Type 2 Diabetes Mellitus. From the start - combination therapy

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Modern treatment of T2DM requires a shift in paradigm with appropriate intensification of therapy from the very first time of diabetes diagnosis. This is supported by data showing how even a moderate delay in achieving good glycemic control can translate into a later increased risk of developing diabetic complications. The recognition of the complexity of the pathogenesis of T2DM leads to the appreciation of the importance of attacking the disease from different angles, i.e. simultaneous tackling of multiple mechanisms contributing to hyperglycemia. From the turn of century a growing number of new anti-hyperglycemic agents have been made available. As compared to the older ones, these new medicines have a more targeted mechanism of action as they act at the level of the specific pathophysiologic disturbances accounting the development and progression of hyperglycemia. Because of that drugs can be use in combination taking advantage of their complementary mechanisms of action and synergistic. If introduced earlier in the natural history of the disease combination therapy may contribute avoiding undesirable exposure to even mild chronic hyperglycemia and provide early benefits. With respect to that in this review we will discuss advantages, disadvantages and still unanswered questions related to the use of early combination therapy in type 2 diabetes.

About the authors

Francesco Indovina

University of Pisa

Email: indofrancesco@gmail.com

Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes

Italy, Nuovo Ospedale Santa Chiara -  Via Paradisa, 2 - 56124 Pisa

Pierpaolo Falcetta

University of Pisa

Email: falcetta.pierpaolo@gmail.com

Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes

Italy, Nuovo Ospedale Santa Chiara -  Via Paradisa, 2 - 56124 Pisa

Stefano Del Prato

University of Pisa

Author for correspondence.
Email: stefano.delprato@med.unipi.it

MD, Professor for endocrinology, Former vice-president EASD

Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes

Italy, Nuovo Ospedale Santa Chiara -  Via Paradisa, 2 - 56124 Pisa


  1. Tahrani AA, Bailey CJ, Del Prato S, Barnett AH. Management of type 2 diabetes: new and future developments in treatment. Lancet. 2011;378:182-97.
  2. Carls G, Huynh J, Tuttle E, Yee J, Edelman SV. Achievement of Glycated Hemoglobin Goals in the US Remains Unchanged Through 2014. Diabetes Ther. 2017;8:863-873.
  3. Khunti K, Wolden ML, Thorsted BL et al. Clinical Inertia in People With Type 2 Diabetes A retrospective cohort study of more than 80,000 people. Diabetes Care 2013;36:3411–3417
  4. Laiteerapong N, Ham SA, Gao Y, Moffet HH, Liu JY, Huang ES, Karter AJ. The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (the Diabetes & Aging Study). Diabetes Care. 2018 Aug 13. pii: dc171144. doi: 10.2337/dc17-1144.
  5. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068-83.
  6. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58:773– 795
  7. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58:429-42
  8. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Henry RR, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE). Consensus statement by the American Association Of Clinical Endocrinologists and American College Of Endocrinology on the comprehensive type 2 diabetes management algorithm-2016 executive summary. Endocr Pract. 2016;22:84-113.
  9. Phung OJ, Sobieraj DM, Engel SS et al. Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta‐analysis Diab Obes Metab 2014; 16:410–417
  10. Gloyn AL, Drucker DJ. Precision medicine in the management of type 2 diabetes. Lancet Diabetes Endocrinol. 2018 Apr 23. pii: S2213-8587(18)30052-4. doi: 10.1016/S2213-8587(18)30052-4.
  11. Natali A, Ferrannini E Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 2006, 49:434-441
  12. Cho YM, Tieffer TJ New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia 2011;54:219-22
  13. Marchetti P, Lupi R, Bugliani M, Kirkpatrick CL, Sebastiani G, Grieco FA, Del Guerra S, D'Aleo V, Piro S, Marselli L, Boggi U, Filipponi F, Tinti L, Salvini L, Wollheim CB, Purrello F, Dotta F. A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia 2012;55:3262-72
  14. Sancho V, Daniele G, Lucchesi D, Lupi R, Ciccarone A, Penno G, Bianchi C, Dardano A, Miccoli R, Del Prato S. Metabolic regulation of GLP-1 and PC1/3 in pancreatic α-cell line. PLoS One. 2017;12:e0187836.
  15. Poulsen MD, Hansen GH, Dabelsteen E, Høyer PE, Norén O, Sjöström H. Dipeptidyl peptidase IV is sorted to the secretory granules in pancreatic islet A-cells. J Histochem Cytochem. 1993;41:81-8.
  16. Inaba W, Mizukami H, Kamata K, Takahashi K, Tsuboi K, Yagihashi S. Effects of long-term treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet endocrine cells in non-obese type 2 diabetic Goto-Kakizaki rats. Eur J Pharmacol. 2012;691:297-306
  17. Mu J, Petrov A, Eiermann GJ, Woods J, Zhou YP, Li Z, Zycband E, Feng Y, Zhu L, Roy RS, Howard AD, Li C, Thornberry NA, Zhang BB. Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol. 2009;623:148-54.
  18. Furuta Y, Horiguchi M, Sugaru E, Ono-Kishino M, Otani M, Sakai M, Masui Y, Tsuchida A, Sato Y, Takubo K, Hochigai H, Kimura H, Nakahira H, Nakagawa T, Taiji M. Chronic administration of DSP-7238, a novel, potent, specific and substrate-selective DPP IV inhibitor, improves glycaemic control and beta-cell damage in diabetic mice. Diabetes Obes Metab. 2012;14:918-26.
  19. Shah P, Ardestani A, Dharmadhikari G et al. The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through glp-1 stabilization. J Clin Endocrinol Metab. 2013;98:E1163-72
  20. Muscelli E, Casolaro A, Gastaldelli A, Mari A, Seghieri G, Astiarraga B, Chen Y, Alba M, Holst J, Ferrannini E. Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes. J Clin Endocrinol Metab 2012; 97: 2818–2826
  21. Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol 2016;4:525–536
  22. Gastaldelli A, Ferrannini E, Miyazaki Y et al. Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Physiol Endocrinol Metab 2007;292:E871–E883
  23. Lupi R, Del Guerra S, Marselli L, Bugliani M, Boggi U, Mosca F, Marchetti P, Del Prato S. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPARgamma2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab. 2004;286:E560-7.
  24. Rosenstock J, Kim SW, Baron MA, Camisasca RP, Cressier F, Couturier A, Dejager S. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9:175-85.
  25. Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab 2015;17:268–275
  26. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509–514
  27. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499–508
  28. Neschen S, Scheerer M, Seelig A, Huypens P, Schultheiss J, Wu M, Wurst W, Rathkolb B, Suhre K, Wolf E, Beckers J, Hrabé de Angelis M. Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 inhibitor by suppressing endogenous glucose production in diabetic mice. Diabetes 2015; 64:284–290
  29. Rosenstock, Chuck L, González-Ortiz M et al. Initial combination therapy with canagliflozin plus metformin versus each component as monotherapy for drug-naïve type 2 diabetes. Diabetes Care 2016; 39:353–362
  30. Cervera A, Wajcberg E, Sriwijitkamol A, Fernandez M, Zuo P, Triplitt C, Musi N, DeFronzo RA, Cersosimo E. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab. 2008;294:E846-52.
  31. Hansen L, Iqbal N, Ekholm E, Cook W, Hirshberg B. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin Therapy Endocr Pract. 2014;20:1187-1197
  32. Lewin A, DeFronzo RA, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care 2015;38:394-402
  33. Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B, Iqbal N. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 2015;38:376-383
  34. Frías JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, Jabbour SA. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4:1004-1016.
  35. Ludvik B, Frías JP, Tinahones FJ, Wainstein J, Jiang H, Robertson KE, García-Pérez LE, Woodward DB, Milicevic Z. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6:370-381.
  36. Palmer SC, Mavridis D, Nicolucci A et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes a meta-analysis. JAMA. 2016;316:313-324
  37. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-43.
  38. Mishriky BM, Cummings DM, Tanenberg RJ. The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on therapy to metformin in patients with Type 2 diabetes: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2015;109:378-88.
  39. Del Prato S, Camisasca R, Wilson C, Fleck P. Durability of the efficacy and safety of alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study. Diabetes Obes Metab. 2014;16:1239-1246
  40. Del Prato S, Nauck M, Durán-Garcia S et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17:581-90
  41. Del Prato S, Chilton R. Practical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitors. Diabetes Obes Metab. 2018;20:786-799.
  42. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC; EMPA-REG PIO™ trial investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014;16: 147–158
  43. DeFronzo, R. Chilton, L. Norton, G. Clarke, R. E. J. Ryder, M. Abdul-Ghani. Revitalization of pioglitazone: the optimum agent to be combined with a sodium-glucose co-transporter-2 inhibitor. Diabetes Obes Metab 2016; 18:454–462
  44. Del Prato S, Rosenstock J, Garcia-Sanchez R, Iqbal N, Hansen L, Johnsson E, Chen H, Mathieu C. Safety and tolerability of dapagliflozin, saxagliptin and metformin in combination: Post-hoc analysis of concomitant add-on versus sequential add-on to metformin and of triple versus dual therapy with metformin. Diabetes Obes Metab. 2018;20:1542-1546.
  45. Hutchins V, Zhang B, Fleurence RL, Krishnarajah G, Graham J. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin 2011; 27:1157–1168
  46. Cariou B, Charbonnel B, Staels B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol Metab. 2012;23:205-15.
  47. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive Investigators. 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 2005;366:1279–1289
  48. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP Jr, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O'Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321-31
  49. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128
  50. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657
  51. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311–322
  52. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–1844
  53. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, Chan JC, Choi J, Gustavson SM, Iqbal N, Maggioni AP, Marso SP, Öhman P, Pagidipati NJ, Poulter N, Ramachandran A, Zinman B, Hernandez AF; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-1239.
  54. Abdul-Ghani M, DeFronzo RA, Del Prato S, Chilton R, Singh R, Ryder REJ. Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? Diabetes Care 2017;40:813-820.
  55. Avogaro A, Fadini G. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care 2014;37:2884-94
  56. Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, Tornøe K, Zinman B, Buse JB; LEADER Steering Committee and Investigators. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377:839-848.
  57. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016;375:323-34
  58. THE GRADE STUDY RESEARCH GROUP. Rationale and Design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2013;36:2254-61
  59. Del Prato S, Foley JE, Kothny W, Kozlovski P, Stumvoll M, Paldánius PM, Matthews DR. Study to determine the durability of glycaemic control with early treatment with a vildagliptin–metformin combination regimen vs. standard-of-care metformin monotherapy—the VERIFY trial: a randomized double-blind trial. Diabet. Med. 2014; 31:1178–84



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