Jardiance and Metformin Interaction Explained

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Is there a direct drug interaction between empagliflozin and metformin?

The Jardiance drug interaction table lists five clinically relevant interactions: diuretics, insulin and insulin secretagogues, lithium, urine glucose tests, and the 1,5-anhydroglucitol assay [1]. Metformin is not one of them. The metformin label's interaction table lists carbonic anhydrase inhibitors such as topiramate and zonisamide, drugs that reduce metformin clearance (ranolazine, vandetanib, dolutegravir, cimetidine), alcohol, insulin and insulin secretagogues, and drugs that can raise blood glucose [2]. Empagliflozin is not among its examples either.

The two drugs are handled differently by the body. Empagliflozin is metabolized by glucuronidation through UGT enzymes rather than the CYP450 system, has no major metabolites, and does not inhibit or induce CYP450 enzymes; about 95.6% of an oral dose is recovered in feces (41.2%) and urine (54.4%), roughly half of the urinary material unchanged [1]. Metformin is not metabolized, has no metabolites, and is excreted unchanged in urine by tubular secretion [2].

Blood sugar and hypoglycemia when empagliflozin is added to metformin

In the Jardiance label's 24-week trials, empagliflozin added to metformin lowered HbA1c by 0.7 percentage points at 10 mg and 0.8 points at 25 mg, against 0.1 point for placebo added to metformin; the difference from placebo was 0.6 points for both doses. Weight fell 2.5% and 2.9% versus 0.5% [1].

Hypoglycemia with a metformin background was uncommon. In the label's hypoglycemia table, overall events were 0.5% on placebo plus metformin, 1.8% on empagliflozin 10 mg plus metformin, and 1.4% on 25 mg plus metformin, with no severe events in any of those three arms [1]. With metformin plus a sulfonylurea, hypoglycemia occurred in 8.4% of patients receiving placebo, 16.1% receiving empagliflozin 10 mg, and 11.5% receiving 25 mg [1].

The Jardiance label identifies insulin and insulin secretagogues such as sulfonylureas as combinations that increase hypoglycemia risk, and says lower doses of those drugs may be needed when empagliflozin is started [1]. The metformin label gives the same instruction for insulin and secretagogues [2].

Kidney function: where the two labels meet

The metformin label ties its rules to eGFR. It says to check eGFR before starting and at least annually, contraindicates metformin below an eGFR of 30 mL/min/1.73 m2, says starting is not recommended between 30 and 45, says to reassess benefit and risk if eGFR later falls below 45, and says to discontinue it if eGFR falls below 30 [2]. The label also says metformin-associated lactic acidosis cases reported after approval occurred primarily in patients with significant renal impairment [2].

The Jardiance label asks for renal function to be assessed before starting and as clinically indicated, and states that empagliflozin is not recommended for glycemic control when eGFR is below 30 mL/min/1.73 m2 [1].

The Jardiance label also describes an eGFR dip and creatinine rise within weeks of starting that then stabilizes; in the cardiovascular outcomes trial the changes at week 4 were generally no more than 0.1 mg/dL for creatinine and 9.0 mL/min/1.73 m2 for eGFR [1].

Volume status belongs here too. The Jardiance label says to assess volume status and renal function before starting in people with reduced kidney function, in older adults, and in people taking loop diuretics, then to monitor for volume depletion [1]. In adults 75 and older, volume depletion reactions were 2.1% on placebo, 2.3% on 10 mg and 4.4% on 25 mg [1].

Lactic acidosis and ketoacidosis: what each label warns about

Metformin carries a boxed warning for lactic acidosis. Reported cases included death, hypothermia, hypotension and resistant bradyarrhythmias, and the warning describes an often subtle onset with malaise, muscle aches, breathing difficulty, sleepiness and abdominal pain. Named risk factors are renal impairment, use of certain drugs such as carbonic anhydrase inhibitors, age 65 or older, contrast imaging, surgery and other procedures, hypoxic states such as acute heart failure, excessive alcohol intake, hepatic impairment and mitochondrial disease. If lactic acidosis is suspected, the label says to stop metformin and treat in hospital, with prompt hemodialysis recommended [2]. Metformin is also contraindicated in acute or chronic metabolic acidosis, including diabetic ketoacidosis [2].

Empagliflozin's serious risk is ketoacidosis, which the label says can present with blood glucose below 250 mg/dL and has been reported in type 2 as well as type 1 diabetes; use for glycemic control in type 1 diabetes is not recommended because it raises that risk [1]. The label says patients should be educated on the signs of ketoacidosis, which include nausea, vomiting, abdominal pain, general malaise and shortness of breath [1].

Both labels address interrupted eating, illness and procedures. The metformin label says to temporarily discontinue metformin while food and fluid intake is restricted, and to stop it at or before iodinated contrast in patients with eGFR 30 to 60, a history of liver disease, alcoholism or heart failure, or when intra-arterial contrast is used, rechecking eGFR 48 hours later and restarting only if renal function is stable [2]. The Jardiance label says to withhold it 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, such as acute febrile illness, reduced calorie intake, surgery, volume depletion or alcohol abuse, resuming once the patient is clinically stable and eating again [1].

The combination tablet

Synjardy is a fixed-dose tablet containing empagliflozin and metformin, with separate prescribing information [1][3].