Hypovolemia refers to a state of low extracellular fluid volume, which is usually secondary to the combined loss of sodium and water. It is a pathological state of body fluid imbalance and manifests as systemic symptoms. Clinically, it can be manifested as dehydration, hypotension, dizziness, orthostatic hypotension, and other symptoms [13, 14]. A number of studies have confirmed that SGLT2i can cause AEs related to hypovolemia. The mechanism is to reduce the activity and function of sodium-hydrogen exchanger 3 (NHE3), reduce sodium reabsorption, and increase urinary sodium excretion, resulting in body fluid loss [15]. Although diuresis has antihypertensive benefits in patients with cardiovascular diseases such as hypertension, it may also lead to excessive reduction in circulating fluid, promote peripheral neurohormonal activation and tissue ischemia, and lead to a series of systemic reactions. According to our findings, such adverse events were more common in women, younger and older patients, patients using higher doses of medications, patients with concomitant diuretic use, and patients with renal dysfunction.

The incidence of hypovolemia-related adverse events varies with SGLT2 inhibitors. The analysis of our data showed a higher risk of hypovolemia with empagliflozin, a higher risk of orthostatic hypotension with canagliflozin, and a lower risk of hypovolemia related adverse events with dapagliflozin than with the other three drugs. Other studies have proposed that dapagliflozin may have a more transient natriuretic effect and that the kidney may rapidly adapt to maintain sodium balance [16], whereas empagliflozin has a stronger and more durable natriuretic effect [17], possibly related to its differential effect on renal sodium handling [18], which may explain the differences in the incidence of adverse effects associated with volume depletion.

Epidemiological studies on hypotension show that the prevalence of hypotension in young women is higher than that in men, while the prevalence of hypotension gradually reases with the increase of age, and the incidence of hypotension in elderly patients is significantly lower than that in younger patients [19,20,21,22,23]. This phenomenon can be attributed to the physiological structure of the blood vessels. The pulse pressure is related to the elasticity of the vascular wall. With the increase of age, the vascular compliance reases, and the elastic storage function also reases, resulting in the increase of pulse pressure [24]. The greater risk of hypovolemia in women with SGLT2 inhibitors may be attributed to multiple interacting factors. Lower basal total body water in women, hormonal influences, potential renal sodium and water handling differences, and possible differences in water intake behavior could all contribute to their greater vulnerability to the fluid loss caused by SGLT2 inhibitors [25, 26]. This could explain the gender and age differences in the signal intensity of hypovolemia related AEs caused by SGLT2i in this study, with female and younger patients more likely to experience hypovolemia-related AE after using SGLT2i. Moreover, for patients over 75 years old, their vascular fragility increases, coupled with other factors such as underlying diseases, the risk of hypovolemia-related AE after SGLT2i use is also greater. In addition to the physiological factors of the blood vessels, the intensity of physical activity in young patients is greater than that in elderly patients, resulting in greater oxygen consumption of tissue cells and more significant adverse consequences caused by hypovolemia.

There are also gender and age differences in the risk of orthostatic hypotension. The baroreflex sensitivity of women is lower, and the degree of carotid atherosclerosis is higher than that of men, leading to a lower buffering effect of blood pressure during postural changes, so the risk of orthostatic hypotension or orthostatic dizziness is higher [27, 28]. In terms of age, orthostatic hypotension is more prevalent in the elderly, especially in elderly hypertensive patients [29,30,31]. Orthostatic hypotension is associated with symptoms such as dizziness, syncope, and falls, and can lead to functional impairment, increasing disability, cardiovascular disease, and all-cause mortality. Therefore, more attention should be paid to the risk of orthostatic hypotension after SGLT2i use in female and elderly patients.

Since the content reported to the FAERS database does not contain the actual dosage of the drug but only the specifications of the drug used, it is not supported to conduct dose-related AE analysis. However, we still searched some studies on adverse events caused by high doses. While certain SGLT2 inhibitors (e.g., canagliflozin) show a clear dose-dependent increased risk for hypovolemia [32, 33], for others this relationship may be less pronounced or absent within the typical treatment range, and individual patient factors appear to play an important role in overall risk [34]. The increased risk of hypovolemia is an overall effect and not only driven by very high doses.

Since the data reported to the FAERS database did not include the comorbidities and concomitant drugs of the patients, we were also unable to analyze the impact of comorbidities on the hydration status of the patients. However, we still searched for relevant literature for discussion. In patients with heart failure, SGLT2 inhibitors are usually well tolerated, and their hemodynamic effects may be beneficial [35]. For patients with chronic kidney disease, although SGLT2 inhibitors have a significant renal protective effect, the risk of hypovolemia still needs to be vigilant, especially for those with moderate to severe renal insufficiency [36].

According to other studies, renal function and medication use also influence the risk for hypovolemia. Sepsis and hypovolemia are the two most common causes of acute kidney injury(AKI) in clinical practice. The pathophysiological mechanism of AKI is that insufficient blood volume leads to renal hypoperfusion and hypoxia, which causes acute tubular necrosis and cell damage [37, 38]. The effect of reduced renal perfusion depends primarily on preexisting renal physiological conditions. As renal function lines, the risk of hypovolemia related AEs increases. In addition, the concomitant use of diuretics also increases the risk of hypovolemia [39,40,41]. Therefore, patients with renal insufficiency or combined use of diuretics should adjust SGLT2i use according to the current body fluid status and blood pressure to prevent AKI that may be caused by hypotension and dehydration.

The adverse effect of hypovolemia is closely related to a variety of adverse long-term outcomes. Not only may it lead to increased hospitalization rates and longer hospital stays [42], but it is also an important trigger of acute kidney injury, which itself significantly increases the risk of long-term cardiovascular events and death. Epidemiological studies consistently show that disease states associated with hypovolemia, such as shock and AKI, pose a serious threat to the long-term health of patients, including increased risk of cardiovascular complications and reduced quality of life [43]. Elderly patients and those with chronic diseases are more susceptible to the severe and lasting effects of hypovolemia due to their reduced physiological reserve and potential comorbidities.

Overall, patients should be carefully evaluated before using SGLT2i, including the patient’s age, renal function, body fluid volume, blood pressure level, and history of hypotension. It is also necessary to know the patient’s previous medication history in detail, including the name and dose of the SGLT2i being used, the time of initiation, medication adherence, and other drugs, especially the use of antihypertensive drugs such as ACEI/ARB and diuretics. If the above drugs are used at the same time, the dose of other antihypertensive drugs should be appropriately reduced. During the use of SGLT2i, patients should be observed for dizziness, orthostatic hypotension, and other symptoms. The dynamic change trend of blood pressure and the urine volume of patients should be monitored, and the water should be supplemented in time after the urine volume increases. After the occurrence of hypotension, if SGLT2i is continued to be used, the benefit degree should be evaluated, and the relevant therapeutic drugs and doses should be adjusted in time to improve the patient’s tolerance. In addition, excessive exercise may lead to water loss and hypovolemia, which is also the cause of ketosis and hypotension. SGLT2i should be stopped at least 24 h before performing heavy physical activity (such as marathon) [44, 45]. Specific surveillance and management strategies for high-risk patients mentioned above: patient education on the importance of hydration, including recognition of signs of dehydration; more frequent monitoring of blood glucose, electrolytes, and ketone bodies is required; hydration status and blood pressure were carefully assessed; lowering the threshold for discontinuation of SGLT2 inhibitors during the perioperative period; concomitant medications (diuretics, hypotensive drugs) should be carefully combined, and the dose should be adjusted; water supplementation in special populations should be noted: for patients with renal impairment, it should be adjusted according to eGFR and individual needs. In patients with heart failure, the cardiac functional status and ejection fraction should be evaluated.