The effect of diclofenac sodium given alone or in combination with paracetamol in treatment of patients with type-2 diabetes mellitus

Background: Type-2 diabetes mellitus (T2DM), is becoming an important health problem worldwide. Diabetes mellitus may be associated with low grade chronic inflammation and oxidative stress; both of them could contribute to its pathogenesis. The use of anti-inflammatory and/or antioxidant drugs, therefore, represents a promising attempt for treatment and/or prevention of this disease. Objectives: To compare the effect of diclofenac sodium alone and when combined with paracetamol in type-2 diabetic patients not achieving target HbA1c. Patients and Methods: Twenty four, type-2 diabetic patients consulting the Center for Diabetes and Endocrinology in Maysan, south of Iraq, had managed to complete the 3 month period of the first part of this study after meeting a set of inclusion criteria. Their HbA1c was more than 7% despite the continuous use of oral antihyperglycemic drugs. The effect of diclofenac was compared with another group (n=21) that received paracetamol in addition to diclofenac sodium. Blood samples were taken from before, one month and three months after the start of treatments for measurement of HbA1c, C-reactive protein, C-peptide level and more frequently plasma glucose level (fasting/random). Another sixty patients of similar inclusion criteria were also followed for three months but without treatment and served as a control group. Results: The effect of one month treatment with diclofenac sodium alone or in combination with paracetamol resulted respectively in a reduction in HbA1c by 9.4% and 11.4%, a reduction in CRP by 62.1% and 79.6%, an increase in C-peptide by 262.5% and 216%, a reduction in FPG by 11.2% and 18.1% and a reduction in RPG by 40.3% and 24.8% in comparison to pre-treatment levels. The HOMAß C-peptide measured in a limited number of patients treated with diclofenac sodium or its combination with paracetamol showed an increase by 405.3% and 330.6% three months after start of treatment for the two groups respectively. The control, nonintervention group did not show significant changes in the levels of HbA1c over the three-month period. Conclusion: Diclofenac sodium 100mg SR capsule administered once daily for one month seems to be effective in achieving a good glycemic control in patients not achieving target HbA1c. The addition of paracetamol to diclofenac did not show a clear synergistic effect, despite paracetamol beneficial effect that had been shown in a previous study. Key word: diclofenac sodium, paracetamol, type-2 diabetes mellitus يناثلا عونلا نم يركسلا ىضرم ةجلاعم يف لوماتيسارابلا عم وأ هدرفمب هئاطعا دنع مويدوص كانيفولكيادلا ريثأت ةساردلا ةيفلخ : ةئطاو ةنمزم تاباهتلاب "ابوحصم ضرملا اذه نوكي دقو ،ملاعلا ىوتسم ىلع ةمهم ةيحص ةلكشم يناثلا عونلا نم يركسلا ءاد حبصأ داهجإب "اضيأو ةدشلا ةدسكلأا تاداضم عم وأ اهدحول باهتللال ةداضملا ةيودلاا لامعتساف ،يركسلا ةضارم يف امهسي نا نكمي ناذللاو ةدسكلاا .هنم ةياقولاوأ ضرملا ةجلاعمل ةدعاو ةلواحم لثمي ةساردلا نم فدهلا : ىضرم دنع لوماتيسارابلا عم وأ هدرفمب مدختسا اذا مويدوص كانيفولكيادلا ريثات ةنراقمل رطيسملا ريغ يناثلا عونلا نم يركسلا .هيلع لمعلا قئارط و ىضرملا : ةساردلا تلمش 42 دعب ناسيم ةظفاحم يف ءامصلا ددغلاو يركسلا زكرم اوعجار نيذلاو يناثلا عونلا نم يركسلاب "اضيرم نم رثكا مهيدل يمكارتلا نيبولغوميهلا ناكو لامتشلاأ ريياعم نم ةعومجمل مهئافيتسا 7 ع % ةصقنملا ةيودلأل رمتسملا لامعتسلاا نم مغرلا ىل ( ىضرملا نم ىرخا ةعومجم عم كانيفولكيادلا ريثأت ةنراقم تمت دقو .ةساردلا ةعومجم مه اوناكف مفلا قيرط نع ذخؤت يتلا يلاعلا ركسلل 42 تانيع تذخأو .لوماتيسارابلا ىلا ةفاضلااب كانيفولكيادلا تذخأ ةعومجملا هذه تناكو )اضيرم و يمكارتلا نيبولغوميهلا تاصوحف ءارجلا مدلا نم نم رهشأ ةثلاثو رهش دعبو لبق ضيرم لكل يئاوشع لكشب وا موصلا دنع اما مدلا يف ركسلا ىوتسمو دياتبيب يس و يس عون يلعافتلا نيتوربلا ءدب شلاا ريياعم مهيلع قبطنت رهشا ةثلاث ةدمل رخا اًضيرم نيتس ةعباتم تمت امك . جلاعلا ةعومجمك تذختاو لوماتيسارابلاب ةجلاعملا نودب نكلو لامت .ةطباض تنلا ــ جئا : سنب يمكارتلا نيبولغوميهلاب ناصقن يلاوتلا ىلعو هنع جتن دحاو رهش ةدمل لوماتيسارابلا عم وا طقف مويدوص كانيفولكيادلاب ةجلاعملا نا ةب 4.2 و % 22.2 ب يس عون نم لعافتملا نيتوربلا ىوتسمب ناصقنو % ةبسن 14.2 و % 74.1 دياتبيب يسلا ةبسنب ةدايز و % 414.2 % و MJBU, VOL. 32, No.1, 2014 32 421 ةبسنب موصلا دنع ركسلا ىوتسم يف ناصقنو % 22.4 و % 2..2 ةبسنب يئاوشعلا ركسلا ىوتسمب ناصقنو % 2..4 و % 42.. % .جلاعلا لبق ام ىوتسمب ةنراقم اموهلا سايق رهظاو نيذلا ىضرملا نم دودحم ددع يف دياتبيب يسلل اتيب ةبسنب ةدايز لوماتيسارابلا عم كانيفولكيادلا وأ كانيفولكيادلاب اوجلوع 2.2.4 و % 44..1 .جلاعلا فاقيا نم نيرهش دعب اهسايق مت امدنع كلذو % جاتنتسلاا : لوسبك مويدوص كانيفولكيادلاب ةجلاعملا نا ودبي 2.. ف لااعف ناك دحاو رهش ةدمل ايموي ةدحاو ةرم ئطبلا ريرحتلا تاذ مغلم لوصحلا ي لكيادلا ريثأت زيزعت يف حضاو ريثأت لوماتسارابلل نكي ملو .هيلع رطيسملا ريغ يناثلا عونلا نم يركسلا ىضرم ىدل ةديج ةيركس ةرطيس ىلع كانيفو .ةقباس ةسارد هترهظأ يذلا ديفملا لوماتيسارابلا ريثأت نم مغرلا ىلع INTRODUCTION he prevalence of type-2 diabetes mellitus (T2DM), is increasing worldwide, and the total number of people with T2DM is estimated to rise to 526 millions in 2030. [1] In a study published in 2008, the prevalence of T2DM in Basrah (Iraq) was reported to be 7.43%. [2] Both obesity and T2DM share a metabolic event characterized by insulin resistance and chronic inflammation. [3] Chronic inflammation causes insulin resistance by interfering with insulin receptor signaling. Chronic inflammation through proinflammatory cytokines is one of the major factors for progressive loss of beta cell function and mass. [4] Therefore, the use of non-steroidal antiinflammatory drugs (NSAIDs) may contribute to the treatment of T2DM through these mechanisms. Abdullah [5] studied the effect of diclofenac sodium in 54 patients with T2DM not achieving target HbA1c and found it beneficial in significantly reducing HbA1c level in the majority of patients recruited for that study. However, Khathem et al [6] in a similar study and a smaller number of patients found a significant effect on fasting serum glucose but not on HbA1c after 60 days of treatment. Oxidative stress, on the other hand, had been described to play a major role in the pathogenesis of diabetes mellitus; both in its onset and complications. [7,8] Insulin resistance was linked to oxidative damage of essential macromolecules in insulin sensitive tissues. [9] Prolonged exposure to hyperglycemia and impairment of oxidant/antioxidant equilibrium can result in oxidative stress which can, in turn, lead to beta cell dysfunction and decreased insulin secretion. [10] Thus, oxidative stress and hyperglycemia can reinforce each other. Several studies have suggested that many of these offlabel applications of paracetamol such as its beneficial effect on blood glucose levels, may be derived from its ability to function as antioxidant. [11-15] We had already tested the effect of paracetamol 1000mg daily for one month and found it effective in reducing HbA1c level two months after cessation of paracetamol treatment. [16] The aim of the present study is, therefore, to investigate the effect of paracetamol (as antioxidant) when used in combination with diclofenac sodium (as antiinflammatory) on the glycemic control of patients with T2DM. PATIENTS AND METHODS Diabetic patients consulting the Center for Diabetes and Endocrinology in Maysan (southeast of Iraq) during the period from November 2012 to April 2013 were included after meeting a set of inclusion criteria. The study protocol was approved by the College Council and Ethical Committee at the College of Medicine, University of Basrah (south of Iraq). The study is open-label, therapeutic, outpatient-based study to compare one-month treatment with diclofenac sodium alone or in combination with paracetamol on the glycemic control of diabetic patients. All patients were selected during their consultation to the Center for Diabetes and Endocrinology in Maysan. T2DM Patients not achieving target HbA1c level, previously diagnosed for more than one year, age between 30-60 years, no associated cardiovascular diseases, body mass index is 25 or more, on oral antihyperglycemic drugs (both sulfonylureas and metformin) for not less than 6 months, FPG is 126 mg/dl or more, RPG is 200mg/dl or more and HbA1c is 7% or more, no contraindication to the use of paracetamol or NSAIDs, not using aspirin or other antiinflammatory drugs for at least 2 weeks before being included in the study. Patients were randomly divided into two groups according to T MJBU, VOL. 32, No.1, 2014 32 the type of treatment. Randomization lists, one for males and one for females, were prepared in blocks of 10 (5 patients for each treatment). Diclofenac sodium (Voltaren, Mepha, Switzerland), 100 mg SR capsule and paracetamol (Doliprane, Sanofi, France), 1000mg tablet as single daily doses in the morning after meal were used. Because the gastrointestinal adverse effects of NSAIDs may occur without symptoms in the majority of patients, the proton pump inhibitor (Omeprazole, 20mg before meal in the evening) was prescribed to all patients receiving diclofenac sodium. Patients were seen every 2 weeks in the first month to receive the treatments, to check for compliance and to question them about possible side effects. Plasma glucose level (fasting or random) and other laboratory investigations were also done in the meantime. Lipid profile, liver function tests, renal function tests were performed for all patients before starting treatments; and renal function tests were also followed 2 weeks after treatments. All patients were already receiving metformin (Merck, France), 850mg twice daily and glibenclamide (Sanofi-Aventis, France), 5mg daily provided to them by the Center. SPSS (Statistical Package of Social Sciences) version 20 was used for statistical analysis. Paired t test was used to test significance of changes at 0, 1 and 3 months after the start of treatments.