diabetes [Accessed 2011 Jul 25]
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabet Care 2009; 32 Suppl. 1: S62–7
Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabet Care 2004; 27(5): 1047–53
Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in type II diabetes: the epidemiological evidence. Diabetologia 2001; 44(12): 2107–14
Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001; 358(9294): 1709–16
Pratley RE, Gilbert M. Targeting incretins in type 2 diabetes: role of GLP-1 receptor agonists and DPP-4 inhibitors. Rev Diabet Stud 2008; 5(2): 73–94
Del Prato S, LaSalle J, Matthaei S, et al. Tailoring treatment to the individual in type 2 diabetes practical guidelines from the Global Partnership for Effective Diabetes Management. Int J Clin Pract 2010; 64(3): 295–304
Nathan DM, Buse DM, Davidson MB, et al. Medical management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabet Care 2009; 32(1): 193–203
Stolar M. Glycemic control and complications in type 2 diabetes mellitus. Am J Med 2010; 123: S3–11
Johansen OE, Birkeland KI. Defining the role of repaglinide in the management of type 2 diabetes mellitus: a review. Am J Cardiovasc Drugs 2007; 7(5): 319–35
Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycaemia. Arch Intern Med 2003; 163(11): 1306–16
Stolar M. Addressing cardiovascular risk in patients with type 2 diabetes: focus on primary care. Am J Med Sci 2011; 341(2): 132–40
Culy CR, Jarvis B. Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 2001; 61(11): 1625–60
Hatorp V. Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet 2002; 41(7): 471–83
Landgraf R. Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging 2000; 17(5): 411–25
Fuhlendorff J, Rorsman P, Kofod H, et al. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes 1998; 47(3): 345–51
Dabrowski M, Wahl P, Holmes WE, et al. Effect of repaglinide on cloned beta cell, cardiac and smooth muscle types of ATP-sensitive potassium channels. Diabetologia 2001; 44(6): 747–56
Stephan D, Winkler M, Kühner P, et al. Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels. Diabetologia 2006; 49(9): 2039–48
Mark M, Grell W. Hypoglycaemic effects of the novel anti-diabetic agent repaglinide in rats and dogs. Br J Pharmacol 1997 Aug; 121(8): 1597–604
Ladriere L, Malaisse-Lagae F, Fuhlendorff J, et al. Repaglinide, glibenclamide and glimepiride administration to normal and hereditarily diabetic rats. Eur J Pharmacol 1997; 335(2–3): 227–34
Hu S, Wang S, Dunning BE. Glucose-dependent and glucose-sensitizing insulinotropic effect of nateglinide: comparison to sulfonylureas and repaglinide. Int J Exp Diabetes Res 2001; 2(1): 63–72
Strange P, Schwartz SL, Graf RJ, et al. Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes. Diabetes Technol Ther 1999; 1(3): 247–56
Cozma LS, Luzio SD, Dunseath GJ, et al. β-cell response during a meal test: a comparative study of incremental doses of repaglinide in type 2 diabetic patients. Diabetes Care 2005; 28(5): 1001–7
Rosenstock J, Hassman DR, Madder RD, et al. Repaglinide versus nateglinide monotherapy: a randomized, multicenter study. Diabetes Care 2004; 27(6): 1265–70
Landgraf R, Bilo HJG, Muller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol 1999; 55(3): 165–71
Marbury T, Huang W-C, Strange P, et al. Repaglinide versus glyburide: a one-year comparison trial. Diabetes Res Clin Pract 1999; 43(3): 155–66
Wolffenbuttel BHR, Landgraf R. A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. Diabetes Care 1999; 22(3): 463–7
Madsbad S, Kilhovd B, Lager I, et al. Comparison between repaglinide and glipizide in type 2 diabetes mellitus: a 1-year multicentre study. Diabet Med 2001; 18(5): 395–401
Derosa G, Mugellini A, Ciccarelli L, et al. Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin. Diabetes Res Clin Pract 2003; 60(3): 161–9
Li J, Tian H, Li Q, et al. Improvement of insulin sensitivity and β-cell function by nateglinide and repaglinide in type 2 diabetic patients: a randomized controlled double-blind and double-dummy multicentre clinical trial. Diabetes Obes Metab 2007; 9(4): 558–65
Raskin P, Klaff L, McGill J, et al. Efficacy and safety of combination therapy: repaglinide plus metformin versus nateglinide plus metformin. Diabetes Care 2003; 26(7): 2063–8
Qin W, Zhang R, Hu C, et al. A variation in NOS1 AP gene is associated with repaglinide efficacy on insulin resistance in type 2 diabetes of Chinese. Acta Pharmacol Sin 2010; 31(4): 450–4
He J, Qiu Z, Li N, et al. Effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers. Eur J Clin Pharmacol 2011; 67: 701–7
Esposito K, Giugliano D, Nappo F, et al. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004; 110(2): 214–9
Lund SS, Tarnow L, Stehouwer CDA, et al. Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 2008; 158(5): 631–41
Hueb W, Uchida AH, Gersh BJ, et al. Effect of a hypoglycemic agent on ischemic preconditioning in patients with type 2 diabetes and stable angina pectoris. Coron Artery Dis 2007; 18(1): 55–9
Yngen M, Östenson CG, Hjemdahl P, et al. Meal-induced platelet activation in type 2 diabetes mellitus: effects of treatment with repaglinide and glibenclamide. Diabet Med 2006; 23(2): 134–40
Manzella D, Grella R, Abbatecola AM, et al. Repaglinide administration improves brachial reactivity in type 2 diabetic patients. Diabetes Care 2005; 28(2): 366–71
Rizzo MR, Barbieri M, Grella R, et al. Repaglinide has more beneficial effect on cardiovascular risk factors than glimepiride: data from meal-test study. Diabetes Metab 2005; 31 (3 Pt 1): 255–60
Jovanovic L, Hassman DR, Gooch B, et al. Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone. Diabetes Res Clin Pract 2004; 63(2): 127–34
Novo Nordisk. Prandin® repaglinide tablets 0.5, 1, and 2 mg: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020741s035lbl.pdf [Accessed 2011 Dec 18]
Meneilly GS. Effect of repaglinide versus glyburide on postprandial glucose and insulin values in elderly patients with type 2 diabetes. Diabetes Technol Ther 2011; 13(1): 63–5
Dimitriadis G, Boutati E, Lambadiari V, et al. Restoration of early insulin secretion after a meal in type 2 diabetes: effects on lipid and glucose metabolism. Eur J Clin Invest 2004; 34(7): 490–7
Schmitz O, Lund S, Andersen PH, et al. Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide. Diabetes Care 2002; 25(2): 342–6
Derosa G, Mugellini A, Ciccarelli L, et al. Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors. Clin Ther 2003; 25(2): 472–84
Hatorp V, Huang W-C, Strange P. Repaglinide pharmacokinetics in healthy young adult and elderly subjects. Clin Ther 1999; 21(4): 702–10
Hatorp V, Huang W-C, Strange P. Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes. J Clin Endocrinol Metab 1999; 84(4): 1475–8
Hatorp V, Oliver S, Su CAPF. Bioavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers. Int J Clin Pharmacol Ther 1998; 36(12): 636–41
Thomsen MS, Chassard D, Evène E, et al. Pharmacokinetics of repaglinide in healthy Caucasian and Japanese subjects. J Clin Pharmacol 2003; 43(1): 23–8
Hatorp V, Walther KH, Christensen MS, et al. Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease. J Clin Pharmacol 2000; 40(2): 142–52
Marbury TC, Ruckle JL, Hatorp V, et al. Pharmacokinetics of repaglinide in subjects with renal impairment. Clin Pharmacol Ther 2000; 67(1): 7–15
European Medicines Agency. NovoNorm 0.5mg tablets: summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000187/WC500029905.pdf [Accessed 2011 Nov 24]
van Heiningen PN, Hatorp V, Kramer Nielsen K, et al. Absorption, metabolism and excretion of a single oral dose of 14C-repaglinide during repaglinide multiple dosing. Eur J Clin Pharmacol 1999; 55(7): 521–5
Schumacher S, Abbasi I, Weise D, et al. Single- and multiple-dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment. Eur J Clin Pharmacol 2001; 57(2): 147–52
Kalliokoski A, Neuvonen M, Neuvonen PJ, et al. The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range. Br J Clin Pharmacol 2008; 66(6): 818–25
Niemi M, Backman JT, Kajosaari LI, et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 2005; 77(6): 468–78
Niemi M, Kajosaari LI, Neuvonen M, et al. The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br J Clin Pharmacol 2004; 57(4): 441–7
Niemi M, Neuvonen PJ, Kivistö KT. The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2001; 70(1): 58–65
Bidstrup TB, Stilling N, Damkier P, et al. Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. Eur J Clin Pharmacol 2004; 60(2): 109–14
Niemi M, Backman JT, Neuvonen M, et al. Rifampin decreases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2000; 68(5): 495–500
Niemi M, Backman JT, Neuvonen M, et al. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46(3): 347–51
Hatorp V, Thomsen MS. Drug interaction studies with repaglinide: repaglinide on digoxin or theophylline pharmacokinetics and cimetidine on repaglinide pharmacokinetics. J Clin Pharmacol 2000; 40(2): 184–92
Kajosaari LI, Jaakkola T, Neuvonen PJ, et al. Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide. Eur J Clin Pharmacol 2006; 62(3): 217–23
Kajosaari LI, Niemi M, Neuvonen M, et al. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther 2005; 78(4): 388–99
Kajosaari LI, Backman JT, Neuvonen M, et al. Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide. Br J Clin Pharmacol 2004; 58(4): 390–6
Wang W, Ning G, Su Q, et al. Randomized study of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral anti-diabetes therapy. Expert Opin Pharmacother 2011; 12(18): 2791–9
Jovanovic L, Dailey 3rd G, Huang WC, et al. Repaglinide in type 2 diabetes: a 24-week, fixed-dose efficacy and safety study. J Clin Pharmacol 2000; 40(1): 49–57
Kawamori R, Kaku K, Hanafusa T, et al. Efficacy and safety of repaglinide versus nateglinide for treatment of Japanese patients with type 2 diabetes mellitus. J Diabet Invest. Epub 2011 Dec 22
Moses RG, Gomis R, Frandsen KB, et al. Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes. Diabetes Care 2001; 24(1): 11–5
Bech P, Moses R, Gomis R. The effect of prandial glucose regulation with repaglinide on treatment satisfaction, well-being and health status in patients with pharmacotherapy naive type 2 diabetes: a placebo-controlled, multicentre study. Qual Life Res 2003; 12(4): 413–25
Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 2011; 32(15): 1900–8
Papa G, Fedele V, Rizzo MR, et al. Safety of type 2 diabetes treatment with repaglinide compared with glibenclamide in elderly people: a randomized, open-label, two-period, cross-over trial. Diabetes Care 2006; 29(8): 1918–20
Hasslacher C, Multinational Repaglinide Renal Study Group. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care 2003; 26(3): 886–91
Turk T, Pietruck F, Dolff S, et al. Repaglinide in the management of new-onset diabetes mellitus after renal transplantation. Am J Transplant 2006; 6(4): 842–6
He Y-Y, Zhang R, Shao X-Y, et al. Association of KCNJ11 and ABCC8 genetic polymorphisms with response to repaglinide in Chinese diabetic patients. Acta Pharmacol Sin 2008; 29(8): 983–9
Yu M, Xu X-J, Yin J-Y, et al. KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) polymorphisms affect therapeutic efficacy of repaglinide in Chinese patients with type 2 diabetes. Clin Pharmacol Ther 2010; 87(3): 330–5
Huang Q, Yin J-Y, Dai X-P, et al. Association analysis of SLC30A8 rs13266634 and rs16889462 polymorphisms with type 2 diabetes mellitus and repaglinide response in Chinese patients. Eur J Clin Pharmacol 2010; 66(12): 1207–15
Hermans MP, D’Hooge D. Switch from metformin monotherapy to bitherapy with metformin and repaglinide to achieve glycated haemoglobin target in type 2 diabetes (REPAMET Study). Diabetes Metab Syndr Clin Res Rev 2009; 3(4): 224–7
Landgraf R, Frank M, Bauer C, et al. Prandial glucose regulation with repaglinide: its clinical and lifestyle impact in a large cohort of patients with type 2 diabetes. Int J Obes 2000; 24 Suppl. 3: S38–44
Jaiswal S, Mehta R, Musuku M, et al. Repaglinide induced acute hepatotoxicity. J Nepal Med Assoc 2009; 48(174): 162–4
López-García F, Borrás J, Verdú C, et al. Cholestatic hepatitis associated with repaglinide. Diabetes Care 2005; 28(3): 752–3
Surepost® (repaglinide 0.25 mg, and 0.5 mg tablet): Japanese prescribing information. Osaka: Dianippon Sumitomo Pharma Co., Ltd, 2011
International Diabetes Federation. Global guideline for type 2 diabetes [online]. Available from URL: http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf [Accessed 2011 May 23]
National Institute for Health and Clinical Excellence. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. NICE short clinical guideline 87 [online]. Available from URL: http://www.nice.org.uk/nicemedia/live/12165/44318/44318.pdf [Accessed 2011 May 23]
Blonde L. Current antihyperglycaemic treatment guidelines and algorithms for patients with type 2 diabetes mellitus. Am J Med 2010; 123: S12–8
Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on type 2 diabetes mellitus: an algorithm for glycaemic control. Endocr Pract 2009; 15(6): 540–59
Abe M, Okada K, Soma M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr Drug Metab 2011; 12(1): 57–69
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2011; 34 Suppl. 1: S11–61
Novo Nordisk Inc. PrandiMet® (repaglinide/meformin HCl) tablets: US prescribing information [online]. Available from URL: http://www.novo-pi.com/prandimet.pdf [Accessed 2011 Dec 18]
Krentz AJ. Rosiglitazone: trials, tribulations and termination. Drugs 2011; 71(2): 123–30
Loke YK, Kwok CS, Singh S. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ. Epub 2011 Mar 17
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Various sections of the manuscript reviewed by: G. Bertino, Haematology Unit, Department of Internal Medicine and Systemic Diseases, University of Catania-Italy Policlinic, Catania, Italy; G. Dimitriadis, Attikon University Hospital, Second Department of Internal Medicine, Research Institute and Diabetes Center, University of Athens Medical School, Athens, Greece; J. Ducobu, Universite de Mons-Hainaut, Mons, Belgium; T. Levien, Department of Pharmacotherapy, Washington State University Spokane, Spokane,WA, USA; K. Whalen, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA.
Data Selection
Sources: Medical literature (including published and unpublished data) on ‘repaglinide’ was identified by searching databases since 1996 (including MEDLINE and EMBASE and in-house AdisBase), bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘repaglinide’ and (‘diabetes mellitus, type 2’ or ‘non insulin dependent diabetes mellitus’ or ‘type 2 diabetes mellitus’). Searches were last updated 10 Jan 2012.
Selection: Studies in patients with type 2 diabetes mellitus who received repaglinide. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data were also included.
Index terms: Repaglinide, meglitinide, insulin secretagogues, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
An Erratum for this chapter can be found at http://dx.doi.org/10.2165/11631030-000000000-00000
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Scott, L.J. Repaglinide. Drugs 72, 249–272 (2012). https://doi.org/10.2165/11207600-000000000-00000
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DOI: https://doi.org/10.2165/11207600-000000000-00000