SGLT-2 inhibitors and Fournier's gangrene

There was a recent report suggesting a pretty large increase in cases of Fournier’s gangrene (a rare necrotizing infection of the external genitalia, perineum, and perianal regions) associated with the array of available SGLT-2 inhibitors for diabetes (see dm sglt2 inhib fournier gangrene aim2019 in dropbox, or  doi:10.7326/M19-0085).

Details:

--the FDA reported 55 cases of Fournier’s gangrene (FG) in patients on SGLT-2 inihibitors from 1March2013 to 31January 2019, ie a 6-year span

--median age 56 (range 33-87), 39 men/16 women

--SGLT-2 inhibitors: 21 canagliflozin, 16 dapagliflozin, 18 empagliflozin

--concurrent diabetes drugs (in at least 31 patients): metformin (20 cases), insulins (13), sulfonylureas (8), GLP-1 agonists (5), TZDs (4)

Results:

--all patients were hospitalized and severely ill with FG, and all had surgical debridement (per the FDA case definition)

--clinical course complicated by diabetic ketoacidosis (8 patients), sepsis (9 patients), acute kidney injury (4 patients)

--3 patients died

--for other antidiabetic meds, 97 reports from 1984 to 31Jan2019, though 75 excluded for not meeting case definition (22 did meet the case definition, though 3 were also on SGLT-2 inhib, leaving 19 total cases of non-SGLT2 associated FG over this 35-year period)

    --metformin: 8 cases

    --insulin glargine: 6 cases

    --short acting insulin: 2 cases

    --sitagliptin plus metformin: 2 cases

    --dulaglutide: 1 case

--FG developed from 5 days to 49 months after initiation of SGLT-2 treatment

Commentary:

--FG is a rare condition overall, with about 1.6 cases in 100,000 males annually in the US (most cases are in males), most frequently in men 50-79 yo at 3.3 per 100,000; and comprises <0.02% of hospitalizations (though essentially 100% of cases are hospitalized)

--FG has the reported risk factors of alcoholism, HIV, cytotoxic drugs, diabetes (32-66% of cases); also implicated are postcoital trauma, aggressive masturbation, UTIs, genital piercing, penile implants, and rectal foreign bodies.

--The FDA did have a warning about SGLT-2 inhibitors and Fournier’s gangrene on 8/29/2018, see https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes , noting 12 cases at that time

--overall, a rather striking increase in FG in this observational study: by the strict FDA criteria, 55 cases  with SGLT-2 inhibitors over 6 years and 19 cases in other meds over 35 years. 

--there were no doubt some reporting biases over this time period. For example, there has been a significant increase in reporting on SGLT-2’s since the FDA issued their warning in 2018, though there has also been more of a push by the diabetes and cardiology associations to prescribe SGLT-2’s for those with diabetes and concurrent cardiac disease (eg, see http://gmodestmedblogs.blogspot.com/2018/12/am-coll-of-cardiol-diabetes-rx.html ). But, also, there are increasing numbers of cases of diabetes during this time period

--it should be noted that these were 55 unequivocal cases of FG in the SGLT-2 group; another 60 had ?related types of problems: necrotizing fasciitis but site not specified (13 cases), necrotizing fasciitis but other sites of body (22 cases), FG by case narrative without surgery documented (41 cases, though hard to imagine that this many cases really did not have surgery: ??poor documentation), perineal infection (abscess or cellulitis) without documented necrotizing fasciitis (21 cases), and 1 case each of necrotizing fasciitis of perineum without surgery documented and nonnecrotizing fasciitis. (ie, it is quite conceivable that there were more than twice the number of cases than met the strict FDA criteria for documentation)

--potential mechanisms relating SGLT-2 with FG:

    --the known increase in UTIs and mycotic infections with SGLT-2's, or skin breakdown from pruritus (only 2 of the above cases noted prior UTIs, though unclear how aggressively this was documented)

    --the enriched medium for GI bugs to grow, from the glycosuria (SGLT-2 inhibitors specifically cause glycosuria as the presumed mechanism of action)

    --microvascular complications/endothelial dysfunction: notably similar pathologic findings are found in patients with patients with FG as well as in those with leg amputations (!!). And in the FDA cases above, 3 patients with FG required lower-limb amputations while hospitalized with FG

--as an FDA study with voluntary submission of case reports, there are several concerns: one cannot determine causality (but pretty large increase in FG in those on SGLT-2’s; could be reverse causality, though there was no increase in FG with GLP-1’s, and one might assume that these patients had similar comorbidities), there is no doubt under-reporting (part of which may just be that FG has been historically associated with diabetes, so a relationship with SGLT-2's may not be considered by the clinicians); and no denominators to see the relative rates of FG per meds. It would be useful to have large database searches for the association of FG with the different meds, since RCTs would not be helpful given the rarity of this complication

--as a somewhat tangential issue regarding SGLT-2's: though the Am College of Cardiol, for example, recommends using empagliflozin over canagliflozin, a large Swedish and Danish registry study found that dapagliflozin and empagliflozin are likely to be as bad as canagliflozin for amputations, though the FDA warning about amputations is only for canagliflozin (see http://gmodestmedblogs.blogspot.com/2018/11/sglt-2-inhibitors-twice-risk-of.html ), and http://gmodestmedblogs.blogspot.com/2018/09/sglt-2-inhibitors-and-increased-lower.html , which looked at a huge US database and found an increased rate of amputations for the SGLT-2’s

So, a few points here:

--as is clear from my many blogs on this issue (see highlighted URLs above), i am very concerned about the multitude of adverse effects of SGLT-2's, while the GLP-1 agonists offer more benefits:

    --SGLT-2's are associated with severe UTIs (often with urosepsis), ketoacidosis (even with near normal blood sugars), mycotic infections, amputations/fracture risk, and now Fournier's gangrene

    --the primary SGLT-2 studies were problematic (to me) to the point as to challenge the true cardiac benefits claimed for them (eg, see http://gmodestmedblogs.blogspot.com/2015/12/empagliflozin-good-and-bad.html and http://gmodestmedblogs.blogspot.com/2019/04/diabetes-assn-update-dapagliflozin-and.html )

    --and, GLP-1 agonists have cardioprotection, often really dramatic effects on glucose control, and are much more physiologic (restoring a normal physiologic mechanism for glucose control, the incretin effect that is suboptimal in diabetics), instead of causing massive urinary glucose excretion

--if using SGLT-2 inhibitors, clinicians should have a heightened awareness for FG, since it can be so devastating, deforming, and requiring prolonged hospitalization and rehab. In particular, consider FG in patients with local symptoms of tenderness, erythema and swelling, where (in particular) the pain seems to be out of proportion to the clinical findings; and systemic symptoms (fatigue, fever, and malaise) are both nonspecific and variable.

geoff

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