Effect of dapaglifozin on serum magnesium in HNF1β patients with renal hypomagnesemia

Renal hypomagnesemia is caused by different inherited and acquired renal
tubular disorders. One of these hereditary tubular defects leading to renal
magnesium wasting is autosomal dominant tubulointerstitial kidney disease
(ADTKD) subtype HNF1β. Patients with ADTKD-HNF1β can also suffer from diabetes
mellitus (MODY5). Up till now, treatment of this renal hypomagnesemia only
consists of magnesium supplementation, which is limited by the gastrointestinal
side effects. Therefore, this treatment is often insufficient and an optimal
treatment regimen for these patients is still lacking.
Sodium-glucose co-transporter type 2 (SGLT2) inhibitors are a relatively new
type of glucose-lowering agents for patients with type 2 diabetes mellitus.
SGLT2 inhibitors are also increasingly prescribed in patients with heart
failure and chronic kidney disease, with and without diabetes mellitus, with
beneficial effects on cardiovascular and renal outcomes. Furthermore, post hoc
analyses of the large SGLT2 inhibitor trials in diabetes have demonstrated that
treatment with SGLT2 inhibitors moderately increases serum magnesium. Recently,
a case series reported three patients with diabetes and renal magnesium wasting
(two patients had a genetically proven ADTKD-HNF1β) that were treated with
SGLT2 inhibitors and had an even larger and clinically highly relevant increase
in serum magnesium.
Since SGLT2 inhibitors have been demonstrated to increase serum magnesium and
are also increasingly prescribed in non-diabetic patients without safety
issues, these agents might be a novel treatment strategy for patients suffering
from renal magnesium wasting. We hypothesize that SGLT2 inhibition leads to a
clinically relevant increase of serum magnesium in diabetic and non-diabetic
ADTKD-HNF1β patients with renal hypomagnesemia.

This study has been transitioned to CTIS with ID 2024-518855-43-00 check the CTIS register for the current data.

Primary objective:
To evaluate the effect of SGLT2 inhibition with dapagliflozin 10 mg on serum
magnesium in diabetic and non-diabetic ADTKD-HNF1β patients with renal
hypomagnesemia.

Secondary objectives:
- To evaluate the effect of SGLT2 inhibition with dapagliflozin 10 mg on renal
fractional magnesium excretion in diabetic and non-diabetic ADTKD-HNF1β
patients with renal hypomagnesemia.

- To evaluate the effect of SGLT2 inhibition with dapagliflozin 10 mg on
symptoms in diabetic and non-diabetic ADTKD-HNF1β patients with renal
hypomagnesemia.

Multicenter, crossover, placebo-controlled, randomized, double-blinded trial.
The study will take place at three hospitals in the Netherlands, namely at
Radboudumc (Nijmegen), Erasmus MC (Rotterdam), and Amsterdam UMC (Amsterdam).

Dapagliflozin 10 mg or placebo tablet, one tablet per day. Participants will
receive dapagliflozin during one period and placebo during the other period.

The study comprises 4 study visits which include measurement of weight and
blood pressure, blood sampling, 24-hour urine collection, 2-hour spot urine
collection, and filling out a personalized symptom questionnaire. Furthermore,
participants have to make two additional visits to the hospital for blood
sampling and a 2-hour spot urine collection. At this timepoint, the
investigator will also contact the participant by phone. Participants will have
to take study medication for 8 weeks (2x 4 weeks), 1 tablet per day. The risks
of treatment with dapagliflozin are considered to be minimal. Dapagliflozin is
a registered drug in the treatment of patients with diabetes mellitus, heart
failure and, chronic kidney disease. Therefore, a part of the participants will
already have a registered indication for treatment with dapagliflozin. The most
important side effects of dapagliflozin are urinary tract infections, genital
infections, back pain and polyuria. Due to the crossover design, all patients
will be offered the interventional treatment with dapagliflozin, which means
that all patients might benefit from the intervention. Based on the effect on
serum magnesium described in recently published literature, we expect patients
to benefit from the intervention. We expect that the chance of developing
serious side effects outweighs the expected benefit for the participants.