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

1. Authors:
Ana Luísa Caires de Souza
Francisco de Assis Acurcio
Augusto Afonso Guerra Júnior
Renata Cristina Rezende Macedo do Nascimento
Leonardo Maurício Diniz

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. 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. 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.

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 Manager
Keywords
 Portuguese, English, Spanish.
Health Condition Intervention Study Type
T1DM Glargine insulin, NPH insulin, Regular Efficacy
Glycated hemoglobin insulin, Animal NPH Effectiveness
Hypoglycemia insulin, Recombinant NPH Cost effectiveness
Diabetes complications insulin, Animal regular
insulin, Recombinant regular insulin

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 for
comparison and discussion of results.

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. Schematic presentation of the articles included and excluded in the systematic review
Studies initially identified in the search:
803
Excluded abstracts: 79 Excluded titles: 666
Reasons Reasons
Not performed in humans: 6 Not performed in humans: 9
Not related to T1DM: 4 Not related to T1DM: 108
Included titles: 137
Not presenting comparative Not presenting comparative
results regarding the efficacy/ results regarding the efficacy/
effectiveness of the studied drug: effectiveness of the studied drug:
64 546
Not presenting at least one of the Not presenting at least one of the
outcome measures of outcome measures of
efficacy 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. Modified Jadad Scale
Intention to Treat
Randomisation
Randomisation
Randomisation
Inappropriate
Appropriate
Appropriate
Withdrawal
Dropout/
Analysis
Blinding
Blinding
Score
Article
Rosenstock et al., 200017 1 0 0 0 0 1 1 3
Raskin et al., 200015 1 1 0 0 0 1 1 4
Pieber et al., 200013 1 0 0 0 0 0 0 1
Schober et al., 200218 1 0 0 0 0 1 1 3
Doyle et al., 20045 1 1 0 0 0 1 1 4
Chatterjee et al., 20072 1 1 0 0 0 1 0 3
Chase et al., 20081 1 0 0 0 0 1 1 3
White 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. 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. 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. 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.  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. 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.

15. REFERENCES
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comparison with insulin aspart in a basal bolus regimen in type 1 diabetes--the glargine and aspart study (GLASS).
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18. THANK YOU!
Ana Luísa Caires
analuisacaires@gmail.com