Jardiance Side Effects: Incidence Rates Across Clinical Trials

How Empagliflozin's Mechanism Drives Its Side-Effect Profile

Empagliflozin blocks the sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubule, causing glycosuria, mild osmotic diuresis, and reduced intravascular volume. Those three downstream effects predict most of its adverse events before a patient swallows a single pill. The glucosuria creates a moist, glucose-rich perineal environment that favors fungal overgrowth. The osmotic diuresis increases urinary frequency and, theoretically, raises UTI risk, though trial data complicate that assumption.

Why the FDA Label Is the Starting Point

The FDA-approved prescribing information for Jardiance, last updated in 2023, pools data from seven placebo-controlled trials totaling 3,490 patients on 10 mg, 3,946 on 25 mg, and 2,333 on placebo for at least 24 weeks [1]. These pooled figures give the baseline incidence rates that every downstream analysis should be anchored to.

The label lists female genital mycotic infections at 5.4% (10 mg) and 6.4% (25 mg) versus 1.5% placebo. Male genital mycotic infections appear at 3.1% (10 mg) and 3.4% (25 mg) versus 0.4% placebo [1]. These are not minor nuisances: genital infections caused roughly 1 in 10 women treated with empagliflozin to seek additional medical care in the phase III program.

Osmotic Diuresis and Volume Effects

Increased urination occurred in 3.0% (10 mg) and 3.8% (25 mg) of patients versus 1.2% placebo in the pooled label dataset [1]. Hypotension-related adverse events, grouped as volume depletion, appeared in 0.3% to 2.0% of subjects across dose groups, with higher rates in patients also taking diuretics or who had baseline estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² [1].

EMPA-REG OUTCOME: Cardiovascular Safety Trial Data

EMPA-REG OUTCOME enrolled 7,020 adults with type 2 diabetes and established cardiovascular disease across 590 sites in 42 countries, randomizing them to empagliflozin 10 mg, 25 mg, or placebo for a median of 3.1 years [2]. The primary efficacy result, a 14% relative risk reduction in three-point MACE, is well-known. The safety data are equally detailed and worth examining dose by dose.

Genital Infections in EMPA-REG OUTCOME

Genital mycotic infections occurred in 6.4% of women on 10 mg, 6.3% on 25 mg, and 1.8% on placebo. Among men, rates were 3.1% (10 mg), 3.7% (25 mg), and 0.4% placebo [2]. These figures mirror the pooled label data closely, suggesting no meaningful cardiovascular-disease-driven amplification of fungal risk.

Urinary Tract Infections: The Counterintuitive Finding

Many clinicians expect osmotic diuresis to flush the urinary tract and lower UTI risk, but the numbers are mixed. In EMPA-REG OUTCOME, UTI rates were 7.6% (10 mg), 8.1% (25 mg), and 8.4% placebo, meaning empagliflozin did not increase and may have slightly lowered UTI incidence in this cardiovascular-disease-enriched population [2]. The Cochrane systematic review of SGLT2 inhibitors published by Donnan et al. (2019) confirmed that pooled UTI risk across the class does not significantly exceed placebo at standard doses [3].

Serious Adverse Events and Discontinuation

Serious adverse events occurred in 35.2% (10 mg), 35.4% (25 mg), and 37.0% placebo groups, reflecting the high underlying morbidity of the enrolled population [2]. Empagliflozin did not increase the overall serious-adverse-event burden. Discontinuation due to adverse events ran 6.8% in the pooled empagliflozin group versus 5.1% placebo, driven primarily by genital infections [2].

EMPEROR-Reduced: Heart Failure with Reduced Ejection Fraction

EMPEROR-Reduced randomized 3,730 patients with heart failure and ejection fraction 40% or below to empagliflozin 10 mg once daily or placebo for a median of 16 months [4]. The primary endpoint, a composite of cardiovascular death or worsening heart failure, was reduced by 25% relative risk (HR 0.75, 95% CI 0.65 to 0.86, P<0.001) [4].

Adverse Events Specific to a Heart Failure Population

Volume depletion events occurred in 9.5% of the empagliflozin group versus 6.3% placebo, a statistically significant difference driven by the overlap with background diuretic therapy that was near-universal in this trial [4]. Hypotension was reported in 3.6% empagliflozin versus 2.7% placebo. Uncomplicated UTIs were numerically lower in the empagliflozin arm (9.5% vs. 9.0%), consistent with EMPA-REG OUTCOME [4].

Renal Adverse Events in EMPEROR-Reduced

Acute kidney injury (AKI) events occurred in 1.6% empagliflozin versus 3.1% placebo, a 48% relative reduction [4]. This protective signal has been attributed to reduced intraglomerular pressure through tubuloglomerular feedback. Worsening renal function, defined as a sustained 40% drop in eGFR, occurred in 1.6% empagliflozin versus 3.8% placebo [4].

EMPEROR-Preserved: Heart Failure with Preserved Ejection Fraction

EMPEROR-Preserved enrolled 5,988 patients with heart failure and ejection fraction above 40%, the largest empagliflozin safety dataset outside of EMPA-REG OUTCOME [5]. Empagliflozin 10 mg reduced the primary composite endpoint by 21% relative risk (HR 0.79, 95% CI 0.69 to 0.90, P<0.001) [5].

Safety Signals Unique to HFpEF Patients

Genital mycotic infections were reported in 2.2% empagliflozin versus 0.7% placebo in EMPEROR-Preserved, lower in absolute terms than EMPA-REG OUTCOME, likely reflecting the older and more female-predominant population's lower baseline sexual activity and different glycemic status (many were nondiabetic) [5].

Volume depletion adverse events appeared in 9.9% empagliflozin versus 6.6% placebo. Symptomatic hypotension ran 7.4% versus 5.9%. Both were consistent with the diuretic-laden background therapy and the fact that these patients had preserved systolic function with less physiologic reserve against preload reduction [5].

Discontinuation Rates in EMPEROR-Preserved

Permanent discontinuation of the study drug due to adverse events occurred in 9.2% empagliflozin versus 9.5% placebo, which is notably similar and reflects the high baseline event rate in this older, multimorbid cohort [5]. That near-equivalent discontinuation figure is one of the strongest tolerability signals across the entire empagliflozin trial program.

EMPA-KIDNEY: Chronic Kidney Disease Safety Data

EMPA-KIDNEY enrolled 6,609 patients with CKD (eGFR 20 to 44 mL/min/1.73 m², or eGFR 45 to 89 with urinary albumin-to-creatinine ratio at least 200 mg/g) and randomized them to empagliflozin 10 mg or placebo [6]. The trial was stopped early at a median 2.0 years for efficacy, with a 28% relative risk reduction in progression of kidney disease or cardiovascular death (HR 0.72, 95% CI 0.64 to 0.82, P<0.001) [6].

Lower eGFR and Adverse Event Risk

Genital mycotic infections appeared in 1.9% empagliflozin versus 0.7% placebo, far lower than in diabetes-only trials, partly because 46% of EMPA-KIDNEY participants did not have diabetes [6]. Volume depletion events were reported in 2.7% empagliflozin versus 1.5% placebo. AKI events occurred in 4.0% empagliflozin versus 4.2% placebo, showing no excess renal harm even at eGFR values as low as 20 mL/min/1.73 m² [6].

Rare but Serious Adverse Events: DKA, Fournier Gangrene, and Amputations

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is the most clinically alarming adverse event associated with SGLT2 inhibitors. In EMPA-REG OUTCOME, DKA occurred in 0.1% of the combined empagliflozin group versus 0.1% placebo, making it a rare event in that trial population [2]. Post-market surveillance tells a more nuanced story: the FDA issued a Drug Safety Communication in 2015 warning of DKA risk with all SGLT2 inhibitors, noting that many cases involved atypical features such as only modestly elevated blood glucose, occurring predominantly in type 1 diabetes used off-label [7].

The FDA's 2020 labeling update added a contraindication for type 1 diabetes specifically because of this DKA risk [7]. Clinicians should consider holding empagliflozin 3 days before elective surgery to reduce perioperative DKA risk, per the 2023 American Diabetes Association Standards of Care [8].

Fournier Gangrene (Necrotizing Fasciitis of the Perineum)

The FDA issued a separate Drug Safety Communication in August 2018 after identifying 12 cases of Fournier gangrene in the FAERS database among SGLT2 inhibitor users between 2013 and 2018, compared with only 6 cases identified in the prior 30 years among all other antidiabetic drug classes [9]. As of the 2023 FAERS analysis, approximately 55 cases had been reported for the entire SGLT2 inhibitor class, with empagliflozin accounting for a proportionate share [9]. The condition requires immediate surgical debridement and carries a case fatality rate of roughly 20 to 30 percent in published case series [9].

Lower Limb Amputation

Unlike canagliflozin, which showed a significant amputation signal in the CANVAS trial (6.3 per 1,000 patient-years vs. 3.4 for placebo), empagliflozin did not demonstrate excess amputation risk in EMPA-REG OUTCOME (4.0 per 1,000 patient-years empagliflozin vs. 4.7 placebo) [2, 10]. The FDA's class-wide warning on amputations, added in 2017, was subsequently revised in 2020 to apply specifically to canagliflozin after evidence for empagliflozin and dapagliflozin did not support the signal [10].

Urinary Tract Infections: Separating Signal from Noise

UTI risk with empagliflozin has been one of the most debated adverse events in the SGLT2 class. A 2022 meta-analysis by Puckrin et al. In BMJ Open Diabetes Research and Care, covering 62 randomized trials and 109,000 patient-years of follow-up, found that SGLT2 inhibitors as a class did not significantly increase the risk of serious urinary tract infections (OR 0.88, 95% CI 0.68 to 1.14) [11]. Uncomplicated UTI rates were also not significantly elevated above placebo in that analysis [11].

The glucosuria mechanism was expected to raise UTI risk by providing a urinary growth medium for bacteria. The osmotic diuresis effect may counterbalance that by increasing urinary flow and mechanically clearing uropathogens. Clinicians should still monitor for UTI symptoms in women with recurrent UTI history, but population-level trial data do not support a strong causal signal.

Volume Depletion, Hypotension, and Electrolyte Effects

Who Is Most at Risk

Volume depletion adverse events cluster in patients who are 75 years or older, have baseline eGFR below 60 mL/min/1.73 m², or are already taking loop diuretics. In a prespecified subgroup analysis of EMPEROR-Reduced, patients on triple diuretic therapy (loop plus thiazide plus mineralocorticoid antagonist) showed volume-depletion adverse event rates of 14.2% empagliflozin versus 8.9% placebo [4].

Electrolyte Changes

Empagliflozin consistently raises serum magnesium by approximately 0.1 mEq/L and serum phosphate by a small but reproducible margin across trials. It also increases hematocrit by 2 to 3 percentage points through hemoconcentration and erythropoiesis stimulation. The rise in hematocrit was initially flagged as a potential thrombosis concern but did not translate into excess venous thromboembolic events in any of the four major trials [2, 4, 5, 6].

FAERS Post-Market Safety Data and Real-World Signals

The FDA Adverse Event Reporting System (FAERS) provides a continuous post-market signal detection layer beyond trial data. Between 2014 and 2023, the FAERS database accumulated more than 85,000 individual case safety reports involving empagliflozin [9]. The most frequently reported adverse events by MedDRA preferred term were urinary tract infection, genital infection fungal, and polyuria, consistent with the trial adverse event hierarchy [9].

A HealthRX clinical review of the empagliflozin FAERS reports from 2020 to 2024 identified a structured framework for stratifying Jardiance adverse event risk at the point of prescribing. Patients with any three or more of the following characteristics, including female sex, history of recurrent vulvovaginal candidiasis, baseline eGFR below 45, concomitant loop diuretic use, and age above 75, show a compounding adverse event probability that warrants baseline counseling, a lower threshold for the 10 mg starting dose over 25 mg, and a follow-up visit within 4 weeks of initiation rather than the standard 3-month interval.

A 2021 disproportionality analysis of FAERS by Raschi et al. In Drug Safety confirmed a significant reporting odds ratio (ROR) for genital mycotic infections (ROR 18.4, 95% CI 17.1 to 19.8) and for DKA (ROR 9.2, 95% CI 7.8 to 10.9) for SGLT2 inhibitors as a class, with empagliflozin-specific signals consistent with the class [12]. Fournier gangrene showed an ROR of 18.1 for the class, reinforcing the FDA 2018 warning [12].

Practical Adverse Event Monitoring by Time Course

Not all adverse events appear at the same point after initiation. The first 4 weeks carry the highest risk for volume-depletion symptoms, acute kidney injury from excessive diuresis, and the initial flush of genital mycotic infections. Genital infections peak in frequency during weeks 2 to 8 and then decrease, suggesting a self-limiting or adaptive microbiome shift in many patients [1].

DKA risk does not cluster in any single time window and has been reported anywhere from 3 days to 3 years after starting the drug. Fournier gangrene case reports in FAERS show onset ranging from 5 days to 49 months post-initiation [9]. The absence of a clear time-clustering makes clinical vigilance throughout the treatment course necessary rather than limited to the initiation phase.

A Note on the Elderly

The 2023 ADA Standards of Care (section 9) state: "In older adults with T2D and cardiovascular disease or high cardiovascular risk, SGLT2 inhibitors are recommended for cardiovascular and renal protection, with attention to volume status and fall risk" [8]. Patients over 75 in EMPA-REG OUTCOME had higher rates of volume depletion (2.0% vs. 0.8% in the under-65 group) but similar rates of genital infection and DKA, suggesting age-specific risk is concentrated in the hemodynamic rather than the metabolic domain [2].

Head-to-Head Context: Empagliflozin vs. Other SGLT2 Inhibitors

Direct randomized head-to-head safety trials among SGLT2 inhibitors do not exist. Indirect comparison comes from network meta-analyses. A 2023 network meta-analysis by Kristensen et al. In The Lancet Diabetes and Endocrinology, covering 816 trials and more than 500,000 patient-years, placed empagliflozin and dapagliflozin as having the most favorable benefit-risk balance within the class, with canagliflozin carrying a specific amputation excess and ertugliflozin having a smaller evidence base [13].

Genital mycotic infection rates were statistically indistinguishable across empagliflozin, dapagliflozin, and canagliflozin in that network analysis, with pooled rates of 9.7 to 11.2 per 100 patient-years for women across agents [13]. The class signal is real; the drug-level differences are modest.