From drugs to climate : associations between external factors and profound hyponatremia

<p dir="ltr"><b>Background:</b></p><p dir="ltr">Hyponatremia is the most common electrolyte disturbance and associated with substantial morbidity and mortality. Despite its clinical relevance, many aspects of hyponatremia's epidemiology, including pharmacological and environmental influences remain challenging for clinicians. This doctoral thesis addresses key knowledge gaps using population-based register data to investigate drug- induced hyponatremia, climate-related risk factors, and the value of an integrated cohort with sodium concentrations in focus.</p><p dir="ltr"><b>Aims:</b></p><p dir="ltr">The overarching goal of this thesis is to improve understanding of hyponatremia by examining its pharmacological and environmental determinants. Specifically, the aims were to:</p><p dir="ltr">1- Investigate the time-dependent risk of hyponatremia associated with proton pump inhibitors (PPIs).</p><p dir="ltr">2- Establish and describe the Stockholm Sodium Cohort (SSC), a population- based database for sodium research.</p><p dir="ltr">3- Assess the association between outdoor temperature and severe hyponatremia.</p><p dir="ltr">4- Evaluate the risk of profound hyponatremia linked to selective serotonin reuptake inhibitors (SSRIs) and venlafaxine.</p><p dir="ltr"><b>Methods:</b></p><p dir="ltr">All studies used population-based registers. Study 1 obtained data from the National Patient Register on hospitalized patients due to hyponatremia between 2006 and 2014. Studies 2-4 utilized the SSC, a cohort of 1.6 million residents of Stockholm County with at least one recorded serum sodium measurement between 2005 and 2018. Individual-level sodium test results were linked to national registers covering demographics, socioeconomic status, diagnoses, health care contacts, and dispensed medications. Study 1 used a case-control design with over 56,000 individuals to analyze the time-course of hyponatremia after omeprazole/esomeprazole initiation. Study 2 describes the creation and representativeness of the SSC. Study 3 was a retrospective cohort analysis assessing temperature-hyponatremia links using daily temperature data matched to residential area. Study 4 applied a within-individual design including 234,217 new users of SSRIs/venlafaxine to analyze the temporal risk of profound hyponatremia.</p><p dir="ltr"><b>Results:</b></p><p dir="ltr">In Study 1, the adjusted odds ratio (aOR) for hospitalization due to hyponatremia was highest within the first week of PPI treatment (aOR 6.87), declining gradually over five weeks. Ongoing use was associated with a modest risk (aOR 1.10). Study 2 showed that the SSC covered 64% of the regional population and over 90% of patients with major chronic diseases, demonstrating its strong representativeness for clinical and pharmacoepidemiologic research. In Study 3, 51,143 episodes of severe hyponatremia (serum sodium <125 mmol/L) were identified. Risk increased steadily with temperature, with a sharp rise above 20°C, particularly affecting older adults and women. Projections to 2050 estimated a 66-73% increase in cases with 1-2℃ temperature rises, mostly due to demographic changes. Study 4 found a pronounced early risk of profound hyponatremia following SSRI/venlafaxine initiation, peaking in the first two weeks (aOR 10.06) and declining thereafter. Elderly women had the highest incidence, with up to 1 in 15 affected.</p><p dir="ltr"><b>Conclusion:</b></p><p dir="ltr">This thesis demonstrates that hyponatremia is strongly associated with both pharmacologic exposures and environmental factors. The findings emphasize that PPIs and serotonergic antidepressants pose the greatest risk shortly after initiation, supporting early and targeted sodium monitoring in high-risk populations, particularly elderly women. Moreover, outdoor temperature is an important factor in severe hyponatremia risk, which is projected to rise substantially with future climate warming. The establishment of the SSC provides a robust and generalizable platform for studying sodium-related conditions on a population level. Together, these studies provide new, clinically actionable insights that may inform drug safety monitoring, geriatric care, and public health responses to climate change.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Issa I,</b> Skov J, Falhammar H, Calissendorff J, Lindh JD, Mannheimer B. Time- dependent association between omeprazole and esomeprazole and hospitalization due to hyponatremia. Eur J Clin Pharmacol. 2023 Jan;79(1):71-77. <a href="https://doi.org/10.1007/s00228-022-03423-x">https://doi.org/10.1007/s00228-022-03423-x</a></p><p dir="ltr">II. <b>Issa I,</b> Skov J, Falhammar H, Franko MA, Lindh JD, Mannheimer B. Establishment and representativeness of the Stockholm Sodium Cohort: A laboratorial and pharmacoepidemiologic database covering 1.6 million individuals in the Stockholm County. Ann Epidemiol. 2024 Mar;91:1-7. <a href="https://doi.org/10.1016/j.annepidem.2024.01.005">https://doi.org/10.1016/j.annepidem.2024.01.005</a></p><p dir="ltr">III. <b>Issa I,</b> Skov J, Falhammar H, Lindh JD, Mannheimer B. The Association of Outdoor Temperature with Severe Hyponatremia. J Am Soc Nephrol. 2025 Mar 1;36(3):435-440. doi: 10.1681/ASN.0000000519.<br><a href="https://doi.org/10.1681/ASN.0000000519">https://doi.org/10.1681/ASN.0000000519</a></p><p dir="ltr"><br></p><p dir="ltr">IV. <b>Issa I,</b> Skov J, Falhammar H, Roos M, Lindh JD, Mannheimer B. The association of selective serotonin reuptake inhibitors and venlafaxine with profound hyponatremia. Eur J Endocrinol. 2025 Jun 30;193(1):179-187. <a href="https://doi.org/10.1093/ejendo/lvaf140">https://doi.org/10.1093/ejendo/lvaf140</a><br></p>