Evaluation Of Metformin + Sitagliptin versus Metformin + Glibenclamide On Glycemic Control In Iraqis Type 2 Diabetic Patients Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 69 Evaluation of Metformin + Sitagliptin versus Metformin + Glibenclamide on Glycemic Control in Iraqis Type 2 Diabetic Patients Hassan M. Al-Temimi.* , Kassim j.Al-Shamma** ,1 and Salim M.Alrubaie*** * Baghdad Teahing Hospital,Medical City, Baghdad ,Iraq ** Department of Clinical Pharmacy ,College of Pharmacy, University of Baghdad, Baghdad, Iraq *** College of Medicine, University of Baghdad, Baghdad , Iraq Abstract Combination therapy with a dipeptidyl peptidase–4 inhibitor and metformin or metformin+ glibenclamide results in substantial and additive glucose- lowering effects in Iraqis patients with type 2 diabetes mellitus . This study evaluated the glycemic control by using two groups of combinations of drugs metformin + glibenclamide and metformin + sitagliptin in Baghdad teaching hospital / medical city. 68 T2DM patients and 34 normal healthy individuals as control group were enrolled in this study and categorized in to two treatment groups. The group 1 (34 patients ) received ( metformin 500 mg three times daily + glibenclamide 5 mg twice daily ) and the group 2 (34 patients) received (metformin 500 mg three times daily + sitagliptin 100 mg once daily ). From each patients 5 ml of blood was obtained by veinpuncture and the serum was separated and used for estimating plasma glucose level (FPG,PPG) and HbA1c.The mean fasting plasma glucose and postprandial plasma glucose significantly lower for group 2 patients for 3 and 6 months of treatment (129.02 ± 1.96 and 118.4 ± 1.33), (159.38 ± 4.72 and 123.88 ± 2.41 mg / dl) respectively for fasting plasma glucose and postprandial plasma glucose respectively than in group 1 patients (150.76 ± 3.97 and 127.79 ±2.52) ,(173.25 ± 7.99 respectively and 140.67 ± 4.66 mg / dl) for fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) respectively. The mean HbA1c % significantly lower for group 2 patients for 3 and 6 months of treatment (6.12 ± 0.091and 5.83 ± 0.083 ) respectively compared to group 1 patients (7.1 ± 0 .63 and 6.81 ± 0.12 ). In conclusion , the combination of metformin + sitagliptin improved fasting plasma glucose , postprandial plasma glucose & HbA1c % in comparison with metformin + glibenclamide combination. Ker words : Sitagliptin, Metformin , Glibenclamide ,Type 2 Diabetic Patients. ن فعالٍة الوجوعة العالجٍة )الوتفورهٍن + الكلبنكلوٍد( ضد فعالٍة الوجوعة العالجٍة ٍتقٍ )الوتفورهٍن + السٍتكلبتٍن ( على نسبة السكر بالدم لورضى عراقٍٍن هصابٍن بورض السكري هن النوع الثانً **قاسن جلٍل الشواع، *حسن هحود عباس التوٍوً ،1 *** بٍعًسالن هحسن الرو تغذاد ، انعشاق يذٌُح انطة ،،يسرشفى تغذاد انرعهًًٍ * كهٍح انظٍذنح ، ظايعح تغذاد ، تغذاد ، انعشاقفشع انظٍذنح انسشٌشٌح ، ** ، تغذاد ، انعشاق ظايعح تغذاد ،كهٍح انطة *** نخالطحا ٍٍ + انكهثُكهًاٌذ( ذؤدي إنى ذأشٍشاخ إػافٍح ترمهٍم َسثح انسكش تانذو انًعًىعح انعالظٍح ) انًرفىسيٍٍ + انسٍراكهثرٍٍ ( او)انًرفىسي يذٌُح انطة وذحد أششاف طثٍة \نًشػى عشالٍٍٍ يظاتٍٍ تذاء انسكشي يٍ انُىع انصاًَ. هزِ انذساسح أظشٌد فً يسرشفى تغذاد انرعهًًٍ نرمٍى إيكاٍَح انسٍطشج 3123و حرى آراس 3122ساسح يٍ ذًىصاخرظاص وتًىافمح انًشػى إػافح إنى يىافمح انعهاخ انًخرظح واٌ فرشج انذ يشٌغ(ٌعاَىٌ انًشع وذى يماسَرهى ب 76عهى َسثح انسكش تانذو ,َسثح انذهىٌ , انكالٌكٍرذ هًٍىكهىتٍٍ وكزنك صٌادج كرهح انعسى. ذى اخرٍاس) 65-51يشٌغ ذشاوحد أعًاسهى تٍٍ 45األونى :( شخض يٍ األطحاء نغشع انًماسَح. ذى ذىصٌع انًشػى إنى يعًىعرٍٍ:انًعًىعح 45) يهغى يشذٍٍ 6يهغى شالز يشاخ ٌىيٍا + انكهثُكهًاٌذ 611( . إٌ هزِ انًعًىعح ذسرخذو ) انًرفىسيٍٍ 1,67± 63. 6سُح ) انًرىسط = ذسرخذو انًعًىعح هزِ ( . إٌ 1,5 ± 63 . 55) انًرىسط = سُح 65-55 تٍٍ أعًاسهى يشٌغ ذشاوحد 45انصاٍَح : انًعًىعح ٌىيٍا(. كاٌ انًعذل انحساتً نُسثح انسكش تانذو فً حانح انظٍاو وتعذ يهغى ٌىيٍا(. 211يهغى شالز يشاخ ٌىيٍا +انسٍراكهثرٍٍ 611) انًرفىسيٍٍ انذساسح كًماسَح إنى انًعًىعح األونى.انصاٍَح الم تشكم يهحىظ تعذ شالشح و سرح اشهش يٍ تذآ نهًعًىعح تانُسثح انطعاو ذُاول يٍ ساعرٍٍ يم ( تانُسثح انى َسثح انسكش تانذو فً حانح انظٍاو وتعذ \يهغ 3.5± 234.6و 5.34±265.46( و)2.4± 226.5و 235.3±2.57) ( و 3.63± 234.45و 4.54±261.47ساعرٍٍ يٍ ذُاول انطعاو وتانرراتع.إيا تانُسثح إنى انًعًىعح األونى فكاَد انُرائط ) يم ( تانُسثح إنى َسثح انسكش تانذو فً حانح انظٍاو وتعذ ساعرٍٍ يٍ ذُاول انطعاو وتانرراتع.كًا تٍُد \يهغ5.77± 251.74و 244.36±4.55) ٍ تذآ ( الم تشكم يهحىظ تانُسثح انى انًعًىعح انصاٍَح تعذ شالشح و سرح اشهش ي% HbA1cانذساسح اٌ انُسثح انًؤٌح نهكالٌكٍرذ هًٍىغهىتٍٍ) 74±.4.2ايا تانُسثح إنى انًعًىعح األونى )±(6.64و± 7.23انذساسح كًماسَح إنى انًعًىعح األونى.حٍس كاَد انُرائط نهًعًىعح انصاٍَح ) ًٌكٍ االسرُراض اٌ انًعًىعح انعالظٍح يع ) انًرفىسيٍٍ + انسٍراكهثرٍٍ ( لذ شهذخ ذحسُا يهحىظا يٍ حٍس انسٍطشج عهى َسثح (.23±7.62و يماسَح انًعًىعح انعالظٍح يع انًرفىسيٍٍ + انكهثُكهًاٌذ. كًا َالحع HbA1c)انسكش تانذو وكزنك انُسثح انًؤٌح نهكالٌكىكهٍرذ هًٍىغهىتٍٍ ) ذأشٍش انًراتعح وانرعهًٍاخ يٍ لثم فشٌك انعًم حٍس كاٌ نها انرأشٍش ترحسٍ انُرائط نكال انًعًىعرٍٍ. . هرض السكري هن النوع الثانً ، ٌداالكلبنكلو ،الوتفورهٍن،لبتٍن كاالسٍت الكلوات الوفتاحٍة : 1 Corresponding author E- mail :drkassim_alshamaa@yahoo.com. Received : 14/5/2012 Accepted : 27/6/2012 Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 70 Introduction Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia. It is associated with abnormalities in carbohydrate, fat, and protein metabolism and results in chronic complications including microvascular, macrovascular, and neuropathic disorders. Although the prevalence of type 2 DM increases with age, (1) the disorder is increasingly being recognized in adolescence. Much of the increase in adolescent type 2 DM is related to an increase in adiposity and sedentary lifestyle, in addition to an inheritable predisposition. (2) The increase in insulin resistance with weight gain is directly related to the amount of visceral adipose tissue. (3,4) The classical symptoms of diabetes are polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). (5) HbA1c measurements are the gold standard for following long-term glycemic control for the previous 2 to 3 months (6) . Until 1995, only two options for pharmacologic treatment were available for patients with diabetes; sulfonylurea (for type 2 DM only) and insulin (for type 1 or 2). Since 1995, a number of new oral agents, injectables, and insulins have been introduced in therapy. Currently, six classes of oral agents are approved for the treatment of type 2 diabetes: α-glucosidase inhibitors, biguanides, meglitinides, peroxisome proliferator-activated receptor B-agonists (which are also commonly identified as thiazolidinediones [TZDs] or glitazones), DPP-IV inhibitors, and sulfonylurea. It is now known that two hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-releasing peptide (GIP), are responsible for more than 90% of the increased insulin secretion seen in response to an oral glucose load. In patients with type 2 diabetes GLP- 1 levels are reduced whereas GIP levels are increased. Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase – 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP,gastrointestinal hormones released in response to a meal by preventing GLP-1 and GIP inactivation, the are able to the increase secretion of insulin and suppress the release of glucagons by pancreas (7) . The aim of this study is to evaluate effects of combination of metformin + sitagliptin versus the effects of combination of metformin + glibenclamide on fasting plasma glucose, postprandial plasma glucose and HbA1c percentage in Iraqis type 2 diabetic patients. Subjects and Methods This study was carried out at Baghdad teaching hospital / Medical city & the National Diabetes Center for Treatment and Research at Al-mustansuriyah University and the private clinic of consultant physician during the period of July 2011-March 2012 .The study was conducted on ( 100 ) Iraqi type 2 diabetics only 68 patients completed the course of study successfully . These patients were recruited into the following groups : Group (1) : Includes 34 patients tested at zero time and after 3 months and 6 months.The patients were already treated by metformin 500mg three times daily & glibenclamide 5 mg twice daily. Group (2) : Includes 34 patients tested at zero time and after 3 months and 6 months . The patients were previously treated by metformin 500mg three times daily and sitagliptin 100 mg once daily 3-6 months before start the study and they continue on this regime of treatment . The age of patients for group ( 1 ) ranged from 40 – 59 years (52.5 ± 0.86 ), of them 20 patients (58.8 %) were male and 14 patients (41.2 %)were female .The age of patients for group ( 2 ) ranged from 44 – 59 (52.44 ± 0.9),of them 20 patients ( 58.8 % ) were male and 14 patients ( 41.2 % )were female. Diagnosis was made by consultant endocrinologist; for patients as having T2DM depending on patients history ,clinical examination laboratory investigations and vital signs. For the purpose of comparison ,34 control subjects were enrolled. The age of control for group (3) ranged from 44 – 59 (52.44 ± 0.9),of them 20 patients (58.8 %) were male and 14 patients ( 41.2 % )were female.Patients were excluded from this study as having the following criteria : CNS disease, renal dysfunctions, liver dysfunction, pregnancy with diabetes ,concomitant endocrine disease & inflammatory Disease. Collection of blood sample From each patients ,5 ml of blood was obtained by veinpuncture, for fasting and HbA1c.Another 5 ml was withdrawn for postprandial plasma glucose. The blood sample was divided into two aliquots; 2 and 3 ml .The first aliquots was dispended in tube containing ethylene diamine tetracetic acid ( EDTA ) (1.5 mg /ml ). This blood was processed in less than three hours and was used for HbA1c estimation and other portion ( 3 ml ) was dispended in a plane tube and left for an hour http://en.wikipedia.org/wiki/Polyuria http://en.wikipedia.org/wiki/Polydipsia http://en.wikipedia.org/wiki/Polyphagia http://en.wikipedia.org/wiki/Diabetes_mellitus#cite_note-11#cite_note-11 Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 71 to clot at room temperature then, it was centrifuged at 3000 rpm for 10 minutes to collect serum .The serum was separated and used for estimating plasma glucose level (FPG ). By using an enzymatic colorimetric method with a commercially available kit for determination plasma glucose level and Bio- Rad VARIANT Hemoglobin A1c for determination HbA1c. (9,10) Results Fasting plasma glucose (FPG) (9) The results showed significant reduction in fasting plasma glucose for both groups after 3 and 6 months of treatment as compared to 1 st reading. However, there is a significant decline for group 2 treated by metformin + sitagliptin compared to group 1 treated by metformin + glibenclamide (table.1 and fig 1 ). Table 1: Effect of treatment with metformin 500 mg 3 times daily + glibenclamide 5 mg twice daily (group 1) versus metformin 500 mg 3 times daily + sitagliptin 100 mg once daily (group 2) on fasting plasma glucose in patients with T2DM and control normal healthy individuals(group 3 )after 1,3 and 6 months of treatment .( n = 34 individuals for each group ). Values expressed as mean ± standard error of mean. a significant difference (p <0.05) in comparison with control group. b significant difference (p < 0.05) between reading. c significant difference (p < 0.05) between group 1 and 2. FPG 3 FPG 2 FPG 1 Group 3 control Group 1 M + G Group 2 M + S 0 20 40 60 80 100 120 140 160 180 Mg / dl Number of reading Groups Fasting Plasma Glucose ( FPG ) Group 3 control Group 1 M + G Group 2 M + S Figure 1: Histogram showing effect of treatment with metformin 500 mg 3 times daily + glibenclamide 5 mg twice daily group 1 versus metformin 500 mg 3 times daily + sitagliptin 100 mg once daily group 2 on FPG in patients with T2DM and group 3 control normal healthy subjects after 1,3 and 6 months of treatment.( n = 34 individuals for each group) . Postprandial plasma glucose (PPG) (9) Table 2 shows comparison between the effects of two types of treatment ( metformin + glibenclamide and metformin + sitagliptin ) on postprandial plasma glucose in patients with T2DM .There were a significant reductions in postprandial plasma glucose for both groups after 3 and 6 months of treatment as compared to 1 st reading . However, there was a significant decline for group 2 patients treated by metformin + sitagliptin compared to group 1 treated by metformin + glibenclamide. Group3 mg /dl Group 2 mg / dl Group 1 mg /dl Duration months 100 .11 ± 1.76 144.94 ± 3.25 ab 173.97 ± 5.37 a 1 96.02 ± 1.29 129.02 ± 1.96 abc 150.76 ±3.97 ab 3 94.50 ± 1.24 118.4 ± 1.33 abc 127.79 ±2.52 ab 6 Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 72 Table 2 : Effect of treatment with metformin 500 mg 3 times daily + glibenclamide 5 mg twice daily ( group 1) versus metformin 500 mg 3 times daily + sitagliptin 100 mg once daily (group 2) on postprandial plasma glucose PPG in patients with T2DM and control normal healthy individuals (group 3) after 1,3 and 6 months of treatment .( n = 34 individuals for each group ). Values expressed as mean ± standard error of mean. a significant difference (p <0.05) in comparison with control group. b significant difference (p< 0.05) between reading. c significant difference (p < 0.05) between group 1 and 2. Figure 2 : Histogram showing effect of treatment with metformin 500 mg 3 times daily + glibenclamide 5 mg twice daily (group 1) versus group 2 metformin 500 mg 3 times daily + sitagliptin 100 mg once daily (group 2) on PPG in patients with T2DM and group 3 control normal healthy individuals (group 3) after 1,3 and 6 months of treatment.( n = 34 individuals for each group ). Glycosylated hemoglobin(HbA1c) (10) Table.3 shows comparison between the effects of two groups of treatment (metformin + glibenclamide and metformin + sitagliptin) on HbA1c in patients with T2DM. There were a significant reductions in HbA1c for both groups after 3 and 6 months of treatment as compared to 1 st reading. However, there were a significant decline for group 2 patients treated by metformin + sitagliptin compared to group 1 treated by metformin + glibenclamide after 3 and 6 months of treatment . Group 3 mg /dl Group 2 mg / dl Group 1 mg /dl Duration months 108.14 ± 1.34 186.05 ± 6.2ac 203.26± 12.37a 1 104.6 ± 1.19 159.38 ± 4.72abc 173.25 ± 7.99ab 3 96.29 ± 2.41 123.88 ± 2.41abc 140.67 ± 4.66ab 6 Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 73 Table 3 : Effect of treatment with metformin 500 mg 3 times daily + glibenclamide 5 mg twice daily( group 1) versus group 2 metformin 500 mg 3 times daily + sitagliptin 100 mg once daily (group 2) on HbA1c in patients with T2DM and control normal healthy individuals group (3) after 1,3 and 6 months of treatment .( n = 34 individuals for each group ) Values expressed as mean ± standard error of mean. a significant difference (p <0.05) in comparison with control group. b significant difference (p< 0.05) between reading. c significant different (p < 0.05) between group 1 and 2. Figure 3:Histogram showing effect of treatment with metformin 500 mg 3 times daily + glibenclamide 5 mg twice daily (group 1) versus metformin 500 mg 3 times daily + sitagliptin 100 mg once daily (group 2) on HbA1c (%) in patients with T2DM and control normal healthy individuals (group 3 ) after 1,3 and 6 months of treatment .( n = 34 individuals for each group ) . Discussion The epidemic of type 2 diabetes and the recognition that achieving specific glycemic goals can substantially reduce morbidity have made the effective treatment of hyperglycemia a top priority (11,12) . Intensive glycemic management resulting in lower A1C levels has also been shown to have beneficial effect on cardiovascular disease ( CVD ) complication in type 1 diabetes (13,14) ; however, current studies failed to demonstrate a beneficial effect of intensive diabetic therapy on CVD in type 2 diabetes (15,16) . The development of new classes of blood glucose – lowering medication to supplement the older therapies, such as lifestyle – directed interventions, insulin, sulfonylurea, and metformin, has increased in number of treatment options available to practitioners and patients has heightened uncertainty regarding the most a appropriate means of treating this wide spread disease (17) . GLP-1 and glucose-dependent insulinotropic polypeptide ( GPI ),the main insulinotropic peptide of intestinal origin (incretins), are rapidly degraded by dipeptidyl peptidase four ( DPP-4 ).DPP-4 is a member of a family of cell membrane proteins that are expressed in many tissues , including immune cells (18) . The 1 st oral DPP - 4 inhibitor , sitagliptin was approved by the Food and Drug Administration in October 2006 for use as monotherapy or in combination with metformin or TZDs. Another DPP-4 inhibitor, vildagliptin, was approved in Europe in February 2008, and several other compounds are under development. In clinical trial Group 3 (%)HbA1c Group 2 (%) HbA1c Group 1 (%) HbA1c Duration/ months 5.33 ± 0.83 6.32 ±0.09ac 7.38 ± 0.14a 1 5.31 ± 0.86 6.12 ± 0.09ac 7.10 ±0 .63a 3 5.01 ± 0.04 5.83 ± 0.08abc 6.81 ± 0.12a 6 Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 74 performed to date, DPP-4 inhibitors lower A1C levels by 0.6 – 0.9 percentage points and are weight neutral and relatively well tolerated (19,20) They don’t cause hypoglycemia when used as monotherapy.A fixed–dose combination pill with metformin is available.Our results regarding plasma glucose and glycosylated hemoglobin ( HbA1c ) indicate that there was a successful improvement in plasma glucose levels and HbA1c after treatment courses of 3 and 6 months with metformin 500 mg three times daily + glibenclamide 5 mg twice daily and combination of metformin 500 mg three times daily + sitagliptin 100 mg once daily as was shown in tables 1-3; values were improved significantly after treatment with the above mentioned drugs. However, this improvement was not enough to reach that of normal healthy individual values, in other words, there were partial improvements observed by these drugs . Accordingly, and based on the comparison of the treatment groups with that of control group that continue for the same treatment period, we conclude that combination of metformin + sitagliptin significantly reduced the values of FPG, PPG and HbA1c after 3 and 6 months and improve plasma glucose level and HbA1c percentage compared to combination of metformin + glibenclamide. This might due to the additive effect of these two drugs i .e metformin + sitagliptin .These results were in agreement with other results that also indicate effectiveness of additive effect of metformin and sitagliptin (21) . The incretin hormones play a major role in glucose homeostasis by stimulating insulin secretion, suppressing glucagons secretion, inhibiting gastric emptying and reducing appetite and food intake (22-25) . Both incretin hormones are rapidly degraded and removed from circulation by the enzyme dipeptidyl peptidase–4 (DPP-4) (26,27) . Therefore, there is considerable interest in enhancing incretin action for treatment of type 2 diabetes. Sitagliptin , a selective DPP-4 inhibitor , reduces both fasting and postprandial plasma glucose presumably by inhibiting the inactivation of GLP-1 and GIP, thereby prolonging their duration of action on pancreatic islets (28,29) .Also the complementary combination therapy with sitagliptin– metformin lower glucose via enhancement of insulin secretion, suppression of glucagon secretion , and insulin sensitization. Use of this combination in diabetes management will provide a greater degree of glycosylated hemoglobin – lowering than that seen with use of either drug as monotherapy (22) . In clinical trials, the DPP-4 inhibitor, sitagliptin, improved fasting and postprandial glycaemic control and measures of β-cell function in patients with type 2 diabetes, with minimal effects on measures of insulin resistance/ sensitivity (30,31) . Metformin has been found to increase GLP-1 levels in humans (32,33) . Sulfonylurea have the advantage of being quite effective in blood glucose lowering, with an almost instant onset of the effect after start of therapy. Drops in HbA1c of 1–2% can be expected as a mean, with the higher the baseline HbA1c, the bigger the drop. Additive effects are seen when Sulfonylurea are combined with metformin, and the different mechanisms of action of these two agents – one stimulating insulin secretion, the other increasing insulin sensitivity –make them the obvious couple in the dual disease that is type 2 diabetes (34) . The success story of this combination can be seen in many countries where this combination is the standard treatment in type2 diabetes. Suggestions that these drugs ultimately lead to faster beta-cell failure (an observation already made in the 1970s) have not altered their popularity (34) . Because Sulfonylurea (SUs) have been used for so many years, their safety profile and side effects are well known. They increase insulin secretion by binding to a receptor on the surface of the pancreatic beta- cell, resulting in a glucose-independent insulin release. Their mechanism of action also implicates that Sulfonylurea therapy will ultimately fail because of B-cell failure. The main disadvantage of Sulfonylurea is the risk of hypoglycaemia, which rises with advanced age, poor nutrition, alcohol consumption, liver or kidney disease and polypharmacy (35) and is higher than with other oral medications (36) This is a class effect, but differences between different products have been described (37–39) . Another class effect of SUs is that their use leads to weight gain, typically 1–4kg with stabilization after about six months. (40) Here again, data are somewhat different between the products. (41,42) . SUs have a neutral effect on lipid profile or blood pressure and all current SUs – in contrast to the older products, where worrying reports on cardiovascular mortality abound – are neutral to the heart. Most SUs are renally cleared and dose adaptations will be needed in the case of renal insufficiency. Therefore, it makes sense to choose SUs as the next step when metformin is not enough, but care should be taken in older patients because of the risk of hypoglycaemia. To justify its high cost, Sitagliptin should be used to its maximum potential, started early in the disease process to maintain and preserve beta cell function (43) and preferably used in combination with Metformin in order to Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 75 achieve the maximum reduction in HbA1c. (44) All recent clinical trials hint to the benefit of the early use of sitagliptin, alone or in combination, of any antidiabetic medication. More specifically, GLp-1 or DDP4 inhibitors, have their maximum effect observed when the diabetic process is in its early manifestations. (45) Also our study showed that good patients educations and instructions given the workers to the patients are of great value in controlling the fasting plasma glucose, postprandial plasma glucose and HbA1c after the 1 st reading. References 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2007;30(Suppl 1):S42–S47. 2. Jolst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:E199-E206. 3. Montague CT, O’Rahilly S. The perils of portliness: Causes andconsequences of visceral adiposity. Diabetes 2000;49:883– 888. 4. Kelley DE, Williams KV, Price JC, et al. Plasma fatty acids, adiposity and variance of skeletal muscle insulin resistance in type 2 diabetes mellitus. J Clin Endocrinol Metab 2001;86:5412–5419. 5. Manohar, V; Talpur, NA; Echard, BW; Lieberman, S; Preuss, HG. "Effects of a water-soluble extract of maitake mushroom on circulating glucose/insulin concentrations in KK mice". Diabetes, obesity & metabolism 2002 ;4 (1): 43–8. 6. American Diabetes Association : Standards of medical care in diabetes 2012 ( position statement ) . Diabetes Care (Suppl. 1 ) ; S12- S 54 . 7. Committee for Medicinal Products for Human Use. European Public Assessment Report (EPAR) for Onglyza. London, UK, CHMP, 2010. 8. Tietz N.W. Clinical to laboratory tests. 2 nd ed. Philadelphia, Pa:WB Saunderce Co.;1990:246-250. 9. Foller MJ. Microvascular & macrovascular complication of diabetes. Clin. Diabetes 2008; 26(2):77-82. 10. European Diabetes Policy Group : A desktop guide to type two diabetes mellitus . Diabeta Med 1999 ; 16 : 716 – 730 . 11. National Institute for Clinical Excellence : Clinical guide line for T2DM . management of blood glucose 2002 . 12. Diabetes Control and Complication Trial / Epidemiology of Diabetes interventions and Complications Research Group .Intensive Diabetes Therapy and carotid intima – media thickness in type 1 diabetes . N Engl J Med 2003 ; 348 : 2294-2303 . 13. Diabetes Control and Complication Trial / Epidemiology of Diabetes interventions and Complications Research Group: In intensive diabetes treatment and cardiovascular disease in patient with type 1 diabetes . N Engl J Med 2005 ; 353 : 2643-2653 . 14. The Action to Control Cardiovascular Risk in Diabetes Study Group : Effects of intensive glucose lowering in type 2 diabetes N Engl J Med 2008 ; 358 : 2545- 2559 . 15. The AVANCE Collaborative Group : Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes . N Engl J Med 2008 ; 358 : 2560- 2572. 16. Abraira C , Duckworth WC , Moritz : Glycemic separation and risk factor control in Veterans Affairs Diabetes Trial: an internet report . Diabetes Obes Metab . 2008 . 17. Nathan DM : Finding nee treatments for diabetes – how many – how fast ….how good ? N Engl J Med 2007 ; 356 : 437- 440. 18. Richter B , Banderia – Echtler E , Berger hoff K et al : Dipeptidyl peptidase – 4 ( DPP-4 ) inhibitors for type 2 diabetes mellitus . Cochrane Database Syst Rev 2008 ; 2 : CD006739 . 19. Raz I , Hanefeld M , Xu L , et al : Efficacy and safety of DPP-4 inhibitors sitagliptin as monotherapy in patients with T2DM . Diabetologia 2006 ; 49 : 2564 – 2571 . 20. Goldstein B , Feinglos M , Lunceford J , et al : Effect of initial combination therapy with sitagliptin , DPP-4 inhibitor and metformin on glycemic control in patient with diabetes . Diabetes Care 2007 ; 30 : 1979 – 1987 . 21. Karen Barmard , Mary Elizabeth Cox ,Gennifer B Green . Diabetes Metab Synd Obes . 2010 ; 3 : 363- 372 . 22. Combettes MM. GLP-1 and type 2 diabetes: physiology and new clinical advances. Curr Opin Pharmacol 2006; 6: 598-605. 23. Rachman J, Gribble FM, Barrow BA, Levy JC, Buchanan KD, Turner RC. Normalization of insulin responses to glucose by overnight infusion of glucagon- like peptide 1 (7-36) amide in patients with NIDDM. Diabetes 1996; 45: 1524-1530. 24. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of Iraqi J Pharm Sci, Vol.21(2) 2012 Metformin + Sitagliptin versus Metformin + Glibenclamide 76 fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 = amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36: 741-744. 25. Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric = emptying, glucose responses, and insulin secretion after a liquid test meal: = effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 1996; 81: 327-332. 26. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusion of glucagon-like peptide 1lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 1999; 22: 1137-1143. 27. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded fromthe NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44: 1126-1131. 28. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995; 136: 3585-3596. 29. Kim D, Wang L, Beconi M et al. (2R)-4- oxo-4-[3-(trifluoromethyl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]-1-(2,4,5-trifluorophenyl) butan-2- amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005; 48: 141-151. 30. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin 2008; 24: 489–496. 31. Dhillon S. Sitagliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs 2010; 70: 489–512. 32. Migoya EM, Bergeron R, Miller JL et al. Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1. Clin Pharmacol Ther 2010; 88: 801–808. 33. Mannucci E, Ognibene A, Cremasco F et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care 2001; 24: 489–494. 34. Nauck MA, Meininger G, Sheng D, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194– 205. 35. Harrigan RA, Nathan MS, Beattie P, Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity and treatment, Ann Emerg Med 2001;38:68–78. 36. Bolen S, Feldman L, Vassy J, et al.,Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus, Ann Intern Med 2007;147:386–9 37. Schernthaner G, Grimaldi A, Di Mario U, et al., GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients Eur J Clin Invest 2004;34:535–42. 38. Holstein A, Plaschke A, Egberts EH, Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated withglimepiride versus glibenclamide, Diabetes Metab Res Rev, 2001;17:467–73. 39. Dills DG, Schneider J, Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study, Horm Metab Res 1996;28:426–9.9. 40. Krentz AJ, Bailey CJ, Oral antidiabetic agents. Current role in type 2 diabetes mellitus. Drugs 2005;65:385–411. 41. Martin S, Kolb H, Beuth J, et al., Change in patients’ body weight after 12 months of treatment with glimepiride or 42. glibenclamide in Type 2 diabetes: a multicentre retrospective cohort study. Diabetologia 2003;46:1611–17. 43. Weitgasser R, Lechleitner M, Luger A, Klingler A, Effects of glimepiride on HbA(1c) and body weight in Type 2 diabetes: results of a 1.5-year follow-up study. Diabetes Res Clin Pract 2003;61:13– 19. 44. Wajchenberg BL. Beta cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007; 28:187-218. 45. Chia CW, Egan JM. Incretin –based therapies in type 2 diabetes mellitus. J Clin Endocrinol Metab 2008; 93:3703-3716. 46. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457-2471