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

GOVERNMENT DISINVEST?

Authors:Ana Luísa Caires de SouzaFrancisco de Assis AcurcioAugusto Afonso Guerra JúniorRenata Cristina Rezende Macedo do NascimentoLeonardo Maurício Diniz

Insulin analogues: safety, efficacy and comfort

Glargine

• 2000 EMEA• 2003 ANVISA

Expectation

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.

BACKGROUND

Hypoglycaemic episodesComfort

Marketingstrategy

Judicialization Medicines List SES/MG/2005

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.

BACKGROUND

OBJECTIVE

To assess the efficacy and the safety of glargine in order to evaluate the pertinence of maintenance the drug on the list of SUS from Minas Gerais State in Brazil.

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 Manager

Keywords Portuguese, English, Spanish.

METHODS

Health Condition

T1DMGlycated hemoglobinHypoglycemiaDiabetes complications

Intervention

Glargine insulin, NPH insulin, Regular insulin, Animal NPH insulin, Recombinant NPH insulin, Animal regular insulin, Recombinant regular insulin

Study Type

Efficacy Effectiveness Cost effectiveness

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 for comparison and discussion of results.

METHODS

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)

METHODS

RESULTSSchematic presentation of the articles included and excluded in the systematic review

Studies initially identified in the search: 803

Included titles: 137

Excluded titles: 666

Reasons

Not performed in humans: 9

Not related to T1DM: 108

Not presenting comparative results regarding the efficacy/ effectiveness of the studied drug: 546

Not presenting at least one of the outcome measures of efficacy and/or safety consideration: 3

Studies included in the final review: 58 Observational studies: 50

Clinical trials: 8

Excluded abstracts: 79

Reasons

Not performed in humans: 6

Not related to T1DM: 4

Not presenting comparative results regarding the efficacy/ effectiveness of the studied drug: 64

Not presenting at least one of the outcome measures of efficacy and/or safety consideration: 5

RESULTS/DISCUSSION

Mean score: 2,87 None estudy with scored 5-6 No double-blind study Conflict of interest: 7 trials

Modified Jadad Scale

ArticleRandomisatio

n

Appropriate

Randomisatio

n

Inappropriate Randomisatio

n

Blinding

Appropriate

Blinding

Dropout/

Withdrawal

Intention to Treat

Analysis

Score

Rosenstock 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

RESULTS/DISCUSSION

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.

RESULTS/DISCUSSION

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)

RESULTS/DISCUSSION

Advantages in the reduction of hypoglycemia and Glycated Hemoglobin (HbA1c)

Article

Statistically significant advantage in the

reduction of episodes of hypoglycaemia

Statistically significant advantage in the reduction

of HbA1c

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.

RESULTS/DISCUSSION 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).

The present systematic review did not find advantages of the treatment with

glargine compared to other investigated insulin formulations when glycemic

control and the frequency and the severity of episodes of hypoglycemia were

analyzed together. Furthermore, the available evidence is weak and is not enough.

For these reasons, the SUS State Manager was advised to disinvest or to

renegotiate the price of glargine with its manufacturer.

CONCLUSION

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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).

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THANK YOU!

Ana Luísa Cairesanaluisacaires@gmail.com