Inverse association between glucose-lowering medications and severe hyponatremia: a Swedish population-based case-control study

Abstract

Context Glucose-lowering medications have occasionally been reported to cause hyponatremia, but the evidence is scarce. Objectives To explore the association between glucose-lowering medications and severe hyponatremia. Design, setting, and participants Subjects hospitalized with a principal diagnosis of hyponatremia (n = 14,359) were compared with matched controls (n = 57,383). Data were derived by linkage of national population-based registers. Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations, and socioeconomic factors was used to explore the association between hospitalization for hyponatremia and the use of different glucose-lowering medications. Furthermore, newly initiated (≤90 days) and ongoing use was investigated separately. Main outcome measures Hospitalization due to hyponatremia. Results The unadjusted ORs (95% CI) for hospitalization due to hyponatremia were 1.41 (1.29-1.54) for insulins, 1.38 (1.27-1.50) for metformin, and 1.22 (1.07-1.38) for sulfonylureas. However, after adjustment for confounding factors the association was consistently reversed. Thus, for any glucose-lowering medication the adjusted OR was 0.63 (0.58-0.68). For insulins, metformin and sulfonylureas, adjusted ORs (95% CI) were 0.58 (0.52-0.65), 0.81 (0.72-0.90) and 0.81 (0.69-0.94), respectively. Odds ratios for newly initated medications were overall higher while those for ongoing treatment were further decreased. Thus, adjusted ORs (95% CI) for ongoing treatment with insulins, metformin, and sulfonylureas were 0.54 (0.48-0.61), 0.82 (0.73-0.91) and 0.78 (0.66-0.92). Conclusions Glucose-lowering medications did not increase the risk for hospitalization due to severe hyponatremia. In fact, the association was inverse across all investigated drugs. The association may be mediated by pharmacologic mechanisms, but the uniform effects across drug-classes suggest properties of the diabetic disease are of importance.

Associations Between Antihypertensive Medications and Severe Hyponatremia: A Swedish Population–Based Case–Control Study

“…A validation study of the principal diagnosis of hyponatremia, with sodium levels corrected for glucose levels, was performed in one of the larger hospitals ( 11 ). The same cohort has been used in previous studies to analyze other aspects of hyponatremia ( 7 , 11-16 , 28 ).…”

Non‐thiazide diuretics and hospitalization due to hyponatraemia: A population‐based case‐control study

“…for other drugs, most notably lithium, but antidiabetics and lipidlowering agents have also been associated with a reduced risk of severe hyponatraemia, most likely through mechanisms promoting free water clearance, either through reduced sensitivity to ADH or by blunting the effect of ADH through other mechanisms. [25][26][27] It should be noted though that, when patients on treatment with loop diuretics develop hyponatraemia, the outcome is often poor. 28 The higher risk of hyponatraemia observed early on in treatment may reflect severe underlying disease, perhaps leading to non-osmotic release of AHD due to hypotension, or simply that furosemide-induced hyponatraemia develops rapidly in susceptible individuals.…”

Reduced risk for hospitalization due to hyponatraemia in lithium treated patients: A Swedish population-based case–control study

“…Interestingly, glucose-lowering medications also reduce the risk for hospitalization due to hyponatraemia ( Falhammar et al, 2020 ). Whether this is due to the glucose-lowering medications by themselves or the underlying diabetes disorders is not clear but the mechanism may involve osmotic diuresis caused by glucosuria counteracting the water retention associated with SIADH, not unlike the effects in nephrogenic diabetes insipidus secondary to lithium.…”