Thromboxane/Prostacyclin Balance in Type II Diabetes: Gliclazide Effects Za Zh Fu, Tang Yan, Yuslu Chen, and Ji Quang Sang .to-PGF,(6KPGF,) glucose nau, and ipiipoprotain OM Iced frm therapy svithatbonelomde profes in 27 patente wth non inauar-capender cuore i Tate) twat (GLBH] or without phenformin) to giclatide fr 3 months. We found that therapy with glclazide was followed by @ (Jecreogen serum TXBy (281 8 = 128.3 10 149.1 + 77.0 mg/L, P< .001] and an increase in serum 6KPGF, (60.5 > 19.1 1096.0 20.3 mg/L P< 001). This was accompanied by 9 decrease In ttal and low-density Epoprotein (LDU cholesterol and an increase In high-density ipoprotein {HDL cholesterol, within the HOL, chotestert fr tion. Theae changes wore seen despite the foct thet ‘neither fasting plasma glucose nor insulin changed with therapy These fndings sungeet that glazide may have Denese actions ‘On earéhovascular ak factors in these NIDDM patients, Copyright © 1992 by WB. Seunders Company |OME DIABETIC PATIENTS show hemobiological ab- hormlities such as ineveased platelet adhesiveness, platelet hyperaggreaabilty, decreased platelet hall-ule, e- ‘morrheological abnormalities, and altered fibrinolysis, per haps contributing to a procoagulaive state." Glictzide™ has hhemabictogcal properties. and animal studies have shown a correction of this thromboxane Az (TXA;\/prostacyelin (PGI,) imbalance by this drug” Hyperinsulinism has been considered tobe a cardiovascular risk factor, Syndrome X, which associates insulin resistance, hyperinsulinemia, alueose intolerance. increased very-low= density lipoprotein (VLDL), decreased high-density lipopro- {cin (IIDE) cholesterol, and disturbances of flbinolyis, has been desribed." Links with atherosclerosis and hypertension rhave been demonstrated" ‘The aim of our study was to asses the effects of gliclazide oncertin cardiovascular risk factors, focusing on the TXAs/ PGI, imbalance and on lipid/lipoprotein profiles in patients previously treated with insulin or various oral antidiabetic regimens MATERIALS ANO METHODS “Twenty-five patents wih non-intulin-dependent bets mais (NIDDM) were randomly etd from the Diabetic Specials Clinic Sun Yat Sen Memorial Hospital. They were a subgsoup of 114 [NIDDM paints who had been regulary fllowed hee fom Avg 1986 to March 1987, The subgroup oF28 patients comprised group ‘reviously treated with gibenlamide (GLB) o glibenclamide with ‘henformia (GLBH), All paents were switched to glade for 3 months Patients were administered 60 mg except fo fou patents who received eter 8D mgd (a = 2) 0240 mpl (a = 2) Prostaglandins ‘pnthens inhibitors adrenosoricide, nonearoial aninfarmatory Table 1. 1X8, and KPO, After Giclanide Pi wa slow icande 281821203 «Goss 101 Ate ghdanse “GIs 770 WOz403" 18 NOTE Normal anges "Pa 00% * Developed and produce in France by LES LABORATOIRES SERVIER under the registered trademark DIAMICRON®. Metabolic, Vol 43 No 5, Sapp May, 1992: 99 23.98 ‘rugs, slicltes, dipyridamole, thephyline, herbal medicines, tain E anc drugs afeting lipid metabolism were disootinued 3 nec before switehing wo ize, Methods ‘An assessment ofthe paints was performed at baseline ander completion of months of therapy. Thsincuded a detailed medical history. clinical examination, ECG, and determinations of levels of ‘sing plasma gucose (glucose oxidase method), ilycerdes (TC (TG-zceylacetone chomaicgapoy). and total cholesterol (TCH) (choleterie method), HDL cholesterol war subdivided into HDL and HDL, cholesterol glucose suphate/magaesium conde double ‘reciitaon method) Instn vas syed bythe acvimmuncasay ‘ouble antibody method. Thomborane By TXB,)ané 6010 PCF, (6KPGF.)" assessment flowed the method of he Chines Teste ‘of Medical Sciences. Department of Basic Rescarch Low-density poprotein (LDL) cholesterol was akuated flowing te Feedewald formula: LDL choleeral mmol/L) = TChol (mol) L)~ HDL cholesterol (mmcl/L} + 's TG (mmol/L). Standard ets were used o compere hoth subgroups atthe start ‘and ater siclazide treatment Results wre presented 25 the mean 80, ResuLTs Baseline levels of TXB, and 6KPGF, were within the range usually observed in NIDDM patients treated with oral agents [Afr 3 months of gliclazide therapy. TXB, decreased by al- ‘most 50%, and 6KPGF, increased by approximately 50% (Table 1), This changed the calculated TXB3/PGF, rato from 4610 1.6, ‘Similarly, baseline lipid and lipoprotein levels were within ‘the range we usually se in patients treated with oral agents. ‘Afr glclazde therapy, there was no change in plasma TG. fof HDL; cholesterol but there was a significant decrease in ‘TChol and LDL cholesterol, with an increase in HDL cho- lesterol in the HDL; faction Table 2) ‘These changes in arachidonic avi metabolites, lipids, and lipoproteins were seen despite the fact that neither fasting plasma glucose nor insulin levels changed after pliclazide therapy (Table 3) From the Memorial Hospital. Sun Yat-Sen University of Metical Sciones, Guangzhou, People's Republi of China “iiss reprnequets 0 Zu 2 Fu, MD. Memorial Host Sim YaeSen Univeretyof Medical Sciences. 107 Yon Liang Road 1 Guangzhou, People's Republic of China. Consrighe © 1992 by WB Savxders Company (0926-0495/92/4105-1008803.00/0 PU04381 ENGO. or tantoes olin {MATable 2, Lipia/ipoprotsine Ata Switching to Glclaide _ waa aes Before gine sos22 6210 ‘Aer sane perer) 55210r Tiere eee ae ‘ome 02100 osso1 «aso8 hisow oss01 09201" 35208 "NOTE Nowra nges oe Sen 08 piscussion ‘Our study Focused on the TXAx/PGI, ratio and on lipid Iratameters. vat group of patients had abnormal values for the TXAs/PGK; ratio while under treatment with other oral ‘agents. Gliclazide induced an improvement ofthe ratio, which decreased from 4.6 10 1.6. “Gliclazide has been shown to have hemobiological prop- certies that are not found with other hypoglycemic sulpho- nylureas. Gictazide corrects platelet hyperadhesiveness and. hyperaggregation (in animals and in man), anomalies which may be linked tothe TXAy/PGI, ratio disturbances. Tsuboi ct alf have shown in animal that gliclazide treatment can decrease the levels ofthe proauarezting and vasoconstrcting Tuctor, TXAs. Vili et al and, more recently, Florkowski et al” have observed similar effects of glclazide in diabetic pa- lients. Moreover. this effect appeared to be independent of the metabolic eect. Fujitani etal have eported that in diabetic animals, PGlz syathesis and its transformation from endoperoxide and ar- achidonic acid was increased after glclazide, without any ‘correlation with blood glucose levels. GLB, tolbutamide, and ‘chlorpropamide do not share these properties. No data have yet been presented on the plidaide action on PGI; in hu Many studies have evaluated the effects of gliclazide on platelets"? The mechanisms of action appear to be en hancement of eyetic adenosine monophosphatase (cAMPase) ‘or an increase in PGI. Tsuboi etal postulated that such action might be caused by inhibition of the arachidonic acid released by the platelet membrane. The decreased adhesive- ness aggregation, and activities of certain enzymes, and the prolongation of platelet lifespan all indicate a decrease of platelet activity. TXA:, a product of platelet agsregation, causes an irreversible increase ofthe second phase of agpre- xtion AAS PGi: inhibits platelet aggregation and relaxes vascular smooth muscles, the decrease in PGI; levels and the increase in TXA, levels in diabetes could facilitate the development of microthrombi, leading o diabetic microvascular eorpli- cations. The use of liclazide, which normalizes TXA,/PGI, imbalances, may be viewed as beneficial for the prevention of diabetic microvascular complications ‘The improvement in the TXA:/PGl, rato is associated with an improvement of lipid parameters. Only afew reports have focused on the action of gliclazide on lipid metabo- lism.™"" Berber and Tomkin have observed a significant in- crease of HDL cholesterol after glaze therap.'* Our study Iso demonstrated a significant increase of HDI} cholesterol Without modification in HDL2 cholesteral: concurrently TChol and LDL cholesterol have significantly decreased ‘While both insulin and gliclazide improve the TXA,/PGL: ratio, only glclazde will normalize insulin levels and lower lipid levels. This could present some therapeutic advantage in the prevention of atherosclerosis, Table 3, Glucote and ingutn Levels Afar Gelso Bene, ea Before gicaace waza W382 796 ‘Aft gence 102238 1205825 NOTE. Nowmal anges we im pretences, Arevotone FPG, fas pase goss; NS, meu, REFERENCES |, Poma M, Peters AM, Cousins SA, ea A sy’ of platelet: relevant parameters patients with diabetic microangiopathy. Di beologis 2521-2, 1983 2 Danger KIC, Jennings PE, Teop Mi. etal: Platt gestion sn esagulatio actin inslin dependent habetes wth and without Imereansiopathy. Dabetic Med 48, 1987 5. Tindall H, Pane RC, Zvzel M,et a: Plate fe span in diabetes ith and without etoopathy, Thromb Res 2541-64, 98 4 Colvell JA, Halu PV Sai Kea Altered pat funtion te dates meta. Dineen 251826831, 1978 (upp) Sones DB, Caner RD. Haitas Be al: Low phospholipid ar thidonic aid values in diabetic patents. Br Med J 286:17417S. irs} 6. Touboi T, Fujitant B, Maeda. tai Met of ghlrige on prostaglandin and thromboxane synihess in guinea ig pats ‘Thromb Ret 2103-10, 1981 7. 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