Despite extensive research on the renoprotective effects of ARBs in diabetes, their long-term impact on hematological parameters remains understudied. To address this gap, the present study aimed at providing valuable insights into the impact of CCBs and ARBs on hematological parameters in individuals with T2DM. The baseline characteristics of the studied groups were matched concerning age and gender. Additionally, BMI values were also identical in patient groups to exclude any possible effect of these factors on the investigated parameters. Moreover, the enrolled patients in this study were treated with glibenclamide only for their high blood glucose. This is because glibenclamide seems to be safer regarding the potential for predisposing to blood abnormality than other antidiabetic agents such as metformin (14). As antihypertensive agents, the results of this study showed an acceptable blood lowering effects for both, ARBs and CCBs, with more potent action from ARBs in comparison to CCBs. This is in consistence with the previous researches, where both groups have been used for controlling BP in diabetic patients and that ARBs are superior to all other classes (15, 16).
Both, ARBs and CCBs resulted in better glucose control as noticed from the mean values of FSG and HbA1c when compare to T2DM and T2DM + HT groups. In the realm of pathophysiology, RAS assumes a key element in the emergence of HT and DM. Consequently, various mechanisms may contribute to the advantageous effects of RAS inhibitors on glucose homeostasis and metabolism. Notably, ARBs have garnered attention for their potential to enhance insulin sensitivity by impeding the depletion of GLUT-4, a critical protein responsible for glucose transportation and facilitated uptake of glucose-mediated by insulin in muscle and adipose tissues. This proposition underscores the significance of RAS modulation as a potential therapeutic avenue in addressing insulin resistance and related metabolic disturbances (17). Regarding CCBs, it was suggested that oxidative stress and activated proinflammatory cytokines (PIC) could provoke damage to several organs (18–20). Undoubtedly, elevated levels of PIC instigate a transition towards compromised glucose tolerance. Consequently, the well-documented anti-inflammatory properties of CCBs may, to some extent, play a role in enhancing glucose tolerance, thereby elucidating their favourable impact on the glycemic status within the studied group (21).
In the assessed patient groups, it is noteworthy that renal function parameters were still within the normal range, although they are more than control group, which is of critical importance in ruling out potential renal abnormalities that could contribute to anemia and to establishing a clear association between any observed blood irregularities and the investigated drugs. Notably, ARBs and CCBs, did not demonstrate clear adverse effects on renal function parameters, except for a mild elevation in urea and uric acid levels among CCBs users. The literature has extensively elucidated the renoprotective effects associated with the inhibition of calcium channels and RAS. These effects have been attributed to the systemic vasodilation induced by these agents, leading to a reduction in BP and subsequent beneficial outcomes in the treatment of kidney diseases by enhancing renal blood flow. This, in turn, contributes to the amelioration of renal hypoxia. Furthermore, the actual reduction in albumin excretion has been linked to the renoprotective potential of these agents (22, 23). Moreover, besides to blocking angiotensin II (AT2)-related kidney injuries, ARBs can lower AT2 levels intra-renally by lowering renin and angiotensinogen of proximal tubules and collecting duct, preventing AT2 build-up in the kidneys (24). Collectively, these outcomes postulate valuable comprehensions into the favourable impact of ARBs and CCBs on renal function, featuring their potential therapeutic value in kidney-related disorders.
In contrast to the well-established renoprotective potential of ARBs and CCBs, our investigation has revealed certain hematological abnormalities associated with the use of these agents. Initially, during the analysis, no significant impact on hematological parameters was observed, and the results appeared comparable among the studied groups. Nevertheless, a particularly notable finding emerged, indicating that the duration of ARBs and CCBs usage might have an adverse effect on hematological status. Upon closer examination, our analysis demonstrated that individuals using ARBs and CCBs for a duration of less than 5 years did not exhibit any significant blood abnormalities. However, when examining the results for users consuming these agents for more than 5 years, lower Hb concentrations were evident in both groups compared to T2DM + HT group. Moreover, further investigation unveiled a reduction in ferritin levels among ARBs users and a decline in RBCs and Hct levels among CCBs users. In a comparable context, the duration of ARBs usage significantly impacted EPO levels, which is probably not due to the direct action of ARBs but a secondary effect for their long term administration. Conversely, the CCBs group exhibited an elevation in serum EPO levels when compared to all other participants, including the healthy control group. Overall, prolonged duration of DM and HT appeared to exert deleterious effects on the general health of patients (25). Shared paths, such as the augmentation of the RAS, heightened ROS, inflammatory processes, and immunity activation, are probable factors that underlie the intricate interconnection between diabetes, HT, and the development of their respective complications (6). Nonetheless, in the current investigation, we carefully controlled for the duration of DM and HT to ensure equivalence among the studied groups, thus eliminating this factor as a potential confounding variable in any observed blood abnormalities. This meticulous matching process allowed us to directly attribute the obtained results to the long term administration of ARBs or CCBs. While RAS inhibitors are known to confer protective effects on several organs, it is important to acknowledge that they may sporadically be linked to anemia (26). In experimental rat models, the administration of candesartan was found to be associated with a decrease in EPO levels, as well as reductions in erythrocyte count, Hct, and Hb levels (27). In a similar manner, losartan and valsartan were observed to cause reductions in Hb levels, Hct values, and RBCs count among kidney transplantation individuals (28, 29). In contradistinction, the administration of losartan did not exhibit any deleterious impact on the Hb level and RBC count in male Wistar rats. The disparity between our study and the latter study lies in the duration of evaluation, as we conducted an assessment of the effects of ARBs over an extended period, in contrast to the relatively shorter (50-day) duration observed in the aforementioned study (30). Research has provided evidence indicating the presence of angiotensin-converting-enzyme (ACE) expression in hematopoietic progenitors during the developmental stage of mouse embryos. Moreover, in human and animals, renin, ACE, angiotensinogen, AT1, and AT2 receptors are expressed naturally within the para/aortic-splanchnopleura (P-Sp) and the aorta-gonad-mesonephros. The spatial distribution of these components suggests the potential localization of paracrine and/or autocrine RAS in such hemogenic places. Researches on targeted manipulation of RAS through the dispensing of ARBs, have revealed a substantial inhibition of CD45-positive blood cell generation from dissected P-Sp. This compelling finding indicates that AT2 signalling is indeed crucial for the emergence of hematopoietic cells from these specific developmental sites. In contrast, the introduction of exogenous AT2 peptide has been demonstrated to elicit a stimulatory effect on hematopoiesis in culture, leading to a notable increase in the population of immature hematopoietic progenitors vs controls. These findings emphasizing the significant involvement of the local RAS in promoting the development of undifferentiated-hematopoietic-progenitors. Moreover, inhibition of this system through the use of ARBs may potentially predispose individuals to hematological abnormalities (31). In line with these, studies on CCBs revealed significant deficiencies in iron, Hct and Hb levels in the patients using CCBs in comparison to control (32, 33). In this context, previous studies have established that Ca+ 2 can exert regulatory control over hematopoiesis following stimulation by various myeloid cytokines, such as granulocyte-macrophage/colony-stimulating-factor and IL-3. Additionally, ATP and its receptors are implicated in inducing Ca+ 2 increments during hematopoiesis. Furthermore, the involvement of Ca+ 2 in myeloid proliferation and differentiation mediated by cytokines and P2 receptors is a subject of discussion in the scientific literature. These insights draw attention to the significance of calcium-mediated-signalling in the intricate processes governing hematopoiesis, contributing to a better understanding of the underlying regulatory mechanisms (34). However, our study revealed an augmented level of EPO in the CCBs group. This observed increase is likely to be a compensatory response to counteract anemia, as previous reports have demonstrated that the body responds by augmenting the rate of erythropoiesis through a significant rise in EPO production within the kidneys (35). Given the above mentioned observations, other blood parameters investigated in the present study, like MCV, MCH, MCHC, WBCs and platelets, were not affected with long term administration of CCBs or ARBs.
Is crucial to recognize the study's limitations, such as the relatively small size of sample in each group, which needs to be expanded in the future studies to generalize the results to a larger population. Additionally, the study was conducted in a single center, therefore we recommend further multi-center trials with a long follow-up period to verify the observations of this study. Despite these limitations, the study provides some valuable insights into the possible contribution of ARBs and CCBs on hematological abnormalities in T2DM.
In conclusion, the observations of our study demonstrate the need of taking a balanced approach when prescribing ARBs and CCBs to T2DM patients, given their tendency to cause blood abnormalities, particularly in long-term use. In the meantime, patients who are taking these medications should be aware of the potential risks and should be monitored regularly for signs of problems, besides the need for further studies for enhanced understanding of the effects of these drugs on hematological markers.