Effects of Combined SGLT2 Inhibitor and RAAS Blockade ± Thiazide Therapy on Serum Electrolyte Balance in Type 2 Diabetic Patients: A Retrospective Cohort Study

Effects of Combined SGLT2 Inhibitor and RAAS Blockade ± Thiazide Therapy on Serum Electrolyte Balance in Type 2 Diabetic Patients: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Combined SGLT2 Inhibitor and RAAS Blockade ± Thiazide Therapy on Serum Electrolyte Balance in Type 2 Diabetic Patients: A Retrospective Cohort Study Sevgi GULSEN KOC, Lutfullah Zahit KOC, Gokhan KOKER, Yasin SAHİNTURK This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6968533/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are widely used in diabetic patients for their antihyperglycemic and cardioprotective effects. They are frequently co-administered with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and/or thiazide diuretics in clinical practice. However, the combined use of these agents may affect serum electrolyte balance. This study aimed to evaluate the changes in serum sodium, potassium, calcium, magnesium, and phosphorus levels associated with ACEi/ARB ± thiazide therapy and its combination with SGLT2 inhibitors in patients with type 2 diabetes. Methods This retrospective cohort study included 494 adult patients with type 2 diabetes and preserved renal function (eGFR ≥60 mL/min/1.73 m²), who received SGLT2 inhibitors at a tertiary care center between January 2018 and December 2022. Patients were stratified into five groups based on their antihypertensive and antidiabetic medication combinations. Electrolyte levels were recorded before and six weeks after treatment initiation. Intragroup comparisons were performed using the Wilcoxon signed-rank test, and a p-value <0.05 was considered statistically significant. Results SGLT2 inhibitor monotherapy was associated with a significant increase in serum sodium (p = 0.034) and magnesium (p = 0.004) levels. In the ACEi/ARB + SGLT2-i group, post-treatment magnesium (p = 0.001) and phosphorus (p = 0.003) levels were significantly elevated. The triple therapy group (ACEi/ARB + thiazide + SGLT2-i) also showed a significant rise in magnesium levels (p = 0.002). ACEi/ARB monotherapy led to an increase in potassium (p = 0.043) and phosphorus (p = 0.020) levels, whereas the addition of SGLT2-i mitigated the potassium rise. No significant changes in calcium levels were observed in most groups, except a mild increase with thiazide use alone. Conclusions The use of SGLT2 inhibitors in combination with ACEi/ARB ± thiazide diuretics appears to be safe in terms of electrolyte balance and may even provide a stabilizing effect, particularly for serum potassium and magnesium levels. Further prospective studies are needed to confirm these findings and to explore their clinical implications in diabetic patients on multidrug regimens. Trial registration Not applicable. ACE inhibitors Combination therapy Hyperkalemia Hyponatremia Magnesium Serum electrolytes SGLT2 inhibitors Thiazide diuretics Type 2 diabetes mellitus INTRODUCTION Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a new generation of antidiabetic agents that act by inhibiting glucose reabsorption in the proximal renal tubules, the primary site of glucose reabsorption. This inhibition leads to glucosuria, natriuresis, and osmotic diuresis as the main pharmacologic effects of these agents ( 1 , 2 ). In individuals with diabetes, the expression and activity of SGLT2 are upregulated in the proximal tubule, resulting in enhanced reabsorption of both glucose and sodium. The consequent reduction in sodium delivery to the macula densa activates the renin-angiotensin-aldosterone system (RAAS). Decreased production of vasoconstrictive mediators acting on the afferent arteriole increases intraglomerular capillary hydrostatic pressure. These pathophysiological alterations collectively contribute to glomerular hyperfiltration and intraglomerular hypertension, early events in the development of diabetic nephropathy. By inhibiting SGLT2, these agents promote natriuresis and glucosuria, thereby increasing distal sodium delivery, suppressing RAAS activation, and reducing intraglomerular pressure—effects that are partly analogous to those achieved by RAAS blockade. For this reason, SGLT2 inhibitors are sometimes referred to as "smart diuretics" ( 1 , 2 ). The therapeutic benefits of SGLT2 inhibitors include modest weight loss, reductions in blood pressure (by approximately 2–4 mmHg), serum uric acid levels, and albuminuria, as well as decreased risks of cardiovascular death, all-cause mortality, and hospitalization for heart failure ( 3 – 5 ). Commonly reported adverse effects include genitourinary infections—particularly genital mycotic infections in women—polyuria, volume depletion, hypotension, dizziness, and a mild, typically transient increase in serum creatinine, especially during early therapy ( 6 – 8 ). Renin, produced in the kidneys, converts angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II is a potent vasoconstrictor and stimulates aldosterone secretion, resulting in sodium and water retention. ACE inhibitors act by inhibiting the conversion of angiotensin I to angiotensin II ( 9 – 12 ). In contrast, angiotensin receptor blockers (ARBs) do not inhibit the production of angiotensin II but instead block its binding to the angiotensin II receptor, thereby attenuating its physiological effects. Reduced aldosterone levels promote natriuresis, vasodilation, and plasma volume reduction ( 13 ). Both ACE inhibitors and ARBs are considered RAAS blockers. The most frequent adverse events include orthostatic hypotension and hyperkalemia. Additionally, ACE inhibitors are associated with a dry cough, a side effect not commonly seen with ARBs. Thiazide diuretics exert their diuretic effect by inhibiting the sodium-chloride co-transporter in the distal tubule. Their action requires prior secretion into the proximal tubule and is associated with increased calcium reabsorption in the distal nephron ( 14 ). Reported adverse effects of thiazides include hypokalemia, hyperuricemia, hypercalcemia, and hyponatremia. Although SGLT2 inhibitors and ACEi/ARB ± hydrochlorothiazide are often co-prescribed for overlapping indications, they share certain adverse effect profiles. Both can transiently lower glomerular filtration rate (GFR). The combination of thiazides with SGLT2 inhibitors may exacerbate hyponatremia, while the co-administration of ACE inhibitors and SGLT2 inhibitors may heighten the risk of hyperkalemia. Based on these observations, the concurrent use of SGLT2 inhibitors with ACEi/ARB or ACEi/ARB ± thiazide therapy may potentiate the risk of electrolyte disturbances. The present study aims to evaluate these associations and provide clinical insight into the safety of such pharmacologic combinations in real-world practice. METHODS Study Design and Ethical Approval This study was designed as a retrospective cross-sectional analysis of patients who presented to the internal medicine outpatient clinic. Ethical approval was obtained from the Ethics Committee of Antalya Training and Research Hospital on August 25, 2022 (approval number: 2022 − 251). Given the retrospective nature of the study and the impracticality of obtaining informed consent from all participants, the requirement for informed consent was waived. The study was conducted in full compliance with the principles outlined in the Declaration of Helsinki. Study Population, Definitions, and Grouping The final study population consisted of adult patients (≥ 18 years) with a diagnosis of type 2 diabetes mellitus who attended the internal medicine outpatient clinic and were prescribed SGLT2 inhibitors either as monotherapy or in combination with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and/or hydrochlorothiazide. Patients were excluded if they had chronic kidney disease (eGFR < 60 mL/min/1.73 m²), chronic liver disease, active infection, malignancy, pregnancy, missing data, or if they were using medications known to affect electrolyte balance (e.g., loop diuretics, spironolactone, lithium). Clinical and laboratory data were retrieved from electronic medical records at Antalya Training and Research Hospital, a tertiary care center. The study period spanned from January 2018 to December 2022. The date of treatment initiation was confirmed from clinical notes, and follow-up laboratory results were reviewed approximately six weeks after initiation. Medication regimens were determined by the patients' primary care physicians based on individualized treatment plans. Participants were categorized into five groups based on their antihypertensive and antidiabetic therapy: Group 1: SGLT2 inhibitor monotherapy Group 2: ACEi or ARB monotherapy Group 3: ACEi or ARB + SGLT2 inhibitor Group 4: ACEi or ARB + thiazide diuretic Group 5: ACEi or ARB + thiazide diuretic + SGLT2 inhibitor For all participants, serum sodium, potassium, calcium, magnesium, and phosphorus levels were measured at baseline and at follow-up (~ 6 weeks post-treatment initiation). Additional variables such as age, sex, and other laboratory parameters were also recorded. Statistical Analysis Data were compiled using Microsoft Excel. Statistical analyses were conducted using SPSS version 27.0 (IBM Corp., Armonk, NY, USA). Graphs and visualizations were created using GraphPad Prism version 9. Categorical variables were expressed as frequencies and percentages, while continuous variables were presented as mean ± standard deviation (SD). Normality was assessed using the Shapiro–Wilk test, and nonparametric methods were used when distributional assumptions were not met. The Mann–Whitney U test was applied for comparisons between two independent groups. A two-tailed p-value of < 0.05 was considered statistically significant. RESULTS Baseline Characteristics Initially, 1,500 patients were considered for inclusion in the study; however, 1,006 patients were excluded due to incomplete or inconsistent medical records. A total of 494 patients were included in the final analysis. The cohort consisted of 223 males (45.14%) and 271 females (54.86%), with a mean age of 57.39 ± 12.00 years. Patients were categorized based on their treatment regimens: 139 patients (28.14%) received only SGLT2 inhibitors; 103 patients (20.85%) received only ACE inhibitors/ARBs; 61 patients (12.35%) received ACE inhibitors/ARBs + thiazide; 70 patients (14.17%) received ACE inhibitors/ARBs + SGLT2 inhibitors; 116 patients (23.48%) received ACE inhibitors/ARBs + thiazide + SGLT2 inhibitors; and 5 patients (1.01%) received SGLT2 inhibitors + thiazide therapy (Table 1 ). Patients using only thiazides or thiazides + SGLT2 inhibitors were excluded from statistical evaluation due to small group sizes. For each group, serum levels of sodium, potassium, calcium, magnesium, and phosphorus were assessed before and approximately six weeks after treatment initiation. In this study, serum sodium levels were corrected using a glucose-adjustment factor. The post-treatment mean laboratory values for the entire cohort were as follows: serum sodium 138.82 ± 3.19 mmol/L, potassium 4.49 ± 0.40 mmol/L, calcium 9.64 ± 0.52 mg/dL, magnesium 2.01 ± 0.24 mg/dL, and phosphorus 3.56 ± 0.59 mg/dL. Table 1 Distribution of the Study Population by Gender and Medication Use N % Gender Male 223 45,14 Female 271 54,86 SGLT2-i Usage Status Using SGLT2-i 329 66,60 Not using SGLT2-i 165 33,40 Medication Groups SGLT2-i only 139 28,14 SGLT2-i + ACEi/ARB 70 14,17 SGLT2-i + Thiazide 5 1,01 SGLT2-i + ACEi/ARB + Thiazide 116 23,48 ACEi/ARB + Thiazide 61 12,35 ACEi/ARB only 103 20,85 Effect of SGLT2 Inhibitor Among patients receiving SGLT2 inhibitors, there was no statistically significant difference between baseline and post-treatment values for potassium (p = 0.176), calcium (p = 0.227), and phosphorus (p = 0.904). However, post-treatment serum sodium levels were significantly higher compared to baseline (p = 0.034), and a similar increase was observed in serum magnesium levels (p = 0.004) (Table 2 ). Table 2 Electrolyte levels before and after treatment in patients using SGLT2 inhibitors alone Before Treatment (mean ± SD) After Treatment (mean ± SD) p-value Sodium (mEq/L) 137,74 ± 2,97 138,44 ± 3,08 0,034 Potassium (mEq/L) 4,58 ± 0,36 4,52 ± 0,38 0,176 Calcium (mg/dL) 9,54 ± 0,44 9,62 ± 0,57 0,227 Magnesium (mg/dL) 1,94 ± 0,24 2,02 ± 0,27 0,004 Phosphorus (mg/dL) 3,55 ± 0,51 3,56 ± 0,50 0,904 Effect of ACEi/ARB Use In patients using ACEi/ARB, no statistically significant difference was observed between baseline and post-treatment levels of sodium (p = 0.499), calcium (p = 0.878), or magnesium (p = 0.604). In contrast, post-treatment levels of potassium (p = 0.043) and phosphorus (p = 0.020) were significantly higher compared to baseline (Table 3 ). Table 3 Electrolyte levels before and after treatment in patients using ACEi/ARB monotherapy Before Treatment (mean ± SD) After Treatment (mean ± SD) p-value Sodium (mEq/L) 138,95 ± 2,59 139,03 ± 3,38 0,499 Potassium (mEq/L) 4,45 ± 0,42 4,52 ± 0,43 0,043 Calcium (mg/dL) 9,56 ± 0,48 9,58 ± 0,43 0,878 Magnesium (mg/dL) 2,00 ± 0,18 2,02 ± 0,21 0,604 Phosphorus (mg/dL) 3,42 ± 0,55 3,58 ± 0,62 0,020 Effect of Adding SGLT2 Inhibitor to ACEi/ARB Therapy In patients receiving ACEi/ARB + SGLT2 inhibitor therapy, no significant differences were found between baseline and post-treatment values for sodium (p = 0.286), potassium (p = 0.617), or calcium (p = 0.221). However, post-treatment levels of magnesium (p = 0.001) and phosphorus (p = 0.003) were significantly elevated compared to baseline values (Table 4 ). Table 4 Electrolyte levels before and after treatment in patients using ACEi/ARB + SGLT2 inhibitors Before Treatment (mean ± SD) After Treatment (mean ± SD) p-value Sodium (mEq/L) 138,41 ± 3,22 139,01 ± 2,99 0,286 Potassium (mEq/L) 4,54 ± 0,39 4,57 ± 0,34 0,617 Calcium (mg/dL) 9,57 ± 0,57 9,67 ± 0,54 0,221 Magnesium (mg/dL) 1,87 ± 0,20 2,05 ± 0,24 0,001 Phosphorus (mg/dL) 3,23 ± 0,57 3,49 ± 0,48 0,003 Effect of ACEi/ARB + Thiazide Use Among patients treated with ACEi/ARB + thiazide, no statistically significant changes were observed in sodium (p = 0.356), potassium (p = 0.937), magnesium (p = 0.436), or phosphorus (p = 0.092) levels. Post-treatment calcium levels, however, were significantly higher than baseline (p = 0.044) (Table 5 ). Table 5 Electrolyte levels before and after treatment in patients using ACEi/ARB + thiazide diuretics Before Treatment (mean ± SD) After Treatment (mean ± SD) p-value Sodium (mEq/L) 138,89 ± 2,88 139,26 ± 2,75 0,356 Potassium (mEq/L) 4,36 ± 0,46 4,34 ± 0,41 0,937 Calcium (mg/dL) 9,54 ± 0,50 9,70 ± 0,64 0,044 Magnesium (mg/dL) 2,00 ± 0,19 1,99 ± 0,24 0,436 Phosphorus (mg/dL) 3,60 ± 0,60 3,47 ± 0,72 0,092 Effect of Adding SGLT2 Inhibitor to ACEi/ARB + Thiazide Therapy In patients treated with ACEi/ARB + thiazide + SGLT2 inhibitor, there were no significant differences between baseline and post-treatment levels for sodium (p = 0.386), potassium (p = 0.118), calcium (p = 0.588), or phosphorus (p = 0.244). A statistically significant increase in magnesium levels was observed post-treatment compared to baseline (p = 0.002) (Table 6 ). Electrolyte levels before and after treatment were analyzed in 494 patients who were grouped according to their use of ACEi/ARB ± thiazide ± SGLT2 inhibitors. Hyperkalemia associated with ACEi/ARB therapy was not observed when SGLT2 inhibitors were used concurrently. Similarly, the increase in calcium levels typically seen with thiazide use appeared to be attenuated by the addition of SGLT2 inhibitors. The observed increase in serum magnesium levels associated with SGLT2 inhibitor use, whether administered alone or in combination with other agents, was both consistent and statistically significant. These results highlight the clinical relevance of regular electrolyte monitoring in diabetic patients, particularly in the context of frequent polypharmacy. Table 6 Electrolyte levels before and after treatment in patients using ACEi/ARB + thiazide + SGLT2 inhibitors Before Treatment (mean ± SD) After Treatment (mean ± SD) p-value Sodium (mEq/L) 138,61 ± 3,24 138,88 ± 2,92 0,386 Potassium (mEq/L) 4,56 ± 0,40 4,47 ± 0,41 0,118 Calcium (mg/dL) 9,60 ± 0,42 9,64 ± 0,45 0,588 Magnesium (mg/dL) 1,88 ± 0,27 1,96 ± 0,24 0,002 Phosphorus (mg/dL) 3,41 ± 0,58 3,49 ± 0,57 0,244 DISCUSSION In our cohort, the use of SGLT2 inhibitors alone was associated with a statistically significant increase in serum sodium levels following treatment compared to baseline values (p = 0.034). Previous studies investigating the effect of SGLT2 inhibitors on serum sodium have yielded variable results. In two clinical trials involving patients diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH), SGLT2 inhibitors were associated with an increase in serum sodium levels compared to placebo ( 15 , 16 ). However, the limited sample sizes in both studies constrain the generalizability of their findings. Conversely, other studies conducted in patients with type 2 diabetes treated with canagliflozin did not detect any significant changes in serum sodium concentrations (17,18). A meta-analysis later showed that the effect on sodium levels may differ depending on the specific agent, reporting a mean reduction of 0.36 mmol/L with canagliflozin 300 mg and a mean increase of 0.31 mmol/L with empagliflozin 25 mg ( 19 ). In a subanalysis of the EMPA-RESPONSE-AHF trial, which included patients presenting with acute heart failure, empagliflozin had no measurable impact on plasma sodium levels or fractional sodium excretion compared to placebo ( 20 ). Notably, most of these studies did not account for the influence of comorbid conditions or concomitant medications. Our patient population differs from these previous cohorts, as it consisted of individuals with diabetes, preserved renal function (GFR > 60 mL/min/1.73 m²), and no use of loop diuretics. The observed mean increase of 0.7 mmol/L in serum sodium following SGLT2 inhibitor therapy may be attributable to osmotic diuresis. Although statistically significant, the mean post-treatment sodium level remained within the normal physiological range. Previous reports have shown that while SGLT2 inhibitors increase fractional glucose excretion and promote osmotic diuresis, they do not enhance fractional sodium excretion ( 20 ). The rise in serum sodium may also reflect free water loss leading to hypernatremic dehydration and, possibly, secondary hyperaldosteronism due to intravascular volume contraction. In our cohort, inadequate compensation for fluid losses from osmotic diuresis, poor oral intake, and persistent hyperglycemia may have contributed to dehydration and the subsequent elevation in sodium levels. Furthermore, dietary sodium intake was not documented due to the retrospective nature of the study, and its potential influence on serum sodium concentrations remains unknown. Following ACEi/ARB therapy, no statistically significant difference was observed in serum sodium levels compared to baseline values in our study (p = 0.499). It is generally believed that ACEi/ARB use does not significantly affect serum sodium concentrations. However, several studies and case reports have documented hyponatremia associated with these agents. In a pilot study including 50 patients treated with ACEi/ARB, hyponatremia was identified in 50% of cases. Although the incidence was lower in patients receiving ARBs, no statistically significant difference was noted between ACEi and ARB use ( 21 ). In this study, the frequency of hyponatremia was higher among older adults (aged 56–75 years), with a more pronounced sodium-lowering effect observed in those over 66 years. Cases of hyponatremia have also been reported following treatment with captopril and lisinopril ( 22 , 23 ). One case involved a 76-year-old woman who developed SIADH associated with lisinopril use for hypertension ( 24 ). ACE inhibitors exert their effect by inhibiting the conversion of Angiotensin I (Ang I) to Angiotensin II (Ang II) in the peripheral circulation; however, this blockade does not occur in the central nervous system. The elevated Ang I in circulation may enter the brain and be converted to Ang II, which can stimulate thirst and lead to the release of antidiuretic hormone (ADH) from the hypothalamus, potentially resulting in hyponatremia. Additionally, hyponatremia may arise due to aldosterone deficiency secondary to RAAS blockade by ACEi/ARB. Notably, the patients described in both the pilot study and case reports were elderly. In our study population, the mean age was 57.39 ± 12.00 years, and it is plausible that age-related pharmacokinetic and pharmacodynamic changes in drug metabolism contributed to the development of hyponatremia in older individuals. In our study, there was no statistically significant difference between baseline and post-treatment serum sodium levels in patients receiving combined ACEi/ARB and thiazide therapy (p = 0.356). Hyponatremia is a well-recognized electrolyte disturbance associated with thiazide use, particularly in the geriatric population ( 25 ). In a case series of 114 elderly patients, the incidence of thiazide-induced hyponatremia was 11% ( 26 ). A cross-sectional study conducted in the United Kingdom among thiazide users found hyponatremia to be more common than hypokalemia ( 27 ). In that study, the mean age was 68 years, and increasing age was identified as a risk factor for hyponatremia. Due to limited data in our cohort, patients receiving thiazide monotherapy could not be evaluated separately. Instead, we focused on patients treated with ACEi/ARB in combination with thiazides and found no statistically significant reduction in serum sodium levels with combination therapy. A previous study showed that the development of hyponatremia among patients receiving thiazide monotherapy or in combination with ACEi/ARB typically occurred in the presence of triggering conditions such as infections or central nervous system disorders, which may predispose to SIADH ( 28 ). ACE inhibitors and ARBs reduce aldosterone secretion by blocking the effects of Ang II, thereby limiting sodium and water retention in the kidneys while helping to preserve normal renal function to prevent excessive losses. Although combination therapy with ACEi/ARB and thiazide diuretics may increase the risk of hyponatremia at treatment initiation, we believe that over time, renal compensatory mechanisms may restore sodium homeostasis and normalize serum sodium concentrations. The addition of SGLT2 inhibitors to ACEi/ARB or ACEi/ARB + thiazide therapy did not result in any statistically significant change in serum sodium levels compared to baseline. SGLT2 inhibitors induce osmotic diuresis as a consequence of glucosuria. Since the inhibition of sodium reabsorption is indirect in this mechanism, water loss tends to be proportionally greater. The increase in electrolyte-free water loss primarily reduces interstitial volume rather than blood volume, thereby minimizing arterial underfilling and the subsequent activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, ACEi/ARBs and thiazide diuretics promote natriuresis as the mechanism of fluid reduction. Therefore, the absence of a change in serum sodium levels when SGLT2 inhibitors are added to these regimens may be explained by this differing mode of action. Moreover, the addition of SGLT2 inhibitors to ACEi/ARB + thiazide therapy may reduce intravascular volume via natriuresis and diuresis without inducing hemoconcentration-related increases in serum sodium concentration. We acknowledge that there are important gaps in the literature regarding serum sodium dynamics under combination therapy, and we encourage clinicians to undertake further research to address these knowledge deficits. Electrolyte disturbances involving serum potassium concentrations have not been frequently reported in clinical trials with SGLT2 inhibitors. In our study, the use of SGLT2 inhibitors did not produce a statistically significant difference in mean serum potassium levels. This finding is consistent with the results of the CANVAS program. The CANVAS trial enrolled patients with type 2 diabetes and an estimated GFR > 30 mL/min/1.73 m², and consisted of two similarly designed, double-blind, randomized, placebo-controlled studies (CANVAS and CANVAS-Renal), including a total of 10,142 participants. Participants received either 100 or 300 mg of canagliflozin or placebo, and serum potassium measurements were assessed approximately every six months. Interim results from CANVAS initially suggested a higher incidence of hyperkalemia in the canagliflozin arm compared to placebo. However, in the final analysis, this hypothesis was not supported—particularly in patients with renal impairment or those using RAAS-inhibiting medications—thus diminishing concerns about hyperkalemia risk in this subgroup ( 29 ). A meta-analysis of four randomized controlled trials including over 21,000 patients with type 2 diabetes also reported a 28% lower risk of hyperkalemic events in those receiving SGLT2 inhibitors compared to placebo ( 30 ). Similarly, the CREDENCE trial, which assessed canagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD), found no increase in the risk of hyperkalemia with canagliflozin compared to placebo, further supporting these observations ( 31 ). SGLT2 inhibitors are known to reduce blood pressure by approximately 4–5 mmHg, likely due to plasma volume contraction ( 32 ). While a reduction in intravascular volume stimulates renin release and increases aldosterone levels, the increased distal sodium delivery observed with SGLT2 inhibition appears to suppress renin secretion and downstream RAAS activation, ultimately leading to a decrease in aldosterone levels. Therefore, in the medium to long term, no significant changes in serum renin or aldosterone concentrations are expected ( 33 ). The lack of a significant rise in aldosterone levels may explain the absence of hypokalemia in our patient population. The hyperkalemic effect of ACEi/ARB therapy is well-established in clinical literature. ACE inhibitors block the formation of angiotensin II, while ARBs prevent angiotensin II from binding to its receptors. This leads to RAAS inhibition and suppression of aldosterone secretion and vasoconstriction. Reduced aldosterone levels impair potassium excretion, resulting in hyperkalemia. Consistent with this mechanism, our study demonstrated a statistically significant increase in serum potassium levels following ACEi/ARB therapy compared to baseline (p = 0.043). However, when SGLT2 inhibitors were added to this regimen, no significant increase in serum potassium levels was observed (p = 0.617). A meta-analysis of individual patient data from six studies including nearly 50,000 patients showed that SGLT2 inhibitors reduced the risk of hyperkalemia without increasing the risk of hypokalemia, even in patients receiving concomitant diuretic therapy ( 34 ). Similarly, in the CANVAS trial—where approximately 80% of participants were treated with RAAS inhibitors—no significant difference in the risk of potassium increase or decrease was observed between the canagliflozin and placebo groups, regardless of background RAAS blockade. These findings are in line with our results in the ACEi/ARB + SGLT2 inhibitor group. Under normal physiological conditions, potassium delivery to the distal nephron is maintained by glomerular filtration, and the kidneys regulate total body potassium. However, the rate of potassium secretion in the distal nephron is variable and influenced by mineralocorticoid activity, which regulates sodium and water delivery to the distal tubule ( 30 ). SGLT2 inhibitors increase distal sodium delivery, which enhances sodium reabsorption and renders the tubular lumen more electronegative. This change in luminal potential promotes potassium secretion. Additionally, increased tubular flow rates also contribute to enhanced potassium excretion. These mechanisms may explain how SGLT2 inhibitors mitigate ACEi/ARB-induced hyperkalemia. In our study, the combination of ACEi/ARB and thiazide therapy did not result in a statistically significant change in serum potassium levels (p = 0.937). Thiazides act at the distal tubule, increasing urinary sodium excretion and indirectly reducing extracellular fluid volume and peripheral resistance. This volume reduction triggers RAAS activation and promotes aldosterone-mediated potassium loss through the urine. Studies investigating thiazide-induced hypokalemia support this mechanism ( 35 , 36 ). When ACEi/ARBs are co-administered with thiazide diuretics, they tend to counteract thiazide-induced hypokalemia. Furthermore, thiazide-induced RAAS activation may enhance responsiveness to ACEi/ARB therapy. By inhibiting sodium and chloride reabsorption in the distal tubule, thiazides promote diuresis, while concurrent ACEi/ARB therapy helps stabilize potassium balance. Patients with diabetes are at increased risk for hyperkalemia, and this risk is further elevated with RAAS inhibition ( 37 ). As a result, RAAS inhibitors are often down-titrated or discontinued in patients who develop hyperkalemia ( 38 , 39 ), which may compromise the cardioprotective and renoprotective benefits of these agents ( 40 ). However, based on the findings of our study, co-administration of SGLT2 inhibitors with ACEi/ARB appears to attenuate the potassium increase typically associated with ACEi/ARB therapy. Additionally, although the decrease in serum potassium with ACEi/ARB + thiazide + SGLT2 inhibitor therapy did not reach statistical significance, a numerical reduction of 0.09 mmol/L was observed. These results suggest that SGLT2 inhibitors may provide a protective effect against dyskalemia when used in combination with ACEi/ARB and thiazide therapy. The observed reduction in hyperkalemia risk may reflect the renoprotective properties of the SGLT2 inhibitor class. In our study, no statistically significant changes were observed in serum calcium or phosphorus levels following SGLT2 inhibitor therapy. When reviewing prior literature, some studies reported alterations in serum calcium and modest increases in phosphorus levels with canagliflozin use (18,41). However, studies involving empagliflozin did not detect significant changes in serum calcium or 25(OH)D₃ concentrations ( 42 ). In a study by de Jong et al. evaluating dapagliflozin, no changes in serum calcium were observed compared to placebo, while an increase in serum phosphorus levels was noted ( 43 ). This study was a post hoc analysis of the IMPROVE trial and included patients with type 2 diabetes and early-stage chronic kidney disease who were also on stable doses of ACEi/ARB therapy. Our findings—showing no change in serum calcium but an increase in serum phosphorus levels following the addition of SGLT2 inhibitors to ACEi/ARB treatment—are consistent with those results. Furthermore, our sample size of 70 patients exceeds the 33 participants in the aforementioned post hoc analysis, providing a more robust basis for evaluation. Additionally, a meta-analysis incorporating 25 randomized controlled trials reported that SGLT2 inhibitors were associated with an increase in serum phosphate concentrations, while serum calcium levels remained unaffected ( 44 ). However, this meta-analysis did not stratify patients based on concomitant medications such as ACEi, ARBs, thiazides, or other diuretics, limiting interpretation. Therefore, the observed increase in phosphorus levels when SGLT2 inhibitors are added to ACEi/ARB therapy may reflect the effect of RAAS inhibition. Another possible explanation is that RAAS blockade combined with the osmotic diuresis caused by SGLT2 inhibitors may lead to volume contraction, contributing to changes in serum phosphorus. In our study, combined ACEi/ARB + thiazide therapy did not result in a statistically significant change in serum phosphorus levels (p = 0.092), but did lead to a significant increase in serum calcium levels (p = 0.044). This calcium-elevating effect of thiazides is consistent with known physiological mechanisms and is supported by existing literature. Thiazides promote sodium loss and water excretion via inhibition of sodium reabsorption in the distal tubule, resulting in extracellular volume depletion. As a compensatory response, proximal sodium reabsorption is upregulated, which increases the electrochemical gradient across the tubular membrane and facilitates passive calcium reabsorption ( 45 ). Moreover, thiazides stimulate Na⁺/Ca²⁺ exchange activity in the distal tubule, leading to enhanced calcium reabsorption and subsequent hypocalciuria and hypercalcemia. When SGLT2 inhibitors were added to ACEi/ARB + thiazide therapy, no significant increase in serum calcium levels was observed. The normalization of hypercalcemia with SGLT2 inhibitor addition may be explained by the disruption of the electrochemical gradient necessary for enhanced calcium reabsorption. While thiazides induce sodium loss in the distal tubule and promote sodium reabsorption in the proximal tubule, the resulting gradient may facilitate increased calcium reabsorption. However, the addition of SGLT2 inhibitors, which promote sodium excretion in the proximal tubule, may interfere with the formation of this gradient, thereby attenuating calcium reabsorption. In the current literature, the hypercalcemic effect of thiazides has not been clearly defined, and to our knowledge, no studies have investigated how SGLT2 inhibitors may alter this response. Therefore, further research is needed to explore the potential interactions between SGLT2 inhibitors and thiazide-induced changes in calcium and phosphorus homeostasis. In our study, SGLT2 inhibitor therapy was associated with a significant increase in serum magnesium levels. This finding is consistent with previous reports evaluating the effects of SGLT2 inhibitors. Several hypotheses have been proposed to explain the magnesium-raising effects of SGLT2 inhibitors. Passive paracellular magnesium transport in the proximal tubule is determined by both the magnesium concentration and the transmembrane potential gradient (TPMG). By increasing tubular sodium concentrations, SGLT2 inhibition may enhance TPMG and subsequently promote magnesium reabsorption ( 46 , 47 ). Another proposed mechanism involves the elevation of glucagon levels following SGLT2 inhibitor use, which may enhance magnesium reabsorption in the distal renal tubules ( 48 ). An additional hypothesis suggests that SGLT2 inhibitor-induced natriuresis and osmotic diuresis result in hypovolemia, thereby increasing aldosterone concentrations. Aldosterone, in turn, may directly influence magnesium transport and lead to increased magnesium excretion ( 49 ). A meta-analysis by Tang et al., which included 18 randomized controlled trials involving patients with type 2 diabetes and preserved kidney function, demonstrated significant increases in serum magnesium levels following SGLT2 inhibitor treatment ( 50 ). While we observed no significant change in serum magnesium levels with ACEi/ARB ± thiazide therapy alone, the addition of SGLT2 inhibitors resulted in a statistically significant increase in serum magnesium concentrations. Hypomagnesemia has been associated with adverse outcomes in diabetes, contributing to both macrovascular and microvascular complications ( 51 , 52 ). Diabetes itself is also a known cause of hypomagnesemia, and the addition of SGLT2 inhibitors to antidiabetic therapy may help normalize serum magnesium levels. In our study, no extreme or clinically concerning magnesium values were observed after treatment. However, in patients with elevated baseline serum magnesium concentrations, clinicians should exercise caution when initiating SGLT2 inhibitor therapy. Further research and additional data are needed to enhance the current level of evidence regarding the effects of SGLT2 inhibitors on magnesium homeostasis. Strengths and Limitations This study has several notable strengths. First, it provides real-world data from a relatively large cohort of 494 patients, enhancing the clinical applicability of the findings. Second, it is one of the few studies to evaluate the effects of SGLT2 inhibitors on electrolyte balance when used in various therapeutic combinations, including ACEi/ARB and/or thiazide diuretics. The comprehensive assessment of key electrolytes—sodium, potassium, calcium, magnesium, and phosphorus—allows for a broad understanding of biochemical interactions under these drug regimens. However, several limitations should be acknowledged. As a retrospective study, the ability to establish causal relationships is inherently limited. Additionally, the 6-week follow-up period may not adequately reflect long-term electrolyte dynamics. The subgroup of patients receiving SGLT2 inhibitors plus thiazide diuretics was very small (n = 5), limiting the statistical power and generalizability for that specific combination. Furthermore, potential confounding variables such as dietary intake, fluid status, and comorbidities were not controlled, which may have influenced electrolyte fluctuations. CONCLUSION Our study demonstrated that the use of SGLT2 inhibitors in combination with commonly prescribed antihypertensive therapies such as ACE inhibitors, ARBs, and thiazide diuretics in diabetic patients did not lead to significant electrolyte imbalances. Notably, SGLT2 inhibitors did not cause hyponatremia even in patients predisposed to it, such as those with diabetes or heart failure, indicating a possible stabilizing effect on sodium balance through modulation of tubuloglomerular feedback. While ACEi/ARB treatment alone was associated with a slight increase in serum potassium, the addition of SGLT2 inhibitors did not further elevate potassium levels. This finding suggests that SGLT2 inhibitors may help mitigate the risk of hyperkalemia often seen with RAAS blockade. Similarly, although thiazide diuretics are known to increase serum calcium levels, co-administration with SGLT2 inhibitors prevented additional calcium elevation, possibly by interfering with the tubular mechanisms responsible for calcium reabsorption. According to current European Society of Cardiology (ESC) guidelines ( 53 ), combination therapies are preferred in the initial management of hypertension. Therefore, understanding the impact of additional agents like SGLT2 inhibitors on electrolyte balance is clinically important. In conclusion, our findings suggest that SGLT2 inhibitors can be safely added to ACEi/ARB and thiazide-based antihypertensive regimens in diabetic patients without increasing the risk of electrolyte disturbances. Moreover, their use may contribute to the correction of diabetes-induced renal pathophysiological changes, offering a potential protective effect on kidney function. Future prospective, randomized controlled trials are warranted to validate these findings and explore the mechanistic underpinnings of SGLT2 inhibitors’ impact on electrolyte homeostasis. Inclusion of multivariate analysis in future research would also help to identify independent predictors of electrolyte shifts, accounting for variables such as age, eGFR, HbA1c, and concurrent medications. Supplementary materials such as detailed groupwise electrolyte distribution tables and boxplots may enhance transparency and interpretability of subgroup effects. Finally, a clear emphasis should be placed on the clinical utility of these findings in guiding safer and more effective combination therapy in diabetic patients. Abbreviations ACEi – Angiotensin-Converting Enzyme Inhibitor ARB – Angiotensin Receptor Blocker CKD – Chronic Kidney Disease eGFR – Estimated Glomerular Filtration Rate RAAS – Renin-Angiotensin-Aldosterone System SGLT2-i – Sodium-Glucose Co-Transporter 2 Inhibitor SD – Standard Deviation T2DM – Type 2 Diabetes Mellitus Declarations 1. Ethics approval and consent to participate This study was approved by the Ethics Committee of Antalya Training and Research Hospital (Approval number: 2022-251; Date: August 25, 2022). Due to the retrospective nature of the study, the requirement for informed consent was waived by the ethics committee. All procedures were conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. 2. Consent for publication Not applicable. 3. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. 4. Competing interests The authors declare that they have no competing interests. 5. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. 6. Authors' contributions SGK and LZK conceptualized the study. SGK collected and curated the data. GK and YS performed the statistical analysis and data interpretation. SGK drafted the manuscript. All authors critically reviewed and approved the final version of the manuscript. 7. Acknowledgements Not applicable. References Cowie MR, Fisher M. 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Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br J Clin Pharmacol. 2006;61(1):87-95. Pareek A, Chandurkar N, Dharmadhikari S. Risk vs Benefits of Thiazides in Clinical Use: Need for a Holistic Approach. Am J Med. March 1, 2022;135(3):e82-3. Weir MR, Slee A, Sun T, Balis D, Oh R, de Zeeuw D, et al. Effects of canagliflozin on serum potassium in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Clin Kidney J. May 1, 2021;14(5):1396-402. Charlwood C, Chudasama J, Darling AL, Logan Ellis H, Whyte MB. Effect of sodium-glucose co-transporter 2 inhibitors on plasma potassium: A meta-analysis. Diabetes Res Clin Pract. February 1, 2023;196:110239. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. June 13, 2019;380(24):2295-306. Palmer BF, Clegg DJ. Kidney-Protective Effects of SGLT2 Inhibitors. Clin J Am Soc Nephrol. February 2023;18(2):279. Palmer BF, Clegg DJ. SGLT2 Inhibition and Kidney Potassium Homeostasis. Clin J Am Soc Nephrol. March 2024;19(3):399. Neuen BL, Oshima M, Agarwal R, Arnott C, Cherney DZ, Edwards R, et al. Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials. Circulation. May 10, 2022;145(19):1460-70. Leonetti G, Rappelli A, Salvetti A, Scapellato L. Long-Term Effects of Indapamide: Final Results of a Two-Year Italian Multicenter Study in Systemic Hypertension. Am J Cardiol. May 2, 1990;65(17):H67-71. Elliott WJ, Weber RR, Murphy MB. A Double-Blind, Randomized, Placebo-Controlled Comparison of the Metabolic Effects of Low-Dose Hydrochlorothiazide and Indapamide. J Clin Pharmacol. 1991;31(8):751-7. Rafique Z, Weir MR, Onuigbo M, Pitt B, Lafayette R, et al. Expert Panel Recommendations for the Identification and Management of Hyperkalemia and Role of Patiromer in Patients with Chronic Kidney Disease and Heart Failure. J Manag Care Spec Pharm. April 2017;23(4-a Suppl):S10-9. Preventing and treating kidney disease in patients with type 2 diabetes: Expert Opinion on Pharmacotherapy: Vol 20, No 3 [Internet]. [n.p. March 18, 2024]. Available from:https://www.tandfonline.com/doi/abs/10.1080/14656566.2018.1551362 Rastogi A, Arman F, Alipourfetrati S. New Agents in Treatment of Hyperkalemia: an Opportunity to Optimize Use of RAAS Inhibitors for Blood Pressure Control and Organ Protection in Patients with Chronic Kidney Disease. Curr Hypertens Rep. May 26, 2016;18(7):55. Falhammar H, Skov J, Calissendorff J, Nathanson D, Lindh JD, Mannheimer B. Associations Between Antihypertensive Medications and Severe Hyponatremia: A Swedish Population–Based Case–Control Study. J Clin Endocrinol Metab. October 1, 2020;105(10):e3696-705. Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. January 1, 2015;3(1):8-10. Rau M, Thiele K, Hartmann NUK, Möllmann J, Wied S, Hohl M, et al. Effects of empagliflozin on markers of calcium and phosphate homeostasis in patients with type 2 diabetes – Data from a randomized, placebo-controlled study. Bone Rep. June 1, 2022;16:101175. de Jong MA, Petrykiv SI, Laverman GD, van Herwaarden AE, de Zeeuw D, Bakker SJL, et al. Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis. Clin J Am Soc Nephrol CJASN. January 7, 2019;14(1):66-73. Zhang J, Huan Y, Leibensperger M, Seo B, Song Y. Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Serum Electrolyte Levels in Patients with Type 2 Diabetes: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials. Kidney360. January 19, 2022;3(3):477-87. The effect of chronic hydrochlorothiazide administration on renal function in the rat | Clinical Science | Portland Press [Internet]. [n.p. March 23, 2024]. Available from:https://portlandpress.com/clinsci/article-abstract/70/4/379/73798/The-effect-of-chronic-hydrochlorothiazide Kokko JP. Proximal Tubule Potential Difference. DEPENDENCE ON GLUCOSE, HCO3, AND AMINO ACIDS. J Clin Invest. June 1, 1973;52(6):1362-7. Le Grimellec C, Giocondi MC, Philippe P. Micropuncture study along the proximal convoluted tubule electrolyte reabsorption in first convolutions. Pflüg Arch. June 1, 1975;354(2):133-50. Filippatos TD, Tsimihodimos V, Liamis G, Elisaf MS. SGLT2 inhibitors-induced electrolyte abnormalities: An analysis of the associated mechanisms. Diabetes Metab Syndr Clin Res Rev. January 2018;12(1):59-63. Cianciolo G, De Pascalis A, Gasperoni L, Tondolo F, Zappulo F, Capelli I, et al. The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i. Molecules. January 2020;25(12):2757. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6968533","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":478000994,"identity":"5f3c6923-ebb0-40da-8d29-4d2e0720d158","order_by":0,"name":"Sevgi GULSEN KOC","email":"","orcid":"","institution":"Ministry of Health Antalya City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sevgi","middleName":"GULSEN","lastName":"KOC","suffix":""},{"id":478000995,"identity":"4e0f8561-a716-4a48-9cf4-5caa51d434bd","order_by":1,"name":"Lutfullah Zahit KOC","email":"data:image/png;base64,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","orcid":"","institution":"Ministry of Health Antalya Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Lutfullah","middleName":"Zahit","lastName":"KOC","suffix":""},{"id":478000996,"identity":"99ee35ac-ae6e-4cc1-9f8c-ec2b2868ead6","order_by":2,"name":"Gokhan KOKER","email":"","orcid":"","institution":"Ministry of Health Antalya Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gokhan","middleName":"","lastName":"KOKER","suffix":""},{"id":478000997,"identity":"079d1af6-4fe9-4813-a82b-31dfc9cadc98","order_by":3,"name":"Yasin SAHİNTURK","email":"","orcid":"","institution":"Ministry of Health Antalya Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yasin","middleName":"","lastName":"SAHİNTURK","suffix":""}],"badges":[],"createdAt":"2025-06-24 19:23:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6968533/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6968533/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85937421,"identity":"6df42dbd-89bb-4531-8bc1-90db240c30f8","added_by":"auto","created_at":"2025-07-03 10:47:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":900685,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6968533/v1/d5ebc17d-ec11-4b97-9afc-71d4678dd68e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEffects of Combined SGLT2 Inhibitor and RAAS Blockade ± Thiazide Therapy on Serum Electrolyte Balance in Type 2 Diabetic Patients: A Retrospective Cohort Study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a new generation of antidiabetic agents that act by inhibiting glucose reabsorption in the proximal renal tubules, the primary site of glucose reabsorption. This inhibition leads to glucosuria, natriuresis, and osmotic diuresis as the main pharmacologic effects of these agents (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In individuals with diabetes, the expression and activity of SGLT2 are upregulated in the proximal tubule, resulting in enhanced reabsorption of both glucose and sodium. The consequent reduction in sodium delivery to the macula densa activates the renin-angiotensin-aldosterone system (RAAS). Decreased production of vasoconstrictive mediators acting on the afferent arteriole increases intraglomerular capillary hydrostatic pressure. These pathophysiological alterations collectively contribute to glomerular hyperfiltration and intraglomerular hypertension, early events in the development of diabetic nephropathy. By inhibiting SGLT2, these agents promote natriuresis and glucosuria, thereby increasing distal sodium delivery, suppressing RAAS activation, and reducing intraglomerular pressure\u0026mdash;effects that are partly analogous to those achieved by RAAS blockade. For this reason, SGLT2 inhibitors are sometimes referred to as \"smart diuretics\" (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe therapeutic benefits of SGLT2 inhibitors include modest weight loss, reductions in blood pressure (by approximately 2\u0026ndash;4 mmHg), serum uric acid levels, and albuminuria, as well as decreased risks of cardiovascular death, all-cause mortality, and hospitalization for heart failure (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Commonly reported adverse effects include genitourinary infections\u0026mdash;particularly genital mycotic infections in women\u0026mdash;polyuria, volume depletion, hypotension, dizziness, and a mild, typically transient increase in serum creatinine, especially during early therapy (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRenin, produced in the kidneys, converts angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II is a potent vasoconstrictor and stimulates aldosterone secretion, resulting in sodium and water retention. ACE inhibitors act by inhibiting the conversion of angiotensin I to angiotensin II (\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In contrast, angiotensin receptor blockers (ARBs) do not inhibit the production of angiotensin II but instead block its binding to the angiotensin II receptor, thereby attenuating its physiological effects. Reduced aldosterone levels promote natriuresis, vasodilation, and plasma volume reduction (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Both ACE inhibitors and ARBs are considered RAAS blockers. The most frequent adverse events include orthostatic hypotension and hyperkalemia. Additionally, ACE inhibitors are associated with a dry cough, a side effect not commonly seen with ARBs.\u003c/p\u003e \u003cp\u003eThiazide diuretics exert their diuretic effect by inhibiting the sodium-chloride co-transporter in the distal tubule. Their action requires prior secretion into the proximal tubule and is associated with increased calcium reabsorption in the distal nephron (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Reported adverse effects of thiazides include hypokalemia, hyperuricemia, hypercalcemia, and hyponatremia.\u003c/p\u003e \u003cp\u003eAlthough SGLT2 inhibitors and ACEi/ARB\u0026thinsp;\u0026plusmn;\u0026thinsp;hydrochlorothiazide are often co-prescribed for overlapping indications, they share certain adverse effect profiles. Both can transiently lower glomerular filtration rate (GFR). The combination of thiazides with SGLT2 inhibitors may exacerbate hyponatremia, while the co-administration of ACE inhibitors and SGLT2 inhibitors may heighten the risk of hyperkalemia. Based on these observations, the concurrent use of SGLT2 inhibitors with ACEi/ARB or ACEi/ARB\u0026thinsp;\u0026plusmn;\u0026thinsp;thiazide therapy may potentiate the risk of electrolyte disturbances. The present study aims to evaluate these associations and provide clinical insight into the safety of such pharmacologic combinations in real-world practice.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Ethical Approval\u003c/h2\u003e \u003cp\u003eThis study was designed as a retrospective cross-sectional analysis of patients who presented to the internal medicine outpatient clinic. Ethical approval was obtained from the Ethics Committee of Antalya Training and Research Hospital on August 25, 2022 (approval number: 2022\u0026thinsp;\u0026minus;\u0026thinsp;251). Given the retrospective nature of the study and the impracticality of obtaining informed consent from all participants, the requirement for informed consent was waived. The study was conducted in full compliance with the principles outlined in the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population, Definitions, and Grouping\u003c/h3\u003e\n\u003cp\u003eThe final study population consisted of adult patients (\u0026ge;\u0026thinsp;18 years) with a diagnosis of type 2 diabetes mellitus who attended the internal medicine outpatient clinic and were prescribed SGLT2 inhibitors either as monotherapy or in combination with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and/or hydrochlorothiazide.\u003c/p\u003e \u003cp\u003ePatients were excluded if they had chronic kidney disease (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min/1.73 m\u0026sup2;), chronic liver disease, active infection, malignancy, pregnancy, missing data, or if they were using medications known to affect electrolyte balance (e.g., loop diuretics, spironolactone, lithium).\u003c/p\u003e \u003cp\u003eClinical and laboratory data were retrieved from electronic medical records at Antalya Training and Research Hospital, a tertiary care center. The study period spanned from January 2018 to December 2022. The date of treatment initiation was confirmed from clinical notes, and follow-up laboratory results were reviewed approximately six weeks after initiation. Medication regimens were determined by the patients' primary care physicians based on individualized treatment plans.\u003c/p\u003e \u003cp\u003eParticipants were categorized into five groups based on their antihypertensive and antidiabetic therapy:\u003c/p\u003e \u003cp\u003eGroup 1: SGLT2 inhibitor monotherapy\u003c/p\u003e \u003cp\u003eGroup 2: ACEi or ARB monotherapy\u003c/p\u003e \u003cp\u003eGroup 3: ACEi or ARB\u0026thinsp;+\u0026thinsp;SGLT2 inhibitor\u003c/p\u003e \u003cp\u003eGroup 4: ACEi or ARB\u0026thinsp;+\u0026thinsp;thiazide diuretic\u003c/p\u003e \u003cp\u003eGroup 5: ACEi or ARB\u0026thinsp;+\u0026thinsp;thiazide diuretic\u0026thinsp;+\u0026thinsp;SGLT2 inhibitor\u003c/p\u003e \u003cp\u003eFor all participants, serum sodium, potassium, calcium, magnesium, and phosphorus levels were measured at baseline and at follow-up (~\u0026thinsp;6 weeks post-treatment initiation). Additional variables such as age, sex, and other laboratory parameters were also recorded.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were compiled using Microsoft Excel. Statistical analyses were conducted using SPSS version 27.0 (IBM Corp., Armonk, NY, USA). Graphs and visualizations were created using GraphPad Prism version 9. Categorical variables were expressed as frequencies and percentages, while continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Normality was assessed using the Shapiro\u0026ndash;Wilk test, and nonparametric methods were used when distributional assumptions were not met. The Mann\u0026ndash;Whitney U test was applied for comparisons between two independent groups. A two-tailed p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e \u003cp\u003eInitially, 1,500 patients were considered for inclusion in the study; however, 1,006 patients were excluded due to incomplete or inconsistent medical records. A total of 494 patients were included in the final analysis. The cohort consisted of 223 males (45.14%) and 271 females (54.86%), with a mean age of 57.39\u0026thinsp;\u0026plusmn;\u0026thinsp;12.00 years. Patients were categorized based on their treatment regimens: 139 patients (28.14%) received only SGLT2 inhibitors; 103 patients (20.85%) received only ACE inhibitors/ARBs; 61 patients (12.35%) received ACE inhibitors/ARBs\u0026thinsp;+\u0026thinsp;thiazide; 70 patients (14.17%) received ACE inhibitors/ARBs\u0026thinsp;+\u0026thinsp;SGLT2 inhibitors; 116 patients (23.48%) received ACE inhibitors/ARBs\u0026thinsp;+\u0026thinsp;thiazide\u0026thinsp;+\u0026thinsp;SGLT2 inhibitors; and 5 patients (1.01%) received SGLT2 inhibitors\u0026thinsp;+\u0026thinsp;thiazide therapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients using only thiazides or thiazides\u0026thinsp;+\u0026thinsp;SGLT2 inhibitors were excluded from statistical evaluation due to small group sizes. For each group, serum levels of sodium, potassium, calcium, magnesium, and phosphorus were assessed before and approximately six weeks after treatment initiation. In this study, serum sodium levels were corrected using a glucose-adjustment factor. The post-treatment mean laboratory values for the entire cohort were as follows: serum sodium 138.82\u0026thinsp;\u0026plusmn;\u0026thinsp;3.19 mmol/L, potassium 4.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.40 mmol/L, calcium 9.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52 mg/dL, magnesium 2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24 mg/dL, and phosphorus 3.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59 mg/dL.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of the Study Population by Gender and Medication Use\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e45,14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e54,86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSGLT2-i Usage Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eUsing SGLT2-i\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e329\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e66,60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eNot using SGLT2-i\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33,40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eMedication Groups\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSGLT2-i only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28,14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSGLT2-i\u0026thinsp;+\u0026thinsp;ACEi/ARB\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14,17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSGLT2-i\u0026thinsp;+\u0026thinsp;Thiazide\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1,01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSGLT2-i\u0026thinsp;+\u0026thinsp;ACEi/ARB\u0026thinsp;+\u0026thinsp;Thiazide\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23,48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eACEi/ARB\u0026thinsp;+\u0026thinsp;Thiazide\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12,35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eACEi/ARB only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20,85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEffect of SGLT2 Inhibitor\u003c/h2\u003e \u003cp\u003eAmong patients receiving SGLT2 inhibitors, there was no statistically significant difference between baseline and post-treatment values for potassium (p\u0026thinsp;=\u0026thinsp;0.176), calcium (p\u0026thinsp;=\u0026thinsp;0.227), and phosphorus (p\u0026thinsp;=\u0026thinsp;0.904). However, post-treatment serum sodium levels were significantly higher compared to baseline (p\u0026thinsp;=\u0026thinsp;0.034), and a similar increase was observed in serum magnesium levels (p\u0026thinsp;=\u0026thinsp;0.004) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eElectrolyte levels before and after treatment in patients using SGLT2 inhibitors alone\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e137,74\u0026thinsp;\u0026plusmn;\u0026thinsp;2,97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e138,44\u0026thinsp;\u0026plusmn;\u0026thinsp;3,08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4,58\u0026thinsp;\u0026plusmn;\u0026thinsp;0,36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4,52\u0026thinsp;\u0026plusmn;\u0026thinsp;0,38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9,54\u0026thinsp;\u0026plusmn;\u0026thinsp;0,44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9,62\u0026thinsp;\u0026plusmn;\u0026thinsp;0,57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,227\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnesium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1,94\u0026thinsp;\u0026plusmn;\u0026thinsp;0,24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2,02\u0026thinsp;\u0026plusmn;\u0026thinsp;0,27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphorus (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3,55\u0026thinsp;\u0026plusmn;\u0026thinsp;0,51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3,56\u0026thinsp;\u0026plusmn;\u0026thinsp;0,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,904\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEffect of ACEi/ARB Use\u003c/h3\u003e\n\u003cp\u003eIn patients using ACEi/ARB, no statistically significant difference was observed between baseline and post-treatment levels of sodium (p\u0026thinsp;=\u0026thinsp;0.499), calcium (p\u0026thinsp;=\u0026thinsp;0.878), or magnesium (p\u0026thinsp;=\u0026thinsp;0.604). In contrast, post-treatment levels of potassium (p\u0026thinsp;=\u0026thinsp;0.043) and phosphorus (p\u0026thinsp;=\u0026thinsp;0.020) were significantly higher compared to baseline (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eElectrolyte levels before and after treatment in patients using ACEi/ARB monotherapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e138,95\u0026thinsp;\u0026plusmn;\u0026thinsp;2,59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e139,03\u0026thinsp;\u0026plusmn;\u0026thinsp;3,38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,499\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4,45\u0026thinsp;\u0026plusmn;\u0026thinsp;0,42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4,52\u0026thinsp;\u0026plusmn;\u0026thinsp;0,43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9,56\u0026thinsp;\u0026plusmn;\u0026thinsp;0,48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9,58\u0026thinsp;\u0026plusmn;\u0026thinsp;0,43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,878\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnesium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2,00\u0026thinsp;\u0026plusmn;\u0026thinsp;0,18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2,02\u0026thinsp;\u0026plusmn;\u0026thinsp;0,21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,604\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphorus (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3,42\u0026thinsp;\u0026plusmn;\u0026thinsp;0,55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3,58\u0026thinsp;\u0026plusmn;\u0026thinsp;0,62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eEffect of Adding SGLT2 Inhibitor to ACEi/ARB Therapy\u003c/h3\u003e\n\u003cp\u003eIn patients receiving ACEi/ARB\u0026thinsp;+\u0026thinsp;SGLT2 inhibitor therapy, no significant differences were found between baseline and post-treatment values for sodium (p\u0026thinsp;=\u0026thinsp;0.286), potassium (p\u0026thinsp;=\u0026thinsp;0.617), or calcium (p\u0026thinsp;=\u0026thinsp;0.221). However, post-treatment levels of magnesium (p\u0026thinsp;=\u0026thinsp;0.001) and phosphorus (p\u0026thinsp;=\u0026thinsp;0.003) were significantly elevated compared to baseline values (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eElectrolyte levels before and after treatment in patients using ACEi/ARB\u0026thinsp;+\u0026thinsp;SGLT2 inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e138,41\u0026thinsp;\u0026plusmn;\u0026thinsp;3,22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e139,01\u0026thinsp;\u0026plusmn;\u0026thinsp;2,99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,286\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4,54\u0026thinsp;\u0026plusmn;\u0026thinsp;0,39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4,57\u0026thinsp;\u0026plusmn;\u0026thinsp;0,34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,617\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9,57\u0026thinsp;\u0026plusmn;\u0026thinsp;0,57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9,67\u0026thinsp;\u0026plusmn;\u0026thinsp;0,54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,221\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnesium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1,87\u0026thinsp;\u0026plusmn;\u0026thinsp;0,20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2,05\u0026thinsp;\u0026plusmn;\u0026thinsp;0,24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphorus (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3,23\u0026thinsp;\u0026plusmn;\u0026thinsp;0,57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3,49\u0026thinsp;\u0026plusmn;\u0026thinsp;0,48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEffect of ACEi/ARB\u0026thinsp;+\u0026thinsp;Thiazide Use\u003c/h2\u003e \u003cp\u003eAmong patients treated with ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide, no statistically significant changes were observed in sodium (p\u0026thinsp;=\u0026thinsp;0.356), potassium (p\u0026thinsp;=\u0026thinsp;0.937), magnesium (p\u0026thinsp;=\u0026thinsp;0.436), or phosphorus (p\u0026thinsp;=\u0026thinsp;0.092) levels. Post-treatment calcium levels, however, were significantly higher than baseline (p\u0026thinsp;=\u0026thinsp;0.044) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eElectrolyte levels before and after treatment in patients using ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide diuretics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e138,89\u0026thinsp;\u0026plusmn;\u0026thinsp;2,88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e139,26\u0026thinsp;\u0026plusmn;\u0026thinsp;2,75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,356\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4,36\u0026thinsp;\u0026plusmn;\u0026thinsp;0,46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4,34\u0026thinsp;\u0026plusmn;\u0026thinsp;0,41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,937\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9,54\u0026thinsp;\u0026plusmn;\u0026thinsp;0,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9,70\u0026thinsp;\u0026plusmn;\u0026thinsp;0,64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,044\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnesium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2,00\u0026thinsp;\u0026plusmn;\u0026thinsp;0,19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1,99\u0026thinsp;\u0026plusmn;\u0026thinsp;0,24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,436\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphorus (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3,60\u0026thinsp;\u0026plusmn;\u0026thinsp;0,60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3,47\u0026thinsp;\u0026plusmn;\u0026thinsp;0,72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEffect of Adding SGLT2 Inhibitor to ACEi/ARB\u0026thinsp;+\u0026thinsp;Thiazide Therapy\u003c/h2\u003e \u003cp\u003eIn patients treated with ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide\u0026thinsp;+\u0026thinsp;SGLT2 inhibitor, there were no significant differences between baseline and post-treatment levels for sodium (p\u0026thinsp;=\u0026thinsp;0.386), potassium (p\u0026thinsp;=\u0026thinsp;0.118), calcium (p\u0026thinsp;=\u0026thinsp;0.588), or phosphorus (p\u0026thinsp;=\u0026thinsp;0.244). A statistically significant increase in magnesium levels was observed post-treatment compared to baseline (p\u0026thinsp;=\u0026thinsp;0.002) (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e Electrolyte levels before and after treatment were analyzed in 494 patients who were grouped according to their use of ACEi/ARB\u0026thinsp;\u0026plusmn;\u0026thinsp;thiazide\u0026thinsp;\u0026plusmn;\u0026thinsp;SGLT2 inhibitors. Hyperkalemia associated with ACEi/ARB therapy was not observed when SGLT2 inhibitors were used concurrently. Similarly, the increase in calcium levels typically seen with thiazide use appeared to be attenuated by the addition of SGLT2 inhibitors. The observed increase in serum magnesium levels associated with SGLT2 inhibitor use, whether administered alone or in combination with other agents, was both consistent and statistically significant. These results highlight the clinical relevance of regular electrolyte monitoring in diabetic patients, particularly in the context of frequent polypharmacy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eElectrolyte levels before and after treatment in patients using ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide\u0026thinsp;+\u0026thinsp;SGLT2 inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter Treatment (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e138,61\u0026thinsp;\u0026plusmn;\u0026thinsp;3,24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e138,88\u0026thinsp;\u0026plusmn;\u0026thinsp;2,92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,386\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4,56\u0026thinsp;\u0026plusmn;\u0026thinsp;0,40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4,47\u0026thinsp;\u0026plusmn;\u0026thinsp;0,41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9,60\u0026thinsp;\u0026plusmn;\u0026thinsp;0,42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9,64\u0026thinsp;\u0026plusmn;\u0026thinsp;0,45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,588\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnesium (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1,88\u0026thinsp;\u0026plusmn;\u0026thinsp;0,27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1,96\u0026thinsp;\u0026plusmn;\u0026thinsp;0,24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphorus (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3,41\u0026thinsp;\u0026plusmn;\u0026thinsp;0,58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3,49\u0026thinsp;\u0026plusmn;\u0026thinsp;0,57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,244\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn our cohort, the use of SGLT2 inhibitors alone was associated with a statistically significant increase in serum sodium levels following treatment compared to baseline values (p\u0026thinsp;=\u0026thinsp;0.034). Previous studies investigating the effect of SGLT2 inhibitors on serum sodium have yielded variable results. In two clinical trials involving patients diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH), SGLT2 inhibitors were associated with an increase in serum sodium levels compared to placebo (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, the limited sample sizes in both studies constrain the generalizability of their findings.\u003c/p\u003e \u003cp\u003eConversely, other studies conducted in patients with type 2 diabetes treated with canagliflozin did not detect any significant changes in serum sodium concentrations (17,18). A meta-analysis later showed that the effect on sodium levels may differ depending on the specific agent, reporting a mean reduction of 0.36 mmol/L with canagliflozin 300 mg and a mean increase of 0.31 mmol/L with empagliflozin 25 mg (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In a subanalysis of the EMPA-RESPONSE-AHF trial, which included patients presenting with acute heart failure, empagliflozin had no measurable impact on plasma sodium levels or fractional sodium excretion compared to placebo (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Notably, most of these studies did not account for the influence of comorbid conditions or concomitant medications.\u003c/p\u003e \u003cp\u003eOur patient population differs from these previous cohorts, as it consisted of individuals with diabetes, preserved renal function (GFR\u0026thinsp;\u0026gt;\u0026thinsp;60 mL/min/1.73 m\u0026sup2;), and no use of loop diuretics. The observed mean increase of 0.7 mmol/L in serum sodium following SGLT2 inhibitor therapy may be attributable to osmotic diuresis. Although statistically significant, the mean post-treatment sodium level remained within the normal physiological range. Previous reports have shown that while SGLT2 inhibitors increase fractional glucose excretion and promote osmotic diuresis, they do not enhance fractional sodium excretion (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe rise in serum sodium may also reflect free water loss leading to hypernatremic dehydration and, possibly, secondary hyperaldosteronism due to intravascular volume contraction. In our cohort, inadequate compensation for fluid losses from osmotic diuresis, poor oral intake, and persistent hyperglycemia may have contributed to dehydration and the subsequent elevation in sodium levels. Furthermore, dietary sodium intake was not documented due to the retrospective nature of the study, and its potential influence on serum sodium concentrations remains unknown.\u003c/p\u003e \u003cp\u003eFollowing ACEi/ARB therapy, no statistically significant difference was observed in serum sodium levels compared to baseline values in our study (p\u0026thinsp;=\u0026thinsp;0.499). It is generally believed that ACEi/ARB use does not significantly affect serum sodium concentrations. However, several studies and case reports have documented hyponatremia associated with these agents. In a pilot study including 50 patients treated with ACEi/ARB, hyponatremia was identified in 50% of cases. Although the incidence was lower in patients receiving ARBs, no statistically significant difference was noted between ACEi and ARB use (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In this study, the frequency of hyponatremia was higher among older adults (aged 56\u0026ndash;75 years), with a more pronounced sodium-lowering effect observed in those over 66 years. Cases of hyponatremia have also been reported following treatment with captopril and lisinopril (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e23\u003c/span\u003e). One case involved a 76-year-old woman who developed SIADH associated with lisinopril use for hypertension (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eACE inhibitors exert their effect by inhibiting the conversion of Angiotensin I (Ang I) to Angiotensin II (Ang II) in the peripheral circulation; however, this blockade does not occur in the central nervous system. The elevated Ang I in circulation may enter the brain and be converted to Ang II, which can stimulate thirst and lead to the release of antidiuretic hormone (ADH) from the hypothalamus, potentially resulting in hyponatremia. Additionally, hyponatremia may arise due to aldosterone deficiency secondary to RAAS blockade by ACEi/ARB. Notably, the patients described in both the pilot study and case reports were elderly. In our study population, the mean age was 57.39\u0026thinsp;\u0026plusmn;\u0026thinsp;12.00 years, and it is plausible that age-related pharmacokinetic and pharmacodynamic changes in drug metabolism contributed to the development of hyponatremia in older individuals.\u003c/p\u003e \u003cp\u003eIn our study, there was no statistically significant difference between baseline and post-treatment serum sodium levels in patients receiving combined ACEi/ARB and thiazide therapy (p\u0026thinsp;=\u0026thinsp;0.356). Hyponatremia is a well-recognized electrolyte disturbance associated with thiazide use, particularly in the geriatric population (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In a case series of 114 elderly patients, the incidence of thiazide-induced hyponatremia was 11% (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e26\u003c/span\u003e). A cross-sectional study conducted in the United Kingdom among thiazide users found hyponatremia to be more common than hypokalemia (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In that study, the mean age was 68 years, and increasing age was identified as a risk factor for hyponatremia. Due to limited data in our cohort, patients receiving thiazide monotherapy could not be evaluated separately. Instead, we focused on patients treated with ACEi/ARB in combination with thiazides and found no statistically significant reduction in serum sodium levels with combination therapy.\u003c/p\u003e \u003cp\u003eA previous study showed that the development of hyponatremia among patients receiving thiazide monotherapy or in combination with ACEi/ARB typically occurred in the presence of triggering conditions such as infections or central nervous system disorders, which may predispose to SIADH (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e28\u003c/span\u003e). ACE inhibitors and ARBs reduce aldosterone secretion by blocking the effects of Ang II, thereby limiting sodium and water retention in the kidneys while helping to preserve normal renal function to prevent excessive losses. Although combination therapy with ACEi/ARB and thiazide diuretics may increase the risk of hyponatremia at treatment initiation, we believe that over time, renal compensatory mechanisms may restore sodium homeostasis and normalize serum sodium concentrations.\u003c/p\u003e \u003cp\u003eThe addition of SGLT2 inhibitors to ACEi/ARB or ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide therapy did not result in any statistically significant change in serum sodium levels compared to baseline. SGLT2 inhibitors induce osmotic diuresis as a consequence of glucosuria. Since the inhibition of sodium reabsorption is indirect in this mechanism, water loss tends to be proportionally greater. The increase in electrolyte-free water loss primarily reduces interstitial volume rather than blood volume, thereby minimizing arterial underfilling and the subsequent activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, ACEi/ARBs and thiazide diuretics promote natriuresis as the mechanism of fluid reduction. Therefore, the absence of a change in serum sodium levels when SGLT2 inhibitors are added to these regimens may be explained by this differing mode of action. Moreover, the addition of SGLT2 inhibitors to ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide therapy may reduce intravascular volume via natriuresis and diuresis without inducing hemoconcentration-related increases in serum sodium concentration. We acknowledge that there are important gaps in the literature regarding serum sodium dynamics under combination therapy, and we encourage clinicians to undertake further research to address these knowledge deficits.\u003c/p\u003e \u003cp\u003eElectrolyte disturbances involving serum potassium concentrations have not been frequently reported in clinical trials with SGLT2 inhibitors. In our study, the use of SGLT2 inhibitors did not produce a statistically significant difference in mean serum potassium levels. This finding is consistent with the results of the CANVAS program. The CANVAS trial enrolled patients with type 2 diabetes and an estimated GFR\u0026thinsp;\u0026gt;\u0026thinsp;30 mL/min/1.73 m\u0026sup2;, and consisted of two similarly designed, double-blind, randomized, placebo-controlled studies (CANVAS and CANVAS-Renal), including a total of 10,142 participants. Participants received either 100 or 300 mg of canagliflozin or placebo, and serum potassium measurements were assessed approximately every six months. Interim results from CANVAS initially suggested a higher incidence of hyperkalemia in the canagliflozin arm compared to placebo. However, in the final analysis, this hypothesis was not supported\u0026mdash;particularly in patients with renal impairment or those using RAAS-inhibiting medications\u0026mdash;thus diminishing concerns about hyperkalemia risk in this subgroup (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA meta-analysis of four randomized controlled trials including over 21,000 patients with type 2 diabetes also reported a 28% lower risk of hyperkalemic events in those receiving SGLT2 inhibitors compared to placebo (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Similarly, the CREDENCE trial, which assessed canagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD), found no increase in the risk of hyperkalemia with canagliflozin compared to placebo, further supporting these observations (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSGLT2 inhibitors are known to reduce blood pressure by approximately 4\u0026ndash;5 mmHg, likely due to plasma volume contraction (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e32\u003c/span\u003e). While a reduction in intravascular volume stimulates renin release and increases aldosterone levels, the increased distal sodium delivery observed with SGLT2 inhibition appears to suppress renin secretion and downstream RAAS activation, ultimately leading to a decrease in aldosterone levels. Therefore, in the medium to long term, no significant changes in serum renin or aldosterone concentrations are expected (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The lack of a significant rise in aldosterone levels may explain the absence of hypokalemia in our patient population.\u003c/p\u003e \u003cp\u003eThe hyperkalemic effect of ACEi/ARB therapy is well-established in clinical literature. ACE inhibitors block the formation of angiotensin II, while ARBs prevent angiotensin II from binding to its receptors. This leads to RAAS inhibition and suppression of aldosterone secretion and vasoconstriction. Reduced aldosterone levels impair potassium excretion, resulting in hyperkalemia. Consistent with this mechanism, our study demonstrated a statistically significant increase in serum potassium levels following ACEi/ARB therapy compared to baseline (p\u0026thinsp;=\u0026thinsp;0.043). However, when SGLT2 inhibitors were added to this regimen, no significant increase in serum potassium levels was observed (p\u0026thinsp;=\u0026thinsp;0.617).\u003c/p\u003e \u003cp\u003eA meta-analysis of individual patient data from six studies including nearly 50,000 patients showed that SGLT2 inhibitors reduced the risk of hyperkalemia without increasing the risk of hypokalemia, even in patients receiving concomitant diuretic therapy (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Similarly, in the CANVAS trial\u0026mdash;where approximately 80% of participants were treated with RAAS inhibitors\u0026mdash;no significant difference in the risk of potassium increase or decrease was observed between the canagliflozin and placebo groups, regardless of background RAAS blockade. These findings are in line with our results in the ACEi/ARB\u0026thinsp;+\u0026thinsp;SGLT2 inhibitor group.\u003c/p\u003e \u003cp\u003eUnder normal physiological conditions, potassium delivery to the distal nephron is maintained by glomerular filtration, and the kidneys regulate total body potassium. However, the rate of potassium secretion in the distal nephron is variable and influenced by mineralocorticoid activity, which regulates sodium and water delivery to the distal tubule (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e30\u003c/span\u003e). SGLT2 inhibitors increase distal sodium delivery, which enhances sodium reabsorption and renders the tubular lumen more electronegative. This change in luminal potential promotes potassium secretion. Additionally, increased tubular flow rates also contribute to enhanced potassium excretion. These mechanisms may explain how SGLT2 inhibitors mitigate ACEi/ARB-induced hyperkalemia.\u003c/p\u003e \u003cp\u003eIn our study, the combination of ACEi/ARB and thiazide therapy did not result in a statistically significant change in serum potassium levels (p\u0026thinsp;=\u0026thinsp;0.937). Thiazides act at the distal tubule, increasing urinary sodium excretion and indirectly reducing extracellular fluid volume and peripheral resistance. This volume reduction triggers RAAS activation and promotes aldosterone-mediated potassium loss through the urine. Studies investigating thiazide-induced hypokalemia support this mechanism (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e36\u003c/span\u003e). When ACEi/ARBs are co-administered with thiazide diuretics, they tend to counteract thiazide-induced hypokalemia. Furthermore, thiazide-induced RAAS activation may enhance responsiveness to ACEi/ARB therapy. By inhibiting sodium and chloride reabsorption in the distal tubule, thiazides promote diuresis, while concurrent ACEi/ARB therapy helps stabilize potassium balance.\u003c/p\u003e \u003cp\u003ePatients with diabetes are at increased risk for hyperkalemia, and this risk is further elevated with RAAS inhibition (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e37\u003c/span\u003e). As a result, RAAS inhibitors are often down-titrated or discontinued in patients who develop hyperkalemia (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e39\u003c/span\u003e), which may compromise the cardioprotective and renoprotective benefits of these agents (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e40\u003c/span\u003e). However, based on the findings of our study, co-administration of SGLT2 inhibitors with ACEi/ARB appears to attenuate the potassium increase typically associated with ACEi/ARB therapy. Additionally, although the decrease in serum potassium with ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide\u0026thinsp;+\u0026thinsp;SGLT2 inhibitor therapy did not reach statistical significance, a numerical reduction of 0.09 mmol/L was observed. These results suggest that SGLT2 inhibitors may provide a protective effect against dyskalemia when used in combination with ACEi/ARB and thiazide therapy. The observed reduction in hyperkalemia risk may reflect the renoprotective properties of the SGLT2 inhibitor class.\u003c/p\u003e \u003cp\u003eIn our study, no statistically significant changes were observed in serum calcium or phosphorus levels following SGLT2 inhibitor therapy. When reviewing prior literature, some studies reported alterations in serum calcium and modest increases in phosphorus levels with canagliflozin use (18,41). However, studies involving empagliflozin did not detect significant changes in serum calcium or 25(OH)D₃ concentrations (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e42\u003c/span\u003e). In a study by de Jong et al. evaluating dapagliflozin, no changes in serum calcium were observed compared to placebo, while an increase in serum phosphorus levels was noted (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e43\u003c/span\u003e). This study was a post hoc analysis of the IMPROVE trial and included patients with type 2 diabetes and early-stage chronic kidney disease who were also on stable doses of ACEi/ARB therapy. Our findings\u0026mdash;showing no change in serum calcium but an increase in serum phosphorus levels following the addition of SGLT2 inhibitors to ACEi/ARB treatment\u0026mdash;are consistent with those results. Furthermore, our sample size of 70 patients exceeds the 33 participants in the aforementioned post hoc analysis, providing a more robust basis for evaluation.\u003c/p\u003e \u003cp\u003eAdditionally, a meta-analysis incorporating 25 randomized controlled trials reported that SGLT2 inhibitors were associated with an increase in serum phosphate concentrations, while serum calcium levels remained unaffected (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e44\u003c/span\u003e). However, this meta-analysis did not stratify patients based on concomitant medications such as ACEi, ARBs, thiazides, or other diuretics, limiting interpretation. Therefore, the observed increase in phosphorus levels when SGLT2 inhibitors are added to ACEi/ARB therapy may reflect the effect of RAAS inhibition. Another possible explanation is that RAAS blockade combined with the osmotic diuresis caused by SGLT2 inhibitors may lead to volume contraction, contributing to changes in serum phosphorus.\u003c/p\u003e \u003cp\u003eIn our study, combined ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide therapy did not result in a statistically significant change in serum phosphorus levels (p\u0026thinsp;=\u0026thinsp;0.092), but did lead to a significant increase in serum calcium levels (p\u0026thinsp;=\u0026thinsp;0.044). This calcium-elevating effect of thiazides is consistent with known physiological mechanisms and is supported by existing literature. Thiazides promote sodium loss and water excretion via inhibition of sodium reabsorption in the distal tubule, resulting in extracellular volume depletion. As a compensatory response, proximal sodium reabsorption is upregulated, which increases the electrochemical gradient across the tubular membrane and facilitates passive calcium reabsorption (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Moreover, thiazides stimulate Na⁺/Ca\u0026sup2;⁺ exchange activity in the distal tubule, leading to enhanced calcium reabsorption and subsequent hypocalciuria and hypercalcemia.\u003c/p\u003e \u003cp\u003eWhen SGLT2 inhibitors were added to ACEi/ARB\u0026thinsp;+\u0026thinsp;thiazide therapy, no significant increase in serum calcium levels was observed. The normalization of hypercalcemia with SGLT2 inhibitor addition may be explained by the disruption of the electrochemical gradient necessary for enhanced calcium reabsorption. While thiazides induce sodium loss in the distal tubule and promote sodium reabsorption in the proximal tubule, the resulting gradient may facilitate increased calcium reabsorption. However, the addition of SGLT2 inhibitors, which promote sodium excretion in the proximal tubule, may interfere with the formation of this gradient, thereby attenuating calcium reabsorption.\u003c/p\u003e \u003cp\u003eIn the current literature, the hypercalcemic effect of thiazides has not been clearly defined, and to our knowledge, no studies have investigated how SGLT2 inhibitors may alter this response. Therefore, further research is needed to explore the potential interactions between SGLT2 inhibitors and thiazide-induced changes in calcium and phosphorus homeostasis.\u003c/p\u003e \u003cp\u003eIn our study, SGLT2 inhibitor therapy was associated with a significant increase in serum magnesium levels. This finding is consistent with previous reports evaluating the effects of SGLT2 inhibitors. Several hypotheses have been proposed to explain the magnesium-raising effects of SGLT2 inhibitors. Passive paracellular magnesium transport in the proximal tubule is determined by both the magnesium concentration and the transmembrane potential gradient (TPMG). By increasing tubular sodium concentrations, SGLT2 inhibition may enhance TPMG and subsequently promote magnesium reabsorption (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e47\u003c/span\u003e). Another proposed mechanism involves the elevation of glucagon levels following SGLT2 inhibitor use, which may enhance magnesium reabsorption in the distal renal tubules (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e48\u003c/span\u003e). An additional hypothesis suggests that SGLT2 inhibitor-induced natriuresis and osmotic diuresis result in hypovolemia, thereby increasing aldosterone concentrations. Aldosterone, in turn, may directly influence magnesium transport and lead to increased magnesium excretion (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e49\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA meta-analysis by Tang et al., which included 18 randomized controlled trials involving patients with type 2 diabetes and preserved kidney function, demonstrated significant increases in serum magnesium levels following SGLT2 inhibitor treatment (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e50\u003c/span\u003e). While we observed no significant change in serum magnesium levels with ACEi/ARB\u0026thinsp;\u0026plusmn;\u0026thinsp;thiazide therapy alone, the addition of SGLT2 inhibitors resulted in a statistically significant increase in serum magnesium concentrations.\u003c/p\u003e \u003cp\u003eHypomagnesemia has been associated with adverse outcomes in diabetes, contributing to both macrovascular and microvascular complications (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e52\u003c/span\u003e). Diabetes itself is also a known cause of hypomagnesemia, and the addition of SGLT2 inhibitors to antidiabetic therapy may help normalize serum magnesium levels. In our study, no extreme or clinically concerning magnesium values were observed after treatment. However, in patients with elevated baseline serum magnesium concentrations, clinicians should exercise caution when initiating SGLT2 inhibitor therapy. Further research and additional data are needed to enhance the current level of evidence regarding the effects of SGLT2 inhibitors on magnesium homeostasis.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and Limitations\u003c/h2\u003e \u003cp\u003eThis study has several notable strengths. First, it provides real-world data from a relatively large cohort of 494 patients, enhancing the clinical applicability of the findings. Second, it is one of the few studies to evaluate the effects of SGLT2 inhibitors on electrolyte balance when used in various therapeutic combinations, including ACEi/ARB and/or thiazide diuretics. The comprehensive assessment of key electrolytes\u0026mdash;sodium, potassium, calcium, magnesium, and phosphorus\u0026mdash;allows for a broad understanding of biochemical interactions under these drug regimens.\u003c/p\u003e \u003cp\u003eHowever, several limitations should be acknowledged. As a retrospective study, the ability to establish causal relationships is inherently limited. Additionally, the 6-week follow-up period may not adequately reflect long-term electrolyte dynamics. The subgroup of patients receiving SGLT2 inhibitors plus thiazide diuretics was very small (n\u0026thinsp;=\u0026thinsp;5), limiting the statistical power and generalizability for that specific combination. Furthermore, potential confounding variables such as dietary intake, fluid status, and comorbidities were not controlled, which may have influenced electrolyte fluctuations.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur study demonstrated that the use of SGLT2 inhibitors in combination with commonly prescribed antihypertensive therapies such as ACE inhibitors, ARBs, and thiazide diuretics in diabetic patients did not lead to significant electrolyte imbalances. Notably, SGLT2 inhibitors did not cause hyponatremia even in patients predisposed to it, such as those with diabetes or heart failure, indicating a possible stabilizing effect on sodium balance through modulation of tubuloglomerular feedback.\u003c/p\u003e \u003cp\u003eWhile ACEi/ARB treatment alone was associated with a slight increase in serum potassium, the addition of SGLT2 inhibitors did not further elevate potassium levels. This finding suggests that SGLT2 inhibitors may help mitigate the risk of hyperkalemia often seen with RAAS blockade. Similarly, although thiazide diuretics are known to increase serum calcium levels, co-administration with SGLT2 inhibitors prevented additional calcium elevation, possibly by interfering with the tubular mechanisms responsible for calcium reabsorption.\u003c/p\u003e \u003cp\u003eAccording to current European Society of Cardiology (ESC) guidelines (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e53\u003c/span\u003e), combination therapies are preferred in the initial management of hypertension. Therefore, understanding the impact of additional agents like SGLT2 inhibitors on electrolyte balance is clinically important.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings suggest that SGLT2 inhibitors can be safely added to ACEi/ARB and thiazide-based antihypertensive regimens in diabetic patients without increasing the risk of electrolyte disturbances. Moreover, their use may contribute to the correction of diabetes-induced renal pathophysiological changes, offering a potential protective effect on kidney function.\u003c/p\u003e \u003cp\u003eFuture prospective, randomized controlled trials are warranted to validate these findings and explore the mechanistic underpinnings of SGLT2 inhibitors\u0026rsquo; impact on electrolyte homeostasis. Inclusion of multivariate analysis in future research would also help to identify independent predictors of electrolyte shifts, accounting for variables such as age, eGFR, HbA1c, and concurrent medications. Supplementary materials such as detailed groupwise electrolyte distribution tables and boxplots may enhance transparency and interpretability of subgroup effects. Finally, a clear emphasis should be placed on the clinical utility of these findings in guiding safer and more effective combination therapy in diabetic patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eACEi\u003c/strong\u003e – Angiotensin-Converting Enzyme Inhibitor\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eARB\u003c/strong\u003e – Angiotensin Receptor Blocker\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eCKD\u003c/strong\u003e – Chronic Kidney Disease\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eeGFR\u003c/strong\u003e – Estimated Glomerular Filtration Rate\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eRAAS\u003c/strong\u003e – Renin-Angiotensin-Aldosterone System\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eSGLT2-i\u003c/strong\u003e – Sodium-Glucose Co-Transporter 2 Inhibitor\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eSD\u003c/strong\u003e – Standard Deviation\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eT2DM\u003c/strong\u003e – Type 2 Diabetes Mellitus\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003ch4\u003e\u003cstrong\u003e1. Ethics approval and consent to participate\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Antalya Training and Research Hospital (Approval number: 2022-251; Date: August 25, 2022). Due to the retrospective nature of the study, the requirement for informed consent was waived by the ethics committee. All procedures were conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments.\u003c/p\u003e\n\u003ch4\u003e\u003cstrong\u003e2. Consent for publication\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch4\u003e\u003cstrong\u003e3. Availability of data and materials\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003e4. Competing interests\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003e5. Funding\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003e6. Authors' contributions\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eSGK and LZK conceptualized the study. SGK collected and curated the data. GK and YS performed the statistical analysis and data interpretation. SGK drafted the manuscript. All authors critically reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003e7. Acknowledgements\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCowie MR, Fisher M. 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July 1, 2001;32(4):300-3.\u003c/li\u003e\n\u003cli\u003eCorrection to: 2024 ESC Guidelines for the management of elevated blood pressure and hypertension: Developed by the task force on the management of elevated blood pressure and hypertension of the European Society of Cardiology (ESC) and endorsed by the European Society of Endocrinology (ESE) and the European Stroke Organisation (ESO). European Heart Journal. April 7, 2025;46(14):1300.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ACE inhibitors, Combination therapy, Hyperkalemia, Hyponatremia, Magnesium, Serum electrolytes, SGLT2 inhibitors, Thiazide diuretics, Type 2 diabetes mellitus","lastPublishedDoi":"10.21203/rs.3.rs-6968533/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6968533/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003cbr\u003e\n\u003c/strong\u003eSodium-glucose co-transporter 2 inhibitors (SGLT2-i) are widely used in diabetic patients for their antihyperglycemic and cardioprotective effects. They are frequently co-administered with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and/or thiazide diuretics in clinical practice. However, the combined use of these agents may affect serum electrolyte balance. This study aimed to evaluate the changes in serum sodium, potassium, calcium, magnesium, and phosphorus levels associated with ACEi/ARB ± thiazide therapy and its combination with SGLT2 inhibitors in patients with type 2 diabetes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003cbr\u003e\n \u003c/strong\u003eThis retrospective cohort study included 494 adult patients with type 2 diabetes and preserved renal function (eGFR ≥60 mL/min/1.73 m²), who received SGLT2 inhibitors at a tertiary care center between January 2018 and December 2022. Patients were stratified into five groups based on their antihypertensive and antidiabetic medication combinations. Electrolyte levels were recorded before and six weeks after treatment initiation. Intragroup comparisons were performed using the Wilcoxon signed-rank test, and a p-value \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003cbr\u003e\n\u003c/strong\u003eSGLT2 inhibitor monotherapy was associated with a significant increase in serum sodium (p = 0.034) and magnesium (p = 0.004) levels. In the ACEi/ARB + SGLT2-i group, post-treatment magnesium (p = 0.001) and phosphorus (p = 0.003) levels were significantly elevated. The triple therapy group (ACEi/ARB + thiazide + SGLT2-i) also showed a significant rise in magnesium levels (p = 0.002). ACEi/ARB monotherapy led to an increase in potassium (p = 0.043) and phosphorus (p = 0.020) levels, whereas the addition of SGLT2-i mitigated the potassium rise. No significant changes in calcium levels were observed in most groups, except a mild increase with thiazide use alone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003cbr\u003e\n\u003c/strong\u003eThe use of SGLT2 inhibitors in combination with ACEi/ARB ± thiazide diuretics appears to be safe in terms of electrolyte balance and may even provide a stabilizing effect, particularly for serum potassium and magnesium levels. Further prospective studies are needed to confirm these findings and to explore their clinical implications in diabetic patients on multidrug regimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003cbr\u003e\n\u003c/strong\u003eNot applicable.\u003c/p\u003e","manuscriptTitle":"Effects of Combined SGLT2 Inhibitor and RAAS Blockade ± Thiazide Therapy on Serum Electrolyte Balance in Type 2 Diabetic Patients: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-01 17:17:41","doi":"10.21203/rs.3.rs-6968533/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"adaa082b-664c-485c-8bea-a1014ea78acb","owner":[],"postedDate":"July 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-03T10:38:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-01 17:17:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6968533","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6968533","identity":"rs-6968533","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}