Efetividade dos análogos da insulina comparados às insulinas humanas em gestantes com diabetes mellitus: Revisão sistemática com metanálise

Santos, Leyna Leite; Santos, Jamilly Leite; Barbosa, Luciano Timbó; Silva, Ivan do Nascimento da; Sousa-Rodrigues, Célio Fernando de; Barbosa, Fabiano Timbó

doi:10.1055/s-0038-1676510

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Review Article • Rev. Bras. Ginecol. Obstet. 41 (02) • Fev 2019 • https://doi.org/10.1055/s-0038-1676510 copiar

Efetividade dos análogos da insulina comparados às insulinas humanas em gestantes com diabetes mellitus: Revisão sistemática com metanálise

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Diabetes durante a gestação tem sido relacionado a desfechos materno-fetais desfavoráveis. As insulinas humanas são a primeira escolha medicamentosa, devido à comprovada segurança no seu uso. Entretanto, ainda há questionamentos sobre o uso dos análogos da insulina na gestação. O objetivo do presente estudo foi determinar a efetividade dos análogos da insulina comparados às insulinas humanas no tratamento de gestantes com diabetes por meio de uma revisão sistemática com metanálise. A busca compreendeu desde o início de cada base de dados até julho de 2017, e foi realizada nos seguintes bancos de dados: MEDLINE, CINAHL, EMBASE, ISI Web of Science, LILACS, Scopus, SIGLE e Google Scholar. Selecionamos 29 artigos originais, sendo 11 ensaios clínicos randomizados e 18 estudos observacionais. Exploramos dados de 6.382 participantes. Todos os artigos foram classificados como sendo de intermediário a alto risco de viés. A variável que demonstrou resultado favorável ao uso dos análogos da insulina foi idade gestacional, com uma diferençamédia de - 0.26 (95% índice de confiança [IC]: 0.03-0.49; p = 0.02), porém com heterogeneidade significativa (teste de Higgins [I2] = 38%; teste do qui quadrado [χ2] =16.24; graus de liberdade [GL] =10; p = 0.09). Esse resultado, na prática clínica, não compromete o bem-estar fetal, uma vez que todos os bebês nasceram a termo. Houve viés de publicação nas variáveis idade gestacional e peso neonatal. Até o momento, as evidências analisadas possuem um risco de viés moderado a elevado e não permitem concluir que os análogos da insulina sejam mais efetivos em comparação às insulinas humanas para tratar gestantes diabéticas.

Palavras-chave:
diabetes mellitus; diabetes gestacional; insulina humana; análogos da insulina; gestação

Databases	Search Strategy
PUBMED	diabetes, gestational [MeSH Terms] OR (diabetes [All Fields] AND gestational [All Fields]) OR gestational diabetes [All Fields] OR (gestational [All Fields] AND diabetes [All Fields]) AND insulin, isophane [MeSH Terms] OR (insulin [All Fields] AND isophane [All Fields]) OR isophane insulin [All Fields] OR (nph [All Fields] AND insulin [All Fields]) OR nph insulin [All Fields]
EMBASE	NPH insulin OR glargine OR lispro OR aspart AND gestational diabetes
LILACS	(gestational diabetes)
CINAHL	NPH insulin OR glargine OR lispro OR aspart AND gestational diabetes
SCOPUS	(diabetes) AND (gestation) AND (insulin) OR (nph) OR (glargine) OR (lispro) OR (aspart) OR (regular AND insulin)
ISI Web of Science	NPH insulin OR Glargine OR Lispro OR Aspart AND Gestational Diabetes
GOOGLE SCHOLAR	pregnancy,, insulin
SIGLE	(gestational diabetes)

Author, year of publication	Type of study	Pregnant women treated with insulin	Human insulin	Insulin analog	Type of Diabetes	Conclusions
Aydin, 2008¹²12 Aydin Y, Berker D, Direktör N, et al. Is insulin lispro safe in pregnant women: Does it cause any adverse outcomes on infants or mothers? Diabetes Res Clin Pract 2008;80(03):444-448. Doi: 10.1016/j.diabres.2008.02.004 https://doi.org/10.1016/j.diabres.2008.0...	Observational	86	Regular	Lispro	Previous DM + GDM	Congenital anomalies were more frequent with lispro and similar with regular insulin, but HbA1c was lower. Other outcomes were similar.
Balaji, 2012¹³13 Balaji V, Balaji MS, Alexander C, et al. Premixed insulin aspart 30 (BIAsp 30) versus premixed human insulin 30 (BHI 30) in gestational diabetes mellitus: a randomized open-label controlled study. Gynecol Endocrinol 2012;28(07):529-532. Doi: 10.3109/ 09513590.2011.650661	RCT	320	Premixed human 30(BIH 30)	Premixed aspart 30 (BIAsp 30)	GDM	BIAsp 30 was not inferior than BIH 30, with comparable fetal results. Based on final dosages, BIAsp 30 may offer a better potential of treatment.
Banerjee, 2009¹⁴14 Banerjee M, Bhattacharya A, Hughes SM, Vice PA. Efficacy of insulin lispro in pregnancies complicated with pregestational diabetes mellitus. Pract Diabetes Int 2009;26:366-370. Doi: 10.1002/pdi.1423 https://doi.org/10.1002/pdi.1423...	Observational	153	Regular	Lispro	Previous DM	Lispro provides a better glycemic control and does not adversely affect maternal and fetal results.
Bhattacharyya, 2001¹⁵15 Bhattacharyya A, Brown S, Hughes S, Vice PA. Insulin lispro and regular insulin in pregnancy. QJM 2001;94(05):255-260	Observational	220	Regular	Lispro	Previous DM + GDM	No increase in the adverse results was found with Lispro insulin. The satisfaction of the patients favored Lispro.
Chico, 2010¹⁶16 Chico A, Saigi I, García-Patterson A, et al. Glycemic control and perinatal outcomes of pregnancies complicated by type 1 diabetes: influence of continuous subcutaneous insulin infusion and lispro insulin. Diabetes Technol Ther 2010;12(12):937-945. Doi: 10.1089/dia.2010.0111 https://doi.org/10.1089/dia.2010.0111...	Observational	315	Regular	Lispro	Previous DM	Lispro was independently associated with less hypoglycemic comas. Its impact on the fetus was favorable or unfavorable, depending on the specific result.
Chico, 2016¹⁷17 Chico A, Herranz L, Corcoy R, et al; GEDE (Group of Diabetes and Pregnancy of the Spanish Diabetes Association). Glycemic control and maternal and fetal outcomes in pregnant women with type 1 diabetes according to the type of basal insulin. Eur J Obstet Gynecol Reprod Biol 2016;206:84-91. Doi: 10.1016/j.ejogrb.2016.07.490 https://doi.org/10.1016/j.ejogrb.2016.07...	Observational	1,210	NPH	Glargina	Previous DM	The type of base insulin was independently associated with metabolic outcomes and fetal endpoints.
Colatrella, 2013¹⁸18 Colatrella A, Visalli N, Abbruzzese S, Leotta S, Bongiovanni M, Napoli A. Visalli N, Abbruzzese S, Leotta S, BongiovanniM, Napoli A. Comparison of insulin lispro protamine suspension with NPH insulin in pregnant women with type 2 and gestational diabetes mellitus: maternal and perinatal outcomes. Int J Endocrinol 2013; 2013:151975. Doi: 10.1155/2013/151975 https://doi.org/10.1155/2013/151975...	Observational	89	NPH	Insulin lispro protamine	Previous DM + GDM	The result with Lispro Protamine insulin was similar to NPH, except for a smaller need for insulin.
Cypryk, 2004¹⁹19 Cypryk K, Sobczak M, Pertynska-Marczewska M, et al. Pregnancy complications and perinatal outcome in diabetic women treated with Humalog (insulin lispro) or regular human insulin during pregnancy. Med Sci Monit 2004;10(02):PI29-PI32	Observational	71	Regular	Lispro	Previous DM	The course of pregnancy and perinatal results were comparable. Humalog seems to be a safe alternative to human insulin.
Dalfra, 2015²⁰20 Dalfrà MG, Soldato A, Moghetti P, et al. Diabetic pregnancy outcomes in mothers treated with basal insulin lispro protamine suspension or NPH insulin: a multicenter retrospective Italian study. J Matern Fetal NeonatalMed 2016;29(07):1061-1065. Doi: 10.3109/14767058.2015.1033619 https://doi.org/10.3109/14767058.2015.10...	Observational	933	NPH	Insulin lispro protamine	Previous DM + GDM	The association of ILPS with fast action analogs during pregnancy is safe regarding maternal and fetal results.
Durnwald, 2008²¹21 Durnwald CP, Landon MB. A comparison of lispro and regular insulin for the management of type 1 and type 2 diabetes in pregnancy. J Matern Fetal Neonatal Med 2008;21(05):309-313. Doi: 10.1080/14767050802022797 https://doi.org/10.1080/1476705080202279...	Observational	107	Regular	Lispro	Previous DM	Lispro showed a better glycemic control and a smaller need for total insulin during pregnancy. Perinatal results were similar.
Egerman, 2009²²22 Egerman RS, Ramsey RD, Kao LW, et al. Perinatal outcomes in pregnancies managed with antenatal insulin glargine. Am J Perinatol 2009;26(08):591-595. Doi: 10.1055/s-0029-1220782 https://doi.org/10.1055/s-0029-1220782...	Observational	114	NPH	Glargine	Previous DM + GDM	Neonatal or maternal adverse effects were not observed with the use of Glargine insulin.
Fang, 2009²³23 Fang YM, MacKeen D, Egan JF, Zelop CM. Insulin glargine compared with Neutral Protamine Hagedorn insulin in the treatment of pregnant diabetics. J Matern Fetal Neonatal Med 2009;22(03): 249-253. Doi: 10.1080/14767050802638170 https://doi.org/10.1080/1476705080263817...	Observational	112	NPH	Glargine	Previous DM + GDM	Glargine is not associated with the increase of maternal and neonatal morbidity. On previous DM, Glargine was associated with less macrosomia, hypoglycemia, and neonatal hyperbilirubinemia.
García-Dominguez, 2011²⁴24 García-Domínguez M, Herranz L, Hillman N, et al. Use of insulin lispro during pregnancy in women with pregestational diabetes mellitus. Med Clin (Barc) 2011;137(13):581-586. Doi: 10.1016/j. medcli.2010.11.021 https://doi.org/10.1016/j...	Observational	351	Regular	Lispro and Aspart	Previous DM	Analogs are safe on previous DM. Glycemic control and maternal and fetal results were similar. Analogs significantly reduced severe hypoglycemia on the mother.
Heller, 2010²⁵25 Heller S, Damm P, Mersebach H, et al. Hypoglycemia in type 1 diabetic pregnancy: role of preconception insulin aspart treatment in a randomized study. Diabetes Care 2010;33(03): 473-477. Doi: 10.2337/dc09-1605 https://doi.org/10.2337/dc09-1605...	RCT	223	Regular	Aspart	Previous DM	The beginning of treatment with insulin analogs at preconception, instead of at the beginning of pregnancy, may result in a smaller risk of severe hypoglycemia in women with DM1.
Herrera, 2015²⁶26 Herrera KM, Rosenn BM, Foroutan J, et al. Randomized controlled trial of insulin detemir versus NPH for the treatment of pregnant women with diabetes. Am J Obstet Gynecol 2015;213(03):426. e1-426.e7. Doi: 10.1016/j.ajog.2015.06.010 https://doi.org/10.1016/j.ajog.2015.06.0...	RCT	87	NPH	Detemir	Previous DM + GDM	Detemir is not inferior to NPH for the treatment of GDM and of DM2 during pregnancy.
Hod, 2008²⁷27 Hod M, Damm P, Kaaja R, et al; Insulin Aspart Pregnancy Study Group. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol 2008;198(02):186. e1-186.e7. Doi: 10.1016/j.ajog.2007.08.005 https://doi.org/10.1016/j.ajog.2007.08.0...	RCT	268	Regular	Aspart	Previous DM	Fetal outcome using Aspart was comparable to human insulin with a trend to less fetal losses and premature births.
Hod, 2014²⁸28 Hod M, Mathiesen ER, Jovanovic L, et al. A randomized trial comparing perinatal outcomes using insulin detemir or neutral protamine Hagedorn in type 1 diabetes. J Matern Fetal Neonatal Med 2014;27(01):7-13. Doi: 10.3109/14767058.2013.799650 https://doi.org/10.3109/14767058.2013.79...	RCT	310	NPH	Detemir	Previous DM	Detemir is as well tolerated as NPH regarding perinatal results in pregnant women with DM1, with no safety issues.
Imbergamo, 2008²⁹29 Imbergamo MP, Amato MC, Sciortino G, et al. Use of glargine in pregnant women with type 1 diabetes mellitus: a case-control study. Clin Ther 2008;30(08):1476-1484. Doi: 10.1016/j.clinthera.2008.08.013 https://doi.org/10.1016/j.clinthera.2008...	Observational	30	NPH	Glargine	Previous DM	There was no significant difference in the glycemic control between glargine and NPH insuline. Use of glargine was associated with a significantly higher frequency of femoral length < 50th centile.
Jovanovic, 1999³⁰30 Jovanovic L, Ilic S, Pettitt DJ, et al. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care 1999;22(09):1422-1427	RCT	42	Regular	Lispro	GDM	Lispro insulin may be considered as a treatment option for women with GDM.
Lapolla, 2008³¹31 Lapolla A, DalfràMG, Spezia R, et al. Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience. Acta Diabetol 2008;45(01):61-66. Doi: 10.1007/s00592-008-0024-0 https://doi.org/10.1007/s00592-008-0024-...	Observational	370	Regular	Lispro	Previous DM	There was a trend for less episodes of hypoglycemia in the Lispro group and also a significant reduction on HbA1c during the first trimester. The congenital malformation rates were similar.
Loukovaara, 2003³²32 Loukovaara S, Immonen I, Teramo KA, Kaaja R. Progression of retinopathy during pregnancy in type 1 diabetic women treated with insulin lispro. Diabetes Care 2003;26(04):1193-1198. Doi: 10.2337/diacare.26.4.1193 https://doi.org/10.2337/diacare.26.4.119...	Observational	69	Regular	Lispro	Previous DM	Lispro insulin improves the glycemic control during pregnancy with no adverse impact on the progression of diabetic retinopathy.
Mathiesen, 2007³³33 Mathiesen ER, Kinsley B, Amiel SA, et al; Insulin Aspart Pregnancy Study Group. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 2007;30(04):771-776. Doi: 10.2337/dc06-1887 https://doi.org/10.2337/dc06-1887...	RCT	322	Regular	Aspart	Previous DM	Aspart is as safe and effective as human insulin when in base therapy with NPH insulin and may offer some benefits for postprandial glycemic control and for the prevention of severe hypoglycemia.
Mathiesen, 2012³⁴34 Mathiesen ER, Hod M, Ivanisevic M, et al; Detemir in Pregnancy Study Group. Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care 2012;35(10):2012-2017. Doi: 10.2337/dc11-2264 https://doi.org/10.2337/dc11-2264...	RCT	310	NPH	Detemir	Previous DM	Treatment with detemir resulted in lower FPG and noninferior A1C in late pregnancy compared with NPH insulin. Rates of hypoglycemia were comparable.
Negrato, 2010³⁵35 Negrato CA, Montenegro RM Jr, Mattar R, et al. Dysglycemias in pregnancy: from diagnosis to treatment. Brazilian consensus statement. Diabetol Metab Syndr 2010;2:27. Doi: 10.1186/1758-5996-2-27 https://doi.org/10.1186/1758-5996-2-27...	Observational	138	NPH	Glargine	Previous DM + GDM	The use of glargine since preconception until birth showed safety because it is associated with a reduction in adverse maternal and neonatal outcomes when compared with NPH.
Persson, 2002³⁶36 Persson B, Swahn ML, Hjertberg R, et al. Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus. Diabetes Res Clin Pract 2002;58(02):115-121	RCT	33	Regular	Lispro	Previous DM	It is possible to obtain a proper glycemic control with Lispro, as well as with regular insulin, in pregnant women with DM1.
Pettit, 2007³⁷37 Pettitt DJ, Ospina P, Howard C, Zisser H, Jovanovic L. Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mellitus. Diabet Med 2007;24(10):1129-1135. Doi: 10.1111/ j.1464-5491.2007.02247.x	RCT	27	Regular	Aspart	GDM	Aspart was more effective than regular insulin in the reduction of postprandial glycemia. General safety and effectiveness were similar.
Price, 2007³⁸38 Price N, Bartlett C, Gillmer M. Use of insulin glargine during pregnancy: a case-control pilot study. BJOG 2007;114(04): 453-457. Doi: 10.1111/j.1471-0528.2006.01216.x https://doi.org/10.1111/j.1471-0528.2006...	Observational	64	NPH	Glargine	Previous DM + GDM	The use of Glargine during pregnancy may not be associated with an increase of macrosomia and of neonatal morbidity.
Pöyhönen-Alho, 2007³⁹39 Pöyhönen-Alho M, Rönnemaa T, Saltevo J, Ekblad U, Kaaja RJ. Use of insulin glargine during pregnancy. Acta Obstet Gynecol Scand 2007;86(10):1171-1174. Doi: 10.1080/00016340701515282 https://doi.org/10.1080/0001634070151528...	Observational	91	NPH	Glargine	Previous DM	Glargine is comparable to NPH on DM1. No adverse effect was associated with Glargine on the moment of conception and during pregnancy.
Vellanki, 2016⁴⁰40 Vellanki P, Umpierrez G. Detemir is non-inferior to NPH insulin in women with pregestational type 2 diabetes and gestational diabetes mellitus. Evid Based Med 2016;21(03):104-105. Doi: 10.1136/ebmed-2015-110309 https://doi.org/10.1136/ebmed-2015-11030...	RCT	87	NPH	Detemir	Previous DM + GDM	Detemir is effective and did not increase the risk of fetal or maternal adverse outcomes on GDM and previous DM.

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[1] Address for correspondence
Leyna Leite Santos, Master, Universidade Federal de Alagoas, Rua Escritor Antônio Saturnino de Mendonça Júnior, 57, Jatiúca, 57036-420, Maceió, AL, Brazil (e-mail: leynaleite@yahoo.com.br).