Trikafta is a novel combined CFTR modulator and potentiator. Enhancing the quantity of correctly processed CFTR proteins and increasing their open-probability once integrated in the cell membrane, this medication has recently improved lung function in CF-patients by increasing the conductance of chloride across the epithelial cells.1 Whereas the primary target is improvement of epithelial lung cell function, the modulator therapy additionally influences the CFTR dependent function in other organs i.e., the pancreas.
CFTR channels are present in pancreatic islet cells. Animal and human studies show that CFTR deficiency leads to islet-intrinsic defects in insulin secretion. Kayani et al give an excellent overview of the role of the CFTR in insulin secretion focusing on the first-phase insulin response, which is depolarization-dependent and therefore possibly related to the CFTR function, whereas the second phase release is not.2 In addition to insulin secretion, CFTR presumably regulates glucagon release from the pancreatic alpha cell. Glucagon secretion was enhanced in response to glucose and forskolin following CFTR inhibition in human islets. The exact impact of CFTR in pancreatic cells remain conflicting and further studies are needed. 3
Therefore, CF related diabetes (CFRD) could partially be explained by a reduction in early-phase insulin secretion, which is considered the initial marker of impaired insulin secretion.3
Hence, some effect on glucose homeostasis is expected from the treatment with CFTR modulators. Hypoglycemic events have been described with the administration of Ivacaftor in patients with a CFRD resulting in reduced insulin-requirements. Ivacaftor also improved the early phase insulin secretion in a relatively young CFpatient group with normal to mildly impaired glucose tolerance comparable to our patient. The extent to which this arises from b-cell-specific effects remains unclear; since CFTR protein expression has been identified also in pancreatic alpha-cells, Ivacaftor and with it Trikafta may have effect on both cell functions. 4; 5
The American FDA (Food and Drug Administration) reports a prevalence of 1% of hypoglycemic events with Trikafta as compared to placebo. The WHOpharmacovigilance database (www.vigylize.who-umc.org) has listed nine cases of hypoglycemia since 2019. According to the criteria of the Institute of Clinical
Pharmacology and Toxicology of the University Hospital of Zurich, a correlation of the hypoglycemic event and administration of Trikafta is possible, given the timely connection.
Our patient reported a sudden change of eating habits with the start of Trikafta, with larger meals and a weight-gain of 5kg in two weeks, which lead us to assume a change in glucose homeostasis. The aforementioned mechanisms in CFRD and documented reduction in early phase insulin secretion even in patients without CFRD, let us speculate on a prediabetic state in our patient. We suggested that the improved insulin secretion from beta cells after the start of Trikafta cumulating with the second phase release and simultaneously impaired glucagon release from alpha cells led to the hypoglycemic event. Christian et all. published a case with postprandial hypoglycemic events during the treatment with Ivacaftor hypothesizing a potentiation of the insulin-effect after meals.4 An additional potential risk factor is the changed eating habit in our patient with the possibility of faster gastric emptying and reduced insulin secretion 3; 5
While limitations lie in the thoroughly evaluation of hypoglycemia (C-peptide, Insulin, fasting-glucose-test), medication-induced hypoglycemia was the most possible solution. Knowing that a glucose of 3mmol/l doesn’t typically lead to general seizures we supposed a lower value during at the initiation, with counter-regulatory mechanisms already working until the first measurement, which we can’t prove
