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Disinvestment. Ana Luísa Caires de Souza

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SIX YEARS OF GLARGINE FINANCED BY THE MINAS GERAIS STATE GOVERNMENT, BRAZIL: SHOULD THE GOVERNMENT DISINVEST?

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Disinvestment. Ana Luísa Caires de Souza

  1. 1. Authors:Ana Luísa Caires de SouzaFrancisco de Assis AcurcioAugusto Afonso Guerra JúniorRenata Cristina Rezende Macedo do NascimentoLeonardo Maurício Diniz
  2. 2.  Insulin analogues: safety, efficacy and comfort Glargine • 2000 EMEA • 2003 ANVISA Expectation Hypoglycaemic episodes Marketing Judicialization Medicines List Comfort strategy SES/MG/2005 Administrative requests: 2,632 Expenses of Minas Gerais State Treasury with glargine grew an average of 291% per year, reaching almost USD 6 million/2011.
  3. 3. Glargine expenses in Minas Gerais State, Brazil (2007-2011) Costs: Glargine > 536% NPH 2009: Glargine and cancer Systematic Review: Efficacy and safety of glargine in T1DM.
  4. 4. OBJECTIVETo assess the efficacy and the safety of glargine in order to evaluate thepertinence of maintenance the drug on the list of SUS from Minas GeraisState in Brazil.
  5. 5. Search  MEDLINE;  Latin American and Caribbean Centre on Health Sciences Information;  Cochrane Controlled Trials Databases ;  National Health Service (NHS) Centre for Reviews and Dissemination.Software  Reference ManagerKeywords  Portuguese, English, Spanish.Health Condition Intervention Study TypeT1DM Glargine insulin, NPH insulin, Regular EfficacyGlycated hemoglobin insulin, Animal NPH EffectivenessHypoglycemia insulin, Recombinant NPH Cost effectivenessDiabetes complications insulin, Animal regular insulin, Recombinant regular insulin
  6. 6. Inclusion Criteria  Intervention: glargine monotherapy or combination regimens with other insulins. Exclusion Criterias  languages other than English, Portuguese or Spanish;  not performed in human;  unrelated to T1DM;  Not present at least one of the outcome measures of efficacy or safety.Systematic Reviews of Clinical Trials identified in the search process were used forcomparison and discussion of results.
  7. 7. Titles and abstracts analysis  2 reviewers;  Discordant: 3rd reviewer.Outcomes measure  blood concentration of glycated hemoglobin;  measures of glucose;  episodes of hypoglycemia;  reduction of microvascular and macrovascular events;  adverse effects.Assessment of risk of bias  Modified Jadad Scale (JADAD, 1996)
  8. 8. Schematic presentation of the articles included and excluded in the systematic review Studies initially identified in the search: 803Excluded abstracts: 79 Excluded titles: 666Reasons ReasonsNot performed in humans: 6 Not performed in humans: 9Not related to T1DM: 4 Not related to T1DM: 108 Included titles: 137Not presenting comparative Not presenting comparativeresults regarding the efficacy/ results regarding the efficacy/effectiveness of the studied drug: effectiveness of the studied drug:64 546Not presenting at least one of the Not presenting at least one of theoutcome measures of outcome measures ofefficacy and/or efficacy and/or safety consideration:safety consideration: 5 3 Studies included in the final review: 58 Observational studies: 50 Clinical trials: 8
  9. 9. Modified Jadad Scale Intention to Treat Randomisation Randomisation Randomisation Inappropriate Appropriate Appropriate Withdrawal Dropout/ Analysis Blinding Blinding Score ArticleRosenstock et al., 200017 1 0 0 0 0 1 1 3Raskin et al., 200015 1 1 0 0 0 1 1 4Pieber et al., 200013 1 0 0 0 0 0 0 1Schober et al., 200218 1 0 0 0 0 1 1 3Doyle et al., 20045 1 1 0 0 0 1 1 4Chatterjee et al., 20072 1 1 0 0 0 1 0 3Chase et al., 20081 1 0 0 0 0 1 1 3White et al., 200922 1 0 0 0 0 1 0 2  Mean score: 2,87  None estudy with scored 5-6  No double-blind study  Conflict of interest: 7 trials
  10. 10. Characteristics of the selected clinical trials 7 Glargine x NPH, 1 Glargine x Aspart , 0 Glargine x Detemir; Median participants: 168 (<32 e >619); Median follow-up: 4 months (1 month, 2 years); Basal therapy: glargine 1x/day x NPH 1x or 2x/day; Prandial component: lispro, aspart or regular.
  11. 11. Characteristics of participants and interventions in selected clinical trials 1591 participants Gender • female: 56,7% Age • Minimum age: 5 years • Maximum age: 80 years Associated comorbidities were investigated but were not discussed in the selected studies. BMI: there were no changes (Chase et al., 2008; Doyle et al., 2004; and Chatterjee et al., 2007)
  12. 12. Advantages in the reduction of hypoglycemia and Glycated Hemoglobin (HbA1c) Statistically significant Statistically significant advantage in the Article advantage in the reduction reduction of episodes of of HbA1c hypoglycaemia Rosenstock et al., 200017 NPH * Raskin et al., 200015 NS NS Pieber et al., 200013 Glargine Glargine Schober et al., 200218 ** NS Doyle et al., 20045 ** Aspart Chatterjee et al., 20072 NS Glargine Chase et al., 20081 Glargine NS White et al., 200922 * NS * Not assessed in the study. NS: No statistically significant advantage found. **It was not presented p-value.
  13. 13.  The trials did not show relevant differences in the adverse effects. Chronic complications of diabetes, mitogenic effects attributed to glargine and other possible long-term undesirable effects; Cost-benefit ratio of glargine does not support its use, particularly in poor countries, although it might be indicated in specific conditions when there are sufficient resources (Gill et al, 2010). In Brazil, the cost of treating with glargine is remarkably higher than that with NPH insulin; The cost-effectiveness ratio seems to favour the use of the NPH. Manufacturer of glargine should present the Unified Health System (SUS) managers reasons justifying the higher cost of this drug, including novel evidence and more precise measurements of its cost-effectiveness and impact on quality-adjusted life years (QALYs).
  14. 14. The present systematic review did not find advantages of the treatment withglargine compared to other investigated insulin formulations when glycemiccontrol and the frequency and the severity of episodes of hypoglycemia wereanalyzed together. Furthermore, the available evidence is weak and is not enough.For these reasons, the SUS State Manager was advised to disinvest or torenegotiate the price of glargine with its manufacturer.
  15. 15. REFERENCES1. Chase HP, Arslanian S, Neil HW, Tamborlane WV. Insulin Glargine Versus Intermediate-Acting Insulin as the Basal Component of Multiple Daily Injection Regimens for Adolescents with Type 1 Diabetes mellitus. J Pediatr. Abr. 2008; 153:547-553.2. Chatterjee S, Jarvis-Kay J, Rengarajan T, Lawrence IG, McNally PG, Davies MJ. Glargine versus NPH insulin: efficacy in comparison with insulin aspart in a basal bolus regimen in type 1 diabetes--the glargine and aspart study (GLASS). Diabetes Res Clin Pract. Ago. 2007; 77(2):215-222.3. Cohen D, Carter P. How small changes led to big profits for insulin manufacturers. BMJ. 2010; 341:c7139.4. Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009; 52:1766-1777.5. Doyle EA, Weinzimer SA, Steffen AT, Ahern JA, Vincent M, Tamborlane WV. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care. Jul. 2004; 27(7):1554-1558.6. Gill GV, Yudkin JS, Keen H, Beran D. The insulin dilemma in resource-limited countries. A way forward? Diabetologia. 2010.7. Hemkens LG, Grouven U, Bender R, Günster C, Gutschmidt S, Selke G W, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. Set. 2009; 52(9): 1732– 1744.8. Institut für qualität und Wirtschaftlichkeit im Gesundheitswesen [Institute of Quality and Efficiency in Health Care]. Long-acting insulin analogues in the treatment of diabetes mellitus type 1 (2010). Http://www.iqwig.de/download/A05-01_Executive-Summary_Long- acting_insulin_analogues_in_diabetes_mellitus_type_1.pdf (Accessed Sep 2010).
  16. 16. REFERENCES9. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996 Feb;17(1):1-12.10. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden. Diabetologia. Set. 2009; 52(9):1745- 54. Epub 2009 Jul 9.11. Machado MAA, Acurcio FA, Brandão CMR, Faleiros DR, Guerra Júnior AA, Cherchiglia ML, Andrade EIG. Judicialização do acesso a medicamentos no Estado de Minas Gerais, Brasil [Judicialisation of access to medicines in the State of Minas Gerais, Brazil]. Rev Saúde Pública. 2011 Jun;45(3):590-8. Epub 2011 Apr 1.12. Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes: a meta-analysis. Diabetes Obes Metab. Abr. 2009; 11(4):372-8.13. Pieber TR, Eugene-Jolchine I, Derobert E. Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes. Diabetes Care. Fev. 2000; 23(2):157-162.14. Plank J, Siebenhofer A, Berghold A, Jeitler K, Horvath K, Mrak P, et al. Systematic Review and Meta-analysis of Short-Acting Insulin Analogues in Patients With Diabetes mellitus. Arch Intern Med. Jun. 2005; 165(12):1325- 1444.15. Raskin P, Klaff L, Bergenstal R, Halle JP, Donley D, Mecca T. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care. Nov. 2000; 23(11):1666-1671.16. Rede Brasileira de Avaliação de Tecnologia em Saúde [Brazilian Network for Health Technology Assessment]. Boletim Brasileiro de Avaliação de Tecnologias em Saúde [Brazilian Bulletin of Health Technology Assessment]. Insulina Glargina e Insulina Detemir no Controle da Diabetes Mellitus Tipo 1 (2010) [Glargine insulin and detemir insulin: the control of type 1 diabetes mellitus (2010)] http://bvsms.saude.gov.br/bvs/ct/pdf/brats2010_n13.pdf (Accessed Feb 2011).
  17. 17. REFERENCES16. Rede Brasileira de Avaliação de Tecnologia em Saúde [Brazilian Network for Health Technology Assessment]. Boletim Brasileiro de Avaliação de Tecnologias em Saúde [Brazilian Bulletin of Health Technology Assessment]. Insulina Glargina e Insulina Detemir no Controle da Diabetes Mellitus Tipo 1 (2010) [Glargine insulin and detemir insulin: the control of type 1 diabetes mellitus (2010)] http://bvsms.saude.gov.br/bvs/ct/pdf/brats2010_n13.pdf (Accessed Feb 2011).17. Rosenstock J, Park G, Zimmerman J. Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. U.S. Insulin Glargine (HOE 901) Type 1. Diabetes Care. Ago. 2000; 23(8):1137-1142.18. Schober E, Schoenle E, Van DJ, Wernicke-Panten K. Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes mellitus. J Pediatr Endocrinol Metab. Abr. 2002; 15(4):369-376.19. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ. Fev. 2009; 180 (4).20. Smith U, Gale EAM. Does diabetes therapy influence the risk of cancer? Diabetologia. 2009; 52:1699–1708.21. Vardi M, Eyal J, Asaph N, Haim B. Intermediate acting versus long acting insulin for type 1 diabetes mellitus. Cochrane Database of Systematic Reviews. 2008.22. White NH, Chase HP, Arslanian S, Tamborlane WV. Comparison of glycaemic variability associated with insulin glargine and intermediate-acting insulin when used as the basal component of multiple daily. Diabetes Care. Mar. 2009; 32 (3):387-393.23. World Health Organization. 18th Expert Committee on the selection and use of Essential Medicines. Review of the Evidence Comparing Insulin (Human or Animal) with Analogue Insulins (2011). http://www.who.int/selection_medicines/committees/expert/18/applications/Insulin_review.pdf (Accessed Feb 2011).24. Zib I, Raskin P. Novel insulin analogues and its mitogenic potential. Diabetes, Obesity and Metabolism. 2006; 8:611–620.
  18. 18. THANK YOU! Ana Luísa Cairesanaluisacaires@gmail.com

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