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Acta Diabetologica

, Volume 46, Issue 3, pp 173–181 | Cite as

Is the current therapeutic armamentarium in diabetes enough to control the epidemic and its consequences? What are the current shortcomings?

  • Dario GiuglianoEmail author
  • Eberhard Standl
  • Tina Vilsbøll
  • John Betteridge
  • Riccardo Bonadonna
  • Ian W. Campbell
  • Gerit-Holger Schernthaner
  • Bart Staels
  • Antonia Trichopoulou
  • Eduardo Farinaro
Review Article

Abstract

The prevalence of diabetes is expected to rise together with an increase in morbidity and a reduction in life expectancy. A leading cause of death is cardiovascular disease, and hypertension and diabetes are additive risk factors for this complication. Selected treatment options should neither increase cardiovascular risk in patients with diabetes, nor increase risk of hyperglycaemia in patients with hypertension. The efficacy of present antihyperglycaemic agents is limited and new therapies, such as incretin-targeted agents, are under development. Even though most patients do not achieve glycated haemoglobin targets, trial data show that such interventions reduce the incidence of macrovascular events; however, intensive lowering may be detrimental in patients with existing cardiovascular disease. Currently available oral drugs do not address the key driver of type 2 diabetes—loss of functional beta-cell mass. In the future, new oral treatments must improve this, whilst providing durable blood glucose control and long-term tolerability.

Keywords

Antidiabetic drugs Diabetes mellitus, type 2 Disease management Beta-cell function Cardiovascular disease 

Abbreviations

ACCORD

Action to Control Cardiovascular Risk in Diabetes

ACE

Angiotensin-converting-enzyme

ADA

American Diabetes Association

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

ARBs

Angiotensin-receptor blockers

CVD

Cardiovascular disease

DPP-IV

Dipeptidyl peptidase-IV

EASD

European Association for the Study of Diabetes

ESC

European Society of Cardiology

ESOCAP

European Society for Cardiovascular Prevention

GIP

Glucose-dependent insulinotropic peptide

GLP-1

Glucagon-like peptide-1

LVEF

Left ventricular ejection fraction

MRFIT

Multiple Risk Factor Intervention Trial

UKPDS

United Kingdom Prospective Diabetes Study

Notes

Acknowledgments

The discussion on which this manuscript is based was supported by an unrestricted grant from Merck & Co. Writing support for this article was provided by Bioscript Stirling Ltd, UK, and funded by ESOCAP.

Conflict of interest statement

Dario Giugliano, Riccardo Bonadonna, Antonia Trichopoulou and Eduardo Farinaro have declared no conflicts of interest. Eberhard Standl has been an advisory board member for/received speaker’s fees from Novartis, Bayer, Takeda, MSD, Johnson & Johnson, Merck, Bristol-Myers Squibb, AstraZeneca and Solvay, as well as being a member of the data and safety monitoring boards for the PROactive, NAVIGATOR and ACE trials, and a member of the steering committee of the TECOS trial. Tina Vilsbøll has received fees for being a consultant, speaker and/or advisory board member for Eli Lilly, MannKind, MSD, Novartis and Novo Nordisk; she has also received scientific funding from MSD. John Betteridge has received honoraria for lectures and advisory boards from Takeda. Ian W. Campbell has received honoraria for lecturing and support to attend medical meetings from AstraZeneca, MSD, Merck Serono, Novo Nordisk, Sanofi-Aventis and Takeda. Gerit-Holger Schernthaner is a member of the Actos Strategic Advisory Board of Europe. Bart Staels has participated in advisory boards for Merck and Takeda Pharmaceuticals.

References

  1. 1.
    International Diabetes Federation (2006) Diabetes atlas, 3rd edn. International Diabetes Federation, BrusselsGoogle Scholar
  2. 2.
    Rydén L, Standl E, Bartnik M et al (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 28:88–136PubMedCrossRefGoogle Scholar
  3. 3.
    Hu FB, Stampfler MJ, Haffner SM, Solomon CG, Willett WC, Manson JE (2002) Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 25:1129–1134PubMedCrossRefGoogle Scholar
  4. 4.
    Standl E, Stiegler H (1993) Microalbuminuria in a random cohort of recently diagnosed type 2 (non-insulin-dependent) diabetic patients living in the greater Munich area. Diabetologia 36:1017–1020PubMedCrossRefGoogle Scholar
  5. 5.
    Gregg EW, Sorlie P, Paulose-Ram R et al (2004) Prevalence of lower-extremity disease in the US adult population ≥40 years of age with and without diabetes: 1999–2000 national health and nutrition examination survey. Diabetes Care 27:1591–1597PubMedCrossRefGoogle Scholar
  6. 6.
    MacGregor AS, Price JF, Hau CM, Lee AJ, Carson MN, Fowkes FG (1999) Role of systolic blood pressure and plasma triglycerides in diabetic peripheral arterial disease. The Edinburgh Artery Survey. Diabetes Care 22:453–458PubMedCrossRefGoogle Scholar
  7. 7.
    Kallio M, Forsblom C, Groop PH, Groop L, Lepäntalo M (2003) Development of new peripheral arterial occlusive disease in patients with type 2 diabetes during a mean follow-up of 11 years. Diabetes Care 26:1241–1245PubMedCrossRefGoogle Scholar
  8. 8.
    Bird CE, Criqui MH, Fronek A, Denenberg JO, Klauber MR, Langer RD (1999) Quantitative and qualitative progression of peripheral arterial disease by non-invasive testing. Vasc Med 4:15–21PubMedCrossRefGoogle Scholar
  9. 9.
    Choose Control Survey Data (2006) Available from http://www.idf.org/home/index.cfm?node=295. Accessed 23 April 2008
  10. 10.
    Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL (2000) Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis risk in communities study. N Engl J Med 342:905–912PubMedCrossRefGoogle Scholar
  11. 11.
    Geiss LS, Rolka DB, Engelgau MM (2002) Elevated blood pressure among U.S. adults with diabetes, 1988–1994. Am J Prev Med 22:42–48PubMedCrossRefGoogle Scholar
  12. 12.
    Stamler J, Vaccaro O, Neaton JD, Wentworth D (1993) Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16:434–444PubMedCrossRefGoogle Scholar
  13. 13.
    August P (2003) Initial treatment of hypertension. N Engl J Med 348:610–617PubMedCrossRefGoogle Scholar
  14. 14.
    Bangalore S, Parkar S, Grossman E, Messerli FH (2007) A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol 100:1254–1262PubMedCrossRefGoogle Scholar
  15. 15.
    Wiysonge CS, Bradley H, Mayosi BM et al (2007) Beta-blockers for hypertension. Cochrane Database Syst Rev Jan 24(1):CD002003Google Scholar
  16. 16.
    Elliott WJ, Meyer PM (2007) Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 369:201–207PubMedCrossRefGoogle Scholar
  17. 17.
    Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr (2005) Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 46:821–826PubMedCrossRefGoogle Scholar
  18. 18.
    Padwal R, Majumdar SR, Johnson JA, Varney J, McAlister FA (2005) A systematic review of drug therapy to delay or prevent type 2 diabetes. Diabetes Care 28:736–744PubMedCrossRefGoogle Scholar
  19. 19.
    DREAM Trial Investigators (2006) Effect of ramipril on the incidence of diabetes. N Engl J Med 355:1551–1562CrossRefGoogle Scholar
  20. 20.
    UK Prospective Diabetes Study Group (1998) 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 352:837–853CrossRefGoogle Scholar
  21. 21.
    UK Prospective Diabetes Study Group (1998) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317:703–713Google Scholar
  22. 22.
    American Diabetes Association (2008) Standards of Medical Care in Diabetes—2008. Diabetes Care 31:S12–S54CrossRefGoogle Scholar
  23. 23.
    European Society of Hypertension–European Society of Cardiology Guidelines Committee (2003) 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 21:1011–1053CrossRefGoogle Scholar
  24. 24.
    Nathan DM, Buse JB, Davidson MB et al (2006) 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 29:1963–1972PubMedCrossRefGoogle Scholar
  25. 25.
    Nathan DM, Buse JB, Davidson MB et al (2008) Management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: update regarding the thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 31:173–175PubMedCrossRefGoogle Scholar
  26. 26.
    Gæde P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383–393PubMedCrossRefGoogle Scholar
  27. 27.
    Stettler C, Alleman S, Jüni P et al (2006) Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J 152:27–38PubMedCrossRefGoogle Scholar
  28. 28.
    Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP et al (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559Google Scholar
  29. 29.
    ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572Google Scholar
  30. 30.
    Monnier L, Lapinski H, Colette C (2003) Contributions of fasting and postprandial plasma increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care 26:881–885PubMedCrossRefGoogle Scholar
  31. 31.
    Standl E, Füchtenbusch M (2003) The role of oral antidiabetic agents: why and when to use an early-phase insulin secretion agent in Type 2 diabetes mellitus. Diabetologia 46(Suppl 1):M30–M36PubMedGoogle Scholar
  32. 32.
    Johnson JA, Majumdar SR, Simpson SH, Toth EL (2002) Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 25:2244–2248PubMedCrossRefGoogle Scholar
  33. 33.
    UK Prospective Diabetes Study Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865CrossRefGoogle Scholar
  34. 34.
    Evans JM, Ogston SA, Emslie-Smith A, Morris AD (2006) Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 49:930–936PubMedCrossRefGoogle Scholar
  35. 35.
    Kahn SE, Haffner SM, Heise MA et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443PubMedCrossRefGoogle Scholar
  36. 36.
    Kahler KH, Rajan M, Rhoads GG, Safford MM, Demissie K, Lu SE, Pogach LM (2007) Impact of oral antihyperglycemic therapy on all-cause mortality among patients with diabetes in the Veterans Health Administration. Diabetes Care 30:1689–1693PubMedCrossRefGoogle Scholar
  37. 37.
    Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (2007) Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298:1180–1188PubMedCrossRefGoogle Scholar
  38. 38.
    Singh S, Loke YK, Furberg CD (2007) Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 298:1189–1195PubMedCrossRefGoogle Scholar
  39. 39.
    Nauck M, Stöckmann F, Ebert R, Creutzfeldt W (1986) Reduced incretin effect in type 2 (non-insulin dependent) diabetes. Diabetologia 29:46–52PubMedCrossRefGoogle Scholar
  40. 40.
    Vilsbøll T, Krarup T, Madsbad S, Holst JJ (2002) Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologica 45:1111–1119CrossRefGoogle Scholar
  41. 41.
    Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W (1993) Normalization of fasting hyperglycemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36:741–744PubMedCrossRefGoogle Scholar
  42. 42.
    Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ (1995) Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44:1126–1131PubMedCrossRefGoogle Scholar
  43. 43.
    Vilsbøll T, Agersø H, Krarup T, Holst JJ (2003) Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab 88:220–224PubMedCrossRefGoogle Scholar
  44. 44.
    Vilsbøll T, Agersø H, Lauritsen T et al (2006) The elimination rates of intact GIP as well as its primary metabolite, GIP 3–42, are similar in type 2 diabetic patients and healthy subjects. Regul Pept 137:168–172PubMedCrossRefGoogle Scholar
  45. 45.
    Chen YE, Drucker DJ (1997) Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard. J Biol Chem 272:4108–4115PubMedCrossRefGoogle Scholar
  46. 46.
    Knudsen LB, Nielsen PF, Huusfeldt PO et al (2000) Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 43:1664–1669PubMedCrossRefGoogle Scholar
  47. 47.
    Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, Sitagliptin Study 024 Group (2007) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 9:194–205PubMedCrossRefGoogle Scholar
  48. 48.
    Purnell JQ, Weyer C (2003) Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity. Treat Endocrinol 2:33–47PubMedCrossRefGoogle Scholar
  49. 49.
    Farilla L, Bulotta A, Hirshberg B et al (2003) Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144:5149–5158PubMedCrossRefGoogle Scholar
  50. 50.
    Nikolaidis LA, Mankad S, Sokos GG et al (2004) Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109:962–965PubMedCrossRefGoogle Scholar
  51. 51.
    Nyström T, Gutniak MK, Zhang Q et al (2004) Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 287:E1209–E1215PubMedCrossRefGoogle Scholar
  52. 52.
    Solomon DH, Winkelmayer WC (2007) Cardiovascular risk and thiazolidinediones: déjà vu all over again? JAMA 298:1216–1218PubMedCrossRefGoogle Scholar
  53. 53.
    Psaty BM, Lumley T (2008) Surrogate end points and FDA approval: a tale of 2 lipid-altering drugs. JAMA 299:1474–1476PubMedCrossRefGoogle Scholar
  54. 54.
    Robinson AC, Burke J, Robinson S, Johnston DG, Elkeles RS (1998) The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care 21:701–705PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Dario Giugliano
    • 1
    Email author
  • Eberhard Standl
    • 2
  • Tina Vilsbøll
    • 3
  • John Betteridge
    • 4
  • Riccardo Bonadonna
    • 5
  • Ian W. Campbell
    • 6
  • Gerit-Holger Schernthaner
    • 7
  • Bart Staels
    • 8
  • Antonia Trichopoulou
    • 9
  • Eduardo Farinaro
    • 10
  1. 1.Division of Metabolic Diseases, Center of Excellence for Cardiovascular DiseasesSecond University of NaplesNaplesItaly
  2. 2.Munich Diabetes Research Institute at the Munich Helmholtz CenterMunichGermany
  3. 3.Department of Internal Medicine F, Gentofte HospitalUniversity of CopenhagenCopenhagenDenmark
  4. 4.Department of Medicine, Royal Free and University College Medical SchoolMiddlesex HospitalLondonUK
  5. 5.Department of Biomedical and Surgical SciencesUniversity of VeronaVeronaItaly
  6. 6.Department of Biological and Biomedical SciencesUniversity of St. AndrewsFifeUK
  7. 7.Department of Internal Medicine IIMedical University of ViennaViennaAustria
  8. 8.Department of AtherosclerosisU545 Inserm, University of Lille 2LilleFrance
  9. 9.Department of HygieneUniversity of Athens Medical SchoolAthensGreece
  10. 10.Department of Preventive Medical SciencesFederico II University of NaplesNaplesItaly

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