Introduction

Hyponatremia (serum sodium level <⁠135 mmol/l) is common in both inpatient and outpatient care and remains a frequent trigger for internal medicine consultation. In hospital cohorts, admission hyponatremia is consistently associated with excess mortality; in a study of 98 411 inpatients, it conferred a 47% higher odds of in‑hospital death (adjusted odds ratio [OR], 1.47; 95% CI, 1.33–1.62), with increased risk evident even in mild hyponatremia (130–134 mmol/l; OR, 1.37; 95% CI, 1.23–1.52).¹ Across broader clinical settings, a meta‑analysis of 81 studies similarly demonstrated higher mortality among hyponatremic patients (relative risk [RR], 2.6; 95% CI, 2.31–2.93).² Although severe acute hyponatremia can cause life‑threatening cerebral edema and seizures, chronic mild‑to‑moderate hyponatremia is not benign and has been associated with gait instability, attention deficits, falls, and fractures, particularly in older adults.^3,4 For pragmatic communication, biochemical severity is often classified as mild (130–134 mmol/l), moderate (125–129 mmol/l), and profound (<⁠125 mmol/l). Importantly, treatment urgency is determined primarily by symptom severity and the estimated acuity of onset rather than by the sodium concentration alone. In this review, we use the term “severe symptomatic hyponatremia” to denote hyponatremia with seizures, coma, or cardiorespiratory compromise requiring immediate hypertonic therapy.

Conceptually, hyponatremia is primarily a disorder of water balance rather than a true deficit of total body sodium. Serum sodium reflects the relationship between total body solute and total body water; therefore, diagnosis and management should focus on factors that limit renal electrolyte‑free water excretion, most commonly arginine vasopressin (AVP)-mediated water retention, as well as on determinants of water intake (thirst and access).^5-7

Drug‑associated hyponatremia is often under‑recognized, because it develops in the context of multimorbidity and polypharmacy, and because “medication effect” can mimic common clinical phenotypes. Medications may lead to hyponatremia through several distinct pathways, including the syndrome of inappropriate antidiuresis (SIAD), renal salt wasting, hypovolemia with nonosmotic AVP release, and endocrine dysfunction.⁸

In recent years, modern therapies have introduced new mechanisms and crucial new diagnostic pitfalls. Sodium‑glucose cotransporter 2 inhibitors (SGLT2is) may confound urine indices through glucosuria‑driven osmotic diuresis and changes in volume status, yet emerging evidence suggests they may also be used as off‑label adjunctive therapy in selected patients with SIAD.^9-11 Immune checkpoint inhibitors (ICIs) increase the likelihood of endocrine causes of “SIAD‑like” hyponatremia, especially adrenal insufficiency and hypophysitis, where delayed recognition can be fatal.¹² Targeted anticancer agents and chemotherapy add further heterogeneity, commonly via gastrointestinal toxicity, renal tubular injury, and multifactorial inpatient illness.^13,14 Key mechanisms and modern therapy–specific diagnostic pitfalls are summarized in Table 1. For bedside completeness, other commonly implicated medications (stratified by strength of association and typical clinical phenotype) are summarized in Supplementary material, Table S1 (eg, thiazide / thiazide‑like diuretics, selective serotonin reuptake inhibitors / serotonin‑norepinephrine reuptake inhibitors, antiepileptic drugs such as carbamazepine / oxcarbazepine, and desmopressin / vasopressin analogues). In contrast to classic drug‑focused reviews, we center this article on practical diagnostic traps that now drive real‑world errors: urine indices distorted by SGLT2i‑related glucosuria and “SIAD‑like” biochemical patterns in ICI‑treated patients, in whom adrenal insufficiency must be ruled out urgently. We therefore adopt a phenotype‑based approach, integrate drug timing into interpretation of urine osmolality (Uosm) / urine sodium concentration (UNa), and provide a ward‑ready algorithm with monitoring guidance to support safe correction.

The aim of this review is to provide a practical, clinically actionable framework for hyponatremia associated with modern therapies by 1) linking drug classes to pathophysiological mechanisms, 2) outlining a stepwise diagnostic approach that highlights drug‑specific diagnostic pitfalls, and 3) summarizing treatment and prevention strategies that prioritize neurological safety and avoidance of overly rapid correction and osmotic demyelination.^15-17

Methods

This article is a pragmatic narrative review focused on drug‑associated hyponatremia in the era of modern therapies. To identify relevant evidence, we performed targeted literature searches in PubMed / MEDLINE, Embase, and the Cochrane Library from January 2000 through January 15, 2026. The full database search strategies are provided in Supplementary material, Table S2. Search terms were combined using Boolean operators and included (with synonyms and controlled vocabulary where applicable): hyponatremia / hypernatremia, drug‑induced, SIAD/ SIADH or inappropriate antidiuresis, arginine vasopressin, adrenal insufficiency or hypophysitis, immune checkpoint inhibitor (including specific agents), SGLT2i (including specific agents), targeted therapy, tyrosine kinase inhibitor, mTOR inhibitor, CDK4/6 inhibitor, CAR‑T, and chemotherapy. Reference lists of key clinical practice guidelines, systematic reviews / meta‑analyses, and high‑impact clinical studies were additionally hand‑searched to capture relevant publications not retrieved in database searches.

We prioritized clinical practice guidelines, systematic reviews / meta‑analyses, and randomized controlled trials when available; otherwise, we included observational studies, pharmacovigilance reports, and well‑documented case series. Single case reports and small case series were used selectively to illustrate rare mechanisms or newly recognized associations, and were interpreted as low‑certainty evidence. We focused on studies involving human participants and clinically relevant outcomes; preclinical‑only reports were not used to support clinical recommendations. Evidence was synthesized narratively and organized around clinically meaningful diagnostic phenotypes (eg, inappropriate antidiuresis, renal salt wasting, hypovolemia with nonosmotic AVP release, and endocrine dysfunction). To minimize overinterpretation, we avoided causal claims when data were limited, clearly separated established evidence from emerging signals, and highlighted areas of uncertainty and research gaps.

Conceptual framework for drug‑related hyponatremia

Effective plasma osmolality (tonicity) is tightly regulated by thirst, renal water handling, and AVP secretion. Osmoreceptors and neural circuits generate both homeostatic and anticipatory responses that shape water intake and thus serum sodium level.^6,7,18 In healthy individuals, suppression of AVP allows for excretion of large volumes of dilute urine; sustained hyponatremia therefore almost always implies either 1) impaired free water excretion or 2) excessive water intake, or 3) both.⁹

Drug‑related hyponatremia can be organized along 4 practical axes: 1) nonhypotonic hyponatremia (hyperglycemia or pseudohyponatremia); 2) hypovolemic hypotonic hyponatremia (true salt and water losses with nonosmotic AVP release); 3) hypervolemic hyponatremia (low effective arterial blood volume due to heart failure, cirrhosis, nephrotic syndrome); and 4) euvolemic hypotonic hyponatremia, most commonly SIAD but also adrenal insufficiency and (rarely) severe hypothyroidism.^5,15,19

SIAD is characterized by inappropriately concentrated urine and natriuresis in the absence of hypovolemia, adrenal insufficiency, or hypothyroidism.^15,20 In practice, the “classic” SIAD pattern—hypotonic hyponatremia with Uosm above 100 mOsm/kg and UNa above 30 mmol/l—should be treated as a syndrome rather than a final diagnosis, because several modern drug–related states mimic SIAD biochemically.

Modern therapies create 2 recurring pitfalls. First, they may change urine indices without directly changing AVP biology. For example, glucosuria induced by SGLT2is increases Uosm independently of AVP, potentially masking an otherwise dilute urine pattern. Second, they increase the pretest probability of endocrine etiologies. In patients receiving ICIs, secondary adrenal insufficiency can present with euvolemic hypotonic hyponatremia and urine findings indistinguishable from SIAD; however, management differs fundamentally, and urgent glucocorticoid replacement may be lifesaving.^12,21

Finally, oncology patients represent a high‑risk group where hyponatremia is often multifactorial. Underlying malignancy (including paraneoplastic SIAD), chemotherapy‑associated toxicity, infections, antiemetic and analgesic comedications, and treatment‑related endocrine dysfunction frequently overlap.^13,14 A pragmatic approach that repeatedly reassesses volume status, treatment timing, and evolving laboratory patterns is therefore essential.

Sodium‑glucose cotransporter 2 inhibitors: from confounder to potential therapy

SGLT2is reduce renal glucose reabsorption in the proximal tubule, producing glucosuria and osmotic diuresis. By increasing urinary water excretion, they can increase electrolyte‑free water clearance and thereby raise serum sodium level in selected patients with dilutional hyponatremia.^6,10,11 This profile has led to interest in SGLT2is as “aquaretic‑like” agents, albeit via a different mechanism than vasopressin receptor antagonists.

In a double‑blind randomized trial of hospitalized patients with SIAD‑induced hyponatremia, empagliflozin added to fluid restriction increased plasma sodium level more than placebo over 4 days.¹⁰ A subsequent randomized, double‑blind, placebo‑controlled crossover trial in chronic SIAD demonstrated that empagliflozin improved serum sodium level over 4 weeks, and was associated with improvements in patient‑relevant end points.¹¹ Although the available trials are modest in size, they provide proof‑of‑concept that an SGLT2is can correct hyponatremia in SIAD.

In guidelines and practice, the first‑line therapy for chronic SIAD is fluid restriction; second‑line options include increasing solute intake (eg, oral urea), loop diuretics with salt supplementation, and vasopressin receptor antagonists, such as tolvaptan.^8,15,22,23 An SGLT2is may be considered as an adjunct in selected chronic SIAD scenarios, when fluid restriction is ineffective or poorly tolerated, particularly when urea is unavailable or unacceptable and when tolvaptan is constrained by cost, access, or the need for close monitoring.

Evidence for SGLT2i efficacy in SIAD is based on a limited number of studies (including a short‑term randomized trial), and remains insufficient to position them as the first‑line therapy. In practice, their use is best restricted to stable, nonacute euvolemic SIAD as an off‑label adjunct, with structured monitoring and clear stopping rules if sodium level fails to improve or if volume depletion occurs. Evidence to date pertains mainly to empagliflozin 25 mg daily; the use for hyponatremia remains off‑label and should be individualized.^10,11 Candidates should have stable hemodynamics, no severe acute symptoms, and an SIAD phenotype that has been reasonably established (including exclusion of adrenal insufficiency and hypothyroidism). Clinicians should consider renal function, frailty, concomitant diuretics, and the risk of dehydration. A pragmatic strategy is to initiate therapy under conditions where sodium level and volume status can be monitored closely and to reassess serum sodium level within several days to 1–2 weeks, depending on baseline severity.²⁴

Immune checkpoint inhibitors: when “syndrome of inappropriate antidiuresis–like” hyponatremia may be adrenal failure

ICIs are increasingly used across cancer types and are associated with a broad spectrum of immune‑related adverse events. Hyponatremia is common among ICI‑treated patients, and is often multifactorial.^13,25 The clinical challenge is to promptly identify endocrine causes, especially adrenal insufficiency, because treatment is urgent and differs fundamentally from standard SIAD management.

In a real‑world cohort including 2458 patients treated with ICIs, hyponatremia occurred in 62% and severe hyponatremia (serum sodium level <⁠124 mmol/l) in 6% within the first year. Median time to severe hyponatremia was approximately 5–6 months. Endocrine causes accounted for only a minority of severe cases, but represent a high‑risk diagnosis given the risk of adrenal crisis.²⁵ These estimates come from a retrospective real‑world cohort and reflect hyponatremia occurring during ICI exposure, not necessarily ICI‑caused events. Hyponatremia was defined biochemically by serum sodium level below the prespecified cutoff(s), and the observed rates are likely influenced by comorbid illnesses, concomitant medications, and intercurrent complications in oncology patients.

ICIs can trigger hypophysitis with secondary adrenal insufficiency, primary adrenalitis leading to primary adrenal insufficiency, and thyroid dysfunction (often destructive thyroiditis). Adrenal insufficiency contributes to hyponatremia through a loss of cortisol‑mediated suppression of AVP; in primary adrenal insufficiency, concomitant mineralocorticoid deficiency leads to renal salt wasting and often hyperkalemia.^12,21,26

Targeted anticancer agents and chemotherapy: a brief mechanistic overview

Beyond ICIs, targeted anticancer agents and conventional chemotherapy can contribute to hyponatremia through several mechanisms, including nausea and reduced solute intake, diarrhea, renal tubular dysfunction (including salt wasting), kidney injury, and SIAD‑like inappropriate antidiuresis. At the bedside, it is often helpful to start by identifying the dominant phenotype (gastrointestinal loss / hypovolemia, renal tubular / salt wasting, or SIAD‑like inappropriate antidiuresis), recognizing that overlap is common in oncology inpatients.^8,13 A detailed class‑by‑class overview of anticancer agents associated with hyponatremia (including proposed mechanisms and practical clinical notes) is provided in Table 2. This Table lists representative agents by class (eg, vascular endothelial growth factor receptor–directed multikinase tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, epidermal growth factor receptor / anaplastic lymphoma kinase inhibitors, cyclin‑dependent kinases 4 and 6 inhibitors, Bruton tyrosine kinase inhibitors, venetoclax, and chimeric antigen receptor T‑cell therapies) to facilitate medication review on admission.

Chemotherapy‑associated toxicity and complications, such as infections, frequently coexist and may dominate the etiology of hyponatremia in oncology inpatients. In this setting, “drug‑associated” hyponatremia should not be equated with “drug‑caused” hyponatremia, as supportive medications, intravenous fluids, infections, reduced intake, and the underlying malignancy (including paraneoplastic SIAD) commonly contribute in parallel.³¹ Practical management therefore requires treating the patient’s evolving physiology (volume depletion, inflammation, kidney injury) in parallel with review of the oncologic regimen, supportive medications, and intravenous fluids, with repeated reassessment over time.¹⁴

Some targeted agents may also alter hemodynamics and neurohormonal signaling (including the renin‑angiotensin‑aldosterone system), which can blur bedside volume assessment and contribute to mixed phenotypes.³² For this reason, close sodium monitoring, repeated reassessment, and collaboration with oncology specialists are central to safe correction of hyponatremia in this setting.

Diagnostic approach: a stepwise strategy with modern therapy–specific pitfalls

A pragmatic inpatient diagnostic flow is summarized in Figure 1. Table 3 is intentionally designed as a 1‑page bedside checklist highlighting modern therapy–specific caveats and common points of misinterpretation rather than duplicating the full algorithm. The steps below should be applied iteratively, as volume status and urine indices may change over time particularly in frail and oncology inpatients.

Step 1: Confirm hypotonicity and exclude artefacts. Serum osmolality should be obtained in all patients with hyponatremia. Nonhypotonic hyponatremia due to hyperglycemia (translocational) or pseudohyponatremia due to severe hyperlipidemia or hyperproteinemia should be excluded before proceeding with SIAD algorithms.^15,19 This initial triage is shown in Step 1 of the algorithm (Figure 1).

Step 2: Interpret urine studies in context. In confirmed hypotonic hyponatremia, Uosm indicates whether the kidneys are appropriately excreting electrolyte‑free water (appropriately dilute urine suggests suppressed AVP, whereas inappropriately concentrated urine suggests impaired water excretion, most commonly AVP‑mediated). UNa then helps distinguish low effective arterial blood volume states (typically lower UNa) from euvolemic patterns compatible with SIAD (typically higher UNa), but both indices must be interpreted alongside the clinical picture and recent therapies rather than as stand‑alone cutoffs. Urine indices are frequently confounded by diuretics, recent intravenous fluids, glucosuria, and osmotic diuresis in patients receiving SGLT2is, with reduced renal concentrating / diluting capacity in chronic kidney disease, and low solute intake. Common situations in which urine indices mislead and practical responses are summarized in Table 4.

Step 3: Prioritize endocrine exclusion in euvolemic patterns. Euvolemic hypotonic hyponatremia with inappropriately concentrated urine and an elevated UNa is compatible with SIAD, but an identical biochemical pattern can be seen in secondary adrenal insufficiency (and, less commonly, severe hypothyroidism). Therefore, serum cortisol level should be obtained early in all unexplained euvolemic hypotonic hyponatremia and is mandatory in patients receiving ICIs. In ICI‑treated patients, endocrine causes of SIAD‑like hyponatremia must be actively excluded, as delayed recognition of adrenal insufficiency may be life‑threatening. A bedside checklist for ICI‑treated patients is provided in Table 5.

Step 3.1: Consider adjunct tests and the response to therapy. When SIAD is suspected, additional clues, such as low serum uric acid and high fractional excretion of urate may support the diagnosis and can be helpful when UNa is confounded by diuretics. However, these markers are influenced by kidney function and comorbidities, so they should complement and not replace clinical judgement. In selected stable patients, a cautious isotonic saline challenge (with close sodium monitoring) may help distinguish hypovolemia (sodium rises with volume repletion) from SIAD (limited rise and persistent urine concentration), but this approach is not appropriate in all settings.^15,19,20 Clinical volume assessment should be interpreted together with urinary sodium as outlined in Step 3 (Figure 1).

Step 4: Recognize that volume status is dynamic. In older or frail patients, clinical assessment of volume status is imperfect. Trends in weight, orthostatic blood pressure, blood urea nitrogen / creatinine, and response to cautious isotonic fluid challenge may help, but must be integrated with the clinical context and evolving course. Frequent reassessment is particularly important in oncology inpatients, where diarrhea, sepsis, and nephrotoxic exposures can rapidly change volume status.¹⁴

Step 5: Medication review and temporal association. Review all medications (including supportive drugs) and the timing of initiation or dose changes. Identify and stop or adjust likely contributors when feasible, and pay particular attention to high‑risk combinations (eg, targeted therapy or ICIs plus diuretics, and concomitant classic SIAD‑inducing agents). Medication review should be repeated as the clinical course evolves, alongside close monitoring of sodium correction to avoid overcorrection.

Clinical vignettes: applying the algorithm at the bedside

The following 2 vignettes are illustrative composites based on patterns repeatedly reported in the literature and encountered in routine inpatient care. They are intended to translate the diagnostic steps (Figure 1) into practical management decisions in patients treated with modern therapies.

Treatment principles: prioritizing neurological safety and cause‑directed therapy

The above vignettes highlight why correction strategy and cause‑directed therapy must be tailored to symptom severity, acuity, and therapy‑specific pitfalls. Initial risk stratification should distinguish between acute and chronic hyponatremia and between symptomatic and asymptomatic presentations.The urgency of treatment depends on symptoms and the acuity of onset. Acute symptomatic hyponatremia is a medical emergency; chronic hyponatremia requires slower correction to reduce the risk of osmotic demyelination.^5,15,16

Prevention and monitoring: practical recommendations

Prevention starts with identifying vulnerable patients (older age, frailty, low solute intake, concurrent diuretics, baseline borderline sodium) and with baseline electrolyte assessment before initiating therapies that can influence water balance.⁸ In hospitalized patients, routine medication reconciliation is a high‑yield intervention to identify potential contributors.

Although SGLT2is are being explored as therapy for SIAD, their diuretic effect can precipitate volume depletion in susceptible patients. After initiation, monitor volume status and renal function and consider repeating serum sodium assessment in patients with baseline hyponatremia, concomitant diuretics, or poor oral intake. Provide clear sick‑day guidance (temporary discontinuation during dehydration, vomiting / diarrhea, or reduced intake) to reduce the risk of hypovolemia and AKI.

Research gaps

For SGLT2is in SIAD, larger pragmatic trials are needed to define which phenotypes benefit most, and how this approach compares with urea or tolvaptan with regard to efficacy, safety, patient‑reported outcomes, and cost‑effectiveness.^10,11,22,23

For ICIs, improved shared‑care protocols are needed to streamline endocrine testing in acute presentations and to quantify the frequency with which endocrine causes are missed in routine practice. Standardized monitoring may reduce morbidity from preventable adrenal crisis.^12,25

Conclusions

Modern therapies have reshaped the differential diagnosis of drug‑related hyponatremia. SGLT2is can confound urine indices and may be therapeutically useful in selected chronic SIAD cases, whereas ICIs raise the risk by increasing the likelihood of adrenal insufficiency, a reversible but potentially fatal cause of SIAD‑like hyponatremia. A structured diagnostic approach that integrates medication timing and early endocrine testing, combined with neurological safety–focused correction strategies, can improve outcomes in this increasingly prevalent clinical scenario.