Timely identification and reduction of mortality prognostic factors in COVID-19 patients are now regarded as a matter of vacuity, especially among patients with comorbidities, such as DM. DM has been demonstrated to worsen the course of disease and mortality rates [24]. Zhou et al., revealed that 31% of the patients who died had DM [25]. In the same way and based on a recent Indonesian report, a 21.28% mortality rate was recorded in COVID-19-DM patients compared to 3.41% mortality rate in the non-DM group [26]. These compelling evidences show COVID-19 patients with underlying DM should be prioritized. In this regard, implementation of an intervention program and also designing an effective strategy is crucial to decrease COVID-19 mortality. In this systematic review, we are aimed to investigate a variety of numerous demographic and prognostic factors which increase the mortality rate in diabetic patients infected with COVID-19. Obtained results indicated that older age, male sex, higher D-dimer, CRP levels and blood glucose that were associated with higher mortality rates. Moreover, as compared to the survivors, our evidence suggests that non-survivor patients had lower SPO2 saturation and also higher degree of pulmonary involvement in HRCT. In another aspect, male gender and mechanical ventilation was more common in deceased patients. There is no significant relationship between consumption of azithromycin and tocilizumab and mortality in patients and using hydroxychloroquine still needs further study to evaluate its effect on patients. Statins doesn’t have a protection role on COVID-19_DM patients than non-users.
Based on five studies, older age has a robust significant relationship with an increased rate of mortality in COVID-19_DM patients. These findings were agreed with another study that was conducted on more than 300 patients, age is an independent predictor factor of death [27]. Also, another Chinese retrospective study reported a higher mortality rate of older patients with DM compared to survivors (76.0 vs 63.0 years) [28]. In contrast, data derived from a recent meta-analysis including 87 studies and 35486 patients, DM-related death was attenuated in the elderly age group [29].
A number of notable biological mechanisms may be involved in the higher mortality rate in older patients. Variations in Angiotensin-converting enzyme 2 (ACE2) expression between age-based diversities can result in a weakened immune response against the pathogens [30, 31]. Furthermore, older people immune system is faced with numerous age-related alterations such as immunosenescence, which induces many changes in innate [32], and adaptive immune systems [33], also worsens immune responses coordination [34]. These biochemical responses may be related with increased risk of infection in older patients.
Obtained results indicated that there is a significant correlation between male sex and mortality in COVID-19 infected patients. A study conducted by Mansoura University on 118 patients, revealed that male gender is a predictive factor for COVID-19 mortality, so that diabetic male patients have a higher mortality rate than women (48.1% vs 29.7%) and men face a significant increase in the odds ratio of mortality by 4.788 times [35]. Similar studies have also reported that diabetic male patients have a higher mortality rate than females with COVID-19 [36–39]. Agarwal and colleagues included 1126 hospitalized patients and discovered that men had a higher mortality rate than women. Additionally, with advancing age, male patients had a higher body mass index (BMI) compared to their female counterparts and have higher mortality rate that can be due to worsening insulin resistance caused by higher BMI in men [40]. DM women have more immunity than diabetic men; although DM makes them more vulnerable to COVID-19 and compromises their immune response, in the end men showed higher mortality [41]. The immune response to viral infections may be influenced by variations in estrogen and progesterone levels, which can stimulate the immune system and induce greater resistance in female patients. Moreover, since many immune-related genes are situated on the X-chromosome, this could account for the differences in mortality rates between genders and the superior T-cell activation and inflammatory response in women's immune systems [42–46]. In contrast, two studies have shown that women have higher mortality than male patients that can be due to black race and skin color[47]. A study conducted in South Korea found no correlation between gender and mortality rates from COVID-19 and DM. The lack of relationship could be attributed to differences in ethnicity and a small patient population [24].
In terms of laboratory variables, one study demonstrated that, leukocytosis and low lymphocyte count can play a as prognostic factor in increasing the rate of mortality in COVID-19_DM patients. Asadazzaman, M et al., reported a higher WBC count among 500 patients with COVID-19 can make a significant change in estimating excess mortality. However, a significantly lower lymphocyte count was observed in non-survivors’ group [48]. Compared to non-diabetic patients, four studies revealed that DM had a considerably increasing effect on D-Dimer levels which was consistent with a recent study that investigated numerous factors involved in coagulation and inflammation cascade, especially in diabetic patients [49]. Additionally, according to a recent retrospective report focusing on the importance of D-Dimer in the assessment of the severity and outcomes of COVID-19 patients, D-dimer levels were predictive for the prognosis of survival and mortality in both first and last lab tests. (0.765mg/L and 2.025 mg/L respectively) [50]. However, an increased level of D-dimer cannot play a decisive role in the prediction of mortality in COVID-19_DM patients [51]. One study also indicated that elevated levels of CRP can be a prognostic factor in COVID-19_DM patients. For instance, Aydın et al reported that diabetic conditions may act synergistically for increasing level of CRP compared to non-DM patients [52]. However, they didn’t confirm its prognostic effect on mortality despite of other studies. It should be noted, controversial evidences of serum CRP levels with disease progression were observed in a study that believed the elevated level of CRP within the first 48h of ARDS is related to better prognosis like more survival rates and lower duration of mechanical ventilation [53].
Chinese study results indicated the significant difference in serum ferritin levels in diabetic groups compared to non-diabetics. This marker may have an incremental effect on the severity of the disease and rapid progression of COVID-19. Subsequent to major rise in serum ferritin, monocyte-macrophage system which plays an essential role in inflammatory mechanisms will active [54]. FBG is the other lab data assessing in COVID-19-DM patients. Based on one study which revealed the deleterious effect of FBG ≥ 7mmol/L [19] and also two other studies [20, 21]; Ling et al, explicitly revealed that FBS ≥ 10mmol/L is highly associated with an increased risk of COVID-19 progression to severe illness in more than 700 patients [55]. Patients with HBA1c ≥ 6.5% at admission are highly permissive to infection and mortality. Similarly, a recent meta-analysis derived from six studies and 1180 patients, higher HBA1c was a valuable COVID-19's in-hospital mortality predictor compared with lower HBA1C. The authors demonstrate elegantly that elevated levels of HbA1c is related to a brisk peak in levels of inflammatory markers(i.e. CRP, TNF-α,ferritin) [56]. Additionally, Procalcitonin has been recognized as a specific marker than can be increased remarkably in bacterial sepsis [57]. On the basis of current knowledge of procalcitonin metabolism, increased level of this marker has an important role in the innate immune system’s response against bacterial infection [58]. One of our studies revealed the predictive role of procalcitonin in COVID-19_DM patients. Consistent with this notion and according to a meta-analysis based on 10 cohort studies, increased procalcitonin level was significantly associated with worse outcomes in COVID-19 patients [59].
We were able to disclose in three studies that patients with DM had more severe pneumonia and are highly predisposed to severe course of infection and mortality[18, 21, 22]. Similarly, and based on HRCT lung finding of 220 patients, lung involvement was markedly augmented in COVID-19_DM patients compared to patients without DM (p = 0.002) [60]. Furthermore, Yumin et al., revealed in a cohort study that FBG ≥ 11 mmol/L can be a predictive value for more pulmonary involvement [61]. This could be attributed to the deleterious effect of hyperglycemia on endothelial function and impairment in the microbiocidal capacity which results in ventilatory dysfunction and small airway obstruction [62–64]. Other surveys have shown unsubstantial effects of well-controlled HBA1c level on mortality and outcomes of COVID-19_DM patients [65]. It can be surmised that pulmonary involvement can reduce O2 saturation which was previously demonstrated in two studies [18, 23]. In this regard and base on a recent Russian study, SPO2 level was decreased significantly on day 4–7 after admission in COVID-19_DM patients compared to non-DM patients [66].
We found that mechanical ventilation or intubation can cause higher mortality in diabetic patients who were admitted for COVID-19. According, Barrett et al., showed that individuals with type 1 diabetes have a higher likelihood (9% more) of experiencing intubation and death compared to those with T2DM. However, after Diabetic Ketoacidosis (DKA) adjustment, this difference decreased to only 1%. Overall, individuals with diabetes are more susceptible to intubation than those without DM, with an absolute risk of 65% versus 44% [67]. A recent meta-analysis of 158 surveys, including a patient population of 270212 which 57801 individuals living with DM, revealed that diabetic patients have a significantly higher risk of intubation and mortality. The study found odds ratios of 1.44 and 1.87, respectively [12]. In another three studies, mechanical ventilation is considered as mortality predictor for COVID-19-DM patients [37, 68–70]. In contrast, Emral et al., declared that there is a decrease in need for intubation and death rate for COVID-19-DM patients that can be due to treatment with Dipeptidyl Peptidase IV (DPP-4) drugs [71].
There is a controversy regarding treatments and mortality rate in patients. Soto et al., in 2022 revealed that treatment with azithromycin and ivermectin are associated with higher mortality; on another hand, low to moderate doses of corticosteroids can reduce mortality rate [72]. In general, and without consideration of DM, usage of hydroxychloroquine is not associated with any change in mortality [73–75], we didn’t find any article that investigate effect of hydroxychloroquine on DM-COVID-19 patients at the same time except studies that explained in result section. As we mentioned in results, statin will reduce mortality in COVID-19-DM patients. Kapur et al., concluded that statins with its anti-inflammatory and vasculo-protective effects reduce mortality in all COVID-19 patients, especially in diabetic ones [76].