Efficacy and safety of vildagliptin as a second-line therapy vs other oral antidiabetic agents in patients with type 2 diabetes: Czech results within the worldwide prospective cohort EDGE study

Česká verzia

Authors: M. Haluzík ¹ ; V. Veselá ²; J. Gerle ³; M. Brada ⁴; L. Dohnalová ⁵; T. Edelsberger ⁶; J. Houdová ⁷
Authors place of work: III. interní klinika 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Štěpán Svačina, DrSc., MBA ¹; Novartis s. r. o., Praha, vedoucí pracovník MUDr. Richard Vonka ²; Polymedica Praha, vedoucí pracovník MUDr. Jan Gerle ³; Privátní diabetologická ambulance Břeclav, vedoucí pracovník MUDr. Michal Brada ⁴; Interní oddělení Nemocnice České Budějovice, přednosta prim. MUDr. Pavel Havránek ⁵; Privátní diabetologická ambulance Krnov, vedoucí pracovník MUDr. Tomáš Edelsberger ⁶; Diabetologická ambulance Praha, vedoucí pracovník MUDr. Jana Houdová ⁷
Published in the journal: Vnitř Lék 2013; 59(12): 1049-1056
Category: Original Contributions

Summary

Introduction:
Metformin monotherapy is recommended as initial treatment of type 2 diabetes. The selection of optimal second-line therapy that is often necessary due to the progressive nature of the disease is still a subject of ongoing discussions.

Aim of the study:
The aim of the international EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) study was to prospectively compare the efficacy and safety of vildagliptin vs other oral antidiabetic agents in patients with type 2 diabetes not adequately controlled on monotherapy in a real-life clinical setting. In this paper, we present the data of patients participating in the EDGE study in the Czech Republic.

Material and methods:
Patients with type 2 diabetes not adequately controlled on monotherapy were enrolled into the study, and randomised into either the vildagliptin arm or control arm with another OAD at the discretion of the treating physician. Patients with the addition of other incretin-based medications were not enrolled into the study. The efficiency was evaluated as a proportion of patients reaching the combined endpoint of decreasing HbA_1c> 3 mmol/mol without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects during the 12 months of treatment.

Results:
654 patients were enrolled into the study in the Czech Republic. The mean age of the patients when enrolled into the study (vildagliptin group vs control group) was 59.5 ± 10.6 vs 63.7 ± 8.5 years, mean body mass index was 32.4 ± 5.7 vs 31.7 ± 6.5 kg/m², mean HbA_1c was 62 ± 12 vs 64 ± 11 mmol/mol. The probability of reaching the combined primary endpoint (calculated using a binary logistic regression model to calculate the odds ratios with 95% confidence intervals) was higher for vildagliptin regardless of baseline HbA_1c or type of medication added in the control group. Primary endpoint was reached by 60.6 % of patients in the vildagliptin group vs 51.3 % of patients in the control group, odds ratio 1.46 (1.06, 1.99); p< 0.019. The proportion of patients reaching secondary endpoint (HbA_1c< 54 mmol/mol without hypoglycemic event or weight gain ≥ 3 % with baseline glycated hemoglobin > 54 mmol/mol was higher for vildagliptin 45.7 % vs 31.4 % in the control arm, odds ratio 1.84 (1.26, 2.68), p< 0.001. The rate of adverse events was comparable in both groups.

Conclusion:
In a real-life clinical setting, the percentage of patients reaching the combined endpoint of decreasing HbA_1c> 3 mmol/mol, without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects was higher after the addition of vildagliptin as compared to other antidiabetic agents with comparable rate of side effects.

Key words:
type 2 diabetes mellitus – vildagliptin – combination therapy

Zdroje

1. O‘Rahilly S. Science, medicine, and the future. Non-insulin dependent diabetes mellitus: the gathering storm. BMJ 1997; 314: 955–959.

2. CDC Diabetes Cost-effectiveness Group. Cost-effectiveness of intensive glycemic control, intensified hypertension control, and serum cholesterol level reduction for type 2 diabetes. JAMA 2002; 287: 2542–2551.

3. Adler AI, Stevens RJ, Neil A et al. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes care 2002; 25: 894–899.

4. Adler AI, Stratton IM, Neil HA et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412–419.

5. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234.

6. Skyler JS, Bergenstal R, Bonow RO et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 2009; 53: 298–304.

7. Lachin JM, Genuth S, Nathan DM et al. Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial – revisited. Diabetes 2008; 57: 995–1001.

8. 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: 1577-1589.

9. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129–139.

10. Patel A, Chalmers J, Poulter N. ADVANCE: action in diabetes and vascular disease. J Hum Hypertens 2005; 19 (Suppl 1): S27–S32.

11. Turnbull FM, Abraira C, Anderson RJ et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009; 52: 2288–2298.

12. Baldeweg SE, Yudkin JS. Implications of the United Kingdom prospective diabetes study. Prim care 1999; 26: 809–827.

13. Dormandy JA, Charbonel B, Eckland DJ et al. 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.

14. Martin JH, Deacon CF, Gorell MD et al. Incretin-based therapies--review of the physiology, pharmacology and emerging clinical experience. Intern Med J 2011; 41: 299–307.

15. Ahren B et al. Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans. Diabetes Obes Metab 2011; 13: 775–783.

16. Henness S, Keam SJ. Vildagliptin. Drugs 2006; 66: 1989–2001; discussion 2002–2004.

17. Ahren B Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin – diabetes control and potential adverse events. Best Pract Res Clin Endocrinol Metab 2009; 23: 487–498.

18. Foley JE, Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience. Vasc Health Risk Manag 2010; 6: 541–548.

19. Foley JE, Sreenan S. Efficacy and safety comparison between the DPP-4 inhibitor vildagliptin and the sulfonylurea gliclazide after two years of monotherapy in drug-naive patients with type 2 diabetes. Horm Metab Res 2009; 41: 905–909.

20. Abu-Hamdah R, Rabiee A, Meneilly GS et al. Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides. Journal Clin Endocrinol Metab 2009; 94: 1843–1852.

21. Inzucchi SE et al. 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 2012; 35: 1364–1379.

22. Mathieu C, Barnett AH, Brath H et al. Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2 diabetes: A real-life worldwide observational study (EDGE). Int J Clin Pract 2013; 67: 947–956.

23. Ligueros-Saylan M, Foley JE, Schweizer A et al. An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of Phase II and III clinical trials. Diabetes Obes Metab 2010; 12: 495–509.

24. Bell D. Pathophysiology of type 2 diabetes and its relationship to new therapeutic approaches. Diabetes Educ 2000; 26 (Suppl): 4–7.

25. Grant RW, Pirraglia PA, Meigs JB et al. Trends in complexity of diabetes care in the United States from 1991 to 2000. Arch Intern Med 2004; 164: 1134–1139.

26. Škrha J et al. Diabetes mellitus 2002 v České republice – epidemiologická studie. DMEV 2005; 8: 5–12.

27. Peyrot M, Barnett AH, Meneghini LF et al. Factors associated with injection omission/non-adherence in the Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabetes Obes Metab 2012; doi: 10.1111/j.1463–1326.2012.01636.x.

28. Peyrot M, Barnett AH, Meneghini LF et al. Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabet Med 2012; 29: 682–689.

29. Škrha J et al. Diabetologie. Praha: Galén 2009.

30. Blonde L. Current challenges in diabetes management. Clin Cornerstone 2005; 7 (Suppl 3): S6–S17.

31. Mellbin LG, Malmberg K, Waldenstrom A et al. Prognostic implications of hypoglycaemic episodes during hospitalisation for myocardial infarction in patients with type 2 diabetes: a report from the DIGAMI 2 trial. Heart 2009; 95: 721–727.

32. Fonseca V, Baron M, Shao Q et al. Sustained efficacy and reduced hypoglycemia during one year of treatment with vildagliptin added to insulin in patients with type 2 diabetes mellitus. Horm Metab Res 2008; 40: 427–430.

33. Lukashevich V, Del Prato S, Araga M et al: Efficacy and safety of vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea. Diabetes Obes Metab 2013. doi: 10.1111/dom.12229. In press 2013.

34. Schweizer A, Dejager S, Foley JE. Impact of insulin resistance, body mass index, disease duration, and duration of metformin use on the efficacy of vildagliptin. Diabetes Ther 2012; 3:8.

35. Butler PC, Elashoff M, Elashoff R et al. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes care 2013; 36: 2118–2125.

36. Matveyenko AV, Dry S, Cox HI et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes 2009; 58: 1604–1615.

37. Lundkvist J, Berne C, Bolinder B et al. The economic and quality of life impact of hypoglycemia. Eur J Health Econ 2005; 6: 197–202.

38. Dejager S, Schweizer A. Minimizing the risk of hypoglycemia with vildagliptin: Clinical experience, mechanistic basis, and importance in type 2 diabetes management. Diabetes Ther 2011; 2: 51–66.