Di­a­betes drug fails to shake fears

Reg­u­la­tors are feel­ing the heat as a safety row con­tin­ues to dog Avan­dia, write Robin Pag­na­menta and Adam Cress­well

The Weekend Australian - Travel - - Health -

WHEN he first saw the re­sults of his study about the car­dio­vas­cu­lar risks of the di­a­betes drug rosigli­ta­zone — sold un­der the trade name Avan­dia — sev­eral weeks ago, Steven Nis­sen said that he felt sick and was un­able to sleep.

‘‘ It was very strik­ing,’’ he said af­ter the pub­li­ca­tion of his re­port on the medicine that is Glax­oSmithK­line’s sec­ond best-sell­ing drug. ‘‘ When you see a sig­nal this strong, I was truly fright­ened on be­half of our pa­tients.’’

The out­come of his meta-anal­y­sis of 42 pre­vi­ous clin­i­cial tri­als was, in­deed, trou­bling. It in­di­cated a 43 per cent in­crease in the risk of heart at­tacks. It also showed a 64 per cent in­crease in the risk of death from car­dio­vas­cu­lar causes, al­though this find­ing was said to be of border­line sta­tis­ti­cal sig­nif­i­cance, which means it may not be re­li­able.

‘‘ I moved as quickly as hu­manly pos­si­ble to pub­lish the data,’’ Nis­sen said.

Six days later, on May 22, the pub­li­ca­tion on­line of his re­port in the New Eng­land Jour­nal of Medicine proved ex­plo­sive. Within hours, shares in Glax­oSmithK­line (GSK) had dropped 8 per cent amid fears that the drug, which gen­er­ated $US3 bil­lion in sales last year and is used by mil­lions, could be pulled or could re­sult in an ex­pen­sive le­gal bat­tle.

In Aus­tralia too the drug has proved a hit, reach­ing num­ber 66 on the list of drugs that cost tax­pay­ers the most money in 2005-06. In that year nearly 300,000 pre­scrip­tions for rosigli­ta­zone were writ­ten, each of which cost just over $75 to fill — cost­ing the fed­eral Gov­ern­ment’s Phar­ma­ceu­ti­cal Ben­e­fits Scheme nearly $20 mil­lion.

The pub­li­ca­tion of Nis­sen’s find­ings sparked a furore in both the med­i­cal pro­fes­sion and the me­dia, a furore that was fur­ther stoked by the on­line pub­li­ca­tion of more data by the New Eng­land Jour­nal of Medicine re­cently.

The new data were in­terim find­ings from an on­go­ing trial that was set up with the aim of show­ing that Avan­dia was no worse than ex­ist­ing treat­ments in terms of its ef­fect of car­dio­vas­cu­lar events, in­clud­ing heart at­tack. Un­for­tu­nately for GSK, the new find­ings failed to de­liver the longed-for ex­on­er­a­tion.

Nor do they con­demn the drug, and like Nis­sen’s orig­i­nal meta-anal­y­sis, the latest find­ings have di­vided ex­perts — with some still strongly at­tack­ing sug­ges­tions the drug is un­safe.

Nis­sen, car­di­ol­ogy chief of the Cleve­land Clinic, Ohio, is not to be dis­missed lightly. One of the most re­spected med­i­cal re­searchers in the US, he was among the first to find a link be­tween Vioxx, the anti-in­flam­ma­tory drug, and an in­creased risk of heart at­tacks.

The scan­dal that fol­lowed forced the drug’s with­drawal in 2004 and thrust Merck, Vioxx’s man­u­fac­turer and one of the world’s big­gest phar­ma­ceu­ti­cal com­pa­nies, into a bruis­ing le­gal bat­tle that is still con­tin­u­ing.

Speak­ing be­fore the latest in­terim re­sults were re­leased, Nis­sen made no ef­fort to avoid com­par­i­son be­tween Avan­dia and Vioxx — a par­al­lel that Glaxo has been keen to down­play. ‘‘ I hope that GSK does not go the same way as Merck did,’’ he said. ‘‘ They [GSK] have been mar­ket­ing a drug with very se­ri­ous prob­lems. In my view, a lot of peo­ple have been harmed.’’

When asked for his views on just how many, Nis­sen pointed to com­ments made by US Sen­a­tor Charles Grass­ley, an Iowa Repub­li­can. He claimed that an eval­u­a­tion by the US Food and Drug Ad­min­is­tra­tion (FDA) had sug­gested that be­tween 60,000 and 100,000 heart at­tacks could be linked to the drug since its launch in 1999 — more than 20 per day. ‘‘ I feel pretty strongly that our find­ings are con­clu­sive,’’ Nis­sen said. ‘‘ There is some­thing odd about this drug that in­creases the risk of car­dio­vas­cu­lar prob­lems and death.’’

How­ever, GSK is not the only party that dis­agrees with Nis­sen. While Nis­sen’s anal­y­sis con­ceded it had flaws, many in­de­pen­dent ex­perts say th­ese are so fun­da­men­tal that its hy­poth­e­sis, that Avan­dia causes heart at­tacks, has lit­tle weight. The flaws they point out in­clude the fact that many of the 42 stud­ies Nis­sen re­viewed to reach his con­clu­sions were small and short-term, and dealt with such small num­bers of heart at­tacks that the find­ings were open to sta­tis­ti­cal doubt.

An­other was that few of the stud­ies were de­signed to as­sess ef­fect on heart at­tacks, and so did not es­tab­lish that the events recorded as heart at­tacks were not in fact some­thing less se­ri­ous, such as acute angina.

Within days of the re­lease of Nis­sen’s work The Lancet, the Bri­tish med­i­cal jour­nal, urged cau­tion about the find­ings. In an edi­to­rial pub­lished on­line, it gave warn­ing of the dan­gers of ‘‘ alarmist head­lines and con­fi­dent dec­la­ra­tions that help no­body’’.

In Aus­tralia, many ex­perts have also been scep­ti­cal. As­so­ci­ate Pro­fes­sor Shane Ham­blin, di­rec­tor of di­a­betes at Melbourne’s West­ern Health, told a re­cent edi­tion of the GP weekly Med­i­cal Ob­server there were ‘‘ a lot of holes in this (Nis­sen’s) meta-anal­y­sis’’, while Pro­fes­sor Niko­lai Petro­vsky, di­rec­tor of the di­a­betes and en­docrinol­ogy de­part­ment at Flin­ders Med­i­cal Cen­tre in Ade­laide, was re­ported in Aus­tralianDoc­tor as say­ing he was ‘‘ amazed’’ the NEJM had pub­lished Nis­sen’s study.

All the Aus­tralian ex­perts asked for their views said pa­tients al­ready tak­ing Avan­dia should not stop, al­though some said doc­tors should not pre­scribe it to new pa­tients who had ‘‘ ma­jor car­dio­vas­cu­lar con­di­tions’’.

But the pic­ture was com­pli­cated fur­ther by the NEJM’s pub­li­ca­tion of the sec­ond study — an in­terim anal­y­sis of data from a long-term trial in­volv­ing over 4400 pa­tients that has been specif­i­cally de­signed to demon­strate Avan­dia’s car­dio­vas­cu­lar safety.

Th­ese in­terim find­ings found that pa­tients treated with rosigli­ta­zone had dou­ble the risk of heart fail­ure — in which the heart beats too weakly. While this is a pre­vi­ously recog­nised side-ef­fect, the study sheds light on how com­monly treated pa­tients will ex­pe­ri­ence it.

The in­terim re­sults also found a trend to­wards more heart at­tacks among pa­tients treated with rosigli­ta­zone as op­posed to pa­tients on al­ter­na­tive drugs. But th­ese re­sults were not so stark that the study’s au­thors could con­fi­dently say they were not the play of chance.

This lack of sta­tis­ti­cal sig­nif­i­cance has been in­ter­preted by GSK and some ex­perts as ev­i­dence that Avan­dia is safe, and by oth­ers — in­clud­ing the au­thors of three NEJM edi­to­ri­als — that se­ri­ous safety ques­tions re­main.

But as in the US — where the Food and Drug Ad­min­is­tra­tion is com­ing un­der pres­sure over a grow­ing per­cep­tion that it has been too slow to act over safety fears — some ex­perts say the Avan­dia case raises ques­tions about how ef­fec­tively in Aus­tralia we reg­u­late medicines.

David Henry, pro­fes­sor of clin­i­cal phar­ma­col­ogy at the Univer­sity of New­cas­tle, said fol­low­ing the latest in­terim trial re­sults, it ‘‘ doesn’t look good for rosigli­ta­zone’’ in terms of the drug’s safety.

‘‘ You can be fairly con­fi­dent [from the latest re­sults] that rosigli­ta­zone is no bet­ter — and it may be worse — than ex­ist­ing ther­a­pies,’’ Pro­fes­sor Henry said.

‘‘ The whole pur­pose of the drug is to im­prove di­a­betic con­trol and re­duce com­pli­ca­tions — and here we are sev­eral years down the track since the drug’s launch, be­gin­ning to ques­tion whether the drug is safe.

‘‘ We shouldn’t be ask­ing th­ese ques­tions so long af­ter th­ese drugs have been in­tro­duced. It’s a fail­ure of drug de­vel­op­ment, and a fail­ure of drug reg­u­la­tory pro­cesses.’’

Henry says that just as crit­ics are us­ing the Avan­dia con­tro­versy to ar­gue for more power for the FDA, the Ther­a­peu­tic Goods Ad­min­is­tra­tion should have power to force drug com­pa­nies to con­duct prop­erly de­signed stud­ies to an­swer safety ques­tions much ear­lier.

Pre­vi­ous stud­ies on Avan­dia es­tab­lished that it was ef­fec­tive at con­trol­ling blood sugar lev­els — but the long­stand­ing as­sump­tion that pa­tients would au­to­mat­i­cally be health­ier as a re­sult has been rocked by the find­ings about in­creased car­dio­vas­cu­lar risk.

How­ever, Henry is not hope­ful of this be­ing work­able un­der cur­rent fund­ing ar­range­ments.

‘‘ It’s hard when th­ese agen­cies rely on fees raised from the drug com­pa­nies to pay their staff, and it’s hard when they don’t have strong sup­port from politi­cians,’’ he says. The Times

Doubt: TheLancet, the Bri­tish med­i­cal jour­nal has urged cau­tion over re­search find­ings on Avan­dia use

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