Información del artículo
Está ampliamente demostrado que el control glucémico previene la aparición de complicaciones microvasculares. En la actualidad, contamos con varios tipos de antidiabéticos orales (ADO) e insulinas para lograr este objetivo. Dada la evolución natural de la diabetes, lo habitual es que sea necesaria la asociación de varios fármacos para lograr los objetivos deseados en su control. Además, se ha demostrado que la asociación de fármacos que actúen por diferentes mecanismos da lugar a una mejoría en el control metabólico.
A este respecto, la guía EASD/ADA recomienda, tras el diagnóstico de diabetes mellitus tipo 2, comenzar el tratamiento con cambios en el estilo de vida y la administración de metformina. Si esto no logra un adecuado control glucémico, recomienda añadir un segundo ADO o insulina en un plazo de 2-3 meses. Y, en un tercer paso, si con esto tampoco se consiguen los objetivos deseados, se podría asociar insulina o intensificar el tratamiento con ésta. En el caso de una hemoglobina glucosilada<8% se puede plantear la asociación de 3 ADO.
Palabras clave:
Diabetes mellitus tipo 2
Control metabólico
Antidiabéticos orales
Insulina
Many studies have shown that glycemic control prevents microvascular complications in diabetic patients. Currently, there are several kinds of hypoglycemic agents and forms of insulin to achieve this goal. Given the progressive nature of type 2 diabetes, a combination of drugs is usually required. In addition, the association of drugs that act through different mechanisms improves glycemic control. The European Association for the Study of Diabetes/American Diabetes Association guidelines recommend that initial treatment consist of lifestyle modifications and metformin therapy. If the target objective is not achieved, a second hypoglycemic agent or insulin should be added within 2 or 3 months. If these measures are still insufficient, insulin should be added or treatment intensified. If HbA1c levels are below 8%, 3 oral hypoglycemic agents can be combined.
Key words:
Type 2 diabetes
Metabolic control
Oral hypoglycemic agents
Insulin
El Texto completo está disponible en PDF
Bibliografía
[1.]
R.C. Turner, C.A. Cull, V. Frighi, R.R. Holman.
Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group.
JAMA, 281 (1999), pp. 2005-2012
[2.]
S.E. Kahn, S.M. Haffner, M.A. Heise, W.H. Herman, R.R. Holman, N.P. Jones, et al.
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
N Engl J Med, 355 (2006), pp. 2427-2443
[3.]
American Diabetes Association.
The pharmacological treatment of hyperglycemia in NIDDM.
Diabetes Care, 18 (1995), pp. 1510-1518
[4.]
G. Charpentier.
Oral combination therapy for type 2 diabetes.
Diabetes Metab Res Rev, 18 (2002), pp. S70-S76
[5.]
L.F. Van Gaal, I.H. De Leeuw.
Rationale and options for combination therapy in the treatment of Type 2 diabetes.
Diabetologia, 46 (2003), pp. M44-M50
[6.]
J. Franch Nadal, A. Goday Arno, M. Mata Cases.
COMBO. Actualización 2004. Criterios y pautas de terapia combinada en diabetes tipo 2.
Av Diabetol, 20 (2004), pp. 77-112
[7.]
D.M. Nathan, J.B. Buse, M.B. Davidson, R.J. Heine, R.R. Holman, R. Sherwin, et al.
Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.
Diabetes Care, 29 (2006), pp. 1963-1972
[8.]
UK Prospective Diabetes Study (UKPDS) Group.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
Lancet, 352 (1998), pp. 854-865
[9.]
Standards of medical care in diabetes-2006. Diabetes Care. 2006;29 Suppl 1:S4-42.
[10.]
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, 352 (1998), pp. 837-853
[11.]
P. Gaede, P. Vedel, N. Larsen, G.V. Jensen, H.H. Parving, O. Pedersen.
Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.
N Engl J Med, 348 (2003), pp. 383-393
[12.]
L.S. Hermann, B. Schersten, P.O. Bitzen, T. Kjellstrom, F. Lindgarde, A. Melander.
Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study.
Diabetes Care, 17 (1994), pp. 1100-1109
[13.]
R.A. DeFronzo, A.M. Goodman.
Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group.
N Engl J Med, 333 (1995), pp. 541-549
[14.]
G. Charpentier, F. Fleury, M. Kabir, L. Vaur, S. Halimi.
Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients.
Diabet Med, 18 (2001), pp. 828-834
[15.]
B.J. Goldstein, M. Pans, C.J. Rubin.
Multicenter, randomized, double-masked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea.
Clin Ther, 25 (2003), pp. 890-903
[16.]
D.S. Bell, F. Ovalle.
How long can insulin therapy be avoided in the patient with type 2 diabetes mellitus by use of a combination of metformin and a sulfonylurea?.
Endocr Pract, 6 (2000), pp. 293-295
[17.]
A.J. Garber, J. Larsen, S.H. Schneider, B.A. Piper, D. Henry.
Simultaneous glyburide/metformin therapy is superior to component monotherapy as an initial pharmacological treatment for type 2 diabetes.
Diabetes Obes Metab, 4 (2002), pp. 201-208
[18.]
F. Tosi, M. Muggeo, E. Brun, G. Spiazzi, L. Perobelli, E. Zanolin, et al.
Combination treatment with metformin and glibenclamide versus single-drug therapies in type 2 diabetes mellitus: a randomized, doubleblind, comparative study.
Metabolism, 52 (2003), pp. 862-867
[19.]
M. Marre, H. Howlett, P. Lehert, T. Allavoine.
Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance) in type 2 diabetic patients inadequately controlled on metformin.
Diabet Med, 19 (2002), pp. 673-680
[20.]
G. Erle, S. Lovise, C. Stocchiero, L. Lora, A. Coppini, P. Marchetti, et al.
A comparison of preconstituted, fixed combinations of low-dose glyburide plus metformin versus high-dose glyburide alone in the treatment of type 2 diabetic patients.
Acta Diabetol, 36 (1999), pp. 61-65
[21.]
UK Prospective Diabetes Study Group.
UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes.
Diabetes Care, 21 (1998), pp. 87-92
[22.]
J.A. Johnson, S.R. Majumdar, S.H. Simpson, E.L. Toth.
Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes.
Diabetes Care, 25 (2002), pp. 2244-2248
[23.]
J.M. Evans, S.A. Ogston, A. Emslie-Smith, A.D. Morris.
Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin.
Diabetologia, 49 (2006), pp. 930-936
[24.]
R. Moses, R. Slobodniuk, S. Boyages, S. Colagiuri, W. Kidson, J. Carter, et al.
Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.
Diabetes Care, 22 (1999), pp. 119-124
[25.]
E.S. Horton, J.E. Foley, S.G. Shen, M.A. Baron.
Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naive patients with type 2 diabetes.
Curr Med Res Opin, 20 (2004), pp. 883-889
[26.]
P. Raskin, L. Klaff, J. McGill, S.A. South, P. Hollander, N. Khutoryansky, et al.
Efficacy and safety of combination therapy: repaglinide plus metformin versus nateglinide plus metformin.
Diabetes Care, 26 (2003), pp. 2063-2068
[27.]
J. Gerich, P. Raskin, L. Jean-Louis, D. Purkayastha, M.A. Baron.
PRESERVE- beta: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin.
Diabetes Care, 28 (2005), pp. 2093-2099
[28.]
K.S. Hershon, P.M. Hershon.
Primary, secondary, tertiary, and quaternary treatment with troglitazone in type 2 diabetes mellitus in an outpatient clinical practice.
Endocr Pract, 6 (2000), pp. 20-25
[29.]
G. Umpierrez, M. Issa, A. Vlajnic.
Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial.
Curr Med Res Opin, 22 (2006), pp. 751-759
[30.]
A. Garber, E. Klein, S. Bruce, S. Sankoh, P. Mohideen.
Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.
Diabetes Obes Metab, 8 (2006), pp. 156-163
[31.]
A. Ceriello, D. Johns, M. Widel, D.J. Eckland, K.J. Gilmore, M.H. Tan.
Comparison of effect of pioglitazone with metformin or sulfonylurea (monotherapy and combination therapy) on postload glycemia and composite insulin sensitivity index during an oral glucose tolerance test in patients with type 2 diabetes.
Diabetes Care, 28 (2005), pp. 266-272
[32.]
G. Derosa, A.V. Gaddi, M.N. Piccinni, S. Salvadeo, L. Ciccarelli, E. Fogari, et al.
Differential effect of glimepiride and rosiglitazone on metabolic control of type 2 diabetic patients treated with metformin: a randomized, double-blind, clinical trial.
Diabetes Obes Metab, 8 (2006), pp. 197-205
[33.]
M. Hanefeld, A. Pfutzner, T. Forst, G. Lubben.
Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month, open-label, observational, primary care study.
Curr Med Res Opin, 22 (2006), pp. 1211-1215
[34.]
G. Derosa, A. D’Angelo, P.D. Ragonesi, L. Ciccarelli, M.N. Piccinni, F. Pricolo, et al.
Metformin-pioglitazone and metformin-rosiglitazone effects on non-conventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndrome.
J Clin Pharm Ther, 31 (2006), pp. 375-383
[35.]
G. Derosa, A.F. Cicero, A.V. Gaddi, L. Ciccarelli, M.N. Piccinni, S. Salvadeo, et al.
Long-term effects of glimepiride or rosiglitazone in combination with metformin on blood pressure control in type 2 diabetic patients affected by the metabolic syndrome: a 12-month, double-blind, randomized clinical trial.
Clin Ther, 27 (2005), pp. 1383-1391
[36.]
B.J. Goldstein, P.N. Weissman, M.J. Wooddell, B.R. Waterhouse, A.R. Cobitz.
Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study.
Curr Med Res Opin, 22 (2006), pp. 1715-1723
[37.]
D.J. Betteridge, B. Verges.
Long-term effects on lipids and lipoproteins of pioglitazone versus gliclazide addition to metformin and pioglitazone versus metformin addition to sulphonylurea in the treatment of type 2 diabetes.
Diabetologia, 48 (2005), pp. 2477-2481
[38.]
J.A. Dormandy, B. Charbonnel, D.J. Eckland, E. Erdmann, M. Massi-Benedetti, I.K. Moules, et al.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial.
Lancet, 366 (2005), pp. 1279-1289
[39.]
J. Rosenstock, A. Brown, J. Fischer, A. Jain, T. Littlejohn, D. Nadeau, et al.
Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes.
Diabetes Care, 21 (1998), pp. 2050-2055
[40.]
S. Halimi, M.A. Le Berre, V. Grange.
Efficacy and safety of acarbose add-on therapy in the treatment of overweight patients with type 2 diabetes inadequately controlled with metformin: a double-blind, placebocontrolled study.
Diabetes Res Clin Pract, 50 (2000), pp. 49-56
[41.]
P. Phillips, J. Karrasch, R. Scott, D. Wilson, R. Moses.
Acarbose improves glycemic control in overweight type 2 diabetic patients insufficiently treated with metformin.
Diabetes Care, 26 (2003), pp. 269-273
[42.]
L. Van Gaal, M. Maislos, G. Schernthaner, J. Rybka, P. Segal.
Miglitol combined with metformin improves glycaemic control in type 2 diabetes.
Diabetes Obes Metab, 3 (2001), pp. 326-331
[43.]
J.L. Chiasson, L. Naditch.
The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes.
Diabetes Care, 24 (2001), pp. 989-994
[44.]
J.A. Kiayias, E.D. Vlachou, E. Theodosopoulou, E. Lakka-Papadodima.
Rosiglitazone in combination with glimepiride plus metformin in type 2 diabetic patients.
Diabetes Care, 25 (2002), pp. 1251-1252
[45.]
E. Orbay, M. Sargin, H. Sargin, H. Gozu, O.U. Bayramicli, A. Yayla.
Addition of rosiglitazone to glimepirid and metformin combination therapy in type 2 diabetes.
Endocr J, 51 (2004), pp. 521-527
[46.]
V.L. Roberts, J. Stewart, M. Issa, B. Lake, R. Melis.
Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study.
Clin Ther, 27 (2005), pp. 1535-1547
[47.]
D.S. Bell, F. Ovalle.
Long-term efficacy of triple oral therapy for type 2 diabetes mellitus.
Endocr Pract, 8 (2002), pp. 271-275
[48.]
D.S. Bell, F. Ovalle.
Long-term glycaemic efficacy and weight changes associated with thiazolidinediones when added at an advanced stage of type 2 diabetes.
Diabetes Obes Metab, 8 (2006), pp. 110-115
[49.]
M.T. Tran, M.D. Navar, M.B. Davidson.
Comparison of the glycemic effects of rosiglitazone and pioglitazone in triple oral therapy in type 2 diabetes.
Diabetes Care, 29 (2006), pp. 1395-1396
[50.]
E. Standl, G. Schernthaner, J. Rybka, M. Hanefeld, S.A. Raptis, L. Naditch.
Improved glycaemic control with miglitol in inadequately-controlled type 2 diabetics.
Diabetes Res Clin Pract, 51 (2001), pp. 205-213
[51.]
T.B. Kaye.
Triple oral antidiabetic therapy.
J Diabetes Complications, 12 (1998), pp. 311-313
[52.]
A. Wright, A.C. Burden, R.B. Paisey, C.A. Cull, R.R. Holman.
Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57).
Diabetes Care, 25 (2002), pp. 330-336
[53.]
M. Alvarsson, G. Sundkvist, I. Lager, M. Henricsson, K. Berntorp, E. Fernqvist-Forbes, et al.
Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients.
Diabetes Care, 26 (2003), pp. 2231-2237
[54.]
S.E. Nelson, P.J. Palumbo.
Addition of insulin to oral therapy in patients with type 2 diabetes.
Am J Med Sci, 331 (2006), pp. 257-263
[55.]
S. Schwartz, R. Sievers, P. Strange, W.H. Lyness, P. Hollander.
Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis.
Diabetes Care, 26 (2003), pp. 2238-2243
[56.]
K. Aljabri, S.E. Kozak, D.M. Thompson.
Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial.
Am J Med, 116 (2004), pp. 230-235
[57.]
J. Rosenstock, D. Sugimoto, P. Strange, J.A. Stewart, E. Soltes-Rak, G. Dailey.
Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients.
Diabetes Care, 29 (2006), pp. 554-559
[58.]
C.C. Chow, L.W. Tsang, J.P. Sorensen, C.S. Cockram.
Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients.
Diabetes Care, 18 (1995), pp. 307-314
[59.]
H.U. Janka, G. Plewe, M.C. Riddle, C. Kliebe-Frisch, M.A. Schweitzer, H. Yki-Jarvinen.
Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes.
Diabetes Care, 28 (2005), pp. 254-259
[60.]
I.F. Douek, S.E. Allen, P. Ewings, E.A. Gale, P.J. Bingley.
Continuing metformin when starting insulin in patients with type 2 diabetes: a doubleblind randomized placebo-controlled trial.
Diabet Med, 22 (2005), pp. 634-640
[61.]
H.H. Ponssen, J.W. Elte, P. Lehert, J.P. Schouten, D. Bets.
Combined metformin and insulin therapy for patients with type 2 diabetes mellitus.
Clin Ther, 22 (2000), pp. 709-718
[62.]
L. Aviles-Santa, J. Sinding, P. Raskin.
Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial.
Ann Intern Med, 131 (1999), pp. 182-188
[63.]
M.G. Wulffele, A. Kooy, P. Lehert, D. Bets, J.C. Ogterop, B. Borger van der Burg, et al.
Combination of insulin and metformin in the treatment of type 2 diabetes.
Diabetes Care, 25 (2002), pp. 2133-2140
[64.]
H. Yki-Jarvinen, M. Kauppila, E. Kujansuu, J. Lahti, T. Marjanen, L. Niskanen, et al.
Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus.
N Engl J Med, 327 (1992), pp. 1426-1433
[65.]
V. Mattoo, D. Eckland, M. Widel, S. Duran, C. Fajardo, J. Strand, et al.
Metabolic effects of pioglitazone in combination with insulin in patients with type 2 diabetes mellitus whose disease is not adequately controlled with insulin therapy: results of a six-month, randomized, double-blind, prospective, multicenter, parallel-group study.
Clin Ther, 27 (2005), pp. 554-567
[66.]
J.A. Davidson, A. Pérez, J. Zhang.
Addition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: results of a double-blind, multicentre, randomized study.
Diabetes Obes Metab, 8 (2006), pp. 164-174
[67.]
P. Raskin, M. Rendell, M.C. Riddle, J.F. Dole, M.I. Freed, J. Rosenstock.
A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes.
Diabetes Care, 24 (2001), pp. 1226-1232
[68.]
M. Massi Benedetti, E. Humburg, A. Dressler, M. Ziemen.
A one-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes.
Horm Metab Res, 35 (2003), pp. 189-196
[69.]
J. Rosenstock, S.L. Schwartz, C.M. Clark Jr, G.D. Park, D.W. Donley, M.B. Edwards.
Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.
Diabetes Care, 24 (2001), pp. 631-636
[70.]
M.C. Riddle, J. Rosenstock, J. Gerich.
The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients.
Diabetes Care, 26 (2003), pp. 3080-3086
[71.]
A. Fritsche, M.A. Schweitzer, H.U. Haring.
Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial.
Ann Intern Med, 138 (2003), pp. 952-959
[72.]
H. Yki-Jarvinen, R. Kauppinen-Makelin, M. Tiikkainen, M. Vahatalo, H. Virtamo, K. Nikkila, et al.
Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study.
Diabetologia, 49 (2006), pp. 442-451
[73.]
K. Hermansen, M. Davies, T. Derezinski, G. Martínez Ravn, P. Clauson, P. Home.
A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes.
Diabetes Care, 29 (2006), pp. 1269-1274
[74.]
J.K. Malone, L.F. Kerr, B.N. Campaigne, R.A. Sachson, J.H. Holcombe.
Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus meetformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy.
Clin Ther, 26 (2004), pp. 2034-2044
[75.]
P.R. Raskin, P.A. Hollander, A. Lewin, R.A. Gabbay, B. Bode, A.J. Garber.
Basal insulin or premix analogue therapy in type 2 diabetes patients.
Eur J Intern Med, 18 (2007), pp. 56-62
[76.]
H. De Boer, R. Keizers, M. Jansen, L. Verschoor, J. Ruineman-Koerts.
Glycaemic control without weight gain in insulin requiring type 2 diabetes: 1-year results of the GAME regimen.
Diabetes Obes Metab, 8 (2006), pp. 517-523
[77.]
R.A. DeFronzo, R.M. Bergenstal, W.T. Cefalu, J. Pullman, S. Lerman, B.W. Bode, et al.
Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise: a 12-week, randomized, comparative trial.
Diabetes Care, 28 (2005), pp. 1922-1928
[78.]
R.J. Heine, L.F. Van Gaal, D. Johns, M.J. Mihm, M.H. Widel, R.G. Brodows.
Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial.
Ann Intern Med, 143 (2005), pp. 559-569
[79.]
J. Rosenstock, B. Zinman, L.J. Murphy, S.C. Clement, P. Moore, C.K. Bowering, et al.
Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial.
Ann Intern Med, 143 (2005), pp. 549-558
[80.]
A.H. Barnett, M. Dreyer, P. Lange, M. Serdarevic-Pehar.
An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with metformin as adjunctive therapy in patients with type 2 diabetes poorly controlled on a sulfonylurea.
Diabetes Care, 29 (2006), pp. 1282-1287
Copyright © 2008. Sociedad Española de Endocrinología y Nutrición
