Drugs

, Volume 65, Issue 3, pp 325–340 | Cite as

A Critical Appraisal of the Role of Insulin Analogues in the Management of Diabetes Mellitus

  • Ralph Oiknine
  • Marla Bernbaum
  • Arshag D. Mooradian
Review Article

Abstract

Insulin is one of the oldest and best studied treatments for diabetes mellitus. Despite many improvements in the management of diabetes, the nonphysiological time-action profiles of conventional insulins remain a significant obstacle. However, the advent of recombinant DNA technology made it possible to overcome these limitations in the time-action profiles of conventional insulins. Used as prandial (e.g. insulin lispro or insulin aspart) and basal (e.g. insulin glargine) insulin, the analogues simulate physiological insulin profiles more closely than the older conventional insulins. If rapid-acting insulin analogues are used in the hospital, healthcare providers will need a new mind-set. Any error in coordination between timing of rapid-acting insulin administration and meal ingestion may result in hypoglycaemia. However, guidelines regarding in-hospital use of insulin analogues are few. The safety profile of insulin analogues is still not completely established in long-term clinical studies. Several studies have shown conflicting results with respect to the tumourigenic potential of this new class of agents. The clinical implications of these findings are not clear. Although novel insulin analogues are promising ‘designer drugs’ in our armamentarium to overcome some of the limitations of conventional insulin therapy, cost may be a limiting factor for some patients.

References

  1. 1.
    DDCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86CrossRefGoogle Scholar
  2. 2.
    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: 837–53CrossRefGoogle Scholar
  3. 3.
    Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–67PubMedCrossRefGoogle Scholar
  4. 4.
    Malmberg K, for the DIGAMI (Diabetes Mellitus Insulin — Glucose infusion in Acute Myocardial Infarction) Study Group. Prospective randomized study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997; 314: 1512–5PubMedCrossRefGoogle Scholar
  5. 5.
    Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87: 978–82PubMedCrossRefGoogle Scholar
  6. 6.
    Trence DL, Kelly JL, Hirsh IB. The rationale and management of hyperglycemia for in-patients with cardiovascular disease: time for change. J Clin Endocrinol Metab 2003; 88: 2430–7PubMedCrossRefGoogle Scholar
  7. 7.
    Depres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 34: 952–8CrossRefGoogle Scholar
  8. 8.
    Wang F, Carabino JM, Vergara CM. Insulin glargine: a systematic review of a long-acting insulin analogue. Clin Ther 2003; 25: 1541–77PubMedCrossRefGoogle Scholar
  9. 9.
    Ristic S, Bates PC. Effects of rapid-acting insulin analogs on overall glycemic control in type 1 and type 2 diabetes mellitus. Diabetes Technol Ther 2003; 5: 57–66PubMedCrossRefGoogle Scholar
  10. 10.
    Gerich JE. Novel insulins: expanding options in diabetes management. Am J Med 2002; 113: 308–16PubMedCrossRefGoogle Scholar
  11. 11.
    Vajo Z, Duckworth WC. Advances in the treatment of diabetes-insulin analogues. Minerva Endocrinol 2002; 27: 167–80PubMedGoogle Scholar
  12. 12.
    Vajo Z, Fawcett J, Duckworth WC. Recombinant DNA technology in the treatment of diabetes: insulin analogs. Endocr Rev 2001; 22: 706–17PubMedCrossRefGoogle Scholar
  13. 13.
    Dunn CJ, Plosker GL, Keating GM, et al. Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs 2003; 63(16): 1743–78PubMedCrossRefGoogle Scholar
  14. 14.
    Gomez-Perez FJ, Hernandez-Jimenez S, Aguilar-Salinas CA, et al. Insulin analogues: a critical review. Rev Invest Clin 2002; 54: 527–41PubMedGoogle Scholar
  15. 15.
    Chapman TM, Noble S, Goa KL. Insulin aspart: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs 2002; 62(13): 1945–81PubMedCrossRefGoogle Scholar
  16. 16.
    McKeage K, Goa KL. Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and 2 diabetes mellitus. Drugs 2001; 61(11): 1599–624PubMedCrossRefGoogle Scholar
  17. 17.
    Cook DL, Taborsky Jr GJ. B-cell function and insulin secretion. In: Porte D, Sherwin RS, editors. Ellenberg and Rifkin’s diabetes mellitus. 5th ed. Philadelphia (PA): Lippincott-Raven, 1997: 49–73Google Scholar
  18. 18.
    UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type 2 diabetes: a progressive disease. UK prospective Diabetes Study Group. Diabetes 1995; 44: 1249–58CrossRefGoogle Scholar
  19. 19.
    Gerich JE. Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus. Mayo Clin Proc 2003; 78: 447–56PubMedCrossRefGoogle Scholar
  20. 20.
    Gerich JE. Is insulin resistance the principal cause of type 2 diabetes? Diabetes Obes Metab 1999; 1: 257–63PubMedCrossRefGoogle Scholar
  21. 21.
    American Diabetes Association. Clinical practice recommendations 2004. Diabetes Care 2004; 27 Suppl. 1: S15–35CrossRefGoogle Scholar
  22. 22.
    Chahade JM, Mooradian AD. A rational approach to drug therapy of type 2 diabetes mellitus. Drugs 2000; 60: 95–113CrossRefGoogle Scholar
  23. 23.
    Heinemann L, Richter B. Clinical pharmacology of human insulin. Diabetes Care 1993; 16 Suppl. 3: 90–100PubMedGoogle Scholar
  24. 24.
    Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analogue glargine, NPH insulin, ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000; 49: 2142–8PubMedCrossRefGoogle Scholar
  25. 25.
    Chehade JM, Mooradian AD. Drug therapy: current and emerging agents. In: Sinclair AJ, Finucane P, editors. Diabetes in old age. 2nd ed. Chichester: John Wiley & Sons, 2001: 199–214Google Scholar
  26. 26.
    Howey DC, Bowsher RR, Brunelle RL, et al. (Lys(B28), Pro(B29))-human insulin: a rapidly absorbed analogue of human insulin. Diabetes 1994; 43: 396–402PubMedCrossRefGoogle Scholar
  27. 27.
    Simpson KL, Spencer CM. Insulin aspart. Drugs 1999; 57(5): 759–65PubMedCrossRefGoogle Scholar
  28. 28.
    Barlocco D. Insulin glulisine Aventis Pharma. Curr Opin Investig Drugs 2003; 4: 1240–4PubMedGoogle Scholar
  29. 29.
    Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000; 49: 999–1005PubMedCrossRefGoogle Scholar
  30. 30.
    Chase HP, Lockspeiser T, Peery B, et al. The impact of the Diabetes Control and Complications Trial and Humalog insulin on glycohemoglobin levels and severe hypoglycemia in type1 diabetes. Diabetes Care 2001; 24: 430–4PubMedCrossRefGoogle Scholar
  31. 31.
    Rami B, Schober E. Postprandial glycaemia after regular and lispro insulin in children and adolescents with diabetes. Eur J Pediatr 1997; 156: 838–40PubMedCrossRefGoogle Scholar
  32. 32.
    Rutledge KS, Chase HP, Klingensmith GJ, et al. Effectiveness of postprandial Humalog in toddlers with diabetes. Pediatrics 1997; 100: 968–72PubMedCrossRefGoogle Scholar
  33. 33.
    Hedman CA, Lindston T, Arnqvist HJ. Direct comparison of insulin lispro and aspart shows small differences in plasma insulin profiles after subcutaneous injection in type 1 diabetes. Diabetes Care 2001; 24: 1120–1PubMedCrossRefGoogle Scholar
  34. 34.
    Homko C, Deluzio A, Jimenez C, et al. Comparison of insulin aspart and lispro, pharmacokinetic and metabolic effect. Diabetes Care 2003; 26: 2027–31PubMedCrossRefGoogle Scholar
  35. 35.
    Danne T, Aman J, Schober E, et al. A comparison of postprandial and preprandial administration of insulin aspart in children and adolescents with type 1 diabetes. Diabetes Care 2003; 26: 2359–64PubMedCrossRefGoogle Scholar
  36. 36.
    Becker R, Frick A, Wessels D, et al. Pharmacodynamics and pharmacokinetics of a new, rapidly-acting insulin analog, insulin glulisine [abstract]. Diabetes 2003; 52 Suppl. 1: 471-PGoogle Scholar
  37. 37.
    Wermer U, Gerlach M, Hofmann M, et al. Insulin glulisine is a novel, parenteral, human insulin analog with a rapid-acting time-action profile: a crossover, euglycemic clamp study in normoglycemic dogs [abstract]. Diabetes 2003; 52 Suppl. 1: 590-PGoogle Scholar
  38. 38.
    Rakatzi I, Ramrath S, Ledwig D, et al. A novel insulin analog with unique properties, LysB3, GluB29 insulin induces prominent activation of insulin receptor substrate 2, but marginal phosphorylation of insulin receptor substrate 1. Diabetes 2003; 52: 2227–38PubMedCrossRefGoogle Scholar
  39. 39.
    Rakatzi I, Seipke G, Eckel J. [LysB3, GluB29] insulin: a novel insulin analog with enhanced beta-cell protective action. Biochem Biophys Res Commun 2003; 310: 852–9PubMedCrossRefGoogle Scholar
  40. 40.
    Home PD, Lindholm A, Hylleberg B, et al. Improved glycemic control with insulin aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic patients. Diabetes Care 1998; 21: 1904–9PubMedCrossRefGoogle Scholar
  41. 41.
    Anderson Jr JH, Brunelle RL, Keohane P, et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Arch Intern Med 1997; 157: 1249–55PubMedCrossRefGoogle Scholar
  42. 42.
    Anderson Jr JH, Brunelle RL, Koivisto VA, et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Diabetes 1997; 46: 265–70PubMedCrossRefGoogle Scholar
  43. 43.
    Plank J, Wutte A, Brunner G, et al. A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes. Diabetes Care 2002; 25: 2053–7PubMedCrossRefGoogle Scholar
  44. 44.
    Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med 2003; 163: 1306–16PubMedCrossRefGoogle Scholar
  45. 45.
    Mooradian AD, Thurman JE. Drug therapy of post-prandial hyperglycemia. Drugs 1999; 57: 19–29PubMedCrossRefGoogle Scholar
  46. 46.
    Garg SK, Frias J, Anil S, et al. Insulin lispro therapy in pregnancies complicated by type 1 diabetes: glycemic control and maternal and fetal outcomes. Endocr Pract 2003; 9: 187–93PubMedGoogle Scholar
  47. 47.
    Gamson K, Chia S, Jovanovic L. The safety and efficacy of insulin analogs in pregnancy. J Matern Fetal Neonatal Med 2004; 15: 26–34PubMedCrossRefGoogle Scholar
  48. 48.
    Pettitt DJ, Ospina P, Kolaczynski JW, et al. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care 2003; 26: 183–6PubMedCrossRefGoogle Scholar
  49. 49.
    Hanaire-Broutin H, Schumicki D-M, Hoogma RPLM, et al. Safety of insulin glulisine compared with insulin aspart administered by continuous subcutaneous insulin infusion (CSII) [abstract]. Diabetes 2004; 53 Suppl. 2: A4Google Scholar
  50. 50.
    Bode BW, Strange P. Efficacy, safety, and pump compatibility of insulin aspart used in continuous subcutaneous insulin infusion therapy in patients with type 1 diabetes. Diabetes Care 2001; 24: 68–72CrossRefGoogle Scholar
  51. 51.
    Guerci B, Meyer L, Salle A, et al. Comparison of metabolic deterioration between insulin analog and regular insulin after a 5-hour interruption of a continuous subcutaneous insulin infusion in type 1 diabetic patients. J Clin Endocrinol Metab 1999; 84: 2673–8PubMedCrossRefGoogle Scholar
  52. 52.
    Ottensen JL, Nilsson P, Jami J, et al. The potential immunogenicity of human insulin and insulin analogues evaluated in transgenic mouse model. Diabetologia 1994; 37: 1178–85CrossRefGoogle Scholar
  53. 53.
    Takata H, Kumon Y, Osaki F, et al. The human insulin analogue Aspart is not the almighty solution for insulin allergy. Diabetes Care 2003; 26: 253–4PubMedCrossRefGoogle Scholar
  54. 54.
    Heise T, Weyer C, Serwas A, et al. Time-action profiles of novel premixed preparations of insulin lispro and NPL insulin. Diabetes Care 1998; 21: 800–3PubMedCrossRefGoogle Scholar
  55. 55.
    Roach P, Yue L, Arora V. Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Humalog Mix25 study group. Diabetes Care 1999; 22: 1258–61CrossRefGoogle Scholar
  56. 56.
    Scholtz HE, Pretorius SG, Wessels DH, et al. An assessment of the variability in the pharmacodynamics of HOE 901 compared to NPH and ultralente human insulins using euglycemic clamp technique [abstract]. Clin Pharmacol Ther 2000; 67: 123Google Scholar
  57. 57.
    Heinemann L, Sinha K, Weyer C, et al. Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN 304. Diabet Med 1999; 16: 332–8PubMedCrossRefGoogle Scholar
  58. 58.
    Rosskamp RH, Park G. Long-acting insulin analogs. Diabetes Care 1999; 22 Suppl. 2: B109–13PubMedGoogle Scholar
  59. 59.
    Gerich JE. Insulin glargine: long-acting basal insulin analog for improved metabolic control. Curr Med Res Opin 2004; 20: 31–7PubMedCrossRefGoogle Scholar
  60. 60.
    Yki-Jarvinen H, Dressier A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000; 23: 1130–6PubMedCrossRefGoogle Scholar
  61. 61.
    Riddle M, Rosenstock J, Gerich J. The Treat-to-Target Trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26(11): 3080–6PubMedCrossRefGoogle Scholar
  62. 62.
    Hamann A, Matthaei S, Rosak C, et al. A randomized clinical trial comparing breakfast, dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes. Diabetes Care 2003; 26: 1738–44PubMedCrossRefGoogle Scholar
  63. 63.
    Lepore G, Dodesini AR, Nosari I, et al. Effect of continuous subcutaneous insulin infusion vs multiple daily insulin injection with glargine as basal insulin: an open parallel long-term study. Diabetes Nutr Metab 2004; 17: 84–9PubMedGoogle Scholar
  64. 64.
    Harmel AP, Mathur R. Similar A1C outcomes in type 1 diabetic patients undergoing intensive diabetes management with preprandial rapid-acting insulin and either CSII or glargine. Diabetes Care 2004; 27: 272–3PubMedCrossRefGoogle Scholar
  65. 65.
    Markussen J, Havelund S, Kurtzhals P, et al. Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs. Diabetologia 1996; 39: 281–8PubMedCrossRefGoogle Scholar
  66. 66.
    Kurtzhals P, Haveland S, Jonassen I, et al. Albumin binding and time action of acylated insulins in various species. J Pharm Sci 1996; 85: 304–8PubMedCrossRefGoogle Scholar
  67. 67.
    Pieber TR, Plank J, Goerzer E, et al. Duration of action, pharmacodynamic profile and between-subject variability of insulin detemir in subjects with type 1 diabetes [abstract]. Diabetes 2002; 51 Suppl. 2: A53Google Scholar
  68. 68.
    Danne T, Lupke K, Walte K, et al. Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 2003; 26: 3087–92PubMedCrossRefGoogle Scholar
  69. 69.
    Vague P, Selam JL, Skeie S, et al. Insulin Detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type1 diabetes on a basal-bolus regimen with premeal insulin Aspart. Diabetes Care 2003; 26: 590–6PubMedCrossRefGoogle Scholar
  70. 70.
    Kurtzhals P. Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir. Int J Obes 2004; 28 Suppl. 2: S23–8CrossRefGoogle Scholar
  71. 71.
    Fritsche A, Haring H. At last, a weight neutral insulin? Int J Obes 2004; 28 Suppl. 2: S41–6CrossRefGoogle Scholar
  72. 72.
    Ross EM. Pharmacodynamics: mechanisms of drug action and the relationship between drug concentration and effect. In: Hardman JG, Gilman AG, Limbird LE, editors. Goodman and Gillman’s: the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 29–41Google Scholar
  73. 73.
    Pscherer S, Schreyer-Zell G, Gottsmann M. Experience with insulin glargine in patients with end-stage renal disease [abstract]. Diabetes 2002; 51 Suppl. 2: A53Google Scholar
  74. 74.
    Grajower MM, Fraser CG, Holcombe JH, et al. How long should insulin be used once a vial is started. Diabetes Care 2003; 26: 2665–9PubMedCrossRefGoogle Scholar
  75. 75.
    Gallo M, Comoglio M, De Micheli A, et al. Insulin storage in Europe. Diabetes Care 2004; 27: 1225–6PubMedCrossRefGoogle Scholar
  76. 76.
    Durand-Gonzalez KN, Guillausseau N, Pecquet C, et al. Glargine insulin is not an alternative in insulin allergy [letter]. Diabetes Care 2003; 26: 2216PubMedCrossRefGoogle Scholar
  77. 77.
    Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs 2004; 64(22): 2577–95PubMedCrossRefGoogle Scholar
  78. 78.
    Schwartz GP, Burke T, Katsoyannis PG. A super active insulin: (B10-Aspartic acid) insulin (human). Proc Natl Acad Sci U S A 1987; 84: 6408–11PubMedCrossRefGoogle Scholar
  79. 79.
    Ciaraldi TP, Carter L, Seipke G, et al. Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-1. J Clin Endocrinol Metab 2001; 86: 5838–47PubMedCrossRefGoogle Scholar
  80. 80.
    Blakesley VA, Stannard BS, Kalebic T, et al. The role of the IGF-1 receptor in mutagenesis and tumor promotion. J Endocrinol 1997; 152: 339–44PubMedCrossRefGoogle Scholar
  81. 81.
    Grant MB, Names RN, Fitzgerald C, et al. Insulin-like growth factor I acts as an angiogenic agent in rabbit cornea and retina: comparative studies with basic fibroblast growth factor. Diabetologia 1993; 36: 282–91PubMedCrossRefGoogle Scholar
  82. 82.
    Stammberger I, Bube A, Durchfeld-Meyer B, et al. Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice. Int J Toxicol 2002; 21: 171–9PubMedCrossRefGoogle Scholar
  83. 83.
    Hofmann T, Horstmann G, Stammberger I. Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits. Int J Toxicol 2002; 21: 181–9PubMedCrossRefGoogle Scholar
  84. 84.
    Glister BC, Vigersky RA. Perioperative management of type 1 diabetes mellitus. Endocrinol Metab Clin N Am 2003; 32: 411–36CrossRefGoogle Scholar
  85. 85.
    Owens DR. New horizons: alternative routes for insulin therapy. Nat Rev Drug Discov 2002; 1: 529–40PubMedCrossRefGoogle Scholar
  86. 86.
    Still JG. Development of oral insulin: progress and current status. Diabetes Metab Res Rev 2002; 18 Suppl. 1: S29–37CrossRefGoogle Scholar
  87. 87.
    Clement S, Still JG, Kosutic G, et al. Oral insulin product Hexyl-Insulin Monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM 2. Diabetes Technol Ther 2002; 4: 459–66PubMedCrossRefGoogle Scholar
  88. 88.
    Laube BL. Treating diabetes with aerosolized insulin. Chest 2001; 120: 99–106CrossRefGoogle Scholar
  89. 89.
    Cefalu WT. Inhaled human insulin treatment in patients with type2 diabetes mellitus. Ann Intern Med 2001; 134: 203–7PubMedGoogle Scholar
  90. 90.
    Skyler JS, Cefalu WT, Kourides IA, et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof of concept study. Lancet 2001; 357: 331–5PubMedCrossRefGoogle Scholar
  91. 91.
    Quattrin T, Belanger A, Bohannon NJ, et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneaous insulin therapy in patients with type 1 diabetes: resuilts of a 6-month, randomized, comparative trial. Exubera Phase III Study Group. Diabetes Care 2004; 27: 2622–7Google Scholar
  92. 92.
    Bott U, Ebrahim S, Hirschberger S, et al. Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with type 1 diabetes. Diabet Med 2003; 20: 626–34PubMedCrossRefGoogle Scholar
  93. 93.
    Dunn CJ, Plosker GL. Insulin lispro: a pharmacoeconomic review of its use in diabetes mellitus. Pharmacoeconomics 2002; 20: 989–1025PubMedCrossRefGoogle Scholar
  94. 94.
    Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews 2004; (2): CD003287Google Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Ralph Oiknine
    • 1
  • Marla Bernbaum
    • 1
  • Arshag D. Mooradian
    • 1
  1. 1.Division of Endocrinology, Department of Internal Medicine, Diabetes, and MetabolismSaint Louis University Medical SchoolSt LouisUSA

Personalised recommendations