Abstract
Background
COVID-19 is affecting all kinds of patients including diabetics. This article provides an overview of conducted meta-analyses regarding the effect of diabetes on the deaths of COVID-19 patients.
Methodology
The study was conducted as per preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement.
Data sources
The relevant meta-analyses were searched on PubMed till April 2021 and data was extracted from 24 relevant meta-analyses. The overall estimate was calculated in terms of odds ratio or relative risk with a 95% confidence interval.
Results
A total of 09 meta-analyses showed the association of diabetes with the death of COVID-19 patients and 15 meta-analyses have reported the association of diabetes with other comorbidities in the death of COVID-19 patients. The pooled odds ratio or relative risk has shown a significant association of diabetes alone or its associated comorbidities with deaths of COVID-19 patients
Conclusion
Patients with diabetes and its associated comorbidities need more monitoring if get SARS-Cov-2 infection to reduce deaths.
Keywords: Diabetes, Covid-19 patients, Mortality, Meta-analysis
1. Introduction
Coronaviruses (CoVs) are a large group of viruses with positive-sense, single-stranded RNA causing diseases in animals and humans. The first human coronavirus was found in 1962 and these are found to be associated with upper and lower respiratory tract infections. Over the last two decades, severe acute respiratory syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS) emerged in different parts of the world [1], however, not as much lethal as SARS-CoV-2 is. The first case of SARS-CoV-2 was reported in China [2]. It is believed that the SARS-CoV-2 infection is correlated to the Huanan seafood market but the exact source is still not verified. The infection caused by SARS-CoV-2 is already stated as a pandemic by world health organization (WHO) [3]. The symptoms of SARS-CoV-2 infection such as low- and high-grade fever, dry cough, difficulty in breathing, severe headache, fatigue, loss of taste, smell, etc. vary from person to person. The SARS-CoV-2 infection results in a series of immune responses causing cytokine syndrome which further can result in organ failure such as acute respiratory distress syndrome (ARDS), liver dysfunction, acute kidney injury, cardiac injury, and so on and even in the death of the patients [4].
Emerging studies have indicated high deaths of COVID-19 patients with comorbidities as compared to patients without any kind of co-morbidity [5,6]. This might be due to immunocompromised conditions of co-morbid patients (diabetes, cancer, hypertension, heart diseases, autoimmune disorders, organ transplant, etc.).
Diabetes mellitus (DM) cases are increasing day by day which is characterized by a high level of glucose [7]. Currently, DM is considered to be the seventh leading cause of death worldwide. In 2019, it was estimated that 9.3% of the total population was suffering from diabetes mellitus [8]. According to recent data from International Diabetes Federation, diabetes led to 4.2 million deaths worldwide [9]. Thus, diabetes is one of the common co-morbid conditions in COVID-19 patients.
It has been observed that diabetic patients with SARS-Cov-2 infection are more susceptible to enter into serious conditions [10]. You and colleagues [11] have reported a higher risk of death of diabetic COVID-19 patients as compared to non-diabetic patients in Korea. In a retrospective cohort study, it was observed that diabetes comorbidity was related with an increased risk of ICU admission and/or mortality [12]. Hui et al. [13] have reported a high risk of death in COVID-19 patients with diabetes as compared to non-diabetic patients. Studies conducted in New York city (NYC), also reported that the patients with diabetes were more expected to need mechanical ventilation or ICU admission [[14], [15]]. Another large population-based study in England including 264,390 patients with type 1 DM and 2874,020 patients with type 2 DM also reported higher death in COVID-19 patients with DM, renal complications, cardiovascular diseases, obesity, etc. [16]. Recently, many meta-analyses have been published regarding the association of diabetes and COVID-19. However, still there is confusion among physicians and healthcare professionals regarding the same. Thus, we have extracted the information from a published meta-analysis and discussed it in this article.
2. Methodology
The study was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [17].
2.1. Data sources
The published meta-analysis was searched in PubMed with the followings search terms (COVID 19) OR (COVID-19 virus infection) OR (COVID-19 infection) OR (2019 novel coronavirus infection) OR (2019-nCoV infection) OR (2019-nCoV disease) AND (diabetes mellitus) OR (type 2 DM)) OR (Type 1 DM)) OR (DM) AND (meta-analysis). AG and MKP both cross-check the studies. The conflict among studies was resolved after discussion with third author (AK).
2.2. Study selection
All meta-analyses on the impact of diabetes on the death of COVID-19 patients were considered which were published until April 2021. The death should be one of the outcomes of the metanalysis.
2.3. Data extraction
The data was extracted from a published meta-analysis in an Excel sheet which contained the following titles: references, year of publication, place of conduct of the study, number of included studies, pooled analysis results, limitations, etc. The demographic and clinical characteristics of included meta-analyses are presented in Table 1 and Table 2 .
Table 1.
Meta-analysis of studies containing COVID-19 patients with diabetes.
| S. No | Meta-analysis references | No. of trials included | Patients’ population | Outcome measure | Pooled Analysis | Region | Gender | Mean age |
|---|---|---|---|---|---|---|---|---|
| 1 | Shang et al. (2020) | 76 | 31,067 | Severe infection and mortality risk in COVID-19 patients with DM | DM was found to be associated with a significantly greater risk of severe COVID-19 infection (n = 54, pooled OR = 2.38, 95% CI: 2.05–2.78, p <0.001; I 2 = 39%, p <0.01).COVID-19 patients with DM had a higher risk of death (n = 28, pooled OR = 2.21, 95% CI: 1.83–2.66, p <0.001; I 2 = 50%, p <0.01) | Kuwait, Spain, New York, US, China, Israel, Oman, Iran | 17,042 males | 56.51 |
| 2 | Aggarwal et al. (2019) | 16 | 2564 confirmed COVID-19 patients | Potential associations between DM and infection severity outcomes in COVID-19 patients | Association of DM with increased risk of worse COVID-19 infection (OR: 2.60 [95% CI: 1.96 to 3.45], I2 = 56%, Cochran's Q = 24.9, P = 0.01). Association of DM with increased risk of mortality in COVID-19 patients (n = 4, OR: 2.03 [95% CI: 1.29–3.20] I2 = 0%, Cochran's Q = 2.63, P = 0.45). | nr | 1354 women | 52.6 |
| 3 | Varikasuvu et al. (2021) | 47 | 13,268 | Risk of COVID-19 infection progression associated with diabetes | Association of diabetes with higher risk of COVID-19 severity (OR = 2.20, 95% CI = 1.69–2.86, p < 0.00001). Diabetes association with increased mortality due to COVID-19 (OR = 2.52, 95% CI = 1.93–3.30, p < 0.00001). | US, China | 55.23% males | 50.98 |
| 4 | Mantovani et al. (2020) | 83 | 78,874 confirmed COVID-19 cases | The proportion of established diabetes amongst patients with COVID-19 at hospital admission, as well as the risk of patients with established diabetes of having severe/critical illness | Diabetic patients had greater risk of severe/critical COVID-19 illness (n = 22; random-effects odds ratio 2.10, 95% CI= 1.71–2.57; I 2 = 41.5%). Diabetes associated with greater risk of in-hospital mortality associated with COVID-19 (n = 15; random-effects odds ratio 2.68, 95% CI= 2.09–3.44; I 2 = 46.7%). | Asia (China) Europe (Italy, France, UK), Australia, US | 52.1% men | 54 |
| 5 | Guo et al. (2020) | 9 | 8807 | Disease severity or mortality | Comorbid diabetes significantly associated with disease severity or death of COVID-19 (pooled RR = 2.96 (95% CI: 2.31– 3.79; p < 0.001)). | 83.3% of the cases were derived from Hubei Province | 48.1% males | 52.5 |
| 6 | Kumar et al. (2020) | 33 | 16,003 | Severity and mortality | Diabetes associate with severe COVID-19 (pooled odds ratio 2.75 [95% CI: 2.09–3.62; p < 0.01]) as well as mortality due to COVID-19 (pooled odds ratio 1.90 [95% CI: 1.37–2.64; p < 0.01]). | China, USA, France | 54% males | 52.6 ± 17.4 |
| 7 | Hussain et al. (2020) | 42 | 23,007 | Risk of mortality and ICU admissions in COVID-19 patients with diabetes | Diabetes prevalence in COVID-19 patients, pooled prevalence of 15% (95% CI: 12% to 18%), p = <0.0001. Association of diabetes with mortality in COVID-19 patients with pooled risk ratio of 1.61 (95% CI: 1.16–2.25%), p = 0.005. Risk of ICU admission rate association with diabetes with a pooled risk ratio of 1.88 (1.20%–2.93%), p = 0.006 | China, US, Spain, Korea, and India | 52.65% males | 58 |
| 8 | Wu et al. (2020) | 9 | 926 | Mortality | Association of diabetes and mortality due to COVID-19, with a pooled OR of 1.75 (95% CI 1.31–2.36; P = 0.0002). | China | Females (dead/alive): 158/474 | (dead/alive): 69.86/55.1 |
| 9 | Huang et al. (2020) | 30 | 6452 | Mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care, and disease progression | DM associated with poor outcome (RR 2.38 [1.88, 3.03], p < 0.001; I2: 62%); mortality (RR 2.12 [1.44, 3.11], p < 0.001; I2: 72%), severe COVID-19 (RR 2.45 [1.79, 3.35], p < 0.001; I2: 45%), ARDS (RR 4.64 [1.86, 11.58], p = 0.001; I2: 9%), and disease progression (RR 3.31 [1.08, 10.14], p = 0.04; I2: 0%) | NR | 54.16% male | 50.7 |
Table 2.
Meta-analysis of studies containing COVID-19 patients with diabetes as one of the comorbidities.
| S. No | Meta-analysis refrences | References included in meta-analysis | Patients’ population | Outcome measure | Pooled analysis | Region | Gender | Mean age |
|---|---|---|---|---|---|---|---|---|
| 1 | Tian et al. (2020) | 15 | 4659 | Associations between mortality and patient characteristics, comorbidities, and laboratory abnormalities | Diabetes (OR, 2.0; 95% CI, 1.7‐2.3; P < .00001) | China (2025, 13 studies) and New York (2634) | 2681 participants (57.5%) were male | 59.8 years |
| 2 | Nandy et al. (2020) | 15 | 3994 DM in 8 studies with 1895 patients | Serious events that included ICU admission, Acute respiratory distress syndrome (ARDS), mechanical ventilation, Pneumonia, and death | Diabetes (OR 2.28 95 CI 1.40 to 5.55) (p = 0.004) | China | 1025 females Excluding 1 study consisting 1590 patients | 51.23 |
| 3 | Qiu et al. (2020) | 15 | 904 | Risk factors for the COVID-19-related death | Diabetes 22.2% (95% CI 19.30∼25.10%) | Mostly from China | 302 Female | 70.25 |
| 4 | Lu et al. (2020) | 28 | 16,095 COVID-19: 11,818 SARS: 3292 MERS: 985 | Risk factors leading to mortality in COVID-19,SARS, and MERS patients | Diabetes comorbidity (OR = 3.73, 95% CI 2.35- 5.90) | SARS: China (Beijing, Guangdong, Shanxi, Hong Kong, Taiwan), Toronto MERS: Saudi Arabia and South Korea COVID-19: China, Italy, South Korea, US) | NR | NR |
| 5 | Mesas et al. (2020) | 60 | 51,225 | Explored variables as potential for increasing risk of mortaliy in COVID-19 patients | Diabetes pooled odds ratio 2.12 (1.79, 2.52), p-value=<0.001, I²=77.9 | Italy, Israel, Pakistan, Brazil, Spain, UK, China, Switzerland, France, Germany, USA, South Korea, Iran | 56.59% males | 58.97 |
| 6 | Dorjee et al. (2020) | 78 | 38,906 | Association between variables and disease severity or mortality | Of the COVID-19 patients that died, 33% [95% CI: 32–44%; I2 = 83%; n = 29] were diabetics. Relative risk of death in COVID-19 patients due to diabetes [sRR: 1.50; 95% CI: 1.35–1.66; I2 = 58%; n = 33]. Risk of severe disease due to diabetes [sRR: 1.48; 95% CI: 1.35–1.63; I2 = 59%; n = 44] | US, Europe, China | 59% males | 59 |
| 7 | Ng et al. (2021) | 49 | 3,75,859 | mortality, severe disease, hospitalization, length of hospitalization, the need for intubation, and development of acute respiratory distress syndrome | Diabetes, hazards ratio of 1.94 (95% CI, 1.54 to 2.46) n = 4 studies. The results indicate a significant 94% increased hazard of COVID-19-related mortality in patients with diabetes. | Brazil, China, India, Iran, Italy, Mexico, Oman, Saudi Arabia, South Korea, Spain, Turkey, Uganda, United Kingdom, and United States | NR | 46.2 |
| 8 | Ssentongo et al. (2020) | 25 | 65,484 | Risk of COVID-19 mortality in patients with and without pre-existing comorbidities | Pooled risk ratio of mortality from COVID-19 in patients with diabetes (1.48 [1.02 to 2.15] p-value=0.04, n = 16) | China, Italy, US, South Africa 1 study representing North America, Europe, Asia, and Africa | 57% male | 61 |
| 9 | Javanmardi et al. (2020) | 31 | 2431 (Mortality cases) | Mortality | overall prevalence of diabetic comorbidities estimated 26% (21%−31%) t = 4.45, P = 0.001; n = 29 studies in fatal cases of COVID-19 | NR | NR | NR |
| 10 | Zhou et al. (2020) | 34 | 16,110 | severe/fatal COVID-19 | The pooled odd ratio in patients with diabetes were 2.73 (95% CI 1.95–3.82), 2.98 (95% CI 1.49–5.98), and 2.08 (95% CI 1.38–3.15) times more likely to progress to severe manifestations, ICU admission, and death, respectively, compared to non-diabetic patients. | NR | NR | 55 |
| 11 | Biswas et al. (2020) | 20 | 64,676 | Risk of mortality | Diabetes (RR 1.97: 95% CI 1.48–2.64; p < 0.00001) | China, Italy, USA | 47,661 males | 52.8 |
| 12 | Gold et al. (2020) | 33 | 29,096 | Severe/fatal cases | The pooled estimate of diabetes among fatal cases as compared to total cases was [24.89% (95%CI: 18.80%, 32.16%)versus 9.65% (95%CI: 6.83%, 13.48%) respectively, p = 0.0001] | Australia, Korea, USA, China, India, Netherland, Singapore, Europe | 51.1% males | 51.2 adults 2.13 children |
| 13 | Zheng et al. (2020) | 13 | 3027 | Critical/mortality cases | diabetes:OR = 3.68, 95% CI (2.68, 5.03), P < 0.00001 | China | 1691 males | 49–70.5 (Critical/mortality cases) 37–62 (non critical group) |
| 14 | Espinosa et al. (2020) | 42 | 98,174 | mortality | The pooled prevalence of diabetes among the fatal cases was 19% (95% CI: 16–22; weight 8.53%) | China, Korea, USA, Singapore, Italy, India | 9882 males except 1 article [43] | 41 to 70 (prevalence of comorbidities) 46–63 (Prevalence of comorbidities in ICU patients) 6–70 (Prevalence of comorbidities among mortality cases) |
| 15 | Chidambaram et al. (2020) | 108 | 20,296 (to determine risk of mortality) 17,992 (association with severe disease) | Death and severe desease in patient | The risk of mortality in patients with diabetes (RR 1.59, 95%CI 1.41–1.78) | China, US, Spain, UK, Italy, Iran | 17,773 males | 54.4 |
NR: Not Reported.
2.4. Methodological assessment
The methodological assessment of the included meta-analyses was evaluated using the checklist [18] having 21 items and is listed in Table 3 . Twenty-four meta-analyses were included in the overview. The selection of meta-analyses is presented in Fig. 1 .
Table 3.
Quality assessment of included studies.
| Criteria | Studies (Author, year) | Shang, et al. (2020) | Aggarwal, et al. (2019) | Varikasuvu, et al. (2021) | Mantovani, et al. (2020) | Guo, et al. (2020) | Kumar, et al. (2020) | Hussain, et al. (2020) | Wu, et al. (2020) | Huang, et al. (2020) | Tian, et al. (2020) | Nandy, et al. (2020) | Qiu, et al. (2020) | Lu, et al. (2020) | Mesas, et al. (2020) | Dorjee, et al. (2020) | Ng, et al. (2021) | Ssentongo, et al. (2020) | Javanmardi, et al. (2020) | Zhou, et al. (2020) | Biswas, et al. (2020) | Gold, et al. (2020) | Zheng, et al. (2020) | Espinosa, et al. (2020) | Chidambaram, et al. (2020) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study Question | Objectives clearly stated | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Clinically relevant and focused study question included | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | |
| Litetatute seatch | Comprehensive literature search conducted | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Searched information sources listed (ie, PubMed, Cochrane database) | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | |
| Terms used for electronic literature search provided | √ | X | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | |
| Reasonable limitations placed on search (ie, English language) | √ | X | X | √ | X | √ | √ | X | √ | X | X | √ | X | X | X | √ | X | √ | √ | √ | X | X | X | √ | |
| Manual search conducted through references of articles, abstracts | √ | √ | √ | √ | √ | √ | √ | √ | X | √ | √ | √ | √ | √ | X | √ | √ | √ | √ | X | X | √ | √ | X | |
| Attempts made at collecting unpublished data | √ | X | √ | √ | √ | X | X | X | √ | X | √ | √ | √ | X | X | X | √ | X | X | X | X | X | X | X | |
| Data Abstraction | Number of authors (>2) who abstracted data given | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Disagreements listed between authors and how they were resolved | √ | X | X | √ | √ | X | X | X | X | √ | √ | √ | √ | √ | X | X | √ | √ | √ | √ | X | √ | X | √ | |
| Characteristics of studies listed (ie, sample size, patient demographics) | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | X | √ | √ | √ | √ | √ | √ | |
| Inclusion and exclusion criteria provided for studies | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | |
| Number of excluded studies and reasons for exclusion included | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | |
| Evaluation of results | Studies were combinable | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Appropriate statistical methods used to combine results | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | |
| Results displayed | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | |
| Sensitivity analysis conducted | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | X | √ | √ | √ | √ | X | √ | √ | √ | √ | X | √ | √ | √ | |
| Evaluation for publication bias | Publication bias addressed through evaluation methods such as funnel plot or sensitivity analysis | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | X | √ | √ | √ | √ | X | √ | √ | √ | √ | X | √ | √ | √ |
| Applicability of results | Results were generalizable | √ | X | √ | √ | X | X | √ | X | √ | X | X | X | X | √ | X | √ | √ | X | √ | √ | √ | X | X | √ |
| Funding source | Funding source(s) stated | √ | √ | X | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | X | X | √ | √ |
| No conflict of interest seen | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | X | X | X | √ | X | √ | √ | √ | X | X | √ |
Fig. 1.
The scheme of selection of meta-analysis.
3. Results and discussion
The results of individual metanalysis were compiled in Tables 1 & 2 and are discussed below.
3.1. Meta-analysis of studies containing COVID-19 patients with diabetes
Nine meta-analyses showed that diabetes was associated with the death of COVID-19 patients. Shang et al. [19] have done a meta-analysis of 28 studies and the overall estimate was measured in terms of odd ratio (OR) with 95% CI. The pooled OR was reported 2.21 with 95% CI (1.83–2.66), and p <0.001 which indicates the significant association of diabetes with death of COVID-19 patients. The heterogeneity among studies was calculated by I2 statistics and reported as 50%. Aggarwal et al. [20] have also shown an association of diabetes with death of COVID-19 patients [OR: 2.03, 95% CI: 1.29–3.20]. There is no heterogeneity among studies (I2 = 0%, Cochran's Q = 2.63, P = 0.45). However, the number of included studies for statistical analysis was less (n = 4). The result of meta-analysis done by Varikasuvu et al. [21] showed a significant increase in death of COVID-19 patients with diabetes [OR = 2.52, (1.93–3.30), p < 0.00001]. Mantovani, et al. [22] have done a meta-analysis of 15 studies using the random-effect model and reported pooled OR 2.68 with 95% CI (2.09–3.44) which indicates a greater risk of in-hospital mortality associated with COVID-19 diabetic patients. The I2 was reported to be 46.7% which indicates heterogeneity among studies. Guo et al. [23] have reported pooled relative risk (RR) 2.96 (95% CI: 2.31– 3.79; p < 0.001) which indicates diabetes is associated with disease severity or death of COVID-19 patients. Kumar et al. [24] have done a metanalysis to find out the association of diabetes with the severity and mortality of COVID-19 patients. The pooled OR 2.75 [95% CI: 2.09–3.62; p < 0.01 indicates a significant association of diabetes with the severity of COVID-19 patients. The pooled OR with mortality was reported 1.90 [95% CI: 1.37–2.64; p < 0.01]) which also indicates a significant association of diabetes with mortality of COVID-19 patients. Hussain, et al. [25] have also reported an association of diabetes with mortality in COVID-19 patients with a pooled risk ratio of 1.61 (95% CI: 1.16–2.25%), p = 0.005. Wu et al. [26] have reported pooled OR of 1.75 (95% CI 1.31–2.36; p= 0.0002) which indicates a significant association of diabetes with mortality of COVID-19 patients. Huang et al. [27] reported RR 2.12 [1.44, 3.11], p < 0.001 which also indicates a significant correlation. The I2 was found to be 72% which indicates heterogeneity among studies. All these meta-analyses of studies containing COVID-19 patients with diabetes as one of the comorbidities are compiled in Table 1.
3.2. Meta-analysis of studies containing COVID-19 patients with diabetes as one of the comorbidities
In most cases, diabetes is associated with other medical conditions such as hypertension, obesity, hyperlipidemia, etc. The search of the current study has found 15 meta-analyses which are mentioned as follows. Tian et al. [28] have reported high mortality of patients with hypertension (56.8%) followed by diabetes (31.2%) and coronary heart disease/cardiovascular disease (CHD/CVD) (21.5%). The pooled OR in diabetic patients was reported 2.0 with 95% CI, 1.7‐2.3; P < .00001 which indicates a significant correlation. Nandy et al. [29] have reported the effect of various comorbidities as well as diabetes on COVID-19 patients. The pooled OR with diabetes was reported with OR 2.28 (1.40 to 5.55) which indicates a significant correlation. Qiu, et al. [30] have also reported various risk factors such as hypertension, chronic cardiovascular and cerebrovascular disease, diabetes in COVID-19 patients. The risk of complications associated with COVID-19 diabetic patients was reported 22.2% (95% CI 19.30∼25.10%). Lu et al. [31] have conducted a meta-analysis of studies conducted in Wuhan and reported diabetes, chronic lung disease, and hypertension as one of the mortality risks factors. The pooled OR in cases of diabetes was reported with OR = 3.73, 95% CI 2.35- 5.90. Mesas et al. [32] have reported pooled odd ratio for diabetes 2.12 (1.79, 2.52), p-value=<0.001, I²=77.9. Dorjee et al. [33] have found a significant risk of death in diabetic patients. The relative risk was found to be RR: 1.50 [95% CI: 1.35–1.66]. However, the heterogeneity among studies was found to be higher. Ng et al. [34] have done the metanalysis to find out the effect of various co-morbid conditions including diabetes in COVID-19 patients. The pooled hazards ratio was found to be 1.94 (1.54, 2.46) which indicates a significant risk of mortality in COVID-19 patients with diabetes. Ssentongo et al. [35] have also reported significant risk [pooled relative risk: 1.48 (1.02 to 2.15)] of death in COVID-19 patients with diabetes along with other co-morbid conditions. Javanmardi, et al. [36] have analyzed 29 studies and reported an overall prevalence of diabetic comorbidities 26% (21%−31%) in fatal cases of COVID-19 as compared to other co-morbid conditions. Zhou et al. [37] have reported higher risks of severe problems and death in COVID-19 patients with co-morbid conditions. The pooled odd ratio with diabetes was 2.73 (1.95–3.82) times more likely to progress to severe manifestations, 2.98 (1.49–5.98) times more likely for ICU admissions, and 2.08 (1.38–3.15) times more likely to cause death as compared to non-diabetic patients. Biswas et al. [38] metanalysis results have reported pooled relative risk of 1.97 (1.48–2.64) with diabetes which indicates higher risks of death. Gold et al. [39] have also reported a higher risk of death in COVID-19 patients with co-morbid conditions like hypertension, diabetes, and respiratory diseases. The pooled estimate of diabetes among fatal cases as compared to total cases was [24.89% (18.80%, 32.16%) versus 9.65% (6.83%, 13.48%) respectively. Zheng et al. [40] have reported pooled OR in diabetes patients OR = 3.68, (2.68, 5.03) which indicates a higher risk of death in COVID-19 patients with diabetes. Espinosa et al. [41] have reported hypertension, diabetes, heart disease, and COPD as the most prevalent comorbidities in death cases of COVID-19. The pooled prevalence of diabetes among the fatal cases was reported 19% (16–22%). Chidambaram et al. [42] have assessed the effects of various risk factors on the mortality of COVID-19 patients. Authors have concluded that increasing age, male gender, dyspnea, diabetes, hypertension are the most important risk factors. Authors have also reported congestive heart failure, hilar lymphadenopathy, bilateral lung involvement, and reticular patterns associated with severe disease. The risk of mortality in patients with diabetes was found to be (RR 1.59, 1.41–1.78) which indicates a higher risk in patients with diabetes. The meta-analyses containing COVID-19 patients with diabetes as one of the comorbidities are compiled in Table 2.
4. Limitations
One of limitation of the current study is moderate to high heterogeneity in terms of types of the population, sample size, and age of included subjects among studies. In most of the ameta-analysis, authors have not done sub-group analysis due to a limited number of studies. Thus, further studies with large sample sizes are required to do subgroup analysis. We have searched only PubMed and meta-analysis published in the English language is only considered.
5. Future perspectives
Diabetes and its associated comorbidities are significantly associated with the death of COVID-19 patients in all of the published meta-analyses. Therefore, COVID-19 patients with diabetes and its associated comorbidities need much more monitoring to reduce deaths.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Acknowledgments
The authors are thankful to Vice-Chancellor, Delhi Pharmaceutical Sciences & Research University (DPSRU), New Delhi 110017, India for his continuous support, motivation, and providing necessary facilities to carry out this work.
References
- 1.Cui J., Li F., Shi Z.L. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol. 2019;17(3):181–192. doi: 10.1038/s41579-018-0118-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Al-Qahtani A.A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): emergence, history, basic and clinical aspects. Saudi J. Biol. Sci. 2020;27:2531–2538. doi: 10.1016/j.sjbs.2020.04.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.WHO . 2020. [Google Scholar]
- 4.Gordon D.E., Jang G.M., Bouhaddou M., Xu J., Obernier K., White K.M., O'Meara M.J., Rezelj V.V., Guo J.Z., Swaney D.L., Tummino T.A., Hü ttenhain R., Kaake R.M., Richards A.L., Tutuncuoglu B., Foussard H., Batra J., Haas K., Modak M., Kim M., et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583:459–468. doi: 10.1038/s41586-020-2286-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Yang X., Yu Y., Xu J., Shu H., Liu H., Wu Y., Zhang L., Yu Z., Fang M., Yu T., Wang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet. Respir. Med. 2020:e26. doi: 10.1016/S2213-2600(20)30079-5. DOI: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.WJ Ni ZY, Hu Y., Liang W.H., Ou C.Q., He J.X., Liu L., Shan H., Lei C.L., Hui D.S., Du B., et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020;382(18):1708–1720. doi: 10.1056/NEJMoa2002032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Garg A., Kumar A. Risk and benefit profile of dulaglutide in established therapeutic indication. Curr. Drug. Saf. 2018;13(3):165–170. doi: 10.2174/1574886313666180601082412. [DOI] [PubMed] [Google Scholar]
- 8.Arroyave F., Montaño D., Lizcano F. Diabetes mellitus is a chronic disease that can benefit from therapy with induced pluripotent stem cells. Int. J. Mol. Sci. 2020;21(22):8685. doi: 10.3390/ijms21228685. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.IDF Diabetes Atlas Ninth edition 2019. https://idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html#:∼:text=1%20in%202%20(232%20million,living%20with%20type%201%20diabetes
- 10.Corrao S., Pinelli K., Vacca M., Raspanti M., Argano C. Type 2 diabetes mellitus and COVID-19: a narrative review. Front. Endocrinol. (Lausanne) 2021;12 doi: 10.3389/fendo.2021.609470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.You J.H., Lee S.A., Chun S.Y., Song S.O., Lee B.W., Kim D.J., Boyko E.J. Clinical outcomes of COVID-19 patients with type 2 diabetes: a population-based study in Korea. Endocrinol. Metabol. 2020;35(4):901–908. doi: 10.3803/EnM.2020.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Izzi-Engbeaya C., Distaso W., Amin A., Yang W., Idowu O., Kenkre J.S., Shah R.J., Woin E., Shi C., Alavi N., Bedri H. Adverse outcomes in COVID-19 and diabetes: a retrospective cohort study from three London teaching hospitals. BMJ. Open Diabetes Res. Care. 2021;9(1) doi: 10.1136/bmjdrc-2020-001858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hui Y., Li Y., Tong X., Wang Z., Mao X., Huang L., Zhang D. The risk factors for mortality of diabetic patients with severe COVID-19: a retrospective study of 167 severe COVID-19 cases in Wuhan. PLoS. One. 2020;15(12) doi: 10.1371/journal.pone.0243602. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Richardson S., Hirsch J.S., Narasimhan M., Crawford J.M., McGinn T., Davidson K.W., Barnaby D.P., Becker L.B., Chelico J.D., Cohen S.L., Cookingham J. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052–2059. doi: 10.1001/jama.2020.6775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Goyal P., Choi J.J., Pinheiro L.C., Schenck E.J., Chen R., Jabri A., Satlin M.J., Campion T.R., Jr, Nahid M., Ringel J.B., Hoffman K.L. Clinical characteristics of Covid-19 in New York city. N. Engl. J. Med. 2020;382(24):2372–2374. doi: 10.1056/NEJMc2010419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Holman N., Knighton P., Kar P., O'Keefe J., Curley M., Weaver A., Barron E., Bakhai C., Khunti K., Wareham N.J., Sattar N. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet. Diabetes. Endocrinol. 2020;8(10):823–833. doi: 10.1016/S2213-8587(20)30271-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Moher D., Liberati A., Tetzlaff J., Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int. J. Surg. 2010;8(5):336–341. doi: 10.1016/j.ijsu.2010.02.007. [DOI] [PubMed] [Google Scholar]
- 18.Russo M.W. How to review a meta-analysis. Gastroenterol. Hepatol. (N. Y) 2007;3(8):637. [PMC free article] [PubMed] [Google Scholar]
- 19.Shang L., Shao M., Guo Q., Shi J., Zhao Y., Xiaokereti J., Tang B. Diabetes mellitus is associated with severe infection and mortality in patients with COVID-19: a systematic review and meta-analysis. Arch. Med. Res. 2020;51(7):700–709. doi: 10.1016/j.arcmed.2020.07.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Aggarwal G., Lippi G., Lavie C.J., Henry B.M., Sanchis-Gomar F. Diabetes mellitus association with coronavirus disease 2019 (COVID-19) severity and mortality: a pooled analysis. J. Diabetes. 2020;12:851–855. doi: 10.1111/1753-0407.13091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Varikasuvu S.R., Dutt N., Thangappazham B., Varshney S. Diabetes and COVID-19: a pooled analysis related to disease severity and mortality. Prim. Care. Diabetes. 2021;15(1):24–27. doi: 10.1016/j.pcd.2020.08.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Mantovani A., Byrne C.D., Zheng M.H., Targher G. Diabetes as a risk factor for greater COVID-19 severity and in-hospital death: a meta-analysis of observational studies. Nutr,. Metabol. Cardiov. Diseases. 2020;30(8):1236–1248. doi: 10.1016/j.numecd.2020.05.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Guo L., Shi Z., Zhang Y., Wang C., Do Vale Moreira N.C., Zuo H., Hussain A. Comorbid diabetes and the risk of disease severity or death among 8807 COVID-19 patients in China: a meta-analysis. Diabetes Res. Clin. Pract. 2020;166 doi: 10.1016/j.diabres.2020.108346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Kumar A., Arora A., Sharma P., Anikhindi S.A., Bansal N., Singla V., Khare S., Srivastava A. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Clin. Res. Rev. 2020;14(4):535–545. doi: 10.1016/j.dsx.2020.04.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Hussain S., Baxi H., Chand Jamali M., Nisar N., Hussain M.S. Burden of diabetes mellitus and its impact on COVID-19 patients: a meta-analysis of real-world evidence. Diabetes. Metab. Syndr. 2020;14(6):1595–1602. doi: 10.1016/j.dsx.2020.08.014. Nov-Dec. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Wu Z.H., Tang Y., Cheng Q. Diabetes increases the mortality of patients with COVID-19: a meta-analysis. Acta. Diabetol. 2020;58(2):139–144. doi: 10.1007/s00592-020-01546-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Huang I., Lim M.A., Pranata R. Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia–a systematic review, meta-analysis, and meta-regression. Clin. Res. Rev. 2020;14(4):395–403. doi: 10.1016/j.dsx.2020.04.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Tian W., Jiang W., Yao J., Nicholson C.J., Li R.H., Sigurslid H.H., Wooster L., Rotter J.I., Guo X., Malhotra R. Predictors of mortality in hospitalized COVID-19 patients: a systematic review and meta-analysis. J. Med. Virol. 2020;92(10):1875–1883. doi: 10.1002/jmv.26050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Nandy K., Salunke A., Pathak S.K., Pandey A., Doctor C., Puj K., Sharma M., Jain A., Warikoo V. Coronavirus disease (COVID-19): a systematic review and meta-analysis to evaluate the impact of various comorbidities on serious events. Clin. Res. Rev. 2020;14(5):1017–1025. doi: 10.1016/j.dsx.2020.06.064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Qiu P., Zhou Y., Wang F., Wang H., Zhang M., Pan X., Zhao Q., Liu J. Clinical characteristics, laboratory outcome characteristics, comorbidities, and complications of related COVID-19 deceased: a systematic review and meta-analysis. Aging. Clin. Exp. Res. 2020;32(9):1869–1878. doi: 10.1007/s40520-020-01664-3. Sep. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Lu L., Zhong W., Bian Z., Li Z., Zhang K., Liang B., Zhong Y., Hu M., Lin L., Liu J., Lin X. A comparison of mortality-related risk factors of COVID-19, SARS, and MERS: a systematic review and meta-analysis. J. Infect. 2020;81(4):e18–e25. doi: 10.1016/j.jinf.2020.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Mesas A.E., Cavero-Redondo I., Álvarez-Bueno C., Sarriá Cabrera M.A., Maffei de Andrade S., Sequí-Dominguez I., Martínez-Vizcaíno V. Predictors of in-hospital COVID-19 mortality: a comprehensive systematic review and meta-analysis exploring differences by age, sex and health conditions. PLoS. One. 2020;15(11) doi: 10.1371/journal.pone.0241742. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Dorjee K., Kim H., Bonomo E., Dolma R. Prevalence and predictors of death and severe disease in patients hospitalized due to COVID-19: a comprehensive systematic review and meta-analysis of 77 studies and 38,000 patients. PLoS. One. 2020;15(12) doi: 10.1371/journal.pone.0243191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Ng W.H., Tipih T., Makoah N.A., Vermeulen J.G., Goedhals D., Sempa J.B., Burt F.J., Taylor A., Mahalingam S. Comorbidities in SARS-CoV-2 Patients: a systematic review and meta-analysis. mBio. 2021;12(1) doi: 10.1128/mBio.03647-20. e03647-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ssentongo P., Ssentongo A.E., Heilbrunn E.S., Ba D.M., Chinchilli V.M. Association of cardiovascular disease and 10 other pre-existing comorbidities with COVID-19 mortality: a systematic review and meta-analysis. PLoS. One. 2020;15(8) doi: 10.1371/journal.pone.0238215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Javanmardi F., Keshavarzi A., Akbari A., Emami A., Pirbonyeh N. Prevalence of underlying diseases in died cases of COVID-19: a systematic review and meta-analysis. PLoS. One. 2020;15(10) doi: 10.1371/journal.pone.0241265. 23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Zhou Y., Yang Q., Chi J., Dong B., Lv W., Shen L., Wang Y. Comorbidities and the risk of severe or fatal outcomes associated with coronavirus disease 2019: a systematic review and meta-analysis. Int. J. Infect. Dis. 2020;99:47–56. doi: 10.1016/j.ijid.2020.07.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Biswas M., Rahaman S., Biswas T.K., Haque Z., Ibrahim B. Association of sex, age, and comorbidities with mortality in COVID-19 patients: a systematic review and meta-analysis. Intervirology. 2020;9:1–12. doi: 10.1159/000512592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Gold M.S., Sehayek D., Gabrielli S., Zhang X., McCusker C., Ben-Shoshan M. COVID-19 and comorbidities: a systematic review and meta-analysis. Postgrad. Med. 2020;132(8):749–755. doi: 10.1080/00325481.2020.1786964. [DOI] [PubMed] [Google Scholar]
- 40.Zheng Z., Peng F., Xu B., Zhao J., Liu H., Peng J., Li Q., Jiang C., Zhou Y., Liu S., Ye C. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J. Infect. 2020;81(2):e16–e25. doi: 10.1016/j.jinf.2020.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Espinosa O.A., Zanetti A.D.S., Antunes E.F., Longhi F.G., Matos T.A., Battaglini P.F. Prevalence of comorbidities in patients and mortality cases affected by SARS-CoV2: a systematic review and meta-analysis. Rev. Inst. Med. Trop. Sao. Paulo. 2020 Jun 22;62:e43. doi: 10.1590/S1678-9946202062043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Chidambaram V., Tun N.L., Haque W.Z., Majella M.G., Sivakumar R.K., Kumar A., Hsu A.T.W., Ishak I.A., Nur A.A., Ayeh S.K., Salia E.L. Factors associated with disease severity and mortality among patients with COVID-19: a systematic review and meta-analysis. PLoS. One. 2020;15(11) doi: 10.1371/journal.pone.0241541. [DOI] [PMC free article] [PubMed] [Google Scholar]