What are new opportunities for clinical practice the VERIFY study opens and which values for native diabetes patients? Joint conclusion on the advisory board results. November 6, 2019

According to key diabetic studies, the early use of metformin glucose lowering therapy is associated with a reduced risk of developing micro- and, in the long term, 10-year follow-up, macrovascular complications and cardiovascular mortality. Short-term studies results on combined glucose lowering therapy with metformin suggests that combination therapy can have several advantages on the one side from the effectiveness of glycemic control and on another side from positive effect on the development of complications of type 2 diabetes. The question of the start time of combined hypoglycemic therapy remains open. According to the results of recent large-scale studies, real world evidence data, careful glycemic control during the first year from the moment of diagnosis of type 2 diabetes is crucial for further management of the disease and slow the progression of complications.

However, due to the fact that the clinical benefits of early combination therapy were not demonstrated in randomized clinical trials, this approach, despite the theoretical background, was not recommended for widespread use in international guidelines for the treatment diabetes patients. Russian algorithms on the treatment diabetes patients recommend combined glucose lowering therapy at the start of treatment at a HbA1c level of 1% higher than the target.

A 5-year VERIFY study results were demonstrated long-term sustained glycemic control in combination with vildagliptin + metformin prescribed for native diabetes patients with relatively low HbA1c values, as well as the advantages of this approach in comparison with the standard strategy for phased intensification of monotherapy. The results of the VERIFY study provided a wealth of information to discuss early treatment intensification, the clinical benefits of this approach and a possible review of the treatment strategy for native diabetes patients.

diabetes mellitus, vildagliptin, metformin, HbA1c , new onset diabetes mellitus

1. Schwartz SS, Epstein S, Corkey BE, et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema. Diabetes Care. 2016;39(2):179–186. doi: https://doi.org/10.2337/dc15-1585

2. DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes. Diabetes Care. 2013;36(Supplement_2):S127–S138. doi: https://doi.org/10.2337/dcS13-2011

3. Nauck M, Stöckmann F, Ebert R, et al. Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29(1):46–52. doi: https://doi.org/10.1007/BF02427280

4. 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(6):525–536. doi: https://doi.org/10.1016/S2213-8587(15)00482-9

5. Mari A, Sallas WM, He YL, et al. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed b-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab. 2005;90(8):4888–4894. doi: https://doi.org/10.1210/jc.2004-2460

6. Mari A, Scherbaum WA, Nilsson PM, et al. Characterization of the influence of vildagliptin on model-assessed b-cell function in patients with type 2 diabetes and mild hyperglycemia. J Clin Endocrinol Metab. 2008;93(1):103–109. doi: https://doi.org/10.1210/jc.2007-1639

7. Rosenstock J, Foley JE, Rendell M, et al. Effects of the dipeptidyl peptidase-IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance. Diabetes Care. 2008;31(1):30–35. doi: https://doi.org/10.2337/dc07-1616

8. Scherbaum WA, Schweizer A, Mari A, et al. Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. Diabetes, Obes Metab. 2008;10(11):1114–1124. doi: https://doi.org/10.1111/j.1463-1326.2008.00875.x

9. He Y-L, Wang Y, Bullock JM, et al. Pharmacodynamics of Vildagliptin in Patients With Type 2 Diabetes During OGTT. J Clin Pharmacol. 2007;47(5):633–641. doi: https://doi.org/10.1177/0091270006299137

10. Vardarli I, Arndt E, Deacon CF, et al. Effects of Sitagliptin and Metformin Treatment on Incretin Hormone and Insulin Secretory Responses to Oral and "Isoglycemic" Intravenous Glucose. Diabetes. 2014;63(2):663–674. doi: https://doi.org/10.2337/db13-0805

11. Saisho Y. How Can We Develop More Effective Strategies for Type 2 Diabetes Mellitus Prevention? A Paradigm Shift from a Glucose-Centric to a Beta Cell-Centric Concept of Diabetes. EMJ Diabet. 2018;6(1):46–52.

12. 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(9131):837–853.

13. Holman RR, Paul SK, Bethel MA, et al. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med. 2008;359(15):1577–1589. doi: https://doi.org/10.1056/NEJMoa0806470

14. Hoerger TJ, Segel JE, Gregg EW, et al. Is Glycemic Control Improving in U.S. Adults? Diabetes Care. 2008;31(1):81–86. doi: https://doi.org/10.2337/dc07-1572

15. Laiteerapong N, Karter AJ, Moffet HH, et al. Ten-year hemoglobin A1c trajectories and outcomes in type 2 diabetes mellitus: The Diabetes & Aging Study. J Diabetes Complications. 2017;31(1):94–100. doi: https://doi.org/10.1016/j.jdiacomp.2016.07.023

16. Laiteerapong N, Ham SA, Gao Y, et al. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care. 2019;42(3):416–426. doi: https://doi.org/10.2337/dc17-1144

17. Phung OJ, Sobieraj DM, Engel SS, et al. Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes, Obes Metab. 2014;16(5):410–417. doi: https://doi.org/10.1111/dom.12233

18. Matthews DR, Paldánius PM, Proot P, et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet. 2019;394(10208):1519–1529. doi: https://doi.org/10.1016/S0140-6736(19)32131-2