, Volume 17, Issue 4, pp 451–459 | Cite as

The past decade in type 2 diabetes and future challenges

  • Jihad A. HaddadEmail author
  • Aiman N. HaddadEmail author
Review Article


There is today an exponential increase in prevalence of type 2 diabetes mellitus (T2DM), especially in young people. This downward shift in age of onset of T2DM has been shown by abundant evidence to be due to an increase in obesity among the young, the latter mainly attributable to unhealthy dietary habits and a sedentary lifestyle. It is therefore obvious that the prevention of diabetes rather its treatment is of is paramount importance. In the past decade, because concerns about the safety of antidiabetic agents took precedence over the issue of efficacy, almost all studies have been diabetes CVOTs and not traditional CVOTs. Until 2015, the evidence showed that antidiabetic agents are effective in terms of reduction of microvascular, as opposed to macrovascular, complications. However, following publication of the results of some new studies, it became clear that the new class of antidiabetic drugs, e.g., SGLT 2 inhibitors and GLP-1 agonists, are also effective in reducing cardiovascular disease (CVD). In the coming decade, numerous health challenges are expected to arise, the most important being the greater expansion of the therapeutic armamentarium for T2DM and the adoption of strategies for prevention of CVDs. In parallel, the new generation of antidiabetic agents will target the recently investigated pathophysiologic disorders of diabetes, while, ideally, treatments should include smart drugs without side effects.


Type 2 diabetes (T2DM)  Cardiovascular (CV) outcome trial Dipeptidyl peptidase-4 (DPP4) inhibitors  Sodium glucose co-transporter 2 (SGLT 2) inhibitors Glucagon-like peptide (GLP-1) agonists 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Adams F (1990) The extant works of Aretaeus the Cappadocian. Published by Classics of Medicine LibraryGoogle Scholar
  2. 2.
  3. 3.
    Selvin E, Wang D, Lee AK et al (2017) Identifying trends in undiagnosed diabetes in U.S. adults by using a confirmatory definition: a cross-sectional study. Ann Intern Med.
  4. 4.
    DeFronzo RA (2009) From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58(4):773–795. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Schwartz SS, Epstein S, Corkey BE et al (2016) The time is right for a new classification system for diabetes: rationale and implications of the β-cell–centric classification schema. Diabetes Care 39(2):179–186CrossRefGoogle Scholar
  6. 6.
    Nissen SE, Wolski K et al (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2247. CrossRefPubMedGoogle Scholar
  7. 7.
    Gerstein HC, Miller ME, Byington RP et al (2008) Effects of intensive glucose lowering in type 2 diabetes. The action to control cardiovascular risk in diabetes study group. N Engl J Med 358(24):2545–2559. CrossRefPubMedGoogle Scholar
  8. 8.
    Patel A, MacMahon S, Chalmers J, Neal B et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572. CrossRefPubMedGoogle Scholar
  9. 9.
    Duckworth W, Abraira C, Moritz T et al (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360:129–139. CrossRefPubMedGoogle Scholar
  10. 10.
    Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS et al (2009 Jun 20) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373(9681):2125–2135. CrossRefPubMedGoogle Scholar
  11. 11.
    Holman RR, F.R.C.P, Paul SK, Bethel MA et al (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589. CrossRefPubMedGoogle Scholar
  12. 12.
    Gerstein HC (2016) Cardiovascular Disease and Diabetes Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care 39(5):701–708. CrossRefGoogle Scholar
  13. 13.
    Zoungas S, Chalmers J, Neal B, Billot L et al (2014) Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 371:1392–1406. CrossRefPubMedGoogle Scholar
  14. 14.
    Hayward RA, Reaven PD, Wiitala WL, for the VADT Investigators et al (2015) Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 372:2197–2206. CrossRefPubMedGoogle Scholar
  15. 15.
    Simpson SH, Lee J, Choi S, Vandermeer B, Abdelmoneim AS, Travis R (2014) Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol.
  16. 16.
    Bristol-Myers Squibb Company (2006) Bristol-Myers Squibb announces discontinuation of development of muraglitazar, an investigational oral treatment for type 2 diabetesGoogle Scholar
  17. 17.
    Guidance for Industry Diabetes Mellitus (2008) Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Clinical/MedicalGoogle Scholar
  18. 18.
    Dormandy JA, Charbonnel B, Eckland DJA et al (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366(9493):1279–1289CrossRefGoogle Scholar
  19. 19.
    FDA Drug Safety Communication: Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk of bladder cancer, 2011. updated 12-12-2016Google Scholar
  20. 20.
    Erdmann E, Song E, Spanheimer R, van Troostenburg de Bruyn AR, Perez A (2014 Jan) Observational follow-up of the PROactive study: a 6-year update. Diabetes Obes Metab 16(1):63–74. CrossRefPubMedGoogle Scholar
  21. 21.
    Lewis JD, Habel LA, Quesenberry CP, Strom BL et al (2015) Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 314(3):265–277. CrossRefPubMedGoogle Scholar
  22. 22.
    Lewis JD, Habel LA, Quesenberry CP et al (2015) Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. The new 10-year findings, from three large database analyses. J Am Med Assoc 314(3):265–277. CrossRefGoogle Scholar
  23. 23.
    Kernan WN, Viscoli CM, Furie KL et al (2016) Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 374:1321–1331. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gerstein HC, Bosch J, Dagenais GR et al (2012) Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 367:319–328. CrossRefPubMedGoogle Scholar
  25. 25.
    Inzucchi SE (2012) Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35(6):1364–1379. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Murugan R (2015) Movement towards personalised medicine in the ICU. Lancet 3(1):10–12PubMedGoogle Scholar
  27. 27.
    Scirica BM, Bhatt DL, Braunwald E et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326. CrossRefPubMedGoogle Scholar
  28. 28.
    William B (2013) White, Christopher P. Cannon, Simon R. Heller, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369:1327–1335. CrossRefGoogle Scholar
  29. 29.
    Green JB, Angelyn Bethel M, Armstrong PW (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373:232–242J. CrossRefPubMedGoogle Scholar
  30. 30.
    Pfeffer MA, Claggett B, Diaz R et al (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257. CrossRefPubMedGoogle Scholar
  31. 31.
    Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128. CrossRefPubMedGoogle Scholar
  32. 32.
    Comment on Ferrannini et al. Diabetes Care 2016;39:1108–1114. Comment on Mudaliar et al. Comment on Mudaliar et al. Diabetes Care 2016;39:1115–1122 2016;39:1115–1122Google Scholar
  33. 33.
    FDA News Release (2016) FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetesGoogle Scholar
  34. 34.
    Marso SP, Daniels GH, Brown-Frandsen K (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Marso SP, Bain SC, Consoli A et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375:1834–1844. CrossRefPubMedGoogle Scholar
  36. 36.
    Holman RR, F. Med. Sci, Bethel MA, Mentz RJ et al (2017) Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 377:1228–1239. CrossRefPubMedGoogle Scholar
  37. 37.
    Press Releases (2016) Intarcia announces successful cardiovascular safety results in phase FREEDOM-CVO trial for ITCA 650, an investigational therapy for type 2 diabetesGoogle Scholar
  38. 38.
    Neal B, Perkovic V, Mahaffey KW et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:644–657. CrossRefPubMedGoogle Scholar
  39. 39.
    Kosiborod M, Cavender MA, Alex ZF et al (2017) Lower risk of heart failure and death in patients initiated on SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study. Circulation.
  40. 40.
    (2017) FDA approves SGLT2 inhibitor ertugliflozin for type 2 diabetes. MedscapeGoogle Scholar
  41. 41.
    Marso SP, McGuire DK, Zinman B et al (2017) Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 377:723–732. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Riddle MC, Bolli GB, Ziemen M, Muehlen-Bartmer I, Bizet F, Home PD (2014) New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care 37(10):2755–2762CrossRefGoogle Scholar
  43. 43.
    Aroda VR, Rosenstock J, Wysham C et al Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial. Diabetes Care:dc161495.
  44. 44.
    Lingvay I, Pérez Manghi F, García-Hernández P et al (2016) Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial. JAMA 315(9):898–907. CrossRefPubMedGoogle Scholar
  45. 45.
    DeFronzo RA (2015) Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 38(3):384–393CrossRefGoogle Scholar
  46. 46.
    FDA website (2017) FDA approves once-daily QTERN® (dapagliflozin and saxagliptin) tablets for adults with type-2 diabetesGoogle Scholar
  47. 47.
    1st ever “biosimilar” insulin approved in US – potential to come cheaper than other insulins, with launch in December 2016 -
  48. 48.
    ADA (2017) Standards of Medical Care in DiabetesGoogle Scholar
  49. 49.
    (2015) Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study, Vol 3, Issue 11, pp 866–875.
  50. 50.
    AACE/ACE comprehensive type 2 diabetes management algorithm 2018Google Scholar
  51. 51.
    CAROLINA: cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes, Identifier: NCT01243424
  52. 52.
    Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus (CARMELINA), Identifier: NCT01897532
  53. 53.
    Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58), Identifier: NCT01730534
  54. 54.
    Cardiovascular outcomes following ertugliflozin treatment in type 2 diabetes mellitus participants with vascular disease, the VERTIS CV study (MK-8835-004), Identifier: NCT01986881
  55. 55.
    Evaluation of the effects of canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy (CREDENCE) , Identifier: NCT02065791
  56. 56.
    EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with reduced ejection fraction (EMPEROR-Reduced), Identifier: NCT03057977
  57. 57.
    Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes mellitus, Identifier: NCT02465515
  58. 58.
    Researching cardiovascular events with a weekly incretin in diabetes (REWIND) , Identifier: NCT01394952
  59. 59.
    Prato D, Foley JE, Kothny W, Kozlovski P, Stumvoll M, Paldánius PM, Matthews DR (2014) Diabet Med 31(10):1178–1184. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Nathan DM, Buse JB, Kahn SE, Krause-Steinrauf H et al (2013) Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care 36(8):2254–2261. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    RISE Consortium (2014) Restoring Insulin Secretion (RISE): design of studies of β-cell preservation in prediabetes and early type 2 diabetes across the life span. Diabetes Care 37(3):780–788. CrossRefGoogle Scholar
  62. 62.
    Davies M, Pieber TR, Hartoft-Nielsen M-L et al (2017) Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA 318(15):1460–1470. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Zhen G, Aimetti A, Zhang Y et al (2013) Dang Injectable nano-network for glucose-mediated insulin delivery. ACS Nano.
  64. 64.
    Wang C, Ye Y, Sun W et al (2017) Red blood cells for glucose-responsive insulin delivery. Adv Mater.
  65. 65.
    Ang K, Tamborlane WV, Weinzimer SA (2015) Combining glucose monitoring and insulin delivery into a single device: current progress and ongoing challenges of the artificial pancreas. Expert Opin Drug Deliv 12(10):1579–1582.
  66. 66.
    (2015) The future of diabetes management. The Medical Futurist℠ NewsletterGoogle Scholar
  67. 67.
    Singh R, Lather V, Pandita D et al (2017) Synthesis, docking and antidiabetic activity of some newer benzamide derivatives as potential glucokinase activators. Lett Drug Design Discov 14(5):540–553 (14)CrossRefGoogle Scholar
  68. 68.
    Jiang C et al (2017) Dibenzazepine-loaded nanoparticles induce local browning of white adipose tissue to counteract obesity. Mol Ther.
  69. 69.
    Zhang S, Liu H, Chuang CL et al (2014) The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet cells. FASEB J.
  70. 70.
    Tsai S, Clemente-Casares X, Revelo XS et al (2015) Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes Care 64(6):1886–1897. CrossRefGoogle Scholar
  71. 71.
    Muñoz-Garach A, Diaz-Perdigones C, Tinahones FJ et al (2016) Gut microbiota and type 2 diabetes mellitus. Endocrinol Nutr 63(10):560–568. CrossRefPubMedGoogle Scholar
  72. 72.
    Chen L, Tuo B, Dong H (2016) Regulation of intestinal glucose absorption by ion channels and transporters. Nutrients 8(1):43. CrossRefPubMedCentralGoogle Scholar
  73. 73.
    Cappon G, Acciaroli G, Vettoretti M, Facchinetti A, Sparacino G (2017) Wearable continuous glucose monitoring sensors: a revolution in diabetes treatment. Electronics 6(3):65. CrossRefGoogle Scholar
  74. 74.
    Lean MEJ, Leslie WS, Barnes AC (2017) Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet.
  75. 75.
    Pi-Sunyer X (2014) The Look AHEAD Trial: a review and discussion of its outcomes. Curr Nutr Rep 3(4):387–391. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2018

Authors and Affiliations

  1. 1.Center for Endocrinology, Diabetes and MetabolismPrince Hamzah HospitalAmmanJordan
  2. 2.Department of Geriatric Medicine, Princess Royal University HospitalKing’s College Hospital NHS Foundation TrustLondonUK

Personalised recommendations