Skip to main content
Log in

A Rational Approach to Drug Therapy of Type 2 Diabetes Mellitus

  • Disease Management
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Several new pharmacological agents have recently been developed to optimise the management of type 2 (non-insulin—dependent) diabetes mellitus. The aim of this article is to briefly review the various therapeutic agents available for management of patients with type 2 diabetes mellitus and to suggest a potential approach to drug selection. There are three general therapeutic modalities relevant to diabetes care. The first modality is lifestyle adjustments aimed at improving endogenous insulin sensitivity or insulin effect. This can be achieved by increased physical activity and bodyweight reduction with diet and behavioural modification, and the use of pharmacological agents or surgery. This first modality is not discussed in depth in this article. The second modality involves increasing insulin availability by the administration of exogenous insulin, insulin analogues, sulphonylureas and the new insulin secretagogue, repaglinide. The most frequently encountered adverse effect of these agents is hypoglycaemia. Bodyweight gain can also be a concern, especially in patients who are obese. The association between hyper-insulinaemia and premature atherosclerosis is still a debatable question. The third modality consists of agents such as biguanides and thiazolidinediones which enhance insulin sensitivity, or agents that decrease insulin requirements like the α-glucosidase inhibitors.

Type 2 diabetes mellitus is a heterogeneous disease with multiple underlying pathophysiological processes. Therapy should be individualised based on the degree of hyperglycaemia, hyperinsulinaemia or insulin deficiency. In addition, several factors have to be considered when prescribing a specific therapeutic agent. These factors include efficacy, safety, affordability and ease of administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Table I
Table II
Table III
Table IV
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults: the third national health and nutrition examination survey, 1988–1994. Diabetes Care 1998; 21: 518–24

    CAS  Google Scholar 

  2. Kenny SJ, Aubert RE, Geiss LS. Prevalence and incidence of non-insulin-dependent diabetes. In: Harris MI, Cowie CC, Stern MP, et al., editors. Diabetes in America. 2nd ed. Washington (DC): National Institute of Health; 1995: Chap. 4. NIH Publication no.: 95-1468

    Google Scholar 

  3. Jonathan CJ, Yen-Pin C. Diabetes in America. 2nd ed. Washington (DC): National Institute of Health; 1995: Chap. 30. NIH Publication no.: 95-1468

    Google Scholar 

  4. Mooradian AD. Drug therapy of non-insulin-dependent diabetes mellitus in the elderly. Drugs 1996; 51: 931–41

    Article  PubMed  CAS  Google Scholar 

  5. Dagogo-Jack S, Santiago JV. Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions. Arch Intern Med 1997; 157: 1802–17

    Article  PubMed  CAS  Google Scholar 

  6. Groop LC, DeFronzo RA. Sulfonylureas. In: RA DeFronzo, editor. Current management of diabetes mellitus. St Louis (MO): Mosby-Year Book, Inc., 1998: 96–101

    Google Scholar 

  7. De Fronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 131: 281–303

    Google Scholar 

  8. Clark CM. Therapeutic approaches to type 2 diabetes. Diabetes Care 1999; 22 Suppl. 3: C1–79

    Google Scholar 

  9. Scheen AJ. Drug treatment of non-insulin dependent diabetes mellitus in the 1990s: achievement and future developments. Drugs 1997; 54: 355–68

    Article  PubMed  CAS  Google Scholar 

  10. Scheen AJ, Lefebvre PJ. Oral anti-diabetic agents: a guide to selection. Drugs 1998; 55: 225–36

    Article  PubMed  CAS  Google Scholar 

  11. Hartz AJ, Rupley DC, Rimm AA. The association of girth measurements with disease in 32,856 women. Am J Epidemiol 1984; 119: 71–80

    PubMed  CAS  Google Scholar 

  12. Warram JH, Rich SS, Krolewski AS. Epidemiology and genetics of diabetes mellitus. In: Kahn CR, Weir GC, editors. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia (PA): Lea & Febiger, 1994: 201

    Google Scholar 

  13. Wing RR, Marcus MD, Epstein LH, et al. Long-term effects of modest weight loss in type II diabetic patients. Arch Intern Med 1987; 147: 1749–53

    Article  PubMed  CAS  Google Scholar 

  14. Kalkhoff RK, Hartz AH, Rupley D, et al. Relationship of body fat distribution to blood pressure, carbohydrate tolerance and plasma lipids in healthy obese women. J Lab Clin Med 1983; 102: 621–7

    PubMed  CAS  Google Scholar 

  15. Sparron D, Borkan GA, Gerzof SG, et al. Relationship of fat distribution to glucose tolerance: results of computer tomography in male participants of the normative aging study. Diabetes 1986; 35: 411–5

    Article  Google Scholar 

  16. Ducimetiere P, Richard JL. The relationship between subsets of anthropometric upper versus lower body measurements and coronary heart disease risk in middle-aged men: the Paris prospective study I. Int J Obes 1989; 13: 111–21

    PubMed  CAS  Google Scholar 

  17. Terry RB, Wood PD, Haskell WL, et al. Regional adiposity patterns in relation to lipids, lipoprotein cholesterol, and lipoprotein subfraction mass in men. J Clin Endocrinol Metab 1989; 68: 191–9

    Article  PubMed  CAS  Google Scholar 

  18. Björntorp P. Regional obesity. In: Björntorp P, Brodoff B, editors. Obesity. Philadelphia (PA): JB Lippincott, 1992

    Google Scholar 

  19. Hollander P, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care 1998; 21: 1288–94

    Article  PubMed  CAS  Google Scholar 

  20. Hughes TA, Gwynne JT, Switzer BR, et al. Effects of caloric restriction and weight loss on glycemic control, insulin release and resistance, and atherosclerotic risk in obese patients with type II diabetes mellitus. Am J Med 1984; 77: 7–17

    Article  PubMed  CAS  Google Scholar 

  21. Després JP, Pouliot MC, Moorjani S, et al. Loss of abdominal fat and metabolic response to exercise training in obese women. Am J Physiol 1991; 261: E159–67

    PubMed  Google Scholar 

  22. Henry RR, Wallace P, Olefsky JM. Effect of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus. Diabetes 1986; 35: 990–8

    Article  PubMed  CAS  Google Scholar 

  23. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991; 325: 147–52

    Article  PubMed  CAS  Google Scholar 

  24. Horton ES. Exercise and physical training: effects on insulin sensitivity and glucose metabolism. Diabetes Metab Rev 1986; 2: 1–17

    Article  PubMed  CAS  Google Scholar 

  25. Rogers MA, Yamamoto C, King DS, et al. Improvement in glucose tolerance after one week of exercise in patients with mild NIDDM. Diabetes Care 1988; 11: 613–8

    Article  PubMed  CAS  Google Scholar 

  26. Eriksson KF, Lingrade F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. Diabetologia 1991; 34: 891–8

    Article  PubMed  CAS  Google Scholar 

  27. Grundy SM. Dietary therapy in diabetes mellitus: is there a single best diet? Diabetes Care 1991; 14: 796–801

    Article  PubMed  CAS  Google Scholar 

  28. American Diabetes Association. Nutritional recommendations and principles for people with diabetes mellitus. Diabetes Care 1997; 20 Suppl. 1: 14–7

    Google Scholar 

  29. NIH Technology Assessment Conference Panel. Methods for voluntary weight Loss and Control. Ann Intern Med 1993; 119: 764–70

    Google Scholar 

  30. Carek PJ, Dickerson LM. Current concepts in the pharmacological management of obesity. Drugs 1999; 57: 883–904

    Article  PubMed  CAS  Google Scholar 

  31. Després JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 334: 952–7

    Article  PubMed  Google Scholar 

  32. Ducimetriere P, Eshwege E, Papoz L, et al. Relationships between plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middleaged population. Diabetologia 1980; 19: 205–10

    Article  Google Scholar 

  33. Stern MP. Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents? Ann Intern Med 1996; 124: 110–6

    PubMed  CAS  Google Scholar 

  34. Fontbonne A, Charles MA, Thibult N, et al. Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up. Diabetologia 1991; 34: 356–61

    Article  PubMed  CAS  Google Scholar 

  35. Stout RW. Insulin and atheroma: 20-years perspective. Diabetes Care 1990; 13: 631–54

    Article  PubMed  CAS  Google Scholar 

  36. Pyörälä K, Savolainen E, Kaukola S, et al. Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 9½-year follow-up of the Helsinki Policemen Study Population. ActaMed Scand 1985; 701 Suppl.: 38–52

    Google Scholar 

  37. Boyne MS, Sandek CD. Effect of insulin therapy on macro-vascular risk factors in type 2 diabetes. Diabetes Care 1999; 22 Suppl. 3: C45–53

    PubMed  Google Scholar 

  38. Fontbonne AM, Eschwège EM. Insulin and cardiovascular disease: Paris prospective study. Diabetes Care 1991; 14: 461–9

    Article  PubMed  CAS  Google Scholar 

  39. Welborn TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979; 2: 154–60

    Article  PubMed  CAS  Google Scholar 

  40. Shaper AG, Pocock SJ, Walker M, et al. British Regional Heart Study: cardiovascular risk factors in middle-aged men in 24 towns. Br Med J (Clin Res Ed) 1981; 283(6285): 179–86

    Article  CAS  Google Scholar 

  41. Després JP, Lamarche B, Mauriege P, et al. Risk factors for ischaemic heart disease: is it time to measure insulin? Eur Heart J 1996; 17: 1453–4

    Article  PubMed  Google Scholar 

  42. Knatterud GL, Klimt CR, Lelvin ME, et al. Effects of hypoglycemic agents on vascular complications in patients with adultonset diabetes: VII. Mortality and selected nonfatal events with insulin treatment. JAMA 1978; 240: 37–42

    CAS  Google Scholar 

  43. Genuth S. Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med 1996; 124: 104–9

    PubMed  CAS  Google Scholar 

  44. 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

    Article  Google Scholar 

  45. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103–17

    Article  PubMed  CAS  Google Scholar 

  46. Malmberg K, Rydén L, Efendic S, et al., on behalf of the DIGAMI Study Group. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI Study): effects on mortality at 1 year. J Am Coll Cardiol 1995; 26: 57–65

    Article  PubMed  CAS  Google Scholar 

  47. Malmberg K, Norhammar A, Wedel H, et al. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999; 99: 2626–32

    Article  PubMed  CAS  Google Scholar 

  48. Abraira C, Colwell J, Nuttall F, et al., and the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VACSDM) Group. Cardiovascular events and correlates in the veterans affairs diabetes feasibility trial. Arch Intern Med 1997; 157: 181–8

    Article  PubMed  CAS  Google Scholar 

  49. 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 1998; 352: 854–65

    Article  Google Scholar 

  50. Balfour JA, Faulds D. Repaglinide. Drugs Aging 1998; 13: 173–80

    Article  PubMed  CAS  Google Scholar 

  51. Matthaei S, Reibold JP, Hamann A, et al. In vivo metformin treatment ameliorates insulin resistance: evidence of potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa)Zucker rat adipocytes. Endocrinology 1993; 133: 304–11

    Article  PubMed  CAS  Google Scholar 

  52. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334: 574–9

    Article  PubMed  CAS  Google Scholar 

  53. Rossetti L, DeFronzo RA, Gherzi R, et al. Effect of metformin on treatment on insulin action in diabetic rats: in vivo and in vitro correlations. Metabolism 1990; 39: 425–35

    Article  PubMed  CAS  Google Scholar 

  54. Klip A, Leiter LA. Cellular mechanisms of action of metformin. Diabetes Care 1990; 13: 696–704

    Article  PubMed  CAS  Google Scholar 

  55. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998; 338: 867–72

    Article  PubMed  CAS  Google Scholar 

  56. Lehman JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic, thiazolidinedione, is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). J Biol Chem 1995; 270: 12953–6

    Article  Google Scholar 

  57. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996; 45: 1661–4

    Article  PubMed  CAS  Google Scholar 

  58. Suter SL, Nolan JJ, Wallace P, et al. Metabolic effects of new oral hypoglycemic agent troglitazone in NIDDM subjects. Diabetes Care 1992; 15: 193–203

    Article  PubMed  CAS  Google Scholar 

  59. Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331: 1188–93

    Article  PubMed  CAS  Google Scholar 

  60. Plosker GL, Faulds D. Troglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 1999; 57: 409–38

    Article  PubMed  CAS  Google Scholar 

  61. Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med 1994; 121: 928–35

    PubMed  CAS  Google Scholar 

  62. Hillebrand I. Pharmacological modification of digestion and absorption. Diabet Med 1987; 4: 147–50

    Article  PubMed  CAS  Google Scholar 

  63. Clissold SP, Edwards C. Acarbose: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1988; 35: 214–43

    Article  PubMed  CAS  Google Scholar 

  64. Rosenzweig JL. Principles of insulin therapy. In: Kahn CR, Weir GC, editors. Joslin’s diabetes mellitus. 13th ed. Philadelphia (PA): Lea & Febiger, 1994: 460

    Google Scholar 

  65. Galloway JA, Spradlin CT, Nelson RL, et al. Factors influencing the absorption, serum insulin concentration and blood glucose responses after injections of regular insulin and various mixtures. Diabetes Care 1981; 4: 366–76

    Article  PubMed  CAS  Google Scholar 

  66. Heinemann L, Richter B. Clinical pharmacology of human insulin. Diabetes Care 1993; 16 Suppl. 3: 90–100

    PubMed  Google Scholar 

  67. The DCCT Research Group. The effects 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: 977–86

    Article  Google Scholar 

  68. Berger M, Jorgens V, Muhlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care 1999; 22 Suppl. 3: C71–5

    PubMed  Google Scholar 

  69. Buse JB. Overview of current therapeutic options in type 2 diabetes: rationale for combining oral agents with insulin therapy. Diabetes Care 1999; 22 Suppl. 3: C65–70

    PubMed  Google Scholar 

  70. Yki-Jarvinen H, Ryysy L, Nikkila K, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus: a randomized controlled trial. Ann Intern Med 1999; 130: 389–96

    PubMed  CAS  Google Scholar 

  71. Aviles-Santa L, Sinding J, Raskin P. The effects of metformin in poorly controlled insulin-treated type 2 diabetes mellitus [abstract]. Diabetes 1998; 47 Suppl. 1: A89

    Google Scholar 

  72. Buse JB, Gumbinar B, Mathias NP, et al. Troglitazone use in insulin treated type 2 diabetic patients. Diabetes Care 1998; 21: 1455–61

    Article  PubMed  CAS  Google Scholar 

  73. Howey DC, Bowsher RR, Brunelle RL, et al. [Lys(B28), Pro(B29)]-human insulin: a rapidly absorbed analogue of human insulin. Diabetes 1994; 43: 396–402

    Article  PubMed  CAS  Google Scholar 

  74. ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care 1996; 19: 1437–40

    Article  PubMed  Google Scholar 

  75. Torlone E, Fanelli C, Rambotti AM, et al. Pharmacokinetics, pharmacodynamics and glucose counterregulation following subcutaneous injection of the monomeric insulin analogue [Lys(B28), Pro(B29)] in IDDM. Diabetologia 1994; 37: 713–20

    Article  PubMed  CAS  Google Scholar 

  76. Hollerman F, Hoekstra JB. Insulin lispro. N Engl J Med 1997; 337: 176–83

    Article  Google Scholar 

  77. Heinemann L, Heise T, Wahl LC, et al. Prandial glycemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin. Diabet Med 1996; 13: 625–9

    Article  PubMed  CAS  Google Scholar 

  78. Garg SK, Carmain JA, Braddy KC, et al. Pre-meal insulin analogue insulin lispro vs. Humulin® insulin treatment in young subjects with type I diabetes. Diabet Med 1996; 13: 47–52

    CAS  Google Scholar 

  79. Pampanelli S, Torlone E, Lalli C. Improved post-prandial metabolic control after subcutaneous injection of a short-acting insulin analog in IDDM of short duration with residual pancreatic B-cell function. Diabetes Care 1995; 18: 1452–9

    Article  PubMed  CAS  Google Scholar 

  80. Anderson Jr JH, Brunelle RL, Koivisto VA, et al. Reduction of postprandial and frequency of hypoglycemia in IDDM patients on insulin analog treatment. Diabetes 1997; 46: 265–70

    Article  PubMed  CAS  Google Scholar 

  81. Anderson Jr JH, Brunelle RL, Keohene P, et al. Mealtime treatment with insulin analog improves post prandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Arch Intern Med 1997; 157: 1249–55

    Article  PubMed  CAS  Google Scholar 

  82. Zinman B, Tildesley H, Chiasson J–L, et al. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes 1997; 46: 440–3

    Article  PubMed  CAS  Google Scholar 

  83. Schmauss S, Konig A, Landgraf R. Human insulin analogue (Lys[B28], Pro[B29]): the ideal pump insulin? Diabet Med 1998; 15: 247–9

    Article  PubMed  CAS  Google Scholar 

  84. Melki V, Renald E, Lassman-Vague V, et al. Improvement of HbA1c and blood glucose stability in IDDM patients treated with Lispro insulin analog in external pumps. Diabetes Care 1998; 21: 977–82

    Article  PubMed  CAS  Google Scholar 

  85. Del Sindaco P, Ciofetta M, Lalli C, et al. Use of the short-acting insulin analogue lispro in intensive treatment of type 1 diabetes mellitus: importance of appropriate replacement of basal insulin and time-interval injection-meal. Diabet Med 1998; 15: 592–600

    Article  PubMed  Google Scholar 

  86. Mooradian AD, Thurman JE. Drug therapy of postprandial hyperglycemia. Drugs 1999; 57: 19–29

    Article  PubMed  CAS  Google Scholar 

  87. 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: UK Insulin Aspart Study Group. Diabetes Care 1998; 21: 1904–9

    CAS  Google Scholar 

  88. Rosenfalck AM, Thorsky P, Kjems L, et al. Effects of the rapid acting insulin analogue insulin aspart on post prandial glycemic excursions compared to human soluble insulin actrapid given immediately or 30 minutes before a meal in insulin treated type 2 diabetes patients [abstract]. Diabetes 1999; 48 Suppl. 1: A116

    Google Scholar 

  89. Heinemann L, Weyel C, Rauhaus M, et al. Variability of the metabolic effect of soluble insulin and the rapid acting insulin analog insulin aspart. Diabetes Care 1998; 21: 1910–4

    Article  PubMed  CAS  Google Scholar 

  90. Roach P, Yue L, Arora V, The Humalog Mix 25 Study Group, et al. Improved post prandial glycemic control during treatment with Humalog Mix 25, a novel protamine-based insulin lispro formulation. Diabetes Care 1999; 22: 1258–61

    Article  PubMed  CAS  Google Scholar 

  91. Rosskamp RH, Park G. Long-acting insulin analogs. Diabetes Care 1999; 22 Suppl. 2: B109–13

    PubMed  Google Scholar 

  92. Linkeschowa R, Heise T, Rave K, et al. Time-action profile of the long-acting insulin analogue HOE 901 [abstract]. Diabetes 1999; 48 Suppl. 1: A97

    Google Scholar 

  93. Shmitz O, Nyholm B, Ørskov L, et al. Effects of amylin and the amylin agonist pramlintide on glucose metabolism. Diabet Med 1997; 14 Suppl. 2: S19–23

    Article  Google Scholar 

  94. Koda J, Fineman M, Rink T, et al. Amylin concentrations and glucose control. Lancet 1992; 339: 1179–80

    Article  PubMed  CAS  Google Scholar 

  95. Rink TJ, Beaumont K, Koda J, et al. Structure and biology of amylin. Trends Pharmacol Sci 1993; 14: 113–8

    Article  PubMed  CAS  Google Scholar 

  96. Pittner RA, Albrandt K, Beaumont K, et al. Molecular physiology of amylin. J Cell Biochem 1994; 55S: 19–28

    Article  Google Scholar 

  97. Thompson RG, Peterson J, Gottlieb A, et al. Effects of pramlintide, an analog of human amylin, on plasma glucose profiles in patients with IDDM: results of a multicenter trial. Diabetes 1997; 46: 632–6

    Article  PubMed  CAS  Google Scholar 

  98. Kolterman OG, Gottlieb A, Moyses C, et al. Reduction of post-prandial hyperglycemia in subjects with IDDM by intravenous infusion of AC137, a human amylin analogue. Diabetes Care 1995; 18: 1179–82

    Article  PubMed  CAS  Google Scholar 

  99. Thompson RG, Gottlieb A, Organ K, et al. Pramlintide: a human amylin analogue reduced post prandial plasma glucose, insulin and C peptide concentrations in patients with type 2 diabetes. Diabet Med 1997; 14: 547–55

    Article  PubMed  CAS  Google Scholar 

  100. Thompson RG, Pearson L, Schoenfeld SL, et al. The pramlintide in type 2 diabetes group: pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with type 2 diabetes using insulin. Diabetes Care 1998; 21: 987–93

    Article  PubMed  CAS  Google Scholar 

  101. Ratner R, Levetan C, Schoenfeld S, et al. Pramlintide therapy in the treatment of insulin requiring type 2 diabetes: results of a 1-year placebo-controlled trial [abstract]. Diabetes 1998; 47 Suppl. 1: A88

    Google Scholar 

  102. Holst JJ. GLP-1 in NIDDM. Diabet Med 1996; 13 Suppl. 6: S156–60

    PubMed  CAS  Google Scholar 

  103. Williams B, Werner J, Holst JJ et al. Gastric emptying, glucose responses, and insulin secretion after liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 1996; 81: 327–32

    Article  Google Scholar 

  104. Gutniak MK, Larsson H, Sanders SW, et al. GLP-1 tablet in type 2 diabetes in fasting and post prandial conditions. Diabetes Care 1997; 20: 1874–8

    Article  PubMed  CAS  Google Scholar 

  105. Groop LC. Sulfonylureas in NIDDM. Diabetes Care 1992; 15: 737–54

    Article  PubMed  CAS  Google Scholar 

  106. Philipson LH, Steiner DF. Pas de deux or more: the sulfonylurea receptor and K+channels. Science 1995; 268: 372–3

    Article  PubMed  CAS  Google Scholar 

  107. Melander A, Bitzen PO, Faber O, et al. Sulfonylurea anti-diabetic drugs: an update of their clinical pharmacology and rational therapeutic use. Drugs 1989; 37: 58–72

    Article  PubMed  CAS  Google Scholar 

  108. Rosenstock J, Samols E, Muchmore DB, The Glimepiride Study Group, et al. Glimepiride, a new once-daily sulfonylurea: a double-blind, placebo-controlled study of NIDDM patients. Diabetes Care 1996; 19: 1194–9

    Article  PubMed  CAS  Google Scholar 

  109. Groop LC, Luzi L, Melander A, et al. Different effects of glyburide and glipizide on insulin secretion and hepatic glucose production in normal and NIDDM subjects. Diabetes 1987; 36: 1320–8

    Article  PubMed  CAS  Google Scholar 

  110. Groop LC, Wahlin-Boll E, Groop PH, et al. Pharmacokinetics and metabolic effects of glibenclamide and glipizide in type 2 diabetics. Eur J Clin Pharmacol 1985; 28: 697–704

    Article  PubMed  CAS  Google Scholar 

  111. Groop LC, Perlkonen R, Koskimies S, et al. Secondary failure to treatment with oral antidiabetic agents in non-insulin dependent diabetes. Diabetes Care 1986; 9: 129–33

    Article  PubMed  CAS  Google Scholar 

  112. Groop LC, Shalin C, Franssila-Kallunki A, et al. Characteristics of non-insulin dependent diabetic patients with secondary failure to oral antidiabetic therapy. Am J Med 1989; 87: 183–90

    Article  PubMed  CAS  Google Scholar 

  113. Jennings AM, Wilson RM, Ward JD. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care 1989; 12: 203–8

    Article  PubMed  CAS  Google Scholar 

  114. Ferner RE, Neil HAW. Sulphonylureas and hypoglycaemia [editorial]. BMJ 1988; 296: 949–50

    Article  PubMed  CAS  Google Scholar 

  115. Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides. Horm Metab Res 1985; 17 Suppl. 15: 111–5

    Google Scholar 

  116. Seltzer HS. Severe drug-induced hypoglycemia: a review. Compr Ther 1979; 5: 21–9

    PubMed  CAS  Google Scholar 

  117. Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycemia: a report of 57 cases. Diabetologia 1983; 24: 412–7

    Article  PubMed  CAS  Google Scholar 

  118. Lisch HJ, Sailer S. Lipoprotein patterns in diet, sulfonylurea and insulin-treated diabetics. Diabetologia 1981; 20: 118–22

    Article  PubMed  CAS  Google Scholar 

  119. Kennedy AL, Lappin TR, Lavery TD, et al. Relation of high-density-lipoprotein-cholesterol concentration in diabetes mellitus. Lancet 1978; II: 66–8

    Google Scholar 

  120. Moorhouse JA. A comparison of the effects of tolazamide and tolbutamide upon blood glucose and serum insulin and lipid levels in diabetic subjects. Can Med Assoc J 1967; 96: 536–9

    PubMed  CAS  Google Scholar 

  121. Klimt CR, Knatternd GL, Meinert CL, et al. University Group Diabetes Program: a study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970; 19 Suppl. 2: 747–815

    Google Scholar 

  122. University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: VI. Supplementary report on non-fatal events in patients treated with tolbutamide. Diabetes 1976; 25: 1129–53

    Google Scholar 

  123. Schor S. The University Group Diabetes Program: a statistician looks at the mortality results. JAMA 1971; 217: 1673–5

    Article  Google Scholar 

  124. Seltzer HS. Asummary of criticism of the findings and conclusions of the University Group Diabetes Program (UGDP) study. Diabetes 1972; 21: 976–9

    PubMed  CAS  Google Scholar 

  125. Kolata GB. Controversy over study of diabetes drugs continues for nearly a decade. Science 1979; 203: 986–90

    Article  PubMed  CAS  Google Scholar 

  126. American Diabetes Association. Policy statement: the UGDP controversy. Diabetes Care 1979; 2: 1–3

    Google Scholar 

  127. Bailey CJ. Metformin: an update. Gen Pharmacol 1993; 24: 1299–309

    Article  PubMed  CAS  Google Scholar 

  128. Defronzo RA, Goodman AM, Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333: 541–9

    Article  PubMed  CAS  Google Scholar 

  129. Wu MS, Johnston P, Sheu WHH, et al. Effects of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990; 13: 1–8

    Article  PubMed  CAS  Google Scholar 

  130. Stumvoll M, Nurijhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333: 550–4

    Article  PubMed  CAS  Google Scholar 

  131. DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 1991; 73: 1294–301

    Article  PubMed  CAS  Google Scholar 

  132. Nosadini R, Avogaro A, Trevisian R, et al. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care 1987; 10: 62–7

    Article  PubMed  CAS  Google Scholar 

  133. Johnson AB, Webster JM, Sum CF, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism 1993; 42: 1217–22

    Article  PubMed  CAS  Google Scholar 

  134. Makimattila S, Nikkila K, Yki-Jarvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with type 2 diabetes mellitus. Diabetologia 1999; 42: 406–12

    Article  PubMed  CAS  Google Scholar 

  135. Dandona P, Fonseca V, Mier A, et al. Diarrhea and metformin in a diabetic clinic. Diabetes Care 1983; 6: 472–4

    Article  PubMed  CAS  Google Scholar 

  136. Stang M, Wysowski DK, Butler Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care 1999; 22: 925–7

    Article  PubMed  CAS  Google Scholar 

  137. Adams M. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human adipocyte differentiation. J Clin Invest 1997; 100: 3149–53

    Article  PubMed  CAS  Google Scholar 

  138. Iwamoto Y, Kosaka K, Akanuma Y, et al. Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996; 19: 151–6

    Article  PubMed  CAS  Google Scholar 

  139. Antonucci T, Whitcomb R, McLain R, et al. Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 1997; 20: 188–93

    Article  PubMed  CAS  Google Scholar 

  140. Kumar S, Boulton AJM, Beck-Nielsen H, et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996; 39: 701–9

    Article  PubMed  CAS  Google Scholar 

  141. Schwartz S, Raskin P, Fonseca V, et al. Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. N Engl J Med 1998; 338: 861–6

    Article  PubMed  CAS  Google Scholar 

  142. Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized double blind placebo controlled trial. Ann Intern Med 1998; 128: 176–85

    PubMed  CAS  Google Scholar 

  143. Spencer CM, Markham A. Troglitazone. Drugs 1997; 54: 89–102

    Article  PubMed  CAS  Google Scholar 

  144. Ogihara T, Rakugi H, Ikegami H, et al. Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am JHypertens 1995; 8: 316–20

    Article  CAS  Google Scholar 

  145. Imura H. A novel antidiabetic drug, troglitazone: reason for hope and concern. N Engl J Med 1998; 338: 908–9

    Article  PubMed  CAS  Google Scholar 

  146. Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998; 338: 916–7

    Article  PubMed  CAS  Google Scholar 

  147. Scheen AJ, Lefebvre PJ. Troglitazone: anti-hyperglycemic activity and potential role in the treatment of type 2 diabetes. Diabetes Care 1999; 22: 1568–77

    Article  PubMed  CAS  Google Scholar 

  148. Balfour JA, Plosker GL. Rosiglitazone. Drugs 1999; 57: 921–30

    Article  PubMed  CAS  Google Scholar 

  149. Madar Z. The effect of acarbose and miglitol (BAY-M-1099) on post-prandial glucose levels following ingestion of various sources of starch by nondiabetic and streptozotocin-induced diabetic rats. J Nutr 1989; 119: 2023–9

    PubMed  CAS  Google Scholar 

  150. Hanefeld M, Fischer S, Schulze J, et al. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991; 14: 732–7

    Article  PubMed  CAS  Google Scholar 

  151. Reaven GM, Lardinois CK, Greenfield MS, et al. Effect of acarbose on carbohydrate and lipid metabolism in NIDDM patients poorly controlled by sulfonylureas. Diabetes Care 1990; 13: Suppl. 3: 32–6

    PubMed  Google Scholar 

  152. Coniff RF, Shapiro JA, Seaton TB, et al. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutaminde-plus acarbose in non-insulin dependent diabetes mellitus. Am J Med 1995; 98: 443–51

    Article  PubMed  CAS  Google Scholar 

  153. Bischoff H. Pharmacology of α-glucosidase inhibition. Eur J Clin Invest 1994; 24: 3–10

    PubMed  CAS  Google Scholar 

  154. Segal P, Rybka J, Feig PU, et al. The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care 1997; 20: 687–91

    Article  PubMed  CAS  Google Scholar 

  155. Johnston PS, Coniff RF, Hoogwerf BJ, et al. Effect of the CHO inhibitor miglitol in sulfonylurea-treated NIDDM patients. Diabetes Care 1994; 17: 20–8

    Article  PubMed  CAS  Google Scholar 

  156. Johnston PS, Feig PU, Coniff RF, et al. Chronic treatment of African-American type 2 diabetic patients with α-glucosidase inhibition. Diabetes Care 1998; 21: 416–22

    Article  PubMed  CAS  Google Scholar 

  157. Johnston PS, Feig PU, Coniff RF, et al. Long-term titrated dose α-glucosidase inhibition in non-insulin-requiring Hispanic NrDDM patients. Diabetes Care 1998; 21: 409–15

    Article  PubMed  CAS  Google Scholar 

  158. Failla ML, Scidel KE. The absorption and retention of dietary zinc by type 1 diabetic rats are increased by chronic treatment with acarbose. In: JR Vasseri, CA Maggio, A Scriabine, editors. Drugs in development. Vol. 1. Branford (CT): Neva Press, 1993: 155–63

    Google Scholar 

  159. Holman RR, Cull CA, Turner RC, on behalf of the UK Prospective Diabetes Study (UKPDS) study Group. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (UKPDS 44). Diabetes Care 1999; 22: 960–4

    Article  PubMed  CAS  Google Scholar 

  160. Rybka J, Goke B, Sissmann J. European comparative study of 2 alpha-glucosidase inhibitors: miglitol and acarbose [abstract]. Diabetes 1999; 48 Suppl. 1: A101

    Google Scholar 

  161. Van Gaal LF, Van Acker KL, Dambso P, et al. Metabolic effects of Repaglinide, a new oral hypoglycemic agent in therapynaive type 2 diabetic [abstract]. Diabetologia 1995: 38 Suppl. 1: A43

    Google Scholar 

  162. Landgraf R, Bilo H. Repaglinide vs. glibenclamide: a 14-week efficacy and safety comparison [abstract]. Diabetes 1997; 46 Suppl. 1: 162

    Google Scholar 

  163. Moses R, Slobodniuk R, Donnelly T, et al. Additional treatment with repaglinide provides significant improvement in glycemic control in NIDDM patients poorly controlled on metformin [abstract]. Diabetes 1997; 46 Suppl. 1: 93

    Google Scholar 

  164. Tornier B, Marbury TC, Dambso P, et al. A new oral hypoglycemic agent, repaglinide minimizes risk of hypoglycemia in well controlled type 2 diabetic patients [abstract]. Diabetes 1995; 44 Suppl. 1: 70A

    Google Scholar 

  165. Hirschberg Y, McLeod J, Gareffa S, et al. Pharmacodynamics and dose response of nateglinide in type 2 diabetes [abstract]. Diabetes 1999; 48 Suppl. 1: A100

    Google Scholar 

  166. Kalbag J, Hirschberg Y, McLeod JF, et al. Comparison of mealtime glucose regulation by nateglinide and repaglinide in healthy subjects [abstract]. Diabetes 1999; 48 Suppl. 1: A106

    Article  Google Scholar 

  167. Bloomgarden ZT. Non-insulin-dependent diabetes mellitus. Diabetes Care 1995; 18: 1215–9

    PubMed  CAS  Google Scholar 

  168. Flier JS. Syndrome of insulin resistance: from patient to gene and back again. Diabetes 1992; 41: 1207–9

    Article  PubMed  CAS  Google Scholar 

  169. Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus: a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 1996; 334: 777–83

    Article  PubMed  CAS  Google Scholar 

  170. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183–97

    Google Scholar 

  171. Yki-Jarvinen H, Ryysy L, Kauppila M, et al. Effects of obesity on the response to insulin therapy in non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 4037–43

    Article  PubMed  CAS  Google Scholar 

  172. Mooradian AD. Repaglinide: a viewpoint. Drugs Aging 1998; 13: 181–2

    Article  Google Scholar 

  173. Mooradian AD, McLaughlin S, Boyer CC, et al. Diabetes care for older adults. Diabetes Spectrum 1999; 12: 70–7

    Google Scholar 

  174. Reed RL, Mooradian AD. Management of diabetes mellitus in the nursing home. Ann Long Term Care 1998; 6: 102–7

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arshag D. Mooradian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chehade, J.M., Mooradian, A.D. A Rational Approach to Drug Therapy of Type 2 Diabetes Mellitus. Drugs 60, 95–113 (2000). https://doi.org/10.2165/00003495-200060010-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200060010-00006

Keywords

Navigation