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Re cent meta-anal y ses have sug gested that the risks as so ci ated with rosiglitazone may be higher than
those as so ci ated with pioglitazone, par tic u larly when used in el derly pa tients. In No vem ber 2008, a ret -
ro spec tive study pub lished in the Ar chives of In ter nal Med i cine, which looked at about 14,000 pa tients on
Medicare (i.e., older than 65) who were pre scribed Avandia be tween 2000 and 2005, and com pared
these pa tients to 14,000 who were get ting Actos, found that the pa tients who started on Avandia had a
15% higher ‘deaths from all-cause’ rate than the Actos group. The Avandia group had a 13% higher rate
of CHF, but no dif fer ence in the in ci dence of strokes and MI (Avandia in pre vi ous stud ies was linked with
an in creased in ci dence of MI). The au thors con cluded that al though pre vi ous stud ies have in di cated that
the in creased risk with rosiglitazone use re sides pre dom i nantly in car dio vas cu lar out comes, the above
study sug gests that dif fer ences in all-cause mor tal ity risk may be even more im por tant to con sider in el -
derly pa tients. Re gard ing the fact that no dif fer ence in MI be tween the two groups was ob served, the re -
search ers said that since 75% of di a bet ics die from heart-re lated causes, the re search ers think MIs and
strokes likely contributed to the overall increased deaths in the Avandia group
In Oc to ber 2008, new rec om men da tions from ex perts at the Eu ro pean As so ci a tion for the Study of Di a -
be tes and the Amer i can Di a be tes As so ci a tion no lon ger backed the use of Avandia for treat ing Type 2 di a -
bet ics: the rec om men da tions have re tained a ref er ence to the use of Actos, how ever. In the same month,
there was a call by the US ad vo cacy group Pub lic Cit i zen for Avandia to be banned due to a high num ber of
re ports of liver fail ure and death in patients taking the drug.
In creased risk of frac tures in women was also re ported in 2007 with Actos in anal y sis of data con cern ing
over 15,000 pa tients; fur ther anal y sis re ported in 2008 re vealed that the drugs could dou ble this risk.
GSK had pre vi ously warned the FDA of sim i lar risk with Avandia. Fur ther ev i dence in 2007 has as so ci ated
Avandia with links to os teo po ro sis from a com bi na tion of de creased bone for ma tion and in creased bone
re sorp tion al though re sults are in con clu sive to date. As such, the FDA has ad vised healthcare pro fes sion -
als to con sider the risk when pre scrib ing these prod ucts. Re sults of an other study in 2008 showed a dou -
ble or tri ple in crease of bone frac ture in pa tients tak ing the thiazolidinediones over con trol pa tients and
re search ers be lieve that as well as sen si tiz ing the body to in su lin, these drugs also stim u late bone
resorption, making the bones vulnerable to fracture.
Byetta’s (exenatide) im pact on blood glu cose con trol, and par tic u larly its weight re duc ing prop er ties,
gives it a pro file that is very at trac tive to doc tors. Mor gan Stan ley an a lysts think that the DPP-IV in hib i tors
are more likely to be used in ear lier stage dis ease and there fore should not be seen as di rectly com pet i tive
with drugs like Avandia/Byetta. How ever, MS be lieves that the DPP-IV class has sec tor re shap ing po ten -
tial in the same way as PPIs did in the GI field and ACE in hib i tors did in car dio vas cu lar and statins did in
cholesterol.
The FDA is now call ing for higher safety stan dards in ap prov ing di a be tes drugs and the risk ben e fit pro file
of other di a betic drugs is also in ques tion, in clud ing Merck & Co’s DPP4 in hib i tor Januvia
(sitagliptin),which was the first in class fol low ing its US launch in Oc to ber 2006, and is now the ‘gold stan -
dard’ for this class and has had a sig nif i cant im pact. Merck & Co has also launched a com bi na tion prod uct
Janumet (sitagliptin + metformin) in some mar kets. Januvia has been launched in the USA and across
Eu rope and is pend ing ap proval in Ja pan and many other mar kets. Januvia has per haps bene fited from
the neg a tive pub lic ity for Avandia, par tic u larly as it is re ported to have a better side ef fect pro file than
TZD drugs and is as so ci ated with a lack of weight gain. How ever, on the neg a tive side, the DPP-IV path -
way is com plex and long-term prod uct use is as yet un tested. If ap proved, Takeda’s SYR 322 will be the
sec ond DPP-4 in hib i tor af ter Januvia. Novartis’ Galvus (vildagliptin) has been ap proved in the EU where
it is now be ing rolled out, but has faced safety con cerns in the US and fol low ing safety stud ies, fil ing may
now be de layed un til 2010. Galvus was filed for ap proval in Ja pan in April 2008A fil ing in Ja pan is ex pected
in April 2008. In 2007, an ar ti cle in the New Eng land Jour nal of Med i cine ques tioned the safety data avail -
able for the drugs Januvia and Galvus writ ing that it was surprising the FDA decided to clear Januvia given
the questionability of safety data.
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