SGLT2 INHIBITORS IN ADTKD
Initial data from an observational study ambivalent
3/29/2022 - SGLT-2 (sodium
dependent
glucose
transporter) inhibitors are agents originally used to treat type 2 diabetes mellitus. Several studies have shown that they
can slow the progression of chronic renal failure (CKD), even in patients who do not have diabetes. In Europe,
dapagliflozin has been approved for the treatment of patients with CKD since 2021.
Because autosomal dominant tubulointerstitial kidney disease (ADTKD) is very rare and often not correctly diagnosed, it is unlikely that patients with this condition participated in the studies. In addition, the proportion of patients with an unclear diagnosis was very low. However, in order to collect data in ADTKD patients, a small prospective cohort observational study is being conducted in the United States. Preliminary results were presented at the American Society of Nephrology (ASN) Kidney Week.
To assess the effect of SGLT2 inhibitors, data on estimated glomerular filtration rate (eGFR) and KIM-1 were collected before as well as during therapy. KIM-1 (Kidney Injury Molecule-1) is a biomarker indicating tubule damage. These renal tubules are the site of disease in ADTKD patients. Values were assessed before starting treatment, at one week, one month, and 4 months after starting SGLT2 inhibitor administration.
eGFR decreased as expected
In total, data were available from
12 ADTKD patients. Of these, 10 received empagliflozin (not yet approved in Europe) and two dapagliflozin. In patients with baseline eGFR >30 ml/min, mean eGFR increased by 3 ml/min after 1 month. After four months, eGFR was 3 ml/min lower than baseline (-8.5%). With eGFR >30 before initiation of therapy, the decrease in eGFR from baseline was 12% at 1 month and 8% at 4 months. The decrease in eGFR is desirable because it effectively "spares" the kidney in the long term.
Increase of the damage marker KIM-1
The KIM-1 level in blood was unchanged but increased by 100% in urine. This is in contrast to the large studies in which SGLT2 inhibitors were tested: There, the KIM-1 level decreased in the patients. In the observational study, one patient discontinued empagliflozin at his own request after 8 weeks because his eGFR had decreased by 14% from baseline. In two patients who had been treated for 6 months, eGFR was stable. The medications were well tolerated.
What do the results mean?
This is an observational study with very few patients. A decrease in eGFR with treatment with SGLT2 inhibitors was expected and is consistent with the pivotal studies. The increase in urinary KIM-1 is an adverse event. Exactly what this effect means is currently unclear. An update with a follow-up of four months is planned.
Source
Literature
Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease . N Engl J Med. 2020 Oct 8;383(15):1436-1446
https://pubmed.ncbi.nlm.nih.gov/32970396
Press release Lilly from March 16, 2022;
https://investor.lilly.com/news-releases/news-release-details/jardiancer-phase-iii-empa-kidney-trial-will-stop-early-due-clear
(accessed on March 29, 2022)
Dekkers CCJ, et al. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab. 2018 Aug;20(8):1988-1993
https://pubmed.ncbi.nlm.nih.gov/29573529