Jardiance Regret, Stopping, and Restarting: What Real Patients and Clinical Data Actually Show

Side effects the label reports

In pooled placebo-controlled trials in adults with type 2 diabetes (four 24-week trials plus 18-week data from a trial with insulin; placebo 995, empagliflozin 10 mg 999, empagliflozin 25 mg 977), genital yeast 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 came in at 7.6%, 9.3% and 7.6%, and increased urination at 1.0%, 3.4% and 3.2% [1].

Volume depletion events — falling blood pressure, dehydration, orthostatic hypotension, fainting — were reported by 0.3%, 0.5% and 0.3% [1]. The label names who is at higher risk: people with an eGFR below 60 mL/min/1.73 m2, older patients, and patients on loop diuretics [1]. It also notes that a history of chronic or recurrent genitourinary infections makes genitourinary infections more likely on the drug [1].

Empagliflozin causes an osmotic diuresis [1]. In a study of 66 adults with type 2 diabetes, empagliflozin 25 mg produced a median 9.2 g of urinary glucose over 3 fasting hours and 28.2 g over 5 hours after a mixed meal, measured after 4 weeks of treatment [6].

Rare but serious genitourinary infections are also on the label. Urosepsis, pyelonephritis and necrotizing fasciitis of the perineum (Fournier's gangrene) have occurred in patients with and without diabetes, and the label says to evaluate pain, tenderness, erythema or swelling in the genital or perineal area accompanied by fever or malaise immediately [1].

What happens after the last dose

Empagliflozin blocks SGLT2 in the kidney so more glucose leaves in the urine [1]. The label states that urinary glucose excretion persists for 3 days after Jardiance is discontinued, and postmarketing reports describe ketoacidosis or glucosuria lasting beyond 6 days, and in some cases up to 2 weeks, after an SGLT2 inhibitor is stopped [1].

What the outcome trials measured

Four large trials compared empagliflozin with placebo during continuous treatment:

• EMPA-REG OUTCOME: 7,020 adults with type 2 diabetes at high cardiovascular risk, median 3.1 years. Cardiovascular death, non-fatal heart attack or non-fatal stroke occurred in 10.5% versus 12.1% (HR 0.86, 95% CI 0.74 to 0.99); cardiovascular death 3.7% versus 5.9%; heart failure hospitalization 2.7% versus 4.1% [2].
• EMPEROR-Reduced: 3,730 adults with heart failure and ejection fraction of 40% or less, 10 mg daily, median 16 months. Cardiovascular death or heart failure hospitalization 19.4% versus 24.7% (HR 0.75, 95% CI 0.65 to 0.86) [3].
• EMPEROR-Preserved: 5,988 adults with ejection fraction over 40%, median 26.2 months. The same composite occurred in 13.8% versus 17.1% (HR 0.79, 95% CI 0.69 to 0.90), mainly fewer heart failure hospitalizations [4].
• EMPA-KIDNEY: 6,609 adults with chronic kidney disease, median 2.0 years. Kidney disease progression or cardiovascular death 13.1% versus 16.9% (HR 0.72, 95% CI 0.64 to 0.82) [5].

All four counted events while participants were taking empagliflozin or placebo over months to years. The results above describe outcomes during treatment, not after stopping.

Restarting empagliflozin: what the label says

For a restart after ketoacidosis, the label says to monitor patients for resolution of ketoacidosis before restarting Jardiance [1]. Its other pre-treatment instructions are written for initiation: assess renal function before initiating and as clinically indicated, and assess volume status, correcting volume depletion before starting [1]. For blood sugar control, use is not recommended at an eGFR below 30 mL/min/1.73 m2, because the glucose-lowering effect depends on kidney filtration [1].

The label dose is 10 mg once daily in the morning, with or without food, for every indication, and it may be raised to 25 mg for additional glycemic control in patients who tolerate it [1]. EMPEROR-Reduced, EMPEROR-Preserved and EMPA-KIDNEY each used 10 mg once daily [3][4][5].

Medicines the label flags

The label's interaction table covers diuretics, insulin or insulin secretagogues, lithium, and effects on two glucose tests [1]:

• Diuretics: combined use increases urine volume and the chance of volume depletion; the label says to assess volume status and kidney function before starting and to monitor afterwards [1].
• Insulin or sulfonylureas: hypoglycemia risk rises, and the label says a lower dose of the insulin or secretagogue may be needed [1]. Adult hypoglycemia rates were 8.4%, 16.1% and 11.5% with metformin plus a sulfonylurea; 20.6%, 19.5% and 28.4% with basal insulin; and 37.2%, 39.8% and 41.3% with multiple daily insulin (placebo / 10 mg / 25 mg) [1].
• Lithium: SGLT2 inhibitors may decrease serum lithium, and the label says to monitor lithium levels more often when starting and after dose changes [1].
• Urine glucose and 1,5-anhydroglucitol testing: urine glucose tests will be positive and 1,5-AG is unreliable, so the label says to use other ways to monitor glycemic control [1].

Surgery, illness and ketoacidosis

The label says to withhold Jardiance for at least 3 days, if possible, before surgery or procedures with prolonged fasting, and to withhold it, if possible, in temporary situations that could predispose to ketoacidosis, resuming when the patient is clinically stable and has resumed oral intake [1]. Ketoacidosis can present with blood glucose below 250 mg/dL, and the label says to assess for it regardless of the glucose reading [1]. If ketoacidosis is suspected, the label says to discontinue Jardiance, evaluate and treat, and monitor for resolution before restarting [1].

In an analysis of FDA adverse event reports through May 2015, the rate of acidosis reports relative to estimated exposure was about 7-fold higher for SGLT2 inhibitors than for DPP-4 inhibitors among patients with type 2 diabetes [7].

What the drug was doing while you took it

In the label's 24-week monotherapy trial (baseline HbA1c 7.9%), HbA1c fell 0.7 point on 10 mg and 0.8 point on 25 mg, versus a 0.1 rise on placebo. HbA1c under 7% was reached by 35% and 44% of patients versus 12%, and weight fell 2.8% and 3.2% versus 0.4% [1]. Added to metformin, HbA1c fell 0.7 and 0.8 versus 0.1, and weight fell 2.5% and 2.9% versus 0.5% [1].

Empagliflozin has no weight-loss indication [1]. The heart failure and kidney indications are separate from glycemic control, and the label does not restrict the heart failure indication by ejection fraction [1].