Tt/VAN
NHOM THUOC M Q I CHONG OAI THAO Ol/QNG:
THUOC LTC C H E D I P E P T I D Y L PEPTIDASE- 4
Dao Van Phan*
D
e dieu trj dai thao duong typ 2. ngoai viec 'kiem soat che do an uong va tap the due, cac nhom thuoc sau day dang dugc sir dung:- Insulin va cac thuoc lam tang tiet insulin nhu sul- fonylure (glipizid, gliclazid, gliburid), glitinid (repa- glinid, nateglinid).
- Thuoc lam tang nhay cam vdi insulin nhu: thiazo- lidinedion (pioglitazon, rosiglitazon), biguanid (met- formin).
- Thuoc lam giam hap thu glucose tir ruot vao mau nhu thuoc iic che alpha- glucosidase.
May nam gan day. mgt so thuoc moi thuoc nhom thuoc ii'c che dipeptidyl peptidase - 4 dugc phep dua ra thj truong la sitagliptin (Januvia ciia Hang Merck
& Co. dugc Ca quan quan ly thirc pham - thuoc cua My FDA cho phep vao thang 10 nam 2006), sau do la vildagliptin (Galvus ciia Novartis dugc phep luu hanh 6 Chau Au vao thang 2 nam 2008), roi saxagliptin (Onglyza. FDA cho phep nam 2009) va nhieu thuoc dang con o giai doan thir nghiem.
Theo Cochrane Library (2010). eho toi nay da co 12.864 ngudi tham gia trong 25 nghien ciru danh gia 2 che pham thuoc mdi sitagliptin va vildagliptin. Phan Ion dugc theo doi sau 24 tuan diing thuoc, nghien ciru dai nhat la sau 52 tuan. Cac ket qua cho thay 2 thuoc da cai thien dugc mirc duong huyet, thuoc dugc dung nap tot va khong gay ra ha duong huyet nang.
Co' che tac dung ciia thuoc iic che dipeptidyl pepti- dase - 4 (DPP-4 inhibitor)
Duoi tac dung ciia thirc an trong khi an, niem mac
ruot non tiet vao he mach mgt nh6in hormon hudng in- sulin dugc ggi la cac incretin, trong do chu yeu la 2 hor- mon: peptid gidng glucagon 1 (glucagon - like peptide
I - GLP-1) va polypeptid hudng insulin phu thudc vdo glucose (glucose-dependent insulinotropic poly- peptide - GIP). Hai hormon nay dieu hoa bai tiet in- sulin phu thuoc vao glucose. GLP-1 la hormon manh nhat trong so cac incretin, co nhieu vai tro sinh ly:
kich thich sinh tong hgp va bai tiet insulin, iic che bai tiet glucagon, lam cham thao rong da day (giu' thirc an trong da day lau hon binh thudng), lam giam cam giac them an va kich thich tai tao te bao beta ciia dao tuy. GIF thiic day giai phong insulin, nhung trai vai GLP-1, GIP con CO the kich thich giai phong gluca- gon. Tac dung chung ciia 2 hormon nay la lam giam glucose huyet, nhung boat tinh lai phu thuoc vao glu- cose huyet: chimg bj mat hoat tinh khi mii'c glucose huyet ha xuong duoi 65 ing/dL. Trong co the, GLP-1 va GIF CO thdi gian ban thai cyc ngan, nghTa la bj mat hoat tinh chi sau vai phiit bdi enzym dipeptidyl pep- tidase- 4 (DFF-4) CO sin trong nhieu mo: tuy ngoai tiet, luyen mo hoi, tuyen nuac bgt, tuyen sua, hach bach huyet, gan, mat, than, rau thai, tii' eung, tuyen tien liet. da va he mao mach ciia niem mac ruot. Cac thuoc ire che DFF-4 se lam virng ben GIF va GLF-1 ngi sinh. do do co the cai thien dugc benh dai thao duang typ 2.
DFF-4 con co mat trong cac djch ciia co the nhu huyet tuong, djch nao tiiy dudi dang hoa tan, co tac
Trudng Dgi hge Y Hd Ndi
S6 51 (Thang 04/2010) Y HOC L A M S A N G I 59
TtJ" VAN
dung lam mit hoat tinh cua mgt vai hormon va peptid khac. nhu chit P (co vai tro trong dan truyen than kinh cam giac). cac chemokin (ga\ cam irng interferon, ggi dai thuc bao). keo dai tac dung cua neuropeptid Y va hormon giai phong hormon tang truong (growth hormon-releasing hormone).
Sii dung thuoc iic che DPP-4 trong dai thao duong typ 2
Tren benh nhan dai thao duong typ 2 (DTD-2), hieu qua ciia incretin hi giam do mii'c GLP-1 thap hon va tac dung sinh ly ciia GIF kem han so vdi ngirdi co mirc duong huyet binh thirdng. Khi dimg thuoc ire che DPP-4 cho nguai DTD-2 da thiy mirc GLP-1 va GIF ngi sinh tang tro lai, lam tang tiet insulin va iic che tiet glucagon, mirc glucose huyet dugc dieu chinh.
Duoc dong hoc ciia thuoc iic che DPP-4
Hien cd 3 thuoc dang dugc phep luu hanh: sita- gliptin, vildagliptin va saxagliptin. Tat ca deu ire che tren 80% hoat tinh cua DPP-4. la mirc lam ha toi da glucose huyet.
- Sitagliptin: la thuoc dau tien trong nhom dugc lu'u hanh (2006) va thu du'oc nhieu kinh nghien-i sir dung nhat. Lieu 100 mg/lanngay ire che 80% hoat tinh DPP-4 tren 24 gio. Sinh kha dung la 87%, gin vao protein huyet tuang 38%, thdi gian ban thai tir 8 den
14 gid. Fhan ldn khong bj chuyen hoa truac khi bai tiet qua than cho nen dugc chi djnh cho benh nhan co suy than, tuy nhien vin can giam lieu: 50 mg/ngay cho ngudi c6 do thanh thai creatinin tir 30 din < 50 mL/phut; 25 mg/ngay cho do thanh thai creatinin <
30 inL/phiit. Chuyen hoa thuoc khong khac nhau giira ngudi beo- nguoi gay va giira cac nhdm chung tgc.
- Vildagliptin: lien minh chau Au cho phep dimg tir 2008. Lieu dimg 50 mg \ 1-2 lan/ngay. hap thu khong bj anh hudng bai thirc an. Sinh kha dung la 85%. gan vao protein huyet tuong chi khoang 9,3%. Bj chuyen
hoa tai than, thai trii- chii ylu qua than, chi co 22% lieu ulng khong bj chuyin hoa. Thdi gian ban thai la 2-3 gia. Khong thay tuong tac co y nghTa vdi: glyburid.
pioglitazon. ramipin. amlodipin. valsartan. simvasta- tin, digoxin, va warfarin. Khong thay su chuyen hoa khac nhau giua gidi tinh. chi so khoi co the (BMI) va chung tgc.
-Saxagliplin: la thuoc moi dugc phep luu hanh (2009).
Uong lieu 5 mg/lan/ngay. khong phu thuoc vao bua an. Mgt phan bj chuyen hoa d gan thanh chat vin con hoat tinh. Thai trir chii yeu qua than. Tren benh nhan CO suy than (do thanh thai creatinin < 50 ml/phiit) hoac khi phoi hgp thuoc thi giam lieu xuong 2,5 mg/
ngay. Thuoc con dang dugc danh gia lam sang.
Tac dung duoc ly ciia thuoc uc che DPP-4 - Tdc dung hg glucose huyet:
Cac thir nghiem ngau nhien cd kieiu cluing da cho thay 2 thuoc ire che DPP-4 sitagliptin va vildagliptin da lam ha mirc HbAIc mgt each co y nghTa. toi 0.74%. Sitagliptin lam ha glcose huyet khong kem glipizid hoac rosiglitazon, nhung kem metformin hoac exenatid mgt chiit. Con vildagliptin CO hieu qua tuong ty vai rosiglitazon. pioglitazon va acarbose. nhung khdng bang metformin.
Mgt dae diem noi trgi ciia thuoc iic che DPF-4 la lgi the tac dung tren te bao beta ciia dao tuy. Thuc nghiem tren mo hinh loai gam nham cho thay thuoc ire che DPP-4 da ire che sy chet theo chuang trinh (apoptosis), lam tang sir sao chep va tang khoi lugng ciia te bao beta tuy.
Ngoai ra, thuoc con co tac dung ca tren te bao alpha tuy. 0 benh nhan eb DTD-2, te bao alpha cung bj rdi loan chu'c phan, dan den khong dieu hoa dugc san xuat glucagon nen viec san xuat glucose tir gan khong bi ire che khi dirdng huyet tang. Cac incretin lam tang nhay cam cua te bao alpha vdi glucose, vi thi khi dimg cac thudc u'c che DPP-4 da lam giam mgt each thich hgp lirgng glucogon sau an.
60 I Y H O C L A M S A N G S6 51 (Thang 04/2010)
TLf VAN
J*
- Cdc ldc dung khde:
Ngoai tac dung tren chuyen hoa glucose, cac hormon incretin co the con co tac dung tren chuyen hoa lipid, tren huyet ap va tim mach. Mac dau GLP-1 ngi sinh da dugc chirng minh la lam chain su thao rong da day, lam chan an va giam an, nhung khi dimg thuoc ire che DPF-4 lam tang GLP-1 ngi sinh lai khong thay tac dung tuong ty. Trong mgt nghien ciru so sanh vildagliptin vdi rosiglitazon (Rosenstock .1, va cs, 2007) da cho ket qua sau: vildagliptin 50 mg x 2 lan/ngay lam giam triglycerid 9%, cholesterol toan phan 14%, LDL 16% nhieu hon so vdi rosiglitazon.
Vildagliptin chi laiu tang nhe HDL 4%. Dudng nhu sy giam lipid huyet khong lien quan vdi tac dung ha glu- cose huyet ciia cac thuoc nay. Sulfonylure va thiazoli- dinedion vdi hieu qua ha glucose huyet tuong duong da khong cd hieu qua ha lipid huyet tuang duong khi so sanh vdi thuoc ire che DPF-4.
- Cdc ldc dung khdng mong mudn
Fhan tich ggp ciia rat nhieu nghien ciru da cho thay cac thuoc ire che DFP-4 nhin chung dugc dung nap tot. Thuoc khong gay ra ha dudng huyet qua mirc.
khong lam tang can. Cac tac dung khong mong muon thudng nhe nhu rirc dau, nhiem khuan nhe dudng ho hap tren, dirdng tiet nieu. phan irng qua man, roi loan chirc nang gan, doi khi co viem tuy cap.
DPP-4 la peptidase co a mang te bao. trong khi a mang te bao ac tinh thay DPP-4 mat han hoac bi bien doi. vi the DPP-4 dugc coi nhir co vai tro bao ve te bao chong ung thu. Do do, ve mat ly thuyet. cac thuoc ire che DPF-4 co the se lam phat trien mgt so ung tlur. Tuy nhien. theo doi tren chugt thuc nghiem dai ngay vdi thuoc ire che DFF-4 chua phat hien dugc tac dung gay ung thu.
KET LUAN
Mac dii nh6n-i thuoc ire che DPP-4 moi dugc dua vao sir dung, con chua dugc nghien ciru danh gia that day du. tham chi con co vai nhan xet la tac dung ha glucose huyet chua bang mgt so thudc hien dimg, dae biet la insulin, nhung nhirng nghien ciru da cho thay co che tac dung ciia thuoc da bo sung cho cac thuoc truyen thong dang dimg, hieu qua dieu trj tuong duong vdi nhieu thuoc truyen thong. Dae biet la nhom thuoc mai dugc dung nap tot. khong lam tang can. bao ve dugc te bao beta, co tac dung chong tang dudng huyet va khong gay ha dudng huyet qua mirc, khong CO chong chi djnh dang chii y. Nhirng dieu do lam cho nhdm thuoc nay tra nen hap dan de dimg cho ngudi cao tuoi, la nhdm ngudi thuang cd nhieu benh, dimg nhieu thuoc va khd sii- dung insulin.
TAI LIEU THAM KHAO
1. Ahren B, Pacini G, Tiira A. Foley JE, Schweizer A- Improved meal-related insulin processing confi'ibiites to the enhancement of B-cell function hy the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes. Harm Metab Res.
2007:39(II):826-829
2. .lohn Wiley eft Sons- Cochrane Database cf Systemic Reviews 2010 Issii 2. Cochrane Lihraiy (ISSN 1464-780X).
3. Cox M E, Rowell J, Corsino L. Green J B- Dipeptidyl peplidase-4 inhibitors in ihe management of type 2 diabetes:
safet): lolerabilify and efficacy. Drug, Healthcare and Patient Safely 2010: 2:7-19.
4. Monami M, lacomelli I Marchionni N, Manniicci E- Dipeplidyl-peptidase-4 inhibitors in type 2 diabetes: a meta analysis of randomized clinical trials. Niifr Metab Cardiovase Dis. 2009: DOI: 10.10I6/j.mimecd.2009.03.015.
5. Rosenstock J. Baron MA. Dejager S. Schweizer A- Comparison of vildagliptin and rosiglilazone monotherapy in patients with type 2 diabetes: a 24-week, doiible-hlind. randomized trial. Diabetes Care. 2007: 30(2): 217-223.
6. hilp:'en.Wikipedia.(,rg.wiki DipeptidyljK'plidase-4jnhihiior
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