Original Title: Empagliflozina e dapagliflozina para o tratamento de diabetes mellitus tipo 2

Authors' results and conclusions: The CONITEC’s members present at the 86th Ordinary Meeting, on March 5th, 2020, decided to recommend the incorporation of dapagliflozin in the scope of SUS, for the treatment of type 2 diabetes mellitus, and not to recommend the incorporation of empagliflozin for the treatment of type 2 diabetes mellitus. The Deliberation Records No. 515/2020 and No. 516/2020 were signed.

Authors' recommendations: Scientific evidence: A network meta-analysis showed that SGLT2 inhibitors were superior to sulfonylureas, reducing the risk of major adverse cardiac events (MACE) (risk ratio [RR] 0.49, 95% confidence interval [CI] 0.28-0.83), and severe hypoglycemia (RR 0.23, 95% CI 0.14-0.37). There were no significant differences between SGLT2 inhibitors and sulfonylureas and insulin in the outcomes of glycated hemoglobin, mortality and stroke. In pivotal randomized controlled trials, empagliflozin was superior to standard treatment for the following outcomes: mortality (hazard ratio [HR] 0.68, 95% CI 0.57-0.82, with an absolute reduction of 26 deaths per 1,000); MACE (HR 0,86, 95% CI 0.74-0.99, with an absolute reduction of 16 events per 1,000); cardiovascular death (HR 0.62, 95% CI 0.49-0.77, with absolute reduction of 22 deaths per 1000); hospitalization due to heart failure (HR 0.65, 95% CI 0.50-0.85, with an absolute reduction of 14 events per 1000); and kidney disease (HR 0.54, 95% CI 0.40-0.75). Dapagliflozin was superior to standard treatment for hospitalization due to heart failure (HR 0.73, 95% CI 0.61-0.88), and kidney disease (HR 0.53, 95% CI 0.43-0.66). In these studies, patients aged 65 years or older and/or with high cardiovascular risk had the greatest benefit. With regard to safety, there was a higher risk of amputation, fracture and genital infections in 13 patients treated with canagliflozin, but an increased risk was not associated with empagliflozin and dapagliflozin. Cases of Fournier's gangrene (necrotizing fasciitis) were reported in patients taking a SGLT2 inhibitor between 2013 and 2018 in the United States. However, only 12 cases were detected in hundreds of thousands to millions of patients, which suggests that the incidence is very low and less than the potential clinical benefit. The analysis of systematic reviews showed that there was no significant difference between SGLT2 inhibitors, which were superior to the comparators. Regarding the limitations of the evidence presented, the following were highlighted: (a) studies used heterogeneous treatments as co-interventions and comparators (different standard treatments, including drugs not available in SUS), and different levels of intensification; (b) a part of the patients used insulin as standard therapy, but the benefit in those who did not use it was similar or even higher; (c) studies included patients with and without cardiovascular disease in their samples; (d) network analysis has statistical limitations inherent to the analysis method, such as intransitivity due to the number of comparisons involved. However, it is important to note that there were consistent results in different studies and analyzes, including greater benefit in subgroups that are of greater interest for the Brazilian context of incorporation, such as patients over 65 years of age, with increased cardiovascular risk, and without insulin use. Beside this, the comparators (standard treatment), in general, included a large number of drugs, suggesting a conservative bias. It is also important to highlight that the assessment took into account other classes of hypoglycemic agents, many of which are not available in SUS, and, therefore, were not considered for incorporation. Among such hypoglycemic agents are: dipeptidyl peptidase 4 (DPP-4) inhibitors, alpha-glucosidase inhibitors, meglitinides, and thiazolidinediones, which did not provide a clinically significant benefit compared with the alternatives available in SUS, and showed results inferior to SGLT2 inhibitor; glucagon-like peptide 1 (GLP1) analogues, which showed benefits compared with SUS alternatives, but less than SGLT2 inhibitors, with a higher cost. Analogue insulins were not considered in this Report because they had recently been evaluated by CONITEC. Regarding the SGLT2 inhibitors, in all studies considered, the same representative of the class was used, with no evidence for interchangeability, and parameters for withdrawal, once therapy is started, were not established. Budget impact analysis: An incorporation rate of 40% to 90% over a five-year period (2019-2023) was used in the six different scenarios. In scenario 1, based on diabetic patients over 35 years of age who need first intensification with hypoglycemic agents, the incremental cost was BRL 8,850,080,120. In scenario 2, based on diabetic patients with cardiovascular disease who need first intensification with hypoglycemic agents, the incremental cost was BRL 1,539,144,368. In scenario 3, based on diabetic patients with cardiovascular disease over 65 years of age who need first intensification with hypoglycemic agents, the incremental cost was BRL 738,096,682. In scenario 4, based on diabetic patients over 35 years of age who need second intensification with hypoglycemic agents, the incremental cost was BRL 1,110,650,183. In scenario 5, based on diabetic patients with cardiovascular disease who need second intensification with hypoglycemic agents, the incremental cost was BRL 193,156,553. In scenario 6, based on diabetic patients with cardiovascular disease above 65 years of age who need second intensification with hypoglycemic agents, the incremental cost was BRL 92,628,225. A limitation of this analysis is that it is not possible to estimate the appropriate adoption curve for this technology, which was mitigated by carrying out conservative sensitivity analyses. Finally, considering incorporation into specialized care, it is expected that the budget impact would be less.

Project Status: Completed

URL for project: http://conitec.gov.br/images/Consultas/Relatorios/EN2020/20200915_Report524_EmpagliflozinandDapagliflozin_Type2_DiabetesMellitus.pdf

Year Published: 2020

URL for published report: http://conitec.gov.br/images/Relatorios/2020/Relatorio_524_Empagliflozina_e_dapagliflozina_diabetes_mellitus_tipo_2_FINAL.pdf

URL for additional information: http://conitec.gov.br/recomendation-reports

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Brazil

Organisation Name: National Committee for Technology Incorporation (CONITEC)

Contact Address: Esplanada dos Ministérios, Bl. G, Ed. Sede, 8º andar, CEP: 70058-900

Contact Name: Clarice Moreira Portugal

Contact Email: clarice.portugal@saude.gov.br

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