European Journal of Cardiovascular Medicine

Hypertension is being one of the most common chronic diseases affecting large percentage of subjects globally including in India. In these subjects, thiazide diuretics are prescribed commonly either as drug alone or combined with other antihypertensive drugs. Thiazide diuretics are usually well-tolerated and effective drugs, they might cause various adverse drug reactions such as impaired renal functions, metabolic disorders, and electrolyte disturbances. These can lead to syncope and fall particularly in subjects having comorbidities and advanced age.¹

The most probable associated mechanism for increased risk has been attributed to various electrolyte disturbances including AKI (acute kidney injury), metabolic alkalosis, hypercalcemia, hypokalaemia, and hyponatremia. There are various studies in the literature that establish the link between risk of syncope and fall related to thiazide diuretics use in general population and particularly in the elder subjects.²

The existing literature data display limited evidence in addressing the association in hypertensive subjects particularly the subjects that usually have unique clinical profiles and can be particularly vulnerable to the adverse events of using thiazide diuretics considering their potential concomitant use of other medications and the underlying conditions.³

The knowledge of accurate relationship in risk of falls and syncope and thiazide diuretics use will help in forming the clinical decision concerning how to decrease the adverse events in these subjects. Identification of the population and risk factors for vulnerable subjects can help healthcare providers focus on a closer follow-up, individualized prophylactic measures, and alterative treatment for better quality of care and patient safety.⁴ The present study was aimed to assess the relation between the use of thiazide diuretics and occurrence of syncope and fall in subjects with hypertension. The study also assessed if clinical factors, impaired renal function, and electrolyte disturbances can modulate the risk of syncope and fall in these subjects.

The present retrospective study was aimed to assess the relation between the use of thiazide diuretics and occurrence of syncope and fall in subjects with hypertension. The study also assessed if clinical factors, impaired renal function, and electrolyte disturbances can modulate the risk of syncope and fall in these subjects. The study was done at Department of General Medicine, Chandulal Chandrakar Memorial Government Medical College, Durg, Chhattisgarh in the period of January 2023 to January 2025. The study subjects were from Department of Medicine of the Institute. Verbal and written informed consent were taken from all the subjects and school authorities before study participation.

The present study assessed 472 subjects that presented with hypertension to the Institute within the defined study period and were on thiazides and 472 control subjects that were not on thiazides. The inclusion criteria for the study were subjects aged 18 years or above and had thiazide diuretic prescription for management of hypertension. The subjects were identified from the previous medical data and records of the Institute. The exclusion criteria for the study were subjects with incomplete medical data and records and that were lost to follow-up.

All the data were gathered by the trained professionals from the electronic medical record system of the Institute. The data gathered included age, gender, thiazide use duration used most commonly as 12.5mg daily dose, concomitant medication use such as angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), beta-blockers, and calcium channel blockers, body mass index (BMI), duration of comorbidities, and range of thiazide doses (12.5mg to 100mg/ day).

The laboratory data assessed in the study subjects included presence of electrolyte disturbances (hyponatremia, hypokalaemia, hypercalcemia, and metabolic alkalosis), estimated glomerular filtration rate [eGFR]), creatinine levels, and serum electrolyte levels (sodium, potassium, and calcium). Reference equation was used for derivation of eGFR (estimated glomerular filtration rate).⁵ The primary outcome assessed was occurrence of syncope or fall events during the study were occurrence of syncope and fall events during the study as assessed from the previous institutional data.

For Hyponatremia it was defined as serum sodium concentration being 10.2 mg/dl. Acute kidney injury (AKI) and chronic kidney disease (CKD) were defined according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Metabolic alkalosis was defined as a serum bicarbonate level >28 mmol/l.^6,7,8

Collected data were subjected to statistical evaluation using the chi-square test, Fisher’s exact test, Mann Whitney U test, and SPSS (Statistical Package for the Social Sciences) software version 24.0 (IBM Corp., Armonk. NY, USA) using ANOVA, chi-square test, and student's t-test. The significance level was considered at a p-value of <0.05.

The present retrospective study was aimed to assess the relation between the use of thiazide diuretics and occurrence of syncope and fall in subjects with hypertension. The study also assessed if clinical factors, impaired renal function, and electrolyte disturbances can modulate the risk of syncope and fall in these subjects. The mean age of the study subjects in thiazide and non-thiazide groups was statistically non-significant with p=0.544. Similar non-significant difference was seen for gender, mean hypertension duration, mean BMI, congestive heart failure, and diabetes mellitus duration with p-value of 1, 0.166, 0.634, 0.206, 0.672, and 0.334 respectively. For other medications used, non-significant difference was seen for use of calcium channel blockers, beta blockers, and ACE inhibitors with p=0.544, 0.624, and 0.572 respectively. Significantly higher congestive heart failure duration and events of falls and syncope were seen in subjects on thiazides with p-value of 0.04 and 0.002 respectively (Table 1).    

Table 1: Clinical and demographic characteristics in two groups of study subjects

Table 2: Severity and prevalence of electrolyte disturbance in study subjects on thiazide diuretics

Table 3: Assessment of risk factors linked with syncope/fall events in subjects with hypertension

Table 4: Association in risk of syncope/fall events and thiazide use duration

It was seen that for severity and prevalence of electrolyte disturbance in study subjects on thiazide diuretics, metabolic alkalosis and hypercalcemia was significantly higher in subjects on thiazides with p<0.001 and 0.006 respectively. Mild hypokalaemia was signifcantly higher in subjects on thiazides with p=0.02 and was modearte and severe hypokalaemia was comaprable in subjects on and not on thiazides with p=0.81 and 0.2 respectively. Also, hyponatremia was significantly higher in subjects on thiazides with p=0.04 (Table 2).

The study results showed that for assessment of risk factors linked with syncope/fall events in subjects with hypertension, there were 13.9% (n=50) subjects with syncope/fall events from age <65 and 33.2% (n=194) events from >65 years. In subjects with AKI, syncope/fall events were reported in 38.2% (n=68) subjects. In subjects with metabolic alkalosis, syncope/fall events were seen in 33.3% (n=94) subjects, In subjects with hypokalaemia, syncope/fall events were reported in 40.9% (n=60) subejcts, in subjects with hyponatremia in 35.7% (n=72) subjects, and in subjects with congestive heart failure in 37.9% (n=88) study subjects respectively (Table 3).

 On assessing the association in risk of syncope/fall events and thiazide use duration, syncope/fall events were seen in 32.2% (n=152) subejects on thiaxides, for thiazide use duration, syncope/fall events were seen in 19.5% (n=92/472), 27.5% (n=44/160), 33.3% (n=52/156), and 35.9%  (n=56/156) subjects with duration as no use, <12 months, 12-24 months, and >24 months respectively (Table 4).

The present study assessed 472 subjects that presented with hypertension to the Institute within the defined study period and were on thiazides and 472 control subjects that were not on thiazides. The mean age of the study subjects in thiazide and non-thiazide groups was statistically non-significant with p=0.544. Similar non-significant difference was seen for gender, mean hypertension duration, mean BMI, congestive heart failure, and diabetes mellitus duration with p-value of 1, 0.166, 0.634, 0.206, 0.672, and 0.334 respectively. For other medications used, non-significant difference was seen for use of calcium channel blockers, beta blockers, and ACE inhibitors with p=0.544, 0.624, and 0.572 respectively. Significantly higher congestive heart failure duration and events of falls and syncope were seen in subjects on thiazides with p-value of 0.04 and 0.002 respectively. These data were comparable to the previous studies of Charkos TG et al⁹ in 2019 and Abubakar AA et al¹⁰ in 2021 where authors assessed subjects with demographics and disease data comparable to the present study in their respective studies.

The study results showed that for severity and prevalence of electrolyte disturbance in study subjects on thiazide diuretics, metabolic alkalosis and hypercalcemia was significantly higher in subjects on thiazides with p<0.001 and 0.006 respectively. Mild hypokalaemia was signifcantly higher in subjects on thiazides with p=0.02 and was modearte and severe hypokalaemia was comaprable in subjects on and not on thiazides with p=0.81 and 0.2 respectively. Also, hyponatremia was significantly higher in subjects on thiazides with p=0.04. These results were consistent with the findings of Bai X et al¹¹ in 2023 and Ostermann ME et al¹² in 2003 where severity and prevalence of electrolyte disturbance in study subjects on thiazide diuretics reported by the authors in their studies was comparable to the results of the present study.

It was seen that for assessment of risk factors linked with syncope/fall events in subjects with hypertension, there were 13.9% (n=50) subjects with syncope/fall events from age <65 and 33.2% (n=194) events from >65 years. In subjects with AKI, syncope/fall events were reported in 38.2% (n=68) subjects. In subjects with metabolic alkalosis, syncope/fall events were seen in 33.3% (n=94) subjects, In subjects with hypokalaemia, syncope/fall events were reported in 40.9% (n=60) subejcts, in subjects with hyponatremia in 35.7% (n=72) subjects, and in subjects with congestive heart failure in 37.9% (n=88) study subjects respectively. These findings were in agreement with the results of Moranne O et al¹³ in 2009 and Kuo SCH et al¹⁴ in 2017 where results for assessment of risk factors linked with syncope/fall events in subjects with hypertension simialr to the presnet study was also reported by the authors in their studies.

 The study results also showed that on assessing the association in risk of syncope/fall events and thiazide use duration, syncope/fall events were seen in 32.2% (n=152) subejects on thiaxides, for thiazide use duration, syncope/fall events were seen in 19.5% (n=92/472), 27.5% (n=44/160), 33.3% (n=52/156), and 35.9%  (n=56/156) subjects with duration as no use, <12 months, 12-24 months, and >24 months respectively. These results correlated with the findings of Arampatzis S et al¹⁵ in 2013 and Burst V et al¹⁶ in 2017 where association in risk of syncope/fall events and thiazide use duration reported by the authors in their studies was comparable to the results of the present stduy.

Within its limitations, the present study concludes that use of thiazide diuretics in subjects with hypertension is associated with the syncope which is mainly mediated with renal impairment and electrolyte disturbances. These results focus on vital role of individualized treatment and careful monitoring approaches for prescription of thiazide diuretics in subjects having hypertension.

1. Akbari P, Khorasani-Zadeh A. Thiazide Diuretics. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025.
2. Berry SD, Zhu Y, Choi H, Kiel DP, Zhang Y. Diuretic initiation and the acute risk of hip fracture. Osteoporos Int 2013;24:689-95
3. Ostchega Y, Fryar CD, Nwankwo T, Nguyen DT. Hypertension prevalence among adults aged 18 and over: United States, 2017-2018. NCHS Data Brief. 2020;364:1-8.
4. Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988;319:1701-7.
5. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12.
6. Sadiq NM, Anastasopoulou C, Patel G, Badireddy M. Hypercalcemia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024.
7. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group.KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2024;105:S117-S314.
8. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120:c179-84.
9. Charkos TG, Liu Y, Jin L, Yang S. Thiazide use and fracture risk: An updated Bayesian meta-analysis. Sci Rep 2019;9:19754.
10. Abu Bakar AA, Abdul Kadir A, Idris NS, Mohd Nawi SN. Older adults with hypertension: Prevalence of falls and their associated factors. Int J Environ Res Public Health 2021;18:8257.
11. Bai X, Han B, Zhang M, Liu J, Cui Y, Jiang H. The association between diuretics and falls in older adults: A systematic review and meta-analysis. Geriatr Nurs 2023;52 :106-114.
12. Ostermann ME, Girgis-Hanna Y, Nelson SR, Eastwood JB. Metabolic alkalosis in patients with renal failure. Nephrol Dial Transplant 2003;18:2442-8.
13. Moranne O, Froissart M, Rossert J, Gauci C, Boffa JJ, Haymann JP, et al. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol 2009;20:164-71.
14. Kuo SCH, Kuo PJ, Rau CS, Wu SC, Hsu SY, Hsieh CH. Hyponatremia is associated with worse outcomes from fall injuries in the elderly. Int J Environ Res Public Health 2017;14:460.
15. Arampatzis S, Funk GC, Leichtle AB, Fiedler GM, Schwarz C, Zimmermann H, et al. Impact of diuretic therapy-associated electrolyte disorders present on admission to the emergency department: A cross-sectional analysis. BMC Med 2013;11:83.
16. Burst V, Grundmann F, Kubacki T, Greenberg A, Becker I, Rudolf D, et al. Thiazide-associated hyponatremia, report of the hyponatremia registry: An observational multicenter international study. Am J Nephrol 2017;45:420-30.