Use of metformin in patients with sickle cell disease
Authors: Jin Han, Santosh L. Saraf, Robert E. Molokie, Victor R. Gordeuk
Journal: American Journal of Hematology (2018)

Hydroxyurea (HU) is the first FDA-approved medication to treat sickle cell disease (SCD) that increases the fetal hemoglobin (HbF) level in red blood cells and decreases complications such as vaso-occlusive crisis (VOC).1 A recent study demonstrated that metformin induces HbF production via a FOXO3-dependent mechanism in human primary erythroid cells,2 implying that metformin may be a potential agent to manage SCD. Despite the promising results, there is no in vivo data showing the benefit or safety of metformin in patients with SCD. In this report, we found that metformin was safely used in 18 patients with SCD, but had minimal effect on HbF in nonHb SS/Sβ0 patients. Some HbF induction was observed in Hb SS/Sβ0 patients, particularly in those already on HU. This report provides the first preliminary evidence for using metformin in SCD patients, and indicates a need for a prospective study of metformin in SCD. Using a pharmacy prescription reporting system, we identified a cohort of 18 SCD patients who were treated with metformin at the University of Illinois at Chicago Hospital (UIC) from 1/2000 to 12/2017. The HbF levels, metformin doses, use of HU, and other clinical variables were collected through a retrospective chart review. The studied patients did not receive blood transfusions within the previous 3 months when HbF was measured. Descriptive analysis and Wilcoxon signed-rank test were used to analyze the data. The study was approved by the Institutional Review Board. In total 3 of 18 patients were males (17%) with genotypes of Hb SS/Sβ0 (6/18, 33%), Hb SC (9/18, 50%), and Hb Sβ+ (3/18, 17%). Metformin was used to treat T2DM in 17 patients and polycystic ovarian syndrome (PCOS) in one patient. The HbF levels before and after metformin initiation are listed in Table 1 and Supplemental Table S1. Laboratory parameters prior to metformin initiation were not available in 3 patients (Case nos. 6, 14, and 15) because metformin was started in outside facilities prior to transitioning care to UIC. In another 3 patients (Case nos. 12, 13, and 18), the HbF levels either before or after metformin initiation were missing. Among the patients identified, 3 of 5 Hb SS/Sβ0 patients (Case nos. 1-3) showed an increase in the HbF levels (+2.7%-6.6%) after starting metformin, whereas the other 2 (Case nos. 4 and 5) had minimal changes (+0.1% and −0.6%) (Figure 1A). The HbF increase failed to show statistical significance (P = .138). In the Hb SC and Hb Sβ+patients (Case nos. 7-18), the overall changes in HbF were small (median: −0.1%, P = .3), except Case nos. 7 (1.9%) and 9 (−1.6%) (Supporting Information Table S1). The previous report showed that combining HU and metformin has an additive effect in HbF induction in vitro.2 In our study, 5 of 18 patients were treated with stable-dose HU and metformin when the HbF levels were measured. The 5 patients who were treated with HU were adherent to the HU treatment as evidenced by either elevated MCV or HbF or both. In Case nos. 2 and 7, the HbF levels at baseline, when treated with HU alone, and when treated with both HU and metformin were available, whereas the HbF levels on HU alone and on both HU and metformin were measured in Case nos. 1 and 5. Additional increase in HbF was observed in Case nos. 1, 2, and 7 after metformin was used in combination with HU (Figure 1B). There are some safety concerns of using metformin in SCD patients. First, metformin has been linked to lactic acidosis, especially in patients with renal dysfunction.3 Our results did not suggest a trend toward acidosis, as the serum bicarbonate concentration and anion gap were minimally affected by metformin in this study. Second, metformin has been shown to cause B12 deficiency due to malabsorption and anemia in T2DM patients.4 In our study, hemoglobin levels and other hematological parameters were relatively stable when hematological parameters were compared before and after the metformin treatment. Third, the patients presented here were prescribed metformin for either diabetes or PCOS, and the results do not rule out safety concerns, such as hypoglycemia, in patients with SCD who do not have diabetes or PCOS; Therefore, efforts still need to be made to monitor potential metformin side effects in SCD patients in future study. The recent report of induction of HbF by metformin implies that this may be a therapeutic agent utilized in the treatment of SCD2; however, there is no in vivo evidence to support its use in SCD patients other than a case series showing that metformin has a limited impact on the HbF levels in 7 nonSCD patients.5 In this report, we found that 3 out of 5 Hb SS/Sβ0 patients had an increase in HbF after starting metformin, and the other 2 cases showed minimal effects, whereas the HbF changes in the Hb SC or Hb Sβ+ patients were mixed and overall small. It is believed that the erythropoietic stress faced by the Hb SS/Sβ0 patients potentiates the HbF response as HU induces only a modest increase in HbF in Hb SC patients compared with Hb SS/Sβ0 patients.6 This may explain the difference in the HbF response to metformin observed in the different Hb genotypes presented here as well as the lack of response in nonSCD patients in the previous report.5 Here we report the first in vivo evidence of using metformin in SCD patients. We demonstrate HbF increase was minimal in nonHb SS/Sβ0 patients, consistent with the results in previous nonSCD patients.5 Some HbF induction was observed in Hb SS/Sβ0 genotype, and combination of HU with metformin might have additional benefits. Importantly, we did not find evidence that metformin increases anemia or lactic acidosis in SCD patients. Our report is limited by the sample size and variability in the patient baseline characteristics. The compliance to metformin is difficult to assess due to the retrospective design, which may also contribute to some of the inter-individual variation in the HbF response. Our findings require substantiation in prospective clinical trials to evaluate the safety and efficacy of metformin in SCD patients. Nothing to report. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.