A double‐blind, randomized, placebo‐controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users

Soh, Jocelyn Fotso; Beaulieu, Serge; Trepiccione, Francesco; Linnaranta, Outi; Torres-Platas, Gabriela; Platt, Robert W.; Renaud, Suzane; Su, Chien Lin; Mucsi, István; D’Apolito, Luciano; Mulsant, Benoit H.; Levinson, Andrea; Saury, Sybille; Müller, Daniel J.; Schaffer, Ayal; Dols, Annemiek; Low, Nancy; Cervantes, Pablo; Christensen, Birgitte Mønster; Herrmann, Nathan; Rajji, Tarek K.; Rej, Soham

doi:10.1111/bdi.12973

Cited by 11 publications

(9 citation statements)

References 62 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, a preliminary cross‐sectional study of 71 Li users has suggested the use of atorvastatin in treatment of Li‐NDI patients; Elie et al, 2015 ). Recently, we showed, that atorvastatin for 12 weeks (using a relative low dose in order to minimize side effects) did not significantly improve urine osmolality in patients with partial NDI (UOsm < 600 mOsm/kg) and the data suggested potential greater utility of atorvastatin in patients with more severe NDI (UOsm < 300 mOsm/kg; Fotso et al, 2021 ).…”

Section: Discussionmentioning

confidence: 86%

“…Previously, a preliminary crosssectional study of 71 Li users has suggested the use of atorvastatin in treatment of Li-NDI patients; Elie et al, 2015). Recently, we showed, that atorvastatin for 12 weeks (using a relative low dose in order to minimize side effects) did not significantly improve urine osmolality in patients with partial NDI (UOsm < 600 mOsm/kg) and the data suggested potential greater utility of atorvastatin in patients with more severe NDI (UOsm < 300 mOsm/kg; Fotso et al, 2021). Since acute statin treatment, 1 h simvastatin treatment of LLC-AQP2 cells or BB rat slices as well as 6 h fluvastatin treatment of normal mice, have shown increased trafficking of AQP2 (Li et al, 2011;Procino et al, 2011), we tested the acute effects of statins in the mCCD c1l cell line.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Atorvastatin does not ameliorate nephrogenic diabetes insipidus induced by lithium or potassium depletion in mice

Thomsen

Grønkjær

Iervolino

et al. 2021

Physiological Reports

Self Cite

View full text Add to dashboard Cite

Acquired forms of nephrogenic diabetes insipidus (NDI) include lithium (Li)‐induced and hypokalemia‐induced NDI. Both forms are associated with AQP2 downregulation and collecting duct (CD) cellular remodeling. Statins are cholesterol‐lowering drugs appearing to increase AQP2 membrane‐translocation and improve urine concentration in other NDI models. We have investigated if statins are able to prevent or rescue the Li‐induced changes in mice and in a mouse cortical CD cell line (mCCDc1l). Biotinylation assays showed that acute (1hr) atorvastatin, simvastatin, or fluvastatin increased AQP2 membrane accumulation in mCCDc1l cells showing that the cell line responds to acute statin treatment. To see whether chronic statin treatment abolish the Li effects, mCCDc1l cells were treated with 48 h Li, combined Li/atorvastatin or combined Li/simvastatin. Li reduced AQP2, but combined Li/atorvastatin or Li/simvastatin did not prevent AQP2 downregulation. In mice, chronic (21 days) Li increased urine output and reduced urine osmolality, but combined Li/atorvastatin did not prevent these effects. In inner medulla (IM), Li reduced total AQP2 and increased pS261‐AQP2. Combined Li/atorvastatin did not abolish these changes. Atorvastatin did not prevent a Li‐induced increase in intercalated cells and proliferation in IM. In mice with already established NDI, atorvastatin had no effect on the Li‐induced changes either. Mice subjected to 14 days of potassium‐deficient diet developed polyuria and AQP2 downregulation in IM. Co‐treatment with atorvastatin did not prevent this. In conclusion, atorvastatin does not appear to be able to prevent or rescue Li‐NDI or to prevent hypokalemic‐induced NDI.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Atorvastatin does not ameliorate nephrogenic diabetes insipidus induced by lithium or potassium depletion in mice

Thomsen

Grønkjær

Iervolino

et al. 2021

Physiological Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…This secondary analysis will assess serum calcium, thyroid stimulating hormone (TSH), and low-density lipoproteins (LDL) that were previously collected in the original RCT. LDL was previously reported in the original RCT [ 27 ]. Established literature and medical guidelines were used to determine which values were considered within normal ranges for all blood and urine tests [ 29 – 31 ].…”

Section: Methodsmentioning

confidence: 99%

Atorvastatin lowers serum calcium levels in lithium-users: results from a randomized controlled trial

Soh

Bodenstein

et al. 2022

BMC Endocr Disord

Self Cite

View full text Add to dashboard Cite

Background Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects, including parathyroid hormone (PTH) dependent hypercalcemia. Aside from surgery and medication discontinuation, there are limited treatments for hypercalcemia. This paper will assess data from a randomized controlled trial (RCT). Methods This is a secondary analysis of an RCT that explored the effects of atorvastatin (n = 27) versus placebo (n = 33) on lithium-induced nephrogenic diabetes insipidus (NDI) in patients with BD and major depressive disorder (MDD) using lithium (n = 60), over a 12-week period. This secondary analysis will explore serum calcium levels and thyroid stimulating hormone (TSH) measured at baseline, week 4, and week 12. Results At 12-weeks follow-up while adjusting results for baseline, linear regression analyses found that corrected serum calcium levels were significantly lower in the treatment group (mean (M) = 2.30 mmol/L, standard deviation (SD) = 0.07) compared to the placebo group (M = 2.33 mmol/L, SD = 0.07) (β = − 0.03 (95% C.I.; − 0.0662, − 0.0035), p = 0.03) for lithium users. There were no significant changes in TSH. Conclusion In lithium users with relatively normal calcium levels, receiving atorvastatin was associated with a decrease in serum calcium levels. Although exciting, this is a preliminary finding that needs further investigation with hypercalcemic patients. Future RCTs could examine whether atorvastatin can treat PTH dependent hypercalcemia due to lithium and other causes.

show abstract

“…A number of agents are already in use for other indications, and ligands of G protein‐coupled receptor have been investigated as potential drugs for NDI therapy. Secretin with or without fluvastatin, simvastatin and aminoglycosides has been investigated in preclinical and clinical studies, although none of these to date has been able to demonstrate clinically meaningful results 166–168 . Atorvastatin was investigated in a double‐blind, randomised, placebo‐controlled trial in patients on lithium therapy, but, when used at a dose of 20 mg day −1 , did not improve urinary osmolality compared to placebo over a 12‐week period 168 .…”

Section: Treatmentmentioning

confidence: 99%

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP‐deficiency and resistance)

Angelousi

Alexandraki

Mytareli

et al. 2023

J Neuroendocrinology

View full text Add to dashboard Cite

Diabetes insipidus (DI) is a disorder characterised by the excretion of large amounts of hypotonic urine, with a prevalence of 1 per 25,000 population. Central DI (CDI), better now referred to as arginine vasopressin (AVP)‐deficiency, is the most common form of DI resulting from deficiency of the hormone AVP from the pituitary. The less common nephrogenic DI (NDI) or AVP‐resistance develops secondary to AVP resistance in the kidneys. The majority of causes of DI are acquired, with CDI developing when more than 80% of AVP‐secreting neurons are damaged. Inherited/familial CDI causes account for approximately 1% of cases. Although the pathogenesis of NDI is unclear, more than 280 disease‐causing mutations affecting the AVP2 protein or AVP V2 receptor, as well as in aquaporin 2 (AQP2), have been described. Although the cAMP/protein kinase A pathway remains the major regulatory pathway of AVP/AQP2 action, in vitro data have also revealed additional cAMP independent pathways of NDI pathogenesis. Diagnosing partial forms of DI, and distinguishing them from primary polydipsia, can be challenging, previously necessitating the use of the water deprivation test. However, measurements of circulating copeptin levels, especially after stimulation, are increasingly replacing the classical tests in clinical practice because of their ease of use and high sensitivity and specificity. The treatment of CDI relies on desmopressin administration, whereas NDI requires the management of any underlying diseases, removal of offending drugs and, in some cases, administration of diuretics. A better understanding of the pathophysiology of DI has led to novel evolving therapeutic agents that are under clinical trial.

show abstract

A double‐blind, randomized, placebo‐controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users

Cited by 11 publications

References 62 publications

Atorvastatin does not ameliorate nephrogenic diabetes insipidus induced by lithium or potassium depletion in mice

Atorvastatin does not ameliorate nephrogenic diabetes insipidus induced by lithium or potassium depletion in mice

Atorvastatin lowers serum calcium levels in lithium-users: results from a randomized controlled trial

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP‐deficiency and resistance)

Contact Info

Product

Resources

About