July 03, 2013

CHICAGO — The new diabetes drug canagliflozin (Invokana, Janssen Pharmaceuticals) is associated with modestly higher rates of genital mycotic infections in type 2 diabetes patients, but this side effect was generally manageable and very rarely led to discontinuation of the drug. Such were the conclusions of a poster presentation at the recent American Diabetes Association (ADA) 2013 Scientific Sessions.

The poster covered 2 study populations, "and the findings were fairly consistent," lead author Paul Nyirjesy, MD, professor of obstetrics and gynecology and professor of medicine at Drexel University College of Medicine, Philadelphia, Pennsylvania, told Medscape Medical News. The infections occurred more frequently in women, with around 10% of females taking canagliflozin having a yeast infection compared with about 3% of those on placebo in the trials. Among men, these figures were up to 8% and 2%. The bulk of the increase in mycotic infection appears to occur in the first 6 months of treatment, plateauing at around 26 weeks, he said.

Patients who are susceptible to yeast infections appeared to be at higher risk of suffering this side effect than those who are not; the latter generally remain unaffected, Dr. Nyirjesy noted. And he added that diabetes patients, in general, are more vulnerable to such genital mycotic infections than the population on average. Circumcised males were also less likely to develop such infections than uncircumcised men.

"The reassuring part is that this is a relatively uncommon event, [and when it does occur], it responds well to conventional antifungal treatment — a simple course of oral and/or topical medication," said Dr. Nyirjesy. And perhaps more important, "for the most part, the yeast infection did not come back," he noted, adding that 80% of patients had only 1 episode, and even the 20% who did have a recurrent infection "usually had only 1 recurrence."

All told, physicians should not be deterred from using this new diabetes medication, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, because of the possibility of genital yeast infection, he stressed. "It's manageable, it is limited in terms of how bad it gets and in terms of being a chronic issue, and it responds well to treatment."

A second poster detailing pooled data from 4 pivotal phase 3 trials with an investigational SGLT2 inhibitor, empagliflozin (Boehringer Ingelheim/Eli Lilly), revealed a very similar pattern with regard to genital infections, illustrating, said Dr. Nyirjesy "that as expected, this seems to be a class effect."

Glycosuria Likely Contributes to Yeast Infections

Canagliflozin is the first SGLT2 inhibitor available in the United States, having been approved there in March. A second, dapagliflozin (Forxiga, Bristol-Myers Squibb/AstraZeneca), was already approved in Europe, in November 2012. The Food and Drug Administration denied approval of dapagliflozin in January 2012 because of concerns about a cancer signal.

Empagliflozin is in phase 3 trials and has just been filed for approval in the United States, and ipragliflozin (Astellas Pharma) and luseogliflozin (Taisho Pharmaceutical) are awaiting approval in Japan. Further back in development is tofogliflozin (Chugai Pharma), which is in phase 3 studies, and ertugliflozin (Pfizer/Merck), which is expected to begin phase 3 trials later this year.

SGLT2 inhibitors prevent the reabsorption of glucose from the kidneys back into the blood, leading to increased glucose in the urine and reduced glucose levels in the blood. This glycosuria is believed to contribute to the increase in risk for genital mycotic infections, said Dr. Nyirjesy.

This undesirable side effect does seem to be off-putting, with doctors having stated they would rather not use a medication that had such a drawback.

But the companies developing these agents are stressing that clinical-trial data indicate that these infections, when they do occur, are mild in nature, respond well to treatment, and are very unlikely to lead to discontinuation of the drug. Whether this proves to be the case once the SGLT2 inhibitors are in widespread clinical use remains to be seen.

Dr. Nyirjesy said: "I do believe that patients starting any of the medicines in this class of drug should be aware of this effect to help them decide whether to start it." However, in the chronic/recurrent patients, "there's no clear evidence that these medications make this problem tougher to manage," he adds. "Keep in mind, as well, that in the chronic patients, they've often been led to believe that they have yeast, and it often turns out to be something else."

Cangliflozin Poster Reports on Data From 12 Studies

In the canagliflozin poster reported at the ADA meeting, genital mycotic infections were assessed in 2313 patients with type 2 diabetes from 4 randomized, double-blind, 26-week placebo-controlled studies.

Dr. Nyirjesy said that while not all patients had cultures taken, in the ones who were cultured the infection associated with canagliflozin was overwhelmingly a Candida species, and all such infections responded to antifungal agents, so this "is consistent with these being yeast infections," he observed.

Women who were treated with canagliflozin and developed genital mycotic infections were more likely to have a history of vulvovaginitis (29% vs 12%), be premenopausal (35% vs 27%), and reside in North America (60% vs 42%) than those without such infections.

Among men, those who developed genital mycotic infection who were taking canagliflozin were more likely to have a history of balanitis/balanoposthitis (25% vs 2%), have a slightly longer mean duration of type 2 diabetes (9 years vs 7 years), and were more likely to reside in Europe (44% vs 26%) than men without genital mycotic infections.

Overall, 2% and 1% of females and males, respectively, had more than 1 genital mycotic infection.

Sum mary of Genital Mycotic Infection Adverse Events With Canagliflozin

Group Placebo (%) Canagliflozin 100 mg (%) Canagliflozin 300 mg (%)
Females
Genital mycotic infectiona adverse event 3.2 10.4 11.4
Mycotic infection leading to discontinuation 0 0.9 0.5
Males
Genital mycotic infectionb adverse event 0.6 4.2 3.7
Mycotic infection leading to discontinuation 0 0.5 0.5

a. Including genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis

b. Including balanitis, balanitis candida, balanoposthitis, and genital infection fungal

In a second, larger data set of 9439 patients from 8 studies with a longer mean exposure (canagliflozin 68 weeks and controls 64 weeks), also detailed in the poster, a higher rate of genital mycotic infections was seen among males, 8%, vs 2% for controls, and this side effect was more commonly observed among uncircumcised men than circumcised males (11% vs 3%).

Empagliflozin Study Details

In the empagliflozin poster, presented by Gabriel Kim, MD, from Boehringer Ingelheim, Ingelheim, Germany, data on genital mycotic infections among patients in 4 phase 3 trials taking empagliflozin 10 mg (n = 830), 25 mg (n = 822), or placebo (n = 825) were evaluated.

The rate of genital mycotic infection associated with empagliflozin for women who had previously reported a history of chronic or recurrent genital infections appeared quite high, at around 50% of those taking 10 mg, although this dropped to 23% of those taking 25 mg and was set against a rate of 14.3% for those taking placebo from this patient group. But these were small numbers: only 1 of 7 such patients on placebo developed an infection, 2 out of 4 on the 10-mg dose, and 3 of 13 taking 25 mg.

In all cases of yeast infection, the intensity of the worst episode was judged to be only mild or moderate.

"Most patients who reported an event consistent with genital infection experienced only 1 such episode, very few patients discontinued due to such an event, and most events were mild in intensity," the researchers concluded.

Genital Mycotic Infection Adverse Events With Empagliflozin

Group Placebo (%) Empagliflozin 10 mg (%) Empagliflozin 25 mg (%)
Female patients with events consistent with genital infection 1.0 6.3 7.0
Male patients with events consistent with genital infection 0.5 2.6 1.1
Patients without history of chronic or recurrent genital infections 0.6 4.0 3.3
0 episodes per patient 99.3 95.8 96.4
1 episode per patient 0.6 3.6 3.0
2 episodes per patient 0.1 0.4 0.5
> 3 episodes per patient 0 0.2 0.1
Patients with genital infections leading to treatment discontinuation 0 0.1 0.2

Dr. Nyirjesy reports consulting for Janssen Research and Development. Authors of empagliflozin poster either were employees of Boehringer Ingelheim or consulted for the company.

American Diabetes Association 2013 Scientific Sessions. Abstract 1069-P, presented June 23, 2013. Abstract 74-LB, presented June 23, 2013.

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