Jardiance Mental Health and Mood Impact: What the Evidence Actually Shows

Does Jardiance cause depression?

The Jardiance label does not list depression or anxiety among its Warnings and Precautions or its pooled trial reactions [1]. There is no boxed warning; the listed warnings are ketoacidosis, volume depletion and acute kidney injury, genitourinary infections, hypoglycemia, lower limb amputation and serious hypersensitivity such as angioedema [1].

The adverse reactions table from the pooled 24-week placebo-controlled trials (placebo N=995, 10 mg N=999, 25 mg N=977) lists urinary tract infection 7.6% / 9.3% / 7.6%, female genital yeast infection 1.5% / 5.4% / 6.4%, upper respiratory infection 3.8% / 3.1% / 4.0%, increased urination 1.0% / 3.4% / 3.2%, dyslipidemia 3.4% / 3.9% / 2.9%, arthralgia 2.2% / 2.4% / 2.3%, male genital yeast infection 0.4% / 3.1% / 1.6%, nausea 1.4% / 2.3% / 1.1% and thirst 0% / 1.7% / 1.5% [1]. That table covers reactions that occurred in at least 2% of treated patients and more often than on placebo [1]. The postmarketing reactions named on the label are Fournier's gangrene, urosepsis, pyelonephritis, ketoacidosis, acute kidney injury, angioedema, rash, urticaria and constipation [1].

That table is a record of reported events, not a measure of mood.

Does Jardiance cause anxiety?

Anxiety is not listed among the Jardiance label's warnings or pooled trial reactions [1]. The label describes ketoacidosis in physical terms: nausea, vomiting, abdominal pain, generalized malaise and shortness of breath, with blood glucose possibly below the 250 mg/dL usually expected in diabetic ketoacidosis [1]. It also notes that ketoacidosis and glucosuria can last beyond 6 days, and in some reports up to 2 weeks, after stopping [1].

What the label tells patients to watch for

Ketoacidosis. It is significantly more common in type 1 diabetes, where Jardiance is not recommended for glucose control, and fatal cases have been reported after marketing in type 2 diabetes [1]. Risk is higher with under-insulinization, acute febrile illness, reduced food intake, a ketogenic diet, surgery, volume depletion and alcohol abuse [1]. The label says to withhold Jardiance for at least 3 days, if possible, before surgery or procedures with prolonged fasting [1].

Volume depletion. Reported in 0.3% of patients on placebo, 0.5% on 10 mg and 0.3% on 25 mg in the pooled trials; in adults aged 75 and older the rates were 2.1%, 2.3% and 4.4% [1]. Risk is higher with an eGFR under 60 mL/min/1.73 m2, older age and loop diuretics, and the label says to assess volume status and kidney function before starting [1].

Hypoglycemia. Monotherapy rates were 0.4% in every arm, but with metformin plus a sulfonylurea they were 8.4% / 16.1% / 11.5%, with basal insulin 20.6% / 19.5% / 28.4% and with multiple daily insulin 37.2% / 39.8% / 41.3% [1]. The label says a lower insulin or insulin secretagogue dose may be needed when Jardiance is started [1].

Genital and urinary infections. These are the most common reactions on the label, and it says to evaluate pain, tenderness, erythema or swelling in the genital or perineal area with fever or malaise immediately for necrotizing fasciitis of the perineum [1].

High blood glucose, mood and thinking

The clearest glucose-to-mood link in this literature comes from a clamp study, not from empagliflozin. Twenty adults with type 2 diabetes (median age 61.5 years, HbA1c 7.5%) had blood glucose held at either 4.5 or 16.5 mmol/L on two occasions. During hyperglycemia, information processing speed, working memory and some aspects of attention were worse, and participants reported more dysphoria, less energetic arousal and more sadness and anxiety [3]. That study tested acute hyperglycemia, not any drug.

Empagliflozin does lower HbA1c. In the label's 24-week monotherapy trial, HbA1c fell 0.7 points on 10 mg and 0.8 points on 25 mg versus a 0.1-point rise on placebo; 35% and 44% of patients reached HbA1c under 7% versus 12% on placebo; and weight fell 2.8% and 3.2% versus 0.4% [1]. SGLT2 inhibition also shifts substrate use from carbohydrate toward lipid and possibly ketone bodies [7].

How common are depression and anxiety in people who take Jardiance?

Jardiance is used for heart failure, chronic kidney disease, type 2 diabetes with cardiovascular disease, and glycemic control in type 2 diabetes [1]. A meta-analysis of 36 heart failure studies found clinically significant depression in 21.5% of patients (33.6% when measured by questionnaire and 19.3% by diagnostic interview), ranging from 11% in NYHA class I to 42% in class IV, and depression was associated with higher rates of death and secondary events (risk ratio 2.1, 95% CI 1.7 to 2.6) [4]. These data do not show how common depression is among people taking Jardiance.

In diabetes, a systematic review of 14 studies (n = 1,760,800) found baseline anxiety associated with later diabetes (odds ratio 1.47, 95% CI 1.23 to 1.75); the two studies that examined the reverse direction, diabetes leading to anxiety, found no association [5]. The US Preventive Services Task Force recommends screening adults for depression (B recommendation) and found insufficient evidence to assess screening for suicide risk (I statement) [6].

Does Jardiance affect sleep?

Nocturia is one of the reactions the label counts. In the pooled placebo-controlled trials it was reported by 0.4% of patients on placebo, 0.3% on 10 mg and 0.8% on 25 mg, and the broader increased-urination grouping by 1.0%, 3.4% and 3.2% [1]. The label's dosing instruction is 10 mg once daily in the morning, with or without food [1].

Can Jardiance be taken with lithium?

This is the one psychiatric medicine in the label's interaction table. The label states that concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations, and it advises monitoring serum lithium more frequently during initiation of Jardiance and after dose changes [1]. The rest of that table covers diuretics, insulin and insulin secretagogues, urine glucose tests and the 1,5-AG assay [1].

What the outcome trials measured instead

EMPA-REG OUTCOME randomized 7,020 adults with type 2 diabetes at high cardiovascular risk to 10 mg, 25 mg or placebo for a median of 3.1 years. The primary composite of cardiovascular death, nonfatal heart attack or nonfatal stroke occurred in 10.5% versus 12.1% (HR 0.86, 95% CI 0.74 to 0.99; P=0.04 for superiority). Cardiovascular death was 3.7% versus 5.9%, a 38% relative reduction; heart failure hospitalization 2.7% versus 4.1%, a 35% relative reduction; and death from any cause 5.7% versus 8.3%. Heart attack and stroke alone did not differ significantly [2].

The later trials extended this to heart failure and kidney disease. EMPEROR-Reduced enrolled 3,730 adults with heart failure and an ejection fraction of 40% or less and found cardiovascular death or heart failure hospitalization in 19.4% versus 24.7% (HR 0.75, 95% CI 0.65 to 0.86) over a median of 16 months [8]. EMPA-KIDNEY enrolled 6,609 adults with chronic kidney disease and found kidney disease progression or cardiovascular death in 13.1% versus 16.9% (HR 0.72, 95% CI 0.64 to 0.82) over a median of 2.0 years, with no significant difference in all-cause death (4.5% versus 5.1%) [9].