Thiazolidinediones: A 2010 Perspective

Transcription

1 credits vilble for this rticle see pge 95. Thizolidinediones: A 2010 Perspective Ashok Krishnswmi, MD, FACC Shlini Rvi-Kumr, MD John M Lewis, MD Abstrct A lrge number of crdiology clinicl trils hve mortlity s n endpoint unless dequte surrogte endpoints re vilble. Although there re nine clsses of gents used in the tretment of dibetes mellitus, none hve shown mortlity benefit in clinicl trils. The United Kingdom Prospective Dibetic Study ws the first to suggest tht metformin given for dibetes mellitus hd trend towrd lowering mortlity. The ccidentl discovery of peroxisome prolifertor-ctivted receptors (PPARs) led to the introduction of the thizolidinediones (TZD), PPAR gent with suggestion of promise for the future. As the incidence of crdiovsculr complictions relted to dibetes mellitus increses, there is sense of urgency to produce ntidibetic medictions tht chieve not only nontoxic glycemic control but lso improved crdiovsculr outcomes. The gol of this review is to id the clinicin to ppropritely ssess the benefits nd risks of TZD use when prescribing for ptients. Introduction It is well known tht microvsculr disese in type 2 dibetes mellitus cn be hlted with ggressive glycemic control. Even with nine clsses of ntidibetic gents currently on the mrket, only the bigunide metformin hs shown trend towrd decresing mcrovsculr disese. The gol so fr, understndbly, hs been focused on glycemic control. However, with the bundnce of hypoglycemic gents on the mrket, medictions will hve to be chosen to not only chieve glycemic control but lso decrese crdiovsculr mortlity. The thizolidinediones (TZDs) re the first group of ntidibetic medictions tht ttempted to scle this pinncle of reducing crdiovsculr mortlity within highly competitive ren. In July 2008, the US Food nd Drug Administrtion (FDA) convened meeting to discuss the question of whether there should be requirement tht ny ntidibetic medictions without concerning crdiovsculr sfety signl during erly-phse clinicl trils be further studied in long-term crdiovsculr tril. 1 The nswer ws resoundingly in the ffirmtive for the need to hve future ntidibetic medictions chieve beneficil crdiovsculr mortlity profile before FDA pprovl is given. TZDs re clss of medictions currently pproved by the FDA to tret type 2 dibetes mellitus. However, there is significnt debte surrounding its sfety. Troglitzone, the first TZD to be pproved by the FDA to tret type 2 dibetes mellitus ws withdrwn in the yer 2000 becuse of idiosyncrtic heptotoxicity. Currently there re two TZDs on the mrket: rosiglitzone (Avndi) nd pioglitzone (Actos). Becuse they improve insulin sensitivity 2 nd crry low risk of cusing hypoglycemi, they hve been quickly incorported into clinicl prctice nd represent s much s 25% of totl prescriptions for orl hypoglycemi medictions. 3 However, the TZDs specificlly, rosiglitzone hve fced gret del of criticism becuse of the discovery of worrisome dverse ffects. This hs ffected TZD prescribing ptterns within Kiser Permnente Northern Cliforni (KPNC) (Tble 1). The most debted side effect is whether rosiglitzone cuses hert ttcks. The im of this review is to shed light on the overll understnding of TZDs. Subsequently, we hope tht it provokes helthy discussion regrding the pproprite use nd plcement of TZDs (specificlly, pioglitzone) within the KPNC PHASE (Prevent Hert Attck nd Stroke Everydy) progrm. Biology of Peroxisome Prolifertor Activted Receptors Peroxisome prolifertor-ctivted receptors (PPARs) re fmily of intrcellulr receptors for ftty cids nd ftty-cid derivtives. Three types of PPARs re expressed in vriety of metbolic tissues: PPAR-α, PPAR-β/δ, nd PPAR-γ. PPARs, unlike other receptors, re locted within the cell nucleus, where they re thought to exert their effect of regulting gene trnscription directly within the cell. Ech receptor hs unique loctions nd functions. PPAR-α is expressed in metboliclly ctive tis- Ashok Krishnswmi, MD, FACC, is Stff Crdiologist nd Locl Reserch Chir in the Deprtment of Crdiology t the Sn Jose Medicl Center in CA. E-mil: shok.krishnswmi@kp.org. Shlini Rvi-Kumr, MD, is n Internl Medicine Resident t the University of New Mexico in Albuquerque. E-mil: shlini.sreejith@gmil.com. John M Lewis, MD, is n Ophthlmologist with n expertise in retinl diseses t Kiser Permnente Snt Clr Homested in CA. E-mil: john.m.lewis@kp.org. 64 The Permnente Journl/ Fll 2010/ Volume 14 No. 3

2 Thizolidinediones: A 2010 Perspective Tble 1. Crude thizolidinedione (pioglitzone nd rosiglitzone) use within Kiser Permnente Northern Cliforni in two contiguous yers September 2006 August 2007 September 2007 August 2008 Pioglitzone prescriptions 84,882 83,011 Totl number of ptients tking pioglitzone 29,507 28,049 Rosiglitzone prescriptions Totl number of ptients tking rosiglitzone Dt from written personl communiction from Jim Chn, PhrmD, PhD, September 30, sues such s the liver nd plys lrge role in lipid nd lipoprotein metbolism nd lso in suppressing vsculr nd systemic inflmmtion. Fenofibrte nd gemfibrozil re some importnt exmples of lignds for this receptor. PPAR-δ is the most widely distributed PPAR. Its exct role is yet uncler, but it too plys role in lipid metbolism; it lso plys role in cholesterol homeostsis in mcrophges, embryo implnttion, nd cell prolifertion. PPAR-γ is mostly expressed in dipose tissue (dipocytes). It is lso found in skeletl muscle, heptocytes, intestinl tissue, endothelil cells, crdic muscle, the renl collecting duct, nd in mcrophges. The primry role of PPAR-γ ppers to be in regulting dipogenesis long with glucose nd lipid metbolism. PPAR-γ is thought to enhnce the ctions of insulin nd decrese resistnce to insulin. Lignds for PPAR-γ include free ftty cids, certin prostglndin derivtives, nonsteroidl nti-inflmmtory gents, nd TZDs. All TZDs hve vrying selectivity for ech PPAR receptor nd thus hve vriety of effects on the humn body besides their primry ction 3 7 (Tble 2). Effects of Thizolidinediones on Dibetes Mellitus, Lipids, nd Adipocytes TZDs hve dditionl effects besides their primry role s ntihypoglycemics. They typiclly reduce glycted HbA 1c by 1% to 2% when compred with plcebo. This is similr to the hypoglycemic effects of the sulfonylures nd metformin. 8 They do this primrily by incresing skeletl muscle glucose uptke nd less by decresing heptic production of glucose. They lso re thought to preserve β-cell function; this effect hs been shown in niml models s well s in humn studies. They hve vrying effects on lipid metbolism. Both TZDs increse high-density lipoprotein (HDL) cholesterol nd low-density lipoprotein (LDL) cholesterol. A vrition between the two TZDs hs been noted in respect to their effects on LDL prticle concentrtion nd size, producing n overll shift to lrger, more buoynt LDL prticle. Triglyceride levels re lso decresed with both TZDs, with there being lrger decrese with pioglitzone. These effects my be relted to pioglitzone s effect on heptic PPAR-α. TZDs lso increse body weight by differentition of predipocytes to dipocytes nd incresing dipocyte mss. Although it is known tht incresed levels of diposity increse the propensity of crdiovsculr risk, other fetures of TZDs re thought to perhps ttenute this risk. One such exmple is redistribution of ft from viscerl to subcutneous depots, pttern tht is thought to be ssocited with decresed risk for crdiovsculr disese (CVD). 3 This pttern of chnge is lso ssocited with incresed diponectin nd decresed tissue-necrosis fctor α levels. Both re ssocited with fvorble chnges in CVD risk profile. TZDs lso decrese circu- Tble 2. The beneficil nd hrmful effects of thizolidinediones Beneficil effects Hrmful effects Improvement in crdic function Increse in body weight Improvement in crdic metbolism nd glucose uptke Fluid retention Coronry vsodiltion Possible congestive hert filure Regression of left ventriculr hypertrophy Possible mculr edem Improvement in vsculr insulin resistnce Frctures Decrese in blood pressure Increse in LDL-cholesterol Improvement in endothelil function Highly debted risk of myocrdil infrction Increse in HDL cholesterol nd decrese in triglycerides Decrese in HbA 1c by 1-2% Exct risk is unknown. Prospective rndomized clinicl tril plnned by GlxoSmithKline, producer of rosiglitzone hlted by the US Food nd Drug Administrtion. LDL = low-density lipoprotein; HDL = high-density lipoprotein. The Permnente Journl/ Fll 2010/ Volume 14 No. 3 65

3 Thizolidinediones: A 2010 Perspective lting free ftty cids, with resultnt fvorble effects on the liver nd skeletl muscle. 3 Effects of Thizolidinediones on Inflmmtion nd Endothelil Function Vsculr inflmmtion is fundmentl component in the process of therosclerosis. This process, with subsequent thrombosis, is lengthy nd complicted, developing usully over decdes. The finl rupture of the therosclerotic cp, with spillge of the highly thrombogenic infrcp contents into the coronry vessel lumen, is the explntion for most ftl coronry thromboses. However, for coronry plque progression to occur, continued inflmmtion is needed. Numerous meditors of inflmmtion re expressed, such s dhesion molecules nd growth fctors, wheres relese of chemottrctnts nd elbortion of cytokines weken the fibrous therosclerotic cp. It is thought tht trnscription fctor nucler fctor (NF)-kB medites mny of the inflmmtory processes tht occur during the development of therosclerosis. Multiple studies hve suggested tht PPAR ctivtion fvorbly modultes NF-kB ction. 3 TZDs lso fvorbly ffect coronry nd peripherl vsodiltion, long with minimlly improving blood pressure. These effects re thought to be medited by incresing endothelil relese of nitric oxide, incresed expression of vsculr endothelil growth fctor, nd decresed expression of endothelin-1. TZDs lso prtilly inhibit voltge-gted L-type clcium chnnels. These chnnels re the mechnisms of ction on the nondihydropyridine clcium-chnnel blockers. Although the effect of blood pressure reduction is miniml, epidemiologic estimtes suggest tht this smll chnge my provide significnt decrese in the risk of stroke nd myocrdil infrctions. 3 Dt Fvoring Thizolidinediones (the Good or Neutrl) The Dibetes Control nd Complictions Tril (DCCT) conclusively demonstrted tht tight glucose control in persons with type 1 dibetes significntly decresed microvsculr complictions such s retinopthy, nephropthy, nd neuropthy. 9 After follow-up period of 7 to 9 yers of 1205 persons with well-controlled type 1 dibetes who were involved in the DCCT study, the Epidemiology of Dibetes Interventions nd Complictions study showed decresed mcrovsculr complictions (coronry clcifiction). 10 A decrese in microvsculr complictions in persons with type 2 dibetes mellitus is thought to be bcked up by resonbly strong dt. 11,12 Although it ws shown in 1982 tht intensive glycemic control decreses microvsculr complictions in type 1 dibetes mellitus, there is yet no conclusive proof tht current FDA-pproved tretment cn reduce the risk of mcrovsculr complictions in persons with type 2 dibetes mellitus. The University Group Dibetes Progrm ctully showed tht tolbutmide incresed crdiovsculr mortlity. 8 The United Kingdom Prospective Dibetes Study ws the first study to suggest tht dibetic mediction hd fvorble CVD risk profile. It showed nonsignificnt reduction (p = 0.052) in myocrdil infrction in ptients treted intensively with insulin or sulfonylures. It lso showed reduction in dibetes-relted deth nd llcuse mortlity in substudy of 342 overweight persons given metformin. 12 In 10-yer post-tril observtionl follow-up ssessment, the reduction in these CVD events becme sttisticlly significnt. 13 Numerous studies hve ssessed the role of TZDs in persons with type 2 dibetes mellitus. Smll controlled studies using surrogte mrkers such s crotid intimlmedi thickness (IMT) hve shown decrese in the progression of crotid IMT in persons treted with TZD. Protective effects ginst restenosis fter percutneous intervention in TZD-treted ptients hve lso been noted. 3 Lrge rndomized, controlled trils tht hve ssessed the effects of TZDs on mjor CVD events tht re completed or ongoing re described in the following prgrphs. In evluting the results of ll these trils, one should distinguish those tht compre TZDs with plcebo s n dd-on therpy to those tht compre TZDs with other hypoglycemic drugs. PROctive 14 (the PROspective pioglitazone Clinicl Tril In mcrovsculr Events) ws the first study tht ssessed the effect of n ntidibetic mediction on crdiovsculr outcomes. PROctive ws well-run prospective rndomized-controlled tril in 5238 ptients, designed to ssess whether pioglitzone titrted to mximum dose of 45 mg/d, compred with plcebo in ddition to the usul stndrd of glycemic therpy cre, decresed mcrovsculr events. The verge follow-up period ws 34.5 months. The results showed sttisticlly nonsignificnt reduction in the primry endpoint (ll-cuse mortlity, nonftl myocrdil infrction, stroke, cute coronry syndrome, endovsculr or surgicl intervention in the coronry or leg rteries, or bove-the-knee mputtion) in the pioglitzone group. This ws despite n dequte number of events in both rms of the study (514 of 2605 in the pioglitzone group nd 572 of 2633 in the plcebo group; p = 0.095). However, the secondry endpoint tht ws predefined (ll-cuse mortlity, myocrdil infrction, 66 The Permnente Journl/ Fll 2010/ Volume 14 No. 3

4 Thizolidinediones: A 2010 Perspective or stroke) ws significntly reduced in the pioglitzone group (301 ptients in the pioglitzone group nd 358 in the plcebo group; p = 0.027). It is noteworthy tht the time to permnent insulin use ws significntly decresed in the pioglitzone group. ADOPT 15 (A Dibetes Outcome Progression Tril) ws multicenter, rndomized, double-blind, controlled clinicl tril tht sought to nswer whether monotherpy with either rosiglitzone, metformin, or glyburide ws sufficient to mintin euglycemi in persons in whom type 2 dibetes mellitus hd recently been dignosed nd who hd not tken ny dibetes medictions before. The primry outcome ws the time to monotherpy filure (plsm glucose >180 mg/dl fter n overnight fst). Anlysis of the outcomes showed cumultive incidence of monotherpy filure t 5 yers of 15% with rosiglitzone, 21% with metformin, nd 34% with glyburide. This ws 32% greter risk reduction for rosiglitzone compred with metformin, nd 63% greter risk reduction compred with glyburide (p < for both comprisons). However, some importnt limittions of the study should be mentioned: 1) the study ws n efficcy nd sfety tril nd not primry crdiovsculr endpoint tril; 2) there ws lrge withdrwl rte; nd 3) ptients with type 2 dibetes mellitus were in very erly stge in this study, nd thus they my not represent the generl popultion of ptients with type 2 dibetes mellitus. Preliminry crdiovsculr sfety findings hd not detected significnt difference in crdic ischemic event rtes between rosiglitzone nd metformin or glyburide, but mny believe tht n incresed risk cnnot be ruled out. 1 There were understndbly more ptients with hert-filure events with rosiglitzone thn with metformin or glyburide. The DREAM 16 (Dibetes REduction Assessment with rmipril nd rosiglitzone Mediction) tril ws primry prevention study to ssess whether rosiglitzone would prevent type 2 dibetes mellitus in persons t high risk for developing the disese. The inclusion criteri included either impired fsting glucose (fsting plsm glucose of mg/dl nd 2-hour plsm glucose <200 mg/ dl during the orl glucose tolernce test) or impired glucose tolernce (either fsting plsm glucose <126 mg/dl nd 2-hour plsm glucose of mg/dl). The exclusion criteri were history of type 2 dibetes mellitus, CVD, or intolernce of either mediction. For the study, 24,592 ptients were screened (18,784 were excluded), with totl of 5269 ptients rndomized to tretments (2635 to the rosiglitzone rm; 2634 to the plcebo rm) nd followed for medin of 3.0 yers. Rosiglitzone ws titrted to mximum dose of 8 mg/d nd rmipril ws titrted to mximum dose of 15 mg/d in 2 2 fctoril design. The primry outcome ws composite of incident type 2 dibetes mellitus or deth. The results of the study showed tht fewer individuls experienced the composite primry outcome in the rosiglitzone group compred with the plcebo group [306 (11.6%), 686 (26.0%); p < ]. One-hlf of the individuls in the rosiglitzone group nd pproximtely one-third of the plcebo group chieved normoglycemi [1330 (50.5%), 798 (30.3%); p < ]. Also mong individuls with impired fsting glucose or impired glucose tolernce, tking rmipril for 3 yers significntly incresed regression to normoglycemi but did not significntly decrese the incidence of type 2 dibetes mellitus or deth. The ACT NOW 17 tril, presented t the Americn Dibetes Assocition 2008 meeting, rndomized prticipnts to plcebo or pioglitzone titrted to 45 mg/d. Pioglitzone decresed the rte of progression to type 2 dibetes mellitus (1.5% per yer) compred with plcebo (6.8% per yer; hzrd rtio [HR], 0.19; p < ). The risk of frcture, hert filure, nd other dverse events ws similr except for higher rte of edem in the pioglitzone group compred with plcebo (22% vs 15%). In April 2008, results of the PERISCOPE 18 (Comprison of Pioglitzone versus Glimepiride on Progression of Coronry Atherosclerosis in Ptients with Type 2 Dibetes) tril were published. PERISCOPE ws coronry intrvsculr ultrsound (IVUS) study in 547 ptients with type 2 dibetes mellitus who underwent coronry ngiogrphy for clinicl indictions with trget vessel for IVUS tht hd stenosis of <50% in n re of 40 mm or longer. The primry endpoint ws chnge in percent therom volume (PAV) from bseline. They were then rndomized to receive either glimepiride or pioglitzone, which ws then titrted to mximum tolerted dose. If ptient required crdic ctheteriztion for clinicl indiction t point between 12 nd 18 months, followup IVUS study ws performed. Only 181 ptients in the glimepiride group nd 179 ptients in the pioglitzone group were included in the primry nlysis (66% of the initil cohort). The lest-squres men of the PAV incresed in ptients tking glimepiride nd decresed in ptients tking pioglitzone (0.73 vs 0.16; p = 0.002). RECORD (Rosiglitzone Evluted for Crdiovsculr Outcomes in orl gent combintion therpy for type 2 Dibetes) ws multicenter, open-lbel, noninferiority tril tht rndomized persons who hd indequte glycemic control with metformin or sulfonylure to either receive dd-on rosiglitzone or not. An interim nlysis 19 to ssess for incresed rtes of myocrdil the unknown risk of myocrdil infrction with rosiglitzone is the biggest nd most heted debte. The Permnente Journl/ Fll 2010/ Volume 14 No. 3 67

5 Thizolidinediones: A 2010 Perspective no TZD hs shown hrmful effect on crdic structure or function. infrction ws not conclusive. The finl nlysis 20 gin noted no differences in the primry endpoint, with 321 events in the rosiglitzone group nd 323 events in the control group (HR, 0.99; 95% confidence intervl [CI], ). As suspected, there ws n incresed risk of congestive hert filure (HR, 2.10; 95% CI, ) nd frctures (HR, 1.57; 95% CI, ). The APPROACH 21 (Assessment on the Prevention of Progression by ROsiglitzone on Atherosclerosis in dibetes ptients with Crdiovsculr History) tril, the results of which were published recently, ws n IVUS tril tht rndomized ptients presenting to crdic ctheteriztion lbortory who hd t lest one re in their epicrdil coronry rteril system tht contined n therosclerotic plque tht ws not intervened upon prior with stenosis of 10-50%. This tril noted no chnge in the primry endpoint (PAV), wheres one secondry outcome, normlized totl therom volume, ws significntly reduced ( 5.1 mm 3 ; 95% CI, 10.0 to 0.3; p = 0.04). Recently published findings of three clinicl trils Action to Control CrdiOvsculr Risk in Dibetes (ACCORD), 22 the Veterns Administrtion Dibetes Study, 23 nd the Bypss Angioplsty Revsculriztion Investigtion in Type 2 Dibetes (BARI 2D) 24 showed no firm cusl ssocition between rosiglitzone nd ischemic hert disese (IHD) events. Dt Not Fvoring Thizolidinediones (the Bd) Known dverse effects tht occur with the use of TZDs re discussed in the following sections. Some of these re thought be unique to prticulr TZD, nd others my be thought of s clss effect. Some hve more robust bcking of scientific dt; others hve less. The most-recognized dverse effects include peripherl edem, hert filure, mculr edem, nd frctures. The overll medicl community now is well wre of the effects of TZDs on peripherl edem nd hert filure. However, the unknown risk of myocrdil infrction with rosiglitzone is the biggest nd most heted debte. Edem The incidence of new or worsening edem is noted to occur in 2.5% to 16.2% of persons with type 2 dibetes mellitus. This risk increses with incresing ge, higher doses, femle sex, nd incresing cretinine levels, with concomitnt use of insulin. Two mechnisms re thought to contribute to this problem with TZDs. The first is incresing sodium retention nd plsm volume expnsion becuse of the presence of PPAR-γ in the epithelium of the renl collecting duct. There is some thought tht miloride or spironolctone could decrese this effect. The second is the similrity of TZDs to perhps the dihydropyridine type of clcium-chnnel blockers (eg, nifedipine, nicrdipine, mlodipine) tht exert their effects through L-type clcium chnnels tht my cuse n incresed fluid permebility. 3,25 Hert Filure The second nd more serious problem of hert filure is thought to occur much less frequently, in 0.25% to 0.45% of persons with type 2 dibetes mellitus per yer. 3,25 In My 2007, the FDA recommended, on the bsis of clinicl dt, tht TZD use in ptients with ny degree of hert filure be voided. It is of interest, however, tht no TZD hs shown hrmful effect on crdic structure or function. In fct, some smll studies hve shown improvement in hemodynmic vlues such s stroke volume index nd crdic index. One smll rndomized study ssessed the effect of rosiglitzone versus plcebo in ptients with New York Hert Assocition clss I nd II hert filure nd with left ventriculr ejection frction of <45%. This tril showed n increse in peripherl edem in the rosiglitzone group compred with the plcebo group (25.5% vs 8.8%; p = 0.037). There ws no deteriortion of systolic function nd perhps n improvement in distolic function. 3 In the PROctive study, nondjudicted hert-filure events were more common in the pioglitzone group, but no evidence of increse in hert filure mortlity ws noted. 14 A similr finding ws noted in the interim nlysis of the RECORD study. 19 These studies results suggest n overll low but distinct risk of hospitliztions for hert filure. Mculr Edem Although there hve been cse reports, 26 nd retrospective studies in the literture suggesting the ssocition of mculr edem with use of TZD, the overll evidence either proving or disproving it is fir t best. However, most experts in the field believe tht TZDs probbly excerbte mculr edem nd tht with discontinution of TZDs, mculr edem my decrese or bte completely. A cse exmple is given in Figure 1. Bone Loss Another importnt spect of TZDs is its effect on bone. Erly bsic science nd preclinicl work hve shown tht TZDs decrese osteoblst differentition 68 The Permnente Journl/ Fll 2010/ Volume 14 No. 3

6 Thizolidinediones: A 2010 Perspective nd increse osteoclst formtion, suggesting overll bone loss. The mechnism of TZD effect on bone hs not been completely elucidted but gin ppers to be due to its effect on PPAR-γ. There is hope tht eventully selective PPAR-γ modultors my overcome the undesirble extrglycemic effects. In 2006, the ADOPT group published seprte nlysis of the frcture risk ssocited with rosiglitzone in comprison with metformin nd glyburide. Rosiglitzone hd n incresed reltive risk (RR) of 1.81 compred with metformin nd 2.13 compred with glyburide. A sex-bsed ssocition of risk ws noted, with women hving n incresed risk for both upper nd lower limb fctures; men did not hve n incresed risk in this study. The risk rtios clculted showed the lrgest increses in frcture risk for the foot (RR = 3.3), the hnd (RR = 2.6), nd the proximl humerus (RR > 8). There ws n insufficient number of frctures of the hip nd spine to ssess the risks for these frctures. 31,32 Pioglitzone crried similr risk for ll clinicl frctures (1.9 per 100 person-yers). Significnt reserch is needed in mny res in this field. Specificlly, there is need to further define which subgroups re t high risk nd lso to determine the effects of osteoporosis tretment in persons with type 2 dibetes mellitus who re tking TZD. The Ugly? The possible ssocition of TZDs with myocrdil infrction cme to light fter Peto fixed-effects metnlysis, published in 2007, of 42 clinicl trils concerning rosiglitzone use in pproximtely 28,000 ptients suggested n odds rtio (OR) of 1.43, or 43% greter risk, for myocrdil infrction nd n OR of 1.64, or 64% greter risk, for crdiovsculr deth compred with plcebo or other ntidibetics. 33 A subsequent editoril suggested tht there were numerous limittions to this met-nlysis, including possible misclssifiction, scertinment errors, nd vribility of entry criteri nd outcome definitions mong the originl studies. The Peto fixed-effects model tht ws used for nlysis ws lso thought to be more fvorble for obtining sttisticl significnce. The conclusion of the editoril ws tht the risk for myocrdil infrction or deth from crdiovsculr ptients tking rosiglitzone is uncertin: neither incresed nor decresed risk is estblished. 34 Whether ny risk is due to n individul drug or clss effect is not known. Another met-nlysis of rndomized trils concerning pioglitzone use ws undertken tht suggested tht pioglitzone decresed rther thn incresed dverse CVD events. This study evluted 19 clinicl trils, with totl prticipnt Figure 1. Results of opticl coherence tomogrphy (OCT) nd fluorescein ngiogrphy in mn with dibetes. Fovel thickness nd mculr volume re noted for ech dte. On August 2, 2007, only the right eye ws scnned. Rosiglitzone ws stopped fter the visit of My 11, Becuse of residul symptoms, the right eye ws treted by lser on August 2, 2007; follow-up evlution on October 8, 2007, showed significnt resolution. OCT uses lser in technique similr to ultrsound to obtin informtion bout the mcul. Lser light reflected from the retin is detected, nd becuse of the prtil trnsprency of the retin, different lyers reflect differing mounts of lser light. A computer-reconstructed scn is produced tht llows very ccurte mesurements of mculr contour nd thickness. OCT is extremely useful in the dignosis nd evlution of dibetic mculr edem nd cn be used to monitor the effect of tretment on retinl thickness. OD = oculr dextr (right eye); OS = oculr sinistr (left eye). Figure vilble in color t: enrollment of 16,390. The durtion of tretment ws between 4 months nd 3.5 yers. Deth, myocrdil infrction, or stroke occurred in 4.4% (375 of 8554) of prticipnts receiving pioglitzone nd 5.7% (450 of 7836) of prticipnts receiving control therpy (HR, 0.82; 95% CI, ; p = 0.005). 35 An excellent overview of the sfety of TZDs in reltion to IHD risk is provided in recent scientific dvisory reported by Kul et l. 36 The dvisory sttement ddressed 1) rosiglitzone nd IHD risk, 2) pioglitzone nd IHD risk, nd 3) pioglitzone versus rosiglitzone nd IHD risk. Their conclusions were tht 1) n ssocition between rosiglitzone nd IHD outcomes hs not yet been firmly estblished, but sufficient sfety signls hve emerged to rise concerns; 2) the mjority of published study findings do not positively correlte n incresed risk for IHD in ptients treted with pioglitzone, nd hence there hs been no blckbox wrning issued for pioglitzone; nd 3) current evidence suggests tht TZDs should not be used with the expecttion of benefit with respect to IHD events. The Permnente Journl/ Fll 2010/ Volume 14 No. 3 69

7 Thizolidinediones: A 2010 Perspective Figure 2. The dibetes mellitus portion of the current Kiser Permnente Northern Cliforni PHASE (Prevent Hert Attck nd Stroke Everydy) progrm. Cr = cretinine; HF = hert filure; LFT = liver function test; NPH = neutrl protmine Hgedorn (insulin); SMBG = self-monitoring of blood glucose; SQ = subcutneous; ULN = upper limit of norml; bid = twice dily; hs = t bedtime; q2dys = every 2 dys. Updte In June of 2010, Nissen nd Wolksi published yet nother met-nlysis: Rosiglitzone Revisited. 37 The conclusion of this met-nlysis including dt from the RECORD study noted n incresed risk of myocrdil infrction (OR = 1.28; 95% CI , p = 0.04) but not crdiovsculr mortlity (OR = 1.03; 95% CI ; p = 0.86). Excluding the RECORD tril yielded qulittively similr results but quntittively higher odds rtio disfvoring rosiglitzone. 37 The firestorm over TZDs hs continued nd led to n FDA dvisory committee meeting gin on July 14, 2010 to decide the fte of Avndi. Numerous presenttions were mde from mny leders in the cdemic community s well from GlxoSmith- Kline. 38 Two decisions were mde. The first ws to keep Avndi on the mrket but recommend stricter wrning lbels. The second ws tht the postmrketing tril known s TIDE (Thizolidinedione Intervention with vitmin D Evlution) be plced on prtil clinicl hold. 39 Under the prtil clinicl hold no new ptients my be enrolled into the tril until further notice from the FDA. Ptients lredy enrolled in the tril will be llowed to continue to prticipte. Conclusion In medicine, s in mny other res of innovtion, initil enthusism is usully tempered with the relities of subsequent knowledge. The evolution of TZD development is prime exmple. Once seen s holding promise of mortlity reduction, TZDs re currently used with focus on dditionl glycemic control, with creful ptient selection to void possible toxicities. The primry prevention of type 2 dibetes mellitus nd crdiovsculr mortlity in persons with type 2 dibetes mellitus is of the utmost importnce. The current PHASE progrm t KPNC ddresses this exct need of improving the outcome in these high-risk ptients. Without current dt suggesting ny benefits of prescribing TZD except for improving glycemic control, cre should be tken to void subgroups of ptients who my hve higher risk of developing edem, congestive hert filure, frctures, nd possibly mculr edem. These subgroups my include ptients of dvncing ge, those tking higher doses of TZD, women, those with renl insufficiency, nd those who lso tke insulin. The type 2 dibetes mellitus tretment lgorithm currently proposed my need to be further refined to blnce dequte glycemic control, costs, nd expected future risks in individuls (Figure 2-4). 40. Metformin + Pioglitzone b + Secretgogue c, α-glucosidse inhibitor, Sitglipin, or Exentide Insulin d HbA1c < 7.0% HbA 1c < 7.0% HbA 1c < 7.0% Figure 3. Proposed ntihyperglycemic strtegy in the ptient with type 2 dibetes mellitus nd coronry rtery disese. Becuse of the risk of lctic cidosis, metformin should be voided in ptients whose coronry rtery disese is complicted by cute or unstble hert filure. b Becuse of the risk of fluid retention, pioglitzone should be voided in ptients whose coronry rtery disese is complicted by hert filure; it is contrindicted in those with New York Hert Assocition clss III to IV symptoms. Becuse of recent concerns regrding the incresed risk of myocrdil infrction with rosiglitzone, this drug is best voided in coronry rtery disese ptients until further sfety dt become vilble. c Secretgogues include the sulfonylures nd the nonsulfonylure glinides. Certin sulfonylures (eg, glyburide) my impir ischemic preconditioning nd re probbly best voided in ptients with ctive coronry insufficiency. d Insulin cn be dded to or substituted for orl gents t ny point in the disese course. When more dvnced regimens re used, insulin secretgogues trditionlly re discontinued. Reprinted with permission from Inzucchi SE, McGuire DK. New drugs for tretment of dibetes: prt II: Incretin-bsed therpy nd beyond. Circultion 2008 Jn 29;117(4):574-84; Figure The Permnente Journl/ Fll 2010/ Volume 14 No. 3

8 Thizolidinediones: A 2010 Perspective Aleglitzr, promising novel dul PPAR gent tht is currently being tested in phse III clinicl tril, gin brings hope to this field. We will wit the results of this nd other ongoing studies of dibetes medictions tht cn now enter the mrket only if fvorble crdiovsculr risk profile is ttined. v Phrmcy Outcomes Reserch Group, KPNC Disclosure The uthor(s) hve no conflicts of interest to disclose. Acknowledgments We sincerely thnk Sul Genuth, MD, Principl Investigtor nd Director of the Dibetes Mngement Center of the BARI 2D study, Cse Western Reserve, Clevelnd, Ohio, for reviewing our mnuscript. Kthrine O Moore-Klopf, ELS, of KOK Edit provided editoril ssistnce. Secretgogue (nd/or Metformin b ) + Exentide, Sitglipin, or α-glucosidse inhibitor HbA1c 7.0% Insulin c HbA 1c < 7.0% HbA 1c < 7.0% Figure 4. Proposed ntihyperglycemic strtegy in the ptient with type 2 dibetes mellitus nd hert filure. Secretgogues include the sulfonylures nd the nonsulfonylure glinides. Certin sulfonylures (eg, glyburide) my impir ischemic preconditioning nd probbly re best voided in ptients with ctive coronry insufficiency. b Metformin is no longer contrindicted in this setting nd my be used cutiously, but only in stble, compensted hert filure ptients with norml renl function nd cid/bse sttus. c Insulin cn be dded to or substituted for orl gents t ny point in the disese course. When more dvnced regimens re used, insulin secretgogues trditionlly re discontinued. Becuse of the sodium-retining properties of insulin, the lowest effective dose should be used, nd the dose should be titrted crefully. Reprinted with permission from Inzucchi SE, McGuire DK. New drugs for tretment of dibetes: prt II: Incretin-bsed therpy nd beyond. Circultion 2008 Jn 29;117(4):574-84; Figure 2. References 1. Joffe HV. Crdiovsculr ssessment in the pre-pprovl nd post-pprovl settings for drugs nd biologics developed for the tretment of type 2 dibetes mellitus [PowerPoint presenttion on the Internet from meeting on 2008 Jul 1 2]. Silver Spring, MD: Endocrinologic nd Metbolic Drugs Advisory Committee, Dibetes Drug Group, US Food nd Drug Administrtion; 2008 [cited 2010 Jul 15]. Avilble from: 2. Yki-Järvinen H. Thizolidinediones. N Engl J Med 2004 Sep 9;351(11): McGuire DK, Inzucchi SE. New drugs for the tretment of dibetes mellitus: prt I: Thizolidinediones nd their evolving crdiovsculr implictions. Circultion 2008 Jn 22;117(3): Wng CH, Weisel RD, Liu PP, Fedk PW, Verm S. Glitzones nd hert filure: criticl pprisl for the clinicin. Circultion 2003 Mr 18;107(10): Inzucchi SE. Orl ntihyperglycemic therpy for type 2 dibetes: scientific review. JAMA 2002 Jn 16;287(3): Levine TB, Levine AB. Metbolic syndrome nd crdiovsculr disese. Phildelphi, PA: WB Sunders; Little PJ, Topliss DJ, Mdlir S, Lw RE, editors. Dibetes nd crdiovsculr disese: integrting science nd clinicl medicine. Bltimore, MD: Willims & Wilkins; Effects of hypoglycemic gents on vsculr complictions in ptients with dult-onset dibetes. VIII. Evlution of insulin therpy: finl report. Dibetes 1982 Nov;31 Suppl 5: The effect of intensive tretment of dibetes on the development nd progression of long-term complictions in insulin-dependent dibetes mellitus. The Dibetes Control nd Complictions Tril Reserch Group. N Engl J Med 1993 Sep 30;329(14): Clery PA, Orchrd TJ, Genuth S, et l; DCCT/EDIC Reserch Group. The effect of intensive glycemic tretment on coronry rtery clcifiction in type 1 dibetic prticipnts of the Dibetes Control nd Complictions Tril/ Epidemiology of Dibetes Interventions nd Complictions (DCCT/EDIC) Study. Dibetes 2006 Dec;55(12): Intensive blood-glucose control with sulphonylures or insulin compred with conventionl tretment nd risk of complictions in ptients with type 2 dibetes (UKPDS 33). UK Prospective Dibetes Study (UKPDS) Group. Lncet 1998 Sep 12;352(9131): Errtum in: Lncet 1999 Aug 14;354(9178): Effect of intensive blood-glucose control with metformin on complictions in overweight ptients with type 2 dibetes (UKPDS 34). UK Prospective Dibetes Study (UKPDS) Group. Lncet 1998 Sep 12;352(9131): Errtum in: Lncet 1998 Nov 7;352(9139): Holmn RR, Pul SK, Bethel MA, Mtthews DR, Neil HA. 10-yer follow-up of intensive glucose control in type 2 dibetes. N Engl J Med 2008 Oct 9;359(15): Dormndy JA, Chrbonnel B, Ecklnd DJ, et l; PROctive Investigtors. Secondry prevention of mcrovsculr events in ptients with type 2 dibetes in the PROctive Study (PROspective pioglitazone Clinicl Tril In mcrovsculr Events): rndomised controlled tril. Lncet 2005 Oct 8;366(9493): Khn SE, Hffner SM, Heise MA, et l; ADOPT Study Group. Glycemic durbility of rosiglitzone, metformin, or glyburide monotherpy. N Engl J Med 2006 Dec 7;355(23): The Permnente Journl/ Fll 2010/ Volume 14 No. 3 71

9 Thizolidinediones: A 2010 Perspective 16. DREAM Tril Investigtors, Bosch J, Yusuf S, Gerstein HC, et l;. Effect of rmipril on the incidence of dibetes. N Engl J Med 2006 Oct 12;355(15): Phend C. ADA: dibetes prevention hopes revived for thizolidinedione [monogrph on the Internet]. MedPge Tody; 2008 [cited 2010 Jul 12]. Avilble from: www. medpgetody.com/meetingcoverge/ada/ Nissen SE, Nicholls SJ, Wolski K, et l; PERISCOPE Investigtors. Comprison of pioglitzone vs glimepiride on progression of coronry therosclerosis in ptients with type 2 dibetes: the PERISCOPE rndomized controlled tril. JAMA 2008 Apr 2;299(13): Home PD, Pocock SJ, Beck-Nielsen H, et l; RECORD Study Group. Rosiglitzone evluted for crdiovsculr outcomes n interim nlysis. N Engl J Med 2007 Jul 5;357(1): Home PD, Pocock SJ, Beck-Nielsen H, et l; RECORD Study Tem. Rosiglitzone evluted for crdiovsculr outcomes in orl gent combintion therpy for type 2 dibetes (RE- CORD): multicentre, rndomised, open-lbel tril. Lncet 2009 Jun 20;373(9681): Gerstein HC, Rtner RE, Cnnon CP, et l; APPROACH Study Group. Effect of rosiglitzone on progression of coronry therosclerosis in ptients with type 2 dibetes mellitus nd coronry rtery disese: the ssessment on the prevention of progression by rosiglitzone on therosclerosis in dibetes ptients with crdiovsculr history tril. Circultion 2010 Mr 16;121(10): Action to Control Crdiovsculr Risk in Dibetes Study Group, Gerstein HC, Miller ME, Byington RP, et l. Effects of intensive glucose lowering in type 2 dibetes. N Engl J Med 2008 Jun 12;358(24): Duckworth W, Abrir C, Moritz T, et l; VADT Investigtors. Glucose control nd vsculr complictions in veterns with type 2 dibetes. N Engl J Med 2009 Jn 8;360(2): Errtum in: N Engl J Med 2009 Sep 3;361(10):1028; N Engl J Med 2009 Sep 3;361(10); BARI 2D Study Group, Frye RL, August P, Brooks MM, et l. A rndomized tril of therpies for type 2 dibetes nd coronry rtery disese. N Engl J Med 2009 Jun 11;360(24): Nesto RW, Bell D, Bonow RO, et l; Americn Hert Assocition; Americn Dibetes Assocition. Thizolidinedione use, fluid retention, nd congestive hert filure: consensus sttement from the Americn Hert Assocition nd Americn Dibetes Assocition. October 7, Circultion 2003 Dec 9;108(23): Kendll C, Wooltorton E. Rosiglitzone (Avndi) nd mculr edem. CMAJ 2006 Feb 28;174(5): Ttti P, Arrigoni F, Longobrdi A, Costnz F, Di Blsi P, Mernte D. Retrospective nlysis of rosiglitzone nd mculr oedem in ptients with type 2 dibetes mellitus. Clin Drug Investig 2008;28(5): Ryn EH Jr, Hn DP, Rmsy RC, et l. Dibetic mculr edem ssocited with glitzone use. Retin 2006 My Jun;26(5): Lizos E, Brodbent DM, Bere N, Kumr N. Spontneous resolution of dibetic mculr oedem fter discontinution of thizolidinediones. Dibet Med 2008 Jul;25(7): Fong DS, Contrers R. Glitzone use ssocited with dibetic mculr edem. Am J Ophthlmol 2009 Apr;147(4):583 6.e Evns R, Grey A, Clrke BL. Three perspectives on thizolidine nd bone helth. Endocrine News 2008 Sep: Schwrtz AV. TZDs nd bone: review of the recent clinicl evidence. PPAR Res [seril on the Internet] 2008 [2010 Jul 12]: [bout 6 pges]. Avilble from: www. hindwi.com/journls/ppr/2008/ html. 33. Nissen SE, Wolski K. Effect of rosiglitzone on the risk of myocrdil infrction nd deth from crdiovsculr cuses. N Engl J Med 2007 Jun 14;356(24): Errtum in: N Engl J Med 2007 Jul 5;357(1): Dimond GA, Bx L, Kul S. Uncertin effects of rosiglitzone on the risk for myocrdil infrction nd crdiovsculr deth. Ann Intern Med 2007 Oct 16;147(8): Singh S, Loke YK, Furberg CD. Long-term risk of crdiovsculr events with rosiglitzone: met-nlysis. JAMA 2007 Sep 12;298(10): Kul S, Bolger AF, Herrington D, Giuglino RP, Eckel RH. Thizolidinedione drugs nd crdiovsculr risks. science dvisory from the Americn Hert Assocition nd Americn College of Crdiology Foundtion. Circultion 2010 Apr 27;121(16): Nissen SE, Wolski K. Rosiglitzone revisited: An updted met-nlysis of risk for myocrdil infrction nd crdiovsculr mortlity. Arch Intern Med 2010 Jun 28. [Epub hed of print.] 38. GlxoSmithKline. Advisory Committee briefing document: Crdiovsculr sfety of rosiglitzone [monogrph on the Internet]. Silver Spring, MD: US Food nd Drug Administrtion: Endocrinologic nd Metbolic Drugs Advisory Committee, Drug Sfety nd Risk Mngement Advisory Committee; 2010 Jul [cite 2010 Aug 2]. Avilble from: FDA sttement on Avndi TIDE tril [monogrph on the Internet]. Silver Spring, MD: US Food nd Drug Administrtion; updted 2010 Jul 21 [cited 2010 Aug 2]. Avilble from: Inzucchi SE, McGuire DK. New drugs for tretment of dibetes: prt II: Incretin-bsed therpy nd beyond. Circultion 2008 Jn 29;117(4): The Permnente Journl/ Fll 2010/ Volume 14 No. 3