Journal of Research in Pharmacy Practice

Abstract Identification of the severe acute respiratory syndrome coronavirus 2 in humans toward the end of 2019 triggered a rapid, intensive effort to develop a vaccine. Among the first three COVID-19 vaccines granted emergency use authorization by the U. S. Food and Drug Administration (FDA) were two mRNA vaccines, never used on a large scale in humans, and one replication-incompetent human adenovirus vector vaccine. Since the beginning of the vaccination efforts in December 2020, almost 220,000 adverse events (AEs) have been reported through the Vaccine Adverse Event Reporting System, a reporting platform administered jointly by the FDA and the Centers for Disease Control to monitor vaccine-related AEs. We queried this database twice (04/23/21 and 05/14/21) and identified the AE reports with valid manufacturer-specific lot numbers (n = 76,336), a subset representing 33.54% of the total reported AEs. Using vaccine and demographic characteristics at the time of each query date, a model was generated to predict significant AEs, such as death. Our regression analysis revealed that the average age (IRR 1.08) and the number of doses administered in an assisted living facility (IRR 1.01) were significantly associated with the number of deaths observed in each lot, whereas the proportion of remaining vaccine shelf-life (IRR 1.30) and the vaccine manufacturer (IRR 1.09) were not. Studies such as this one are vital, as one of the best answers to vaccine hesitancy is reliable data confirming that the available COVID-19 vaccines are safe and not associated with a significantly higher risk of AEs than vaccines for other conditions.

Abstract  Type 2 diabetes mellitus (T2DM) affects 10% of Americans and is associated with an increased incidence of cancer. Statins are first-line cholesterol-lowering medications in the treatment of hyperlipidemia. Several studies have demonstrated a relationship between statin use and reduced cancer incidence. We examined the cancer benefits of statin subtypes, with specific attention to disease-free survival (DFS) and overall survival (OS). Methods: This retrospective review included adults with T2DM diagnosed with solid tumors at Roswell Park Cancer Institute in Buffalo, NY, USA (2003–2010). Individuals with gestational diabetes, incomplete records, or diagnosed with rare solid tumors were excluded. Follow-up began at the date of diagnosis and ended with the first confirmed recurrence, death, or loss of contact. Demographics were assessed by Chi-square, Kaplan–Meier survival analyses, and Cox proportional hazards regression. Findings: Overall, 1102 patients met inclusion criteria, 52.1% of the study participants were female, and 578 participants (52.5%) died during the follow-up period which ranged from 0 to 156 months. Hydrophilic statin use was associated with improved DFS at 5-year follow-up (41.0% vs. 36.9%, P = 0.0077) compared to lipophilic statin use. Multivariate regression revealed that hydrophilic statins were associated with improved DFS (hazard ratio [HR]: 0.706, 95% confidence interval [CI]: 0.526–0.947) and OS (HR: 0.685, 95% CI: 0.503–0.934). Pravastatin was associated with improved OS (HR: 0.674, 95% CI: 0.471–0.964). Conclusion: In patients with T2DM and cancer, hydrophilic statins, and pravastatin in particular, are associated with improved DFS as well as OS. Further research examining the cancer-specific effects of hydrophilic and lipophilic statins is needed to better understand their beneficial effects.

Abstract  We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). Methods: All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003–December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter-individual variability. Based on this renal function variability evidence, 1000 PK profiles were simulated for multiple metformin regimens with the resultant PK profiles being assessed for safe CrCl thresholds. Findings: Metformin 500 mg up to three times daily was safe for all simulated profiles with CrCl ≥25 mL/min. Furthermore, the estimated overall MALA risk was below 10%, remaining under 5% for 500 mg given once daily. CrCl ≥65.25 mL/min was safe for administration in any of the tested regimens (500 mg or 850 mg up to three times daily or 1000 mg up to twice daily). Conclusion: PK simulation-guided prescribing can maximize metformin's beneficial effects on cancer outcomes while minimizing MALA risk.

Abstract To evaluate whether metformin's cancer-related benefits reported in patients with solid tumors (ST) are also present in acute myeloid leukemia (AML) patients. Methods: Baseline demographic and clinical history for all diabetes mellitus patients newly diagnosed with AML or cancer of the breast, ovary, prostate, gastrointestinal tract, lung, or kidney at Roswell Park Cancer Institute in Buffalo, NY (January 2003–December 2010, n = 924) was collected. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan–Meier (KM) analysis and Cox proportional hazards regression (hazard ratio [HR]). Findings: Baseline metformin use provided significant OS and DFS benefit in ST but not in AML (KM: P_ST-OS= 0.003; P_ST-DFS= 0.002; P_AML-OS= 0.961; P_AML-DFS= 0.943). AML median survival was slightly better with metformin use, but users derived no relapse benefit. In ST, metformin nonusers had shorter median survival, 57.7 versus 86 months, and poorer outcomes (HR_ST-OS= 1.33; P_ST-OS= 0.002; HR_ST-DFS= 1.32; P_ST-DFS= 0.002). These findings remained significant in age-adjusted models (HR_ST-OS= 1.21; P_ST-OS= 0.039; HR_ST-DFS= 1.23; P_ST-DFS= 0.02) but not fully adjusted models (HR_ST-OS= 0.96; P_ST-OS= 0.688; HR_ST-DFS= 1.0; P_ST-DFS= 0.94). Higher mortality was noted in AML patients taking insulin versus oral diabetes pharmacotherapy at baseline (HR_AML-OS= 2.03; P_AML-OS= 0.04). Conclusion: Lack of metformin benefit in AML could be due to advanced age at cancer diagnosis. Metformin substitution with insulin before computed tomography scans with contrast – a frequent AML assessment practice – may also explain the lack of subsequent benefit despite taking metformin at baseline. A temporary metformin substitution is recommended by the package insert due to a possible drug interaction with the contrast dye. Our data suggest that metformin substitution was permanent in many patients. Nonetheless, the observed benefit in other malignancies warrants further investigation of metformin use in AML.