Restarting Jardiance (Empagliflozin) After Acute Illness: A Clinical Guide

What the Jardiance label says about restarting

One instruction answers most of the question: the label says to withhold Jardiance, if possible, in temporary clinical situations that could predispose patients to ketoacidosis, and to resume it when the patient is clinically stable and has resumed oral intake [1]. The situations it names as precipitants are acute febrile illness, reduced caloric intake, surgery, volume depletion, insulin dose reduction or missed insulin doses, a ketogenic diet and alcohol abuse [1].

The same decision appears in the label's ketoacidosis warning, which says patients should be monitored for resolution of ketoacidosis before restarting [1].

For planned procedures the label is more specific: withhold Jardiance for at least 3 days, if possible, before surgery or procedures associated with prolonged fasting [1].

Why ketoacidosis, not glucose, drives the decision

Empagliflozin blocks SGLT2 in the kidney so more glucose leaves in the urine, lowering blood glucose independently of insulin [1].

The label warns that the presentation of ketoacidosis can be deceptive. Blood glucose at presentation may be below 250 mg/dL, and ketoacidosis and glucosuria may last longer than expected: urinary glucose excretion persists for 3 days after stopping, while postmarketing reports describe ketoacidosis or glucosuria lasting more than 6 days and, in some cases, up to 2 weeks [1]. In type 1 diabetes the label states that Jardiance significantly increases the risk of ketoacidosis, with fatal cases reported, and that it is not recommended for glycemic control in type 1 diabetes [1]. Fatal ketoacidosis has also been reported after marketing in type 2 diabetes [1].

The signs the label lists are nausea, vomiting, abdominal pain, generalized malaise and shortness of breath, consistent with dehydration and severe metabolic acidosis [1]. The label says to assess for ketoacidosis regardless of the presenting glucose in anyone with signs and symptoms of severe metabolic acidosis, and that patients should be instructed to discontinue Jardiance and seek medical attention immediately if these occur [1]. If ketoacidosis is suspected, the label directs that the drug be discontinued, the patient promptly evaluated and treated, and resolution confirmed before restarting [1].

Surgery and procedures with prolonged fasting

The label's perioperative instruction is a minimum of 3 days off Jardiance, if possible, before surgery or procedures associated with prolonged fasting [1]. Surgery itself is on the label's list of ketoacidosis precipitants [1].

What kidney numbers to check

The label says to assess renal function before initiating Jardiance and as clinically indicated, to assess volume status, and to correct volume depletion before starting; it also says to monitor renal function after therapy begins [1]. For glycemic control, use is not recommended at an eGFR below 30 mL/min/1.73 m2 [1].

The restart instruction is written around clinical stability and oral intake rather than a specific eGFR number [1]. The eGFR figures in the label do other jobs: they mark where glycemic use stops being recommended (below 30) and they identify who is at higher risk of volume depletion, namely people with eGFR below 60, older adults and those on loop diuretics [1].

The 20 mL/min/1.73 m2 figure in the trial literature is an enrollment criterion, not a restart threshold. EMPA-KIDNEY enrolled adults with chronic kidney disease and an eGFR of at least 20 but under 45, or an eGFR of at least 45 but under 90 with a urine albumin-to-creatinine ratio of at least 200, and found that 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) over a median of 2.0 years [2].

Medicines that change the restart picture

Diuretics. Coadministration increases urine volume and the frequency of voiding, which can add to volume depletion; the label says to assess volume status and renal function before starting and to monitor for signs of volume depletion and changes in renal function afterwards [1]. Volume depletion events in the pooled adult trials were uncommon: 0.3% on placebo, 0.5% on 10 mg and 0.3% on 25 mg. In adults aged 75 and older, volume-depletion reactions were 2.1%, 2.3% and 4.4% respectively [1].

Insulin and sulfonylureas. The label says a lower dose of insulin or the secretagogue may be needed to reduce hypoglycemia risk [1]. Adult trial rates (placebo / 10 mg / 25 mg) were 8.4% / 16.1% / 11.5% with metformin plus a sulfonylurea, 20.6% / 19.5% / 28.4% with basal insulin, and 37.2% / 39.8% / 41.3% with multiple daily insulin injections; as monotherapy the rate was about 0.4% in every arm [1].

Lithium. Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations, so the label says to monitor lithium levels more frequently during initiation and dose changes [1].

Glucose monitoring tests. Urine glucose tests will be positive on empagliflozin and are not a recommended way to monitor control; 1,5-anhydroglucitol measurements are unreliable, and the label says to use alternative methods [1].

What to watch for after restarting

In the pooled 24-week trials in adults with type 2 diabetes (placebo N=995, 10 mg N=999, 25 mg N=977), the rates for placebo, 10 mg and 25 mg were: urinary tract infection 7.6%, 9.3% and 7.6%; female genital mycotic infection 1.5%, 5.4% and 6.4%; male genital mycotic infection 0.4%, 3.1% and 1.6%; increased urination 1.0%, 3.4% and 3.2% [1].

The label also carries a warning for necrotizing fasciitis of the perineum (Fournier's gangrene). It says to evaluate pain, tenderness, erythema or swelling in the genital or perineal area, with fever or malaise, immediately; if suspected, the drug is to be discontinued and medical and surgical treatment started promptly [1].

Lower limb amputation is a Warnings and Precautions item. Across four Jardiance outcome trials the amputation rate was 5.0 versus 4.3 events per 1,000 patient-years (HR 1.05, 95% CI 0.81 to 1.36), and in the long-term kidney trial 4.3 versus 2.9 per 1,000 patient-years; risk is highest with diabetic foot, peripheral artery disease or a prior amputation, and the label advises foot care and monitoring [1]. Serious hypersensitivity including angioedema has occurred, and hypersensitivity to empagliflozin or any excipient is a contraindication [1].

Trial background

The restart instructions above come from the product label. The outcome trials randomized people to once-daily empagliflozin or placebo: EMPA-REG OUTCOME (7,020 adults with type 2 diabetes at high cardiovascular risk, median 3.1 years), EMPEROR-Reduced (3,730 adults, median 16 months), EMPEROR-Preserved (5,988 adults, median 26.2 months) and EMPA-KIDNEY (6,609 adults, median 2.0 years) [3][4][5][2].