Impact of Gliclazide Modified Release or Glimepiride as Add-on Therapy to Metformin on Glycemic and Oxidative Stress Parameters in Type 2 Diabetic Patients


  • Fadhel A. Shehab Ministry of Health and Environment, Thiqar Health Directorate, Nasiriya, Iraq
  • Ali L. Jasim2 Department of Clinical Pharmacy, College of Pharmacy, University of Baghdad, Baghdad, Iraq.
  • Adel Gh. Mohammed Department of Medicine, College of Medicine, University of Thiqar, Thiqar, Iraq



Background: Type 2 diabetes mellitus is a condition characterized by an elevation of oxidative stress, which has been implicated in diabetic progression and its vascular complications.

Aim: Assessing the impact of gliclazide modified release (MR) versus glimepiride on oxidative stress markers, glycemic indices, lipid profile, and estimated glomerular filtration rate in uncontrolled type 2 diabetic patients on metformin monotherapy.

Methods: This was an observational comparative study conducted in Thi-Qar specialized diabetic, endocrine, and metabolism center. Sixty-six patients were randomized into two groups based on the addition of the sulfonylureas (SUs). Group 1 (33 patients) was on gliclazide MR, whereas Group 2 (33 patients) was on glimepiride. The measured oxidative stress markers were reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and protein carbonyl (PC) evaluated before and after 16 weeks of SUs addition.  

Results: There were significant drops in SOD (P < 0.001), MDA (P < 0.001), and PC (P = 0.001) and a significant increase in GSH (p = 0.029) levels after gliclazide MR add-on therapy. There were significant drops in SOD (P = 0.026) and MDA (P < 0.001) levels with non-significant changes in both GSH (P = 0.214) and PC (P = 0.538) after glimepiride add-on therapy. There was a significant difference in improvement of PC level (P = 0.048) in the gliclazide group compared to the glimepiride group, with a non-significant numerically higher improvement of GSH, SOD, and MDA in gliclazide MR than glimepiride. At the end of the study, there were no significant differences in glycemic control, lipid profile, or eGFR improvement between the two groups.

Conclusion: Glycemic control plays a pivotal role in decreasing oxidative stress. The control of diabetes with the gliclazide-MR-metformin combination reduced oxidative stress more than the glimepiride-metformin combination, indicating its antioxidant property.

Keywords: Oxidative Stress, T2DM, Gliclazide MR, Glimepiride, Metformin.




Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022 Jan;183:109119.

American Diabetic Association Professional Practice Committee. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan;45(Suppl 1):S17–38.

UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res. 1990 Jan;13(1):1–11.

Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, 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 May 11;35(6):1364–79.

Mohammed SI, Mikhael EM, Ahmed FT, Al-Tukmagi HF, Jasim AL. Risk factors for occurrence and recurrence of diabetic foot ulcers among Iraqi diabetic patients. Diabet Foot Ankle. 2016;7:29605.

Taher MA, Moustafa MM, Mahmood AS. Measurements of HbA 1 c for Patients with Diabetes Mellitus and Foot Ulceration. Iraqi J Pharm Sci (P-ISSN 1683-3597, E-ISSN 2521-3512). 2011;20(1):19–24.

Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis. Diabetes. 2017 Feb;66(2):241–55.

Burgos-Morón E, Abad-Jiménez Z, Marañón AM de, Iannantuoni F, Escribano-López I, López-Domènech S, et al. Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues. J Clin Med. 2019 Sep;8(9).

Fiorentino TV, Prioletta A, Zuo P, Folli F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 2013;19(32):5695–703.

Bhatti JS, Sehrawat A, Mishra J, Sidhu IS, Navik U, Khullar N, et al. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radic Biol Med. 2022 May;184:114–34.

Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med. 2020 Oct;14(5):583–600.

Papachristoforou E, Lambadiari V, Maratou E, Makrilakis K. Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications. J Diabetes Res. 2020;2020:7489795.

R. G. A. The physiological and biochemical effect of diabetes on the balance between oxidative stress and antioxidant defense system. Med J Islam World Acad Sci. 2005 Aug 12;15.

Yaribeygi H, Sathyapalan T, Atkin SL, Sahebkar A. Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus. Oxid Med Cell Longev. 2020;2020:8609213.

Singh A, Kukreti R, Saso L, Kukreti S. Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes. Molecules. 2022 Jan;27(3).

Nair A, Nair BJ. Comparative analysis of the oxidative stress and antioxidant status in type II diabetics and nondiabetics: A biochemical study. J Oral Maxillofac Pathol JOMFP. 2017;21(3):394.

FA G JJT, George G. Serum total superoxide dismutase enzyme activity in type 2 diabetic patients with retinopathy in Mthatha region of the Eastern Cape Province of South Africa. Biomed Res. 2017;28(2):532–8.

Alaaraji SF, Allah PHS, Alrawi KF, Alkrwi EN. Evaluation of Serum Malondialdehyde , Glutathione and Lipid Profile Levels in Iraqi Females with Type 2 Diabetes Mellitus. Baghdad Sci J (P-ISSN 2078-8665, E-ISSN 2411-7986). 2016;13(2.2NCC SE-article):383.

Mahmood AR. Estimation of Oxidative Stress and Some Trace Elements in Iraqi Men Patients with Type 2 Diabetes Mellitus. Iraqi J Pharm Sci (P-ISSN 1683-3597, E-ISSN 2521-3512). 2016;25(1):17–22.

Yaas AA, Al-Shakour AA, Mansour AA. Assessment of Serum Level of Protein Carbonyl as a Marker of Protein Oxidation in Patients with Type 2 Diabetes Mellitus. AL-Kindy Coll Med J. 2022;18(3):190–5.

Hussein EA, Kadhim DJ, Al-auqbi TF. Belief About Medications Among Type 2 Diabetic Patients Attending the National Diabetes Center in Iraq . Iraqi JPharm Sci (P-ISSN 1683-3597, E-ISSN 2521-3512). 2017;26(2):66–74.

Rossi DL, Sola D, Rossi L, Piero G, Schianca C, Maffioli P, et al. State of the Art Paper Sulfonylureas and Their Use in Clinical Practice. Arch. Med Sci. 2015;11:840–8.

Schernthaner G, Grimaldi A, Di Mario U, Drzewoski J, Kempler P, Kvapil M, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004 Aug;34(8):535–42.

Kalra S, Das AK, Baruah MP, Unnikrishnan AG, Dasgupta A, Shah P, et al. Glucocrinology of Modern Sulfonylureas: Clinical Evidence and Practice-Based Opinion from an International Expert Group. Diabetes Ther Res Treat Educ diabetes Relat Disord. 2019 Oct;10(5):1577–93.

Al-Saleh Y, Sabico S, Al-Furqani A, Jayyousi A, Alromaihi D, Ba-Essa E, et al. Sulfonylureas in the Current Practice of Type 2 Diabetes Management: Are They All the Same? Consensus from the Gulf Cooperation Council (GCC) Countries Advisory Board on Sulfonylureas. Diabetes Ther Res Treat Educ diabetes Relat Disord. 2021 Aug;12(8):2115–32.

Group AC. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.

Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. Jama. 2019;322(12):1155–66.

Roglic G, Norris SL. Medicines for treatment intensification in type 2 diabetes and type of insulin in type 1 and type 2 diabetes in low-resource settings: synopsis of the World Health Organization guidelines on second-and third-line medicines and type of insulin for the control of blood glucose levels in nonpregnant adults with diabetes mellitus. Ann Intern Med. 2018;169(6):394–7.

Federation TID. IDF Clinical Practice Recommendations for Managing Type 2 Diabetes in Primary Care. Brussels Int Diabetes Fed. 2017;34.

O’Brien RC, Luo M, Balazs N, Mercuri J. In vitro and in vivo antioxidant properties of gliclazide. J Diabetes Complications. 2000;14(4):201–6.

Chugh SN, Dhawan R, Kishore K, Sharma A, Chugh K. Glibenclamide vs gliclazide in reducing oxidative stress in patients of noninsulin dependent diabetes mellitus--a double blind randomized study. J Assoc Physicians India. 2001 Aug;49:803–7.

Avogaro A. Treating diabetes today with gliclazide MR: a matter of numbers. Diabetes Obes Metab. 2012 Jan;14 Suppl 1:14–9.

Gebrie D, Manyazewal T, A Ejigu D, Makonnen E. Metformin-Insulin versus Metformin-Sulfonylurea Combination Therapies in Type 2 Diabetes: A Comparative Study of Glycemic Control and Risk of Cardiovascular Diseases in Addis Ababa, Ethiopia. Diabetes Metab Syndr Obes. 2021;14:3345–59.

Allen J. Sample Size Calculation for Two Independent Groups: A Useful Rule of Thumb. Proc Singapore Healthc. 2011 Jun 1;20:138–40.

Aydin S. A short history, principles, and types of ELISA, and our laboratory experience with peptide/protein analyses using ELISA. Peptides. 2015 Oct;72:4–15.

Chandrashekar V. Hb A1c separation by high performance liquid chromatography in hemoglobinopathies. Scientifica (Cairo). 2016;2016:26983. Bishop ML, Fody EP, Schoeff LE. Clinical Chemistry: Techniques,

Principles, and Correlations. Eighth edi. Philadelphia: Wolters Kluwer; 2018.

Ramjee V, Sperling LS, Jacobson TA. Non–high-density lipoprotein cholesterol versus apolipoprotein B in cardiovascular risk stratification: do the math. J Am Coll Cardiol. 2011;58(5):457–63.

Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro III AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.

Bigagli E, Lodovici M. Circulating Oxidative Stress Biomarkers in Clinical Studies on Type 2 Diabetes and Its Complications. Oxid Med Cell Longev. 2019;2019:5953685.

Kalra S, A K D, Md F, K S, P S, A A R, et al. Glucodynamics and glucocracy in type 2 diabetes mellitus: clinical evidence and practice-based opinion on modern sulfonylurea use, from an International Expert Group (South Asia, Middle East & Africa) via modified Delphi method. Curr Med Res Opin. 2021 Mar;37(3):403–9.

Dhindsa P, Davis KR, Donnelly R. Comparison of the micro- and macro-vascular effects of glimepiride and gliclazide in metformin-treated patients with Type 2 diabetes: a double-blind, crossover study. Br J Clin Pharmacol. 2003 Jun;55(6):616–9.

Schrijnders D, Wever R, Kleefstra N, Houweling ST, van Hateren KJJ, de Bock GH, et al. Addition of sulphonylurea to metformin does not relevantly change body weight: a prospective observational cohort study (ZODIAC-39). Diabetes Obes Metab. 2016 Oct;18(10):973–9.

Zhang F, Xiang H, Fan Y, Ganchuluun T-A, Kong W, Ouyang Q, et al. The effects of sulfonylureas plus metformin on lipids, blood pressure, and adverse events in type 2 diabetes: a meta-analysis of randomized controlled trials. Endocrine. 2013 Dec;44(3):648–58.

Polavarapu NK, Kale R, Sethi B, Sahay RK, Phadke U, Ramakrishnan S, et al. Effect of Gliclazide or Gliclazide plus Metformin Combination on Glycemic Control in Patients with T2DM in India: A Real-World, Retrospective, Longitudinal, Observational Study from Electronic Medical Records. Drugs - real world outcomes. 2020 Dec;7(4):271–9.

Pareek A, Chandurkar NB, Salkar HR, Borkar MS, Tiwari D. Evaluation of efficacy and tolerability of glimepiride and metformin combination: a multicentric study in patients with type-2 diabetes mellitus, uncontrolled on monotherapy with sulfonylurea or metformin. Am J Ther. 2013 Jan;20(1):41–7.

Chan SP, Colagiuri S. Systematic review and meta-analysis of the efficacy and hypoglycemic safety of gliclazide versus other insulinotropic agents. Diabetes Res Clin Pract. 2015 Oct;110(1):75–81.

Su X, Kong Y, Peng D. Evidence for changing lipid management strategy to focus on non-high density lipoprotein cholesterol. Lipids Health Dis. 2019;18(1):1–7.

Hassan MH, Abd-Allah GM. Effects of metformin plus gliclazide versus metformin plus glimepiride on cardiovascular risk factors in patients with type 2 diabetes mellitus. Pak J Pharm Sci. 2015 Sep;28(5):1723–30.

Banik S, Hossain MS, Bhatta R, Akter M. Attenuation of lipid peroxidation and atherogenic factors in diabetic patients treated with gliclazide and metformin. J Res Med Sci Off J Isfahan Univ Med Sci. 2018;23:77.

Lee Y-H, Lee CJ, Lee HS, Choe EY, Lee B-W, Ahn CW, et al. Comparing kidney outcomes in type 2 diabetes treated with different sulphonylureas in real-life clinical practice. Diabetes Metab. 2015 Jun;41(3):208–15.

Fan Y, Wang Y, Tang Z, Zhang H, Qin X, Zhu Y, et al. Suppression of pro-inflammatory adhesion molecules by PPAR-delta in human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):315–21.

Fukuen S, Iwaki M, Yasui A, Makishima M, Matsuda M, Shimomura I. Sulfonylurea agents exhibit peroxisome proliferator-activated receptor gamma agonistic activity. J Biol Chem. 2005 Jun;280(25):23653–9.

Schiekofer S, Rudofsky GJ, Andrassy M, Schneider J, Chen J, Isermann B, et al. Glimepiride reduces mononuclear activation of the redox-sensitive transcription factor nuclear factor-kappa B. Diabetes Obes Metab. 2003 Jul;5(4):251–61.

Chen L, Liao Y, Zeng T, Yu F, Li H, Feng Y. Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients. Endocrine. 2010 Oct;38(2):266–75.

Alsharidah M, Algeffari M, Abdel-Moneim A-MH, Lutfi MF, Alshelowi H. Effect of combined gliclazide/metformin treatment on oxidative stress, lipid profile, and hepatorenal functions in type 2 diabetic patients. Saudi Pharm J SPJ Off Publ Saudi Pharm Soc. 2018 Jan;26(1):1–6.

Nakamura I, Oyama J, Komoda H, Shiraki A, Sakamoto Y, Taguchi I, et al. Possible effects of glimepiride beyond glycemic control in patients with type 2 diabetes: a preliminary report. Cardiovasc Diabetol. 2014 Jan;13:15.

Zhao X, Huang P, Yuan J. Influence of glimepiride plus sitagliptin on treatment outcome, blood glucose, and oxidative stress in diabetic patients. Am J Transl Res. 2022;14(10):7459–66.

von Bibra H, Diamant M, Scheffer PG, Siegmund T, Schumm-Draeger P-M. Rosiglitazone, but not glimepiride, improves myocardial diastolic function in association with reduction in oxidative stress in type 2 diabetic patients without overt heart disease. Diabetes Vasc Dis Res. 2008 Nov;5(4):310–8.

Nomoto H, Miyoshi H, Furumoto T, Oba K, Tsutsui H, Inoue A, et al. A Randomized Controlled Trial Comparing the Effects of Sitagliptin and Glimepiride on Endothelial Function and Metabolic Parameters: Sapporo Athero-Incretin Study 1 (SAIS1). PLoS One. 2016;11(10):e0164255.