Step-by-step Individual Intensification of Therapy for Type 2 Diabetes Mellitus. What is Further Choice after Metformin? (Literature Review)

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І.V. Pankiv


Metformin — first-line drug for the treatment of diabetes mellitus (DM) type 2, the use of which reduces the progression of carbohydrate metabolism disorders and helps to reduce mortality rates. The progressive course of DM type 2 leads to the fact that patients, in which initial therapy contained only metformin, ultimately required step-by-step addition of other glucose-lowering drugs to achieve and maintain glycemic control. This literature review examines different approaches to step-by-step individual intensification of therapy for DM type 2. The most popular and most studied combination aimed at both defects determining the development of metabolic disorders in DM type 2 (relative insulin deficiency and insulin resistance) is a combination of metformin with sulfonylurea agents. Glimepiride has a unique combination of insulin secretagogue («careful» stimulation) and insulin sensitizing properties at neutral effect on body weight and lower the risk of hypoglycemia. Therefore, glimepiride today is regarded as the best choice in patients with DM type 2 in the presence of cardiovascular risk compared with other sulfonylurea drugs.

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How to Cite
Pankiv І. “Step-by-Step Individual Intensification of Therapy for Type 2 Diabetes Mellitus. What Is Further Choice After Metformin? (Literature Review)”. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), no. 2.66, May 2015, pp. 89-94, doi:10.22141/2224-0721.2.66.2015.75447.
Literature Review


International Diabetes Federation. Diabetes atlas. — 2013. — 6th edition; Available from:

Inzucchi S.E., Bergenstal R.M., Buse J.B. et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) // Diabetes Care. — 2012. — 35. — 1-16. doi:10.2337/dc12-0413.

Reaven G.M. Relationships among insulin resistance, type 2 diabetes, essential hypertension, and cardiovascular disease: similarities and differences // J. Clin. Hypertens. — 2011. — Vol. 13 (4). — P. 238-243.

Алгоритмы специализированной медицинской помощи больным сахарным диабетом / Под ред. И.И. Дедова, М.В. Шестаковой (7-й выпуск) // Сахарный диабет. — 2015. — № 1. — С. 1-112.

Наказ МОЗ України від 21.12.2012 № 1118 «Про затвердження та впровадження медико-технологічних документів зі стандартизації медичної допомоги при цукровому діабеті 2 типу». — Режим доступу до док.:

Полторак В.В., Горшунська М.Ю., Красова Н.С. Адипонектин та цукровий діабет 2-го типу (патогененетичні аспекти як підґрунтя для оптимізації антидіабетичної фармакотерапії) // Міжнародний ендокринологічний журнал. — 2014. — № 5 (61). — С. 95-104.

Amate J., Lopez-Cuadrado T., Almendro N. et al. Effectiveness and safety of glimepiride and iDPP4, associated with metformin in second line pharmacotherapy of type 2 diabetes mellitus: systematic review and meta-analysis // Int. J. Clin. Pract. — 2015 Mar. — 69(3). — 292-304. doi: 10.1111/ijcp.12605. Epub 2015 Feb 16.

Hemmingsen B., Schroll J.B., Lund S.S. et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus // Cochrane Database Syst Rev. — 2013 Apr 30. — 4. — CD009008. doi: 10.1002/14651858.CD009008.pub2.

Rosenstock J., Seman L.J., Jelaska A. et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia // Diabetes Obes Metab. — 2013 Dec. — 15(12). — 1154-60. doi: 10.1111/dom.12185. Epub 2013 Aug 22.

Kaku K., Watada H., Iwamoto Y. et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study // Cardiovasc. Diabetol. — 2014 Mar 2. — 13. — 65. doi: 10.1186/1475-2840-13-65.

Mikhail N. Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes // World J. Diabetes. — 2014 Dec 15. — 5(6). — 854-9. doi: 10.4239/wjd.v5.i6.854.

Taylor S.I., Blau J.E., Rother K.I. Possible adverse effects of SGLT2 inhibitors on bone // Lancet Diabetes Endocrinol. — 2015 Jan. — 3(1). — 8-10. doi: 10.1016/S2213-8587(14)70227-X. Epub 2014 Dec 16.

Williams-Herman D., Engel S.S., Round E. et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes // BMC Endocr. Disord. — 2010. — 10. — 7.

Joly D., Choukroun G., Combe C. et al. Glycemic control according to glomerular filtration rate in patients with type 2 diabetes and overt nephropathy: A prospective observational study // Diabetes Res. Clin. Pract. — 2015 Feb 12. pii: S0168-8227(15)00049-2. doi: 10.1016/j.diabres.2015.01.029. [Epub ahead of print]

Lee E.J., Marcy T.R. The impact of pioglitazone on bladder cancer and cardiovascular events // Consult. Pharm. — 2014. — Vol. 29, № 8. — P. 555-558.

Nyback-Nakell A., Adamson U., Lins P.E., Landtedt-Hallin L. Adding glimepiride to insulin+metformin in type 2 diabetes of more than 10 years’ duration — A randomised , double-blind, placebo-controlled, cross-over study // Diabetes Res. Clin. Pract. — 2014. — Vol. 103. — P. 286-291.

Lee T.M., Chou T.F. Impairment of myocardial protection in type 2 diabetic patients // J. Clin. Endocrinol. Metab. — 2003. — Vol. 88, № 2. — P. 531-537.

Ferdinandy P., Schulz R., Baxter G.F. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning // Pharmacol. Rev. — 2007. — Vol. 59. — P. 418-458.

Zeller M., Danchin N., Simon D. et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction // J. Clin. Endocrinol. Metab. — 2010. — Vol. 95. — P. 4993-5002.

Mannucci E., Monami M., Masotti G. et al. All-cause mortality in diabetic patients treated with combination of sulfonylureas and biguanides // Diabetes Metab. Res. Rev. — 2004. — Vol. 20. — P. 44-47.

Roumie C.L., Greevy R.A., Grijava C.G. et al. Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes // JAMA. — 2014. — Vol. 311, № 22. — P. 2288-2296.

Grill V., Bjorklund A. Overstimulation and β-cell function // Diabetes. — 2001. — Vol. 50. — P. S122-S124.

Mori R.C., Hirabara S.M., Hirata A.E. et al. Glimepiride as insulin sensitizer: increased liver and muscle responses to insulin // Diabetes Obes. Metab. — 2008. — Vol. 10, № 7. — P. 596-600.

Goldberg RB, Holvey SM, Schneider J. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. The Glimepiride Protocol #201 Study Group // Diabetes Care. — 1996. — 19(8). — 849-856.

Rosenstock J., Samols E., Muchmore D.B., Schneider J. Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group // Diabetes Care. — 1996. — 19(11). — 1194-9