Discussion
In this brief report, we provide evidence based on an analysis of real-world registry data in support of a potential effect of GLP-1 RA treatment on ferritin levels in people with T2D. Ferritin is a recognized surrogate of systemic iron levels, which is increased in HH to an extent that may cause organ damage, including to the pancreas and liver, resulting in or exacerbating diabetes. Further, our analyses show a trend towards a less frequent need of invasive phlebotomy—the current mainstay treatment of the disease—in people with T2D treated with GLP-1 RAs. Of note, ferritin levels appeared to increase towards the end of the 5-year observation period, likely reflecting the chronic and progressive nature of HH and the inability of available treatments to fully suppress the iron accumulations in the longer run. Consequently, even though a favorable effect of GLP-1 RA was identified, the present results underline that the drug class is not a curative intervention in HH. Further, this aspect also highlights the need for early invention to attenuate the rate of iron accumulation as soon as possible.
In the absence of curative interventions to correct the genetically determined abnormal iron absorption and considering the inadequacies of invasive and healthcare recourse intensive phlebotomy, an unmet medical need exists for interventions that address the consequences of the excess iron levels in HH. Furthermore, early intervention is key to avoid development of diabetes mellitus (ie, secondary diabetes), notably diabetes resembling late-onset T1D due to loss of functional pancreatic β-cell mass. While HH is traditionally regarded as a rare disease, genotyping studies have suggested a more common prevalence, supported by the observation that less than 10% with HH-related gene mutations develop clinically manifest disease. This underscores the need to identify susceptible individuals via targeted screening programs and to develop non-invasive and efficacious interventions to avoid the morbidity and premature mortality associated with HH. This is especially relevant for people with both HH and diabetes, who often present with related conditions such as cardiovascular disease and obesity. For such individuals, agents that simultaneously address excess iron levels as well as poor glycemic control and increased cardiovascular risk and body weight are clearly desirable.
GLP-1 RAs are widely used agents that improve glycemic control and, for some of the members of the drug class, reduce cardiovascular risk in people with T2D.9 10 Certain GLP-1 RAs are also licensed to reduce body weight. On this background, GLP-1 RAs may be valuable in the management of HH and comorbid diabetes. To our knowledge, SGLT-2 inhibitors - another widely used pharmacotherapeutic option in T2D – do not have a known effect on ferritin levels or phlebotomy frequency. Of note, treatment with SGLT-2 inhibitors has been shown to result in increased hematocrit values as the result of decreased blood volume and/or increased renal production of erythropoietin11 ; accordingly, use of this drug class in people HH may not be advisable.
The generalizability of our analyses is limited by the sparseness of the available data, especially on phlebotomies. Accordingly, the results of the present analyses are viewed as hypothesis-generating. Further, while we selected for T2D diagnoses only, misclassification of diabetes diagnoses across T1D and T2D and potentially ‘secondary diabetes’ may have been present in the databases used in this register-based study. However, the impact of this potential issue on the results of the analyses is considered minor. In this context, it should be noted that with the exception of dapagliflozin between early 2019 and late 2021, SGLT-2 inhibitors are not licensed in T1D in Denmark. Further, because this information was not available in the dataset, we did not account for use of other HH-specific interventions including the use of iron chelators in people, for whom phlebotomy may have been contraindicated; to our knowledge, however, the use of such drugs in HH is very rare in Denmark and countries such the UK. Further, because data extracted from the DRMPS are by definition data on filled prescriptions and not on actual use, the estimates may have been biased by the possibility that some individuals may have claimed a prescription but not actually taken the drug.
Future follow-on studies should preferably include data from more than one country to further extend the generalizability across regions and ethnicities as well as a broader range of drug prescription patterns. Other aspects that warrant further elucidation in new studies include the identification of the potentially most clinically useful GLP-1 RA in HH; this aspect could not be investigated based on the sparse data available in the present study. Finally, while the available information did not allow us to study these aspects in the present study, any potential effect modification of or mediation through the known marked effects of GLP-1 RAs and SGLT-2 inhibitors on glycemic control and body weight are also relevant to investigate in future studies. A previous report has suggested an association between high body mass index and hyperferritinaemia.12
Overall, the results of our analyses are in line with the early evidence that have indicated that GLP-1 RAs may have a ferritin-lowering effect.6 7 Of note, a case report has suggested that GLP-1 RA treatment in people with HH (and cystic fibrosis) is associated with an increased risk of acute pancreatitis.13 While this association has not been further substantiated, awareness of this aspect should be considered in the benefit/risk evaluation of GLP-1 RA treatment in HH.
In summary, the results of the present analyses support the hypothesis of a beneficial effect of GLP-1 RA treatment in HH. To further qualify and investigate the hypothesis, additional larger and more diverse studies are needed, for example, to explore the mechanisms driving the potential benefit of GLP-1 RAs on excess iron levels in people with HH and T2D.