Perspectives From a Regional Plastic Surgery Centre on Evidence for the Purported Link Between SGLT2 Inhibitors and Fournier's Gangrene

Introduction: The recent report issued by the MHRA indicating an association of Sodium glucose linked transporter type 2 (SGLT2) Inhibitors with the contraction of Fournier's Gangrene (FG), has been drawn with insufficient supporting evidence and without an adequately powered study to make any meaningful assertions or recommendations. We aimed to look specifically at the currently available dataset used to link SGLT2 Inhibitors to FG and highlight what conclusions or inferences can meaningfully be made, in particular the power of any study that would be required to make sensible conclusions.Methods: World literature review of SGLT2 Inhibitors and FG was performed. With a subsequent 10-year review of cases of FG seen in a regional burns and plastics centre. Data was collected retrospectively from the coding department at Whiston Hospital for all patients with necrotising fasciitis. An electronic document management system was used to identify patients with FG specifically as well as their diabetes state and medication history.Results: Seventy-eight patients were admitted with FG, of whom 32 had diabetes mellitus (DM). Of those with DM none was taking an SGLT2 Inhibitor, 17 patients were taking metformin, a further nine patients were taking a second line medication and 14 required insulin injections.Discussions: DM is a known major risk factor for FG, which is clearly observed in our patient cohort. The risk of patients with DM developing FG is irrespective of the medication patients are taking. The current articles and reports published have little ground to claim an association between SGLT2 Inhibitors and FG and are missing the crucial message that needs to be conveyed to the public: that DM is a major risk factor for FG and patients suffering with diabetes need to be extra vigilant.

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SUN-700 Fournier’s Gangrene and Diabetic Ketoacidosis Caused by Canagliflozin

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.984 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

George Alexiades Stamatiades ◽

Kinjal Kasbawala ◽

Aristea Sideri Gugger ◽

Mehreen Elahee ◽

Sachin K Majumdar

Keyword(s):

Adverse Effects ◽

Diabetic Ketoacidosis ◽

Soft Tissues ◽

Sglt2 Inhibitor ◽

Fournier’S Gangrene ◽

Sglt2 Inhibitors ◽

Inhibitor Therapy ◽

Anion Gap ◽

Simultaneous Occurrence ◽

Fournier's Gangrene

Abstract Introduction Sodium glucose co-transporter 2 (SGLT2) inhibitors have become an appealing treatment for diabetes due to their favorable cardiac and renal outcomes. However, reports continue to emerge describing potentially life-threatening adverse events such as Fournier’s gangrene (FG) and diabetic ketoacidosis (DKA) associated with their use. Herein, we report a case of simultaneous FG and DKA in a patient taking canagliflozin. Case Presentation A 37-year-old woman with a history of type 2 diabetes mellitus, peripheral neuropathy, and morbid obesity (BMI of 45.8 kg/m2) presented to the hospital with left gluteal pain associated with dysuria despite 5-day treatment with trimethoprim/sulfamethoxazole for a presumed urinary tract infection. Approximately 1 month prior, sitagliptin and canagliflozin were added to her regimen due to poor glycemic control on metformin (HbA1c 9.8%). On examination her temperature was 36.9oC, pulse 117 beats/minute, blood pressure 144/79 mmHg and respiratory rate was 19 bpm. She appeared lethargic and had suprapubic tenderness and induration in the left gluteal region extending to the perineum. Laboratory findings revealed an arterial pH of 7.23 and PCO2 of 34 mmHg, a blood glucose of 402 mg/dL, serum bicarbonate 12mmol/L (20-30mmol/L), an elevated anion gap of 24mmol/L (7-17mmol/L) and a lactate of 1.8 mmol/L. Urinalysis showed 4+ glucose and 1+ ketones. Serum β-hydroxybutyrate was 2.49 mmol/L (0.02-0.27mmol/L). A CT scan of the abdomen and pelvis showed marked inflammatory changes with subcutaneous edema and air within the medial left gluteal soft tissues and locules of air extending into the presacral soft tissues suggestive of Fournier’s gangrene. The diagnoses of Fournier’s gangrene and DKA were made. The patient was started on empirical antibiotic treatment and required six surgical explorations with debridement. Interestingly, initial DKA management included only subcutaneous insulin. Only when serum ketones were identified and the anion gap persisted, insulin infusion with aggressive fluid resuscitation was initiated with successful resolution of anion gap metabolic acidosis. She was discharged with a urinary catheter, vacuum dressing, colostomy with instructions to start insulin glargine 18U and discontinue the oral anti-diabetic medications. Discussion To the best of our knowledge, this is the first case describing the simultaneous occurrence of two potentially fatal adverse effects of SGLT2 inhibitor therapy; Fournier’s gangrene and DKA. In light of the FDA’s warnings and the growing popularity of SGLT2 inhibitor therapy it is important to be mindful of their more serious and potentially fatal complications. It is also important to promptly terminate SGLT2 inhibitors when harmful adverse effects are suspected to prevent further progression.

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Sodium–Glucose Cotransporter 2 Inhibitor Use Associated With Fournier's Gangrene: A Review of Case Reports and Spontaneous Post-Marketing Cases

10.2337/figshare.15147888 ◽

2021 ◽

Author(s):

Bao Anh Tran ◽

Wendy H. Updike ◽

Krystal Bullers ◽

Erini Serag-Bolos

Keyword(s):

Mortality Rate ◽

Case Reports ◽

Fournier’S Gangrene ◽

Boxed Warning ◽

Sglt2 Inhibitors ◽

Fournier's Gangrene ◽

Sodium Glucose Cotransporter ◽

Potential Development ◽

Post Marketing ◽

The U.S

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are effective for glycemic control and have demonstrated cardiorenal benefits. The U.S. Food and Drug Administration (FDA) released a boxed warning in 2018 regarding the potential development of Fournier’s gangrene (FG) with the use of SGLT2 inhibitors. FG is a serious perineal infection with a mortality rate of up to 88% in some cases.

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MHRA drug safety update: risk of Fournier’s gangrene with SGLT2 inhibitors for diabetes

Drug and Therapeutics Bulletin ◽

10.1136/dtb.2019.000032 ◽

2019 ◽

Vol 57 (8) ◽

pp. 117-117 ◽

Cited By ~ 1

Keyword(s):

Drug Safety ◽

Fournier’S Gangrene ◽

Sglt2 Inhibitors ◽

Fournier's Gangrene

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SGLT2 Inhibitors and the Risk of Hospitalization for Fournier’s Gangrene: A Nested Case–Control Study

Diabetes Therapy ◽

10.1007/s13300-020-00771-8 ◽

2020 ◽

Vol 11 (3) ◽

pp. 711-723 ◽

Cited By ~ 2

Author(s):

Tongtong Wang ◽

Shrita M. Patel ◽

Anne Hickman ◽

Xinyue Liu ◽

Philip LStJ Jones ◽

...

Keyword(s):

Case Control Study ◽

Case Control ◽

Fournier’S Gangrene ◽

Sglt2 Inhibitors ◽

Fournier's Gangrene ◽

Nested Case Control ◽

Control Study

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Reply to Dr. Milito's letter to the Editor concerning “Fournier’s gangrene: is the female gender a risk factor?”

Langenbeck s Archives of Surgery ◽

10.1007/s00423-009-0485-9 ◽

2009 ◽

Vol 394 (4) ◽

pp. 757-758

Author(s):

Ralf Czymek ◽

Philine Frank ◽

Lena Unger ◽

Peter Kujath

Keyword(s):

Risk Factor ◽

Female Gender ◽

Fournier’S Gangrene ◽

Fournier's Gangrene ◽

Letter To The Editor

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Fournier’s Gangrene and Diabetic Ketoacidosis Associated with Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Life-Threatening Complications

American Journal of Case Reports ◽

10.12659/ajcr.921536 ◽

2020 ◽

Vol 21 ◽

Cited By ~ 1

Author(s):

Kinjal Kasbawala ◽

George A. Stamatiades ◽

Sachin K. Majumdar

Keyword(s):

Diabetic Ketoacidosis ◽

Fournier’S Gangrene ◽

Sglt2 Inhibitors ◽

Fournier's Gangrene ◽

Life Threatening

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Impact of early initiation of SGLT2 inhibitor on cardiovascular outcomes in diabetic patients with known atherosclerotic cardiovascular disease or risk factors: propensity score matched analysis

European Heart Journal ◽

10.1093/eurheartj/ehab724.2653 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

W Sun ◽

B Yan

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Risk Factor ◽

Propensity Score ◽

Sglt2 Inhibitor ◽

Sglt2 Inhibitors ◽

Early Initiation ◽

Diabetic Patients ◽

Atherosclerotic Cardiovascular Disease ◽

The Impact

Abstract Purpose Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated cardiovascular benefits in patients with diabetes and atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the impact of early initiation of SGLT2 inhibitor on cardiovascular outcomes in diabetic patients with known and at risk of ASCVD. Methods We retrospectively analyzed 29,309 consecutive patients with type 2 diabetes prescribed empagliflozin (N=18,979, 64.8%) and dapagliflozin (N=10,330, 35.2%) between August 2015 and August 2020 in 16 public hospitals in Hong Kong. Patients with diagnosis of diabetes to first prescription of SGLT2 inhibitors (Dx-to-Rx time) ≤12 months were matched with >12 months using propensity score derived from logistic regression. 3,370 matched patients were divided into 4 groups: (i) patients with known ASCVD involving 1 territory (coronary artery, peripheral artery or cerebrovascular disease); (ii) known ASCVD involving >1 territories; (iii) CV risk factor(s) other than diabetes and (iv) no known ASCVD or additional CV risk factors. Incidence rates of 3-point major adverse cardiovascular events (MACE, including non-fatal stroke, non-fatal myocardial infarction and cardiovascular death) were compared between Dx-to-Rx time ≤12 months and >12 months across 4 subgroups during a median follow-up of 2.8 years (IQR 2.2 to 3.4). Results Of 29,309 patients (mean age 54.9±11.6 years, female 41.0%), 22.9% had single territory and 6.1% multi-territories ASCVD, 53.3% with additional CV risk factors and 17.7% neither risk factor nor ASCVD. Overall, 19.0% of patients had Dx-to-Rx time ≤12 month; 19.3%, 15.7%, 17.6% and 30.0% in each group, respectively. Overall, Dx-to-Rx time ≤12 months was associated with lower rates of MACE (hazard ratio (HR) =0.27, 95% CI: 0.17–0.42). Subgroup analysis showed similar results in patients with CV risk factors of or known ASCVD but not in patients with neither risk factor nor ASCVD (P for interaction=0.001, Table 1). Conclusion Early initiation of SGLT2 inhibitor was associated with significant lower MACE rates in diabetic patients with known ASCVD or additional CV risk factors. The impact was more marked in patients with additional CV risk factors. Our findings suggested early initiation in diabetic patients with known ASCVD and additional CV risk factors. FUNDunding Acknowledgement Type of funding sources: None.

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