Jardiance Autoimmune Disease Considerations: What Clinicians and Patients Need to Know

Does empagliflozin affect the immune system?

Empagliflozin blocks the sodium-glucose co-transporter 2 in the kidney, so more glucose leaves the body in the urine; urinary glucose excretion continues for about 3 days after the drug is stopped [1].

The Jardiance label's warnings and precautions cover ketoacidosis, volume depletion and acute kidney injury, genitourinary infections, hypoglycemia with insulin or insulin secretagogues, lower limb amputation, and serious hypersensitivity such as angioedema [1]. Immune suppression is not among them [1].

In the label's pooled placebo-controlled trials in adults with type 2 diabetes, the reactions occurring at 5% or more were urinary tract infections and female genital mycotic infections [1].

What the label says about people on immunosuppressive treatment

The most direct statement for this population sits in the limitations of use. Empagliflozin is not recommended to treat chronic kidney disease in patients with polycystic kidney disease, in patients who need or recently received intravenous immunosuppression, or in patients taking more than 45 mg per day of prednisone-equivalent for kidney disease [1]. That sentence is written for the kidney indication and appears under limitations of use rather than contraindications [1].

The label also notes that patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections while taking Jardiance [1].

Genital and urinary infections: what the numbers show

In the pooled 24-week placebo-controlled trials in adults with type 2 diabetes (placebo 995, empagliflozin 10 mg 999, 25 mg 977), genital mycotic infections were reported in 1.5%, 5.4% and 6.4% of women and in 0.4%, 3.1% and 1.6% of men [1]. Urinary tract infections occurred in 7.6%, 9.3% and 7.6% overall, and were far more common in women (16.6%, 18.4%, 17.0%) than in men (3.2%, 3.6%, 4.1%) [1]. Volume depletion events were uncommon in the same pool, at 0.3%, 0.5% and 0.3% [1].

Genital infections also increased in EMPA-REG OUTCOME, and in EMPEROR-Preserved genital and urinary tract infections and hypotension were reported more frequently with empagliflozin than with placebo [2][3].

Necrotizing fasciitis of the perineum (Fournier's gangrene) is a rare, life-threatening infection requiring urgent surgical intervention, according to the label; cases have required hospitalization, and serious outcomes have included multiple surgeries and death [1]. The label directs that patients with pain or tenderness, redness, or swelling in the genital or perineal area, together with fever or malaise, be evaluated immediately, and that Jardiance be discontinued if necrotizing fasciitis is suspected, with prompt medical and/or surgical treatment [1].

Ketoacidosis: the risk that rises when eating stops

Ketoacidosis with empagliflozin is not limited to type 1 diabetes. The label describes postmarketing reports of fatal ketoacidosis in type 2 diabetes, and notes that blood glucose at presentation may be below 250 mg/dL [1]. Precipitating conditions it lists include missed or reduced insulin, acute febrile illness, reduced caloric intake, a ketogenic diet, surgery, volume depletion and alcohol abuse [1]. Ketoacidosis and glucosuria have been reported lasting more than 6 days, and some up to 2 weeks, after discontinuation of SGLT2 inhibitors [1].

The label directs withholding Jardiance for at least 3 days, if possible, before surgery or procedures with prolonged fasting, and withholding it in temporary situations that could predispose to ketoacidosis, resuming when the patient is clinically stable and has resumed oral intake [1]. The signs it lists are nausea, vomiting, abdominal pain, general malaise and shortness of breath [1].

Type 1 diabetes, an autoimmune condition, is the population the label singles out: empagliflozin is not recommended to improve glycemic control there because it significantly increases the risk of diabetic ketoacidosis beyond the background rate, with fatal cases reported [1].

Kidney function and the CKD trial

The label says use for glycemic control is not recommended when eGFR is below 30 mL/min/1.73 m2 [1].

EMPA-KIDNEY randomized 6,609 adults with an eGFR of at least 20 but under 45 mL/min/1.73 m2, or 45 to under 90 with a urine albumin-to-creatinine ratio of at least 200 mg/g, to empagliflozin 10 mg or placebo [4]. Over a median of 2.0 years, kidney disease progression or cardiovascular death occurred in 13.1% on empagliflozin versus 16.9% on placebo (HR 0.72, 95% CI 0.64 to 0.82), consistent in patients with and without diabetes [4]. An eGFR under 20 was outside the entry criteria [4].

The label notes that eGFR dips and creatinine rises within weeks and then stabilizes; in the cardiovascular outcomes trial the change at week 4 was generally no more than 0.1 mg/dL for creatinine and 9.0 mL/min/1.73 m2 for eGFR [1].

Co-medications used in autoimmune disease

The label's interaction table lists five entries: diuretics, insulin and insulin secretagogues, lithium, positive urine glucose tests, and interference with the 1,5-anhydroglucitol assay [1]. Methotrexate, mycophenolate, azathioprine, biologics and JAK inhibitors do not appear in it [1].

Diuretics increase urine volume and the potential for volume depletion; the label directs assessing volume status and kidney function before starting and monitoring afterward [1]. Insulin and sulfonylureas raise hypoglycemia risk, with adult rates on placebo, 10 mg and 25 mg of 8.4%, 16.1% and 11.5% when added to metformin plus a sulfonylurea, and 20.6%, 19.5% and 28.4% with basal insulin [1]. The label says lower doses of insulin or an insulin secretagogue may be needed when starting [1]. For lithium, the label states that SGLT2 inhibitors may decrease serum lithium and advises monitoring lithium levels more frequently when starting and after dose changes [1]. Urine glucose tests will turn positive and 1,5-AG is unreliable, so the label says to use other methods to monitor glycemic control [1].

Other label warnings

Volume depletion is more likely with impaired kidney function (eGFR under 60), older age and loop diuretics [1]. Serious hypersensitivity, including angioedema, has occurred and is the listed contraindication [1].

Lower limb amputation is a warning rather than a contraindication: across four Jardiance outcome trials amputation rates were 5.0 versus 4.3 events per 1,000 patient-years (HR 1.05, 95% CI 0.81 to 1.36), and the label advises monitoring for lower limb infections and ulcers [1].