Postoperative short-term mortality between insulin-treated and non-insulin-treated patients with diabetes after non-cardiac surgery: a systematic review and meta-analysis

Background: Diabetes mellitus is an independent risk factor for postoperative complications. It has been reported that insulin-treated diabetes is associated with increased postoperative mortality compared to non-insulin-treated diabetes after cardiac surgery; however, it is unclear whether this finding is applicable to non-cardiac surgery.

Objective: We aimed to assess the effects of insulin-treated and non-insulin-treated diabetes on short-term mortality after non-cardiac surgery.

Methods: Our study was a systematic review and meta-analysis of observational studies. PubMed, CENTRAL, EMBASE, and ISI Web of Science databases were searched from inception to February 22, 2021. Cohort or case-control studies that provided information on postoperative short-term mortality in insulin-treated diabetic and non-insulin-treated diabetic patients were included. We pooled the data with a random-effects model. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to rate the quality of evidence.

Results: Twenty-two cohort studies involving 208,214 participants were included. Our study suggested that insulin-treated diabetic patients was associated with a higher risk of 30-day mortality than non-insulin-treated diabetic patients [19 studies with 197,704 patients, risk ratio (RR) 1.305; 95% confidence interval (CI), 1.127 to 1.511; p < 0.001]. The studies were rated as very low quality. The new pooled result only slightly changed after seven simulated missing studies were added using the trim-and-fill method (RR, 1.260; 95% CI, 1.076–1.476; p = 0.004). Our results also showed no significant difference between insulin-treated diabetes and non-insulin-treated diabetes regarding in-hospital mortality (two studies with 9,032 patients, RR, 0.970; 95% CI, 0.584–1.611; p = 0.905).

Conclusion: Very-low-quality evidence suggests that insulin-treated diabetes was associated with increased 30-day mortality after non-cardiac surgery. However, this finding is non-definitive because of the influence of confounding factors.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021246752, identifier: CRD42021246752.

1. Introduction

Diabetes comprises a group of metabolic disorders that is characterized by hyperglycemia, and it is a rapidly growing health problem worldwide, affecting the quality of life; diabetes had the ninth highest global mortality rate in 2010 (1–3). The International Diabetes Federation estimated that the prevalence of diabetes among adult women and men was 8.4 and 8.9%, respectively, in 2017. It is estimated the prevalence of diabetes in men and women would have increased to 9.9% by 2045 (4). The proportion of patients with diabetes who were undergoing cardiac surgery and non-cardiac surgery increased from 12.3% in 1995 to 21.2% in 2009 (5), and from 20.3% in 2004 to 25.4% in 2013 (6), respectively.

Compared to patients without diabetes, those with diabetes have a higher risk of postoperative complications, including postoperative pneumonia, wound complications, delayed wound healing, unplanned readmission, unplanned reoperation, and extended length of hospital stay (7–14). Diabetes can be divided into insulin-treated diabetes and non-insulin-treated diabetes according to the treatment regimen (15). Insulin-treated diabetes is not necessarily type 1 diabetes; it may also be type 2 diabetes that cannot be controlled with oral hypoglycemic drugs (16). Therefore, insulin-treated diabetes may be an indicator of the degree of progression of type 2 diabetes.

Meta-studies have shown that patients with insulin-treated diabetes have a higher short-term postoperative mortality risk compared to those with non-insulin-treated diabetes during cardiac surgery (17, 18). However, no such meta-analysis has been performed for non-cardiac surgery. According to a report, diabetes treated with insulin alone was an independent risk factor for death 30 days after surgery compared with diabetes treated with oral hypoglycemic drugs alone (19). The Revised Cardiac Risk Index included insulin-treated diabetes as a predictor of cardiac risk after non-cardiac surgery (20). Notably, although studies have reported higher short-term postoperative mortality in insulin-treated diabetes than in non-insulin-treated diabetes, there was no correlation between insulin-treated diabetes and postoperative mortality in multivariate logistic regression analysis (21–23). Another study also showed that in elderly patients with coronary artery disease or heart failure, insulin exposure 3 months before surgery was not associated with 30-day mortality after non-cardiac surgery (24). One study held the opposite view (25); among patients with coronary artery disease, diabetes treated with oral hypoglycemic agents was associated with a higher 2-year all-cause mortality than diabetes treated with insulin after non-cardiac surgery (25). To date, there is disagreement regarding postoperative mortality between insulin-treated diabetes and non-insulin-treated diabetes in non-cardiac surgery. Insulin-treated diabetes has been associated with more diabetes-related comorbidities and coexisting medical conditions than non-insulin-treated diabetes, and diabetes-related comorbidities and coexisting medical conditions were independent risk factors for death 30 days after non-cardiac surgery (19, 22, 26).

Therefore, we hypothesized that in non-cardiac surgery, insulin-treated diabetes would not be associated with postoperative mortality compared with non-insulin-treated diabetes after controlling for confounding factors. Patients with insulin-treated diabetes and those with non-insulin-treated diabetes were grouped according to long-term hypoglycemic regimens before admission. Considering that the hypoglycemic regimens of patients with diabetes may change after surgery, we determined the outcome as short-term postoperative mortality, including 30-day mortality and in-hospital mortality. In summary, we performed a meta-analysis of observational studies that assessed the effect of insulin-treated diabetes and non-insulin-treated diabetes on short-term mortality after non-cardiac surgery.

2. Methods

This study was conducted according to the Meta-analyses of Observational Studies in Epidemiology (MOOSE) (27). This study was registered with PROSPERO (CRD42021246752).

2.1. Data sources and search strategy

We comprehensively searched PubMed, EMBASE, CENTRAL (Cochrane Library), and Web of Science databases from inception to February 22, 2021. The retrieval strategies for each database are described in Supplementary Digital Content 1 (see Text document, Supplementary Digital Content 1, which demonstrates search strategies). The reference lists of relevant reviews were also identified.

2.2. Inclusion and exclusion criteria

We included studies that met each of the following criteria: (1) cohort or case-control studies; (2) inclusion of patients with diabetes who were undergoing non-cardiac surgery; (3) availability of information on 30-day mortality or in-hospital mortality regarding insulin-treated diabetes and non-insulin-treated diabetes; (4) insulin-treated diabetes and non-insulin-treated diabetes grouped according to long-term hypoglycemic regimens before admission; (5) insulin-treated diabetes referred to patients with diabetes who were receiving long-term insulin treatment before admission, including a combination of insulin and non-insulin therapy; and (6) non-insulin-treated diabetes referred to patients with diabetes who were receiving long-term non-insulin treatment before admission, excluding those who received only diet or lifestyle modifications.

We excluded studies that met any of the following criteria: (1) patients were not grouped according to pre-admission diabetes treatment regimens; (2) after contacting the authors three times, the relative risk (RR) of death and its 95% confidence interval (CI) or the odds ratio (OR) and its 95% CI or the number of deaths were not available; and (3) duplicate publications, comprising duplicate publications in different languages, duplicate publications of the same data in the same database, and articles published using the same data in the same research. Duplicate publications in different languages were translated into English using online translation software and were included as one study. For articles that collected the same data from the same database and led to repeated publications, priority was given to studies that had controlled for confounding factors. If the effect size adjusted for confounding factors was unavailable, then the latest published study was selected. For articles published using the same data in the same study, all articles were comprehensively analyzed and included as one study.

There were no language restrictions on search strategies. Non-English articles were translated into English using an online translation software.

2.3. Study selection

Two reviewers (RS and JJ) independently screened the titles and abstracts after using document management software to remove duplicate articles. Full-text analyses of studies that met the inclusion criteria were conducted. Finally, the included studies were determined based on the inclusion and exclusion criteria. Any differences were resolved through discussion.

2.4. Data extraction

Regarding the studies to be included, RS and JJ extracted the following data from the studies: the first author, publication year, study type, surgery type, demographic information of patients with insulin-treated diabetes and non-insulin-treated diabetes, RR or OR of postoperative mortality, and adjusted factors. Any differences were resolved through discussion. We extracted the death outcomes of different surgical types reported in a study.

2.5. Quality assessment

The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the studies (28). A study with a score of ≥7 points was considered high quality (29, 30). In the comparability score criteria, complications and comorbidities of patients with diabetes at admission were considered the most important confounding factors. Age and American Society of Anesthesiologists (ASA) scores were considered the second most important confounding factors.

2.6. Data analyses

In the present study, 30-day mortality was the primary outcome, and hospital mortality was the secondary outcome. We chose the adjusted RR or OR of death to pool the data. Since the 30-day and hospital mortality after non-cardiac surgery are very low, the OR can be considered an approximate estimate of RR. Therefore, for studies in which the adjusted RR was unavailable, the adjusted OR was extracted. For studies in which neither the adjusted RR nor OR was available, we directly extracted or calculated the crude RR or OR to pool data. Although one study reported the outcome of interest, the number of deaths in both cohorts was zero. Since the RR or OR of this study could not be calculated, the data of this study was not pooled with the data of other studies. However, clinical heterogeneity was unavoidable. Therefore, a random-effects model using the DerSimonian-Laird method was used to pool the data.

A standard chi-squared test with a significance level of α = 0.1 and the I² statistic were used to assess the magnitude of heterogeneity. P ≤ 0.1 or I² ≥ 50% was considered to indicate significant heterogeneity. The source of heterogeneity was explored using subgroup and sensitivity analyses. We conducted subgroup analysis by age, surgery type, RR/OR type, NOS comparability score, and mortality type. Sensitivity analysis was performed by restricting the meta-analysis to studies with a NOS score of ≥7 points and studies that controlled for complications and comorbidities of patients with diabetes based on the design or analysis. We excluded studies one by one to assess the impact of a single study. We used the funnel plot, Begg's test, and Egger's test to evaluate publication bias. If publication bias seemed present, we used the trim-and-fill method to describe its potential impact (31). All statistical analyses were performed with STATA version 15.0. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the level of evidence (32).

3. Results

A total of 17,265 studies were retrieved, and 22 studies were eventually included (15, 16, 19, 22, 23, 33–49). Details of the screening process are shown in Figure 1. The excluded articles through full-text evaluation and the reasons for exclusion can be found in Supplemental Digitary Content 2 (see Text document, Supplementary Digital Content 2, which demonstrates excluded studies).

FIGURE 1

Figure 1. Study selection.

3.1. Characteristics of the included studies

Twenty-two studies were included, involving 208,214 patients with diabetes, of which 70,806 were insulin-treated and 137,408 were non-insulin-treated. The average age of participants in 15 studies was over 60 years (15, 19, 22, 33–35, 38–41, 43–46, 49), while the average age of participants in four studies was <60 years (37, 42, 47, 48). We were unable to determine the average age in three studies (16, 23, 36). The type of surgery in one study was breast reconstruction surgery; therefore, only female patients were included (37). Another study was based on the Department of Veterans Affairs Patient Treatment File database; therefore, 99% of the study population was male (33). In the remaining studies, the proportion of men ranged from 29.94 to 68.6%. Two studies in the study population only included patients with type 2 diabetes (19, 35). Detailed characteristics of the study are presented in Table 1.

TABLE 1

Table 1. Characteristics of the included trials.

The NOS scores of the studies ranged from 4 to 7 points. Most of them scored five points. Only two studies were rated as high quality (38, 47). The details of the NOS scores are shown in Table 2. Regarding the comparability score, only three studies controlled for the most important confounding factor (36, 38, 47), and only three studies controlled for the second most important confounding factor (23, 38, 47).

TABLE 2

Table 2. Newcastle-Ottawa Scale (cohort studies).

3.2. Thirty-day mortality

The 20 included studies provided information on the outcome of 30-day mortality. Because four studies provided death outcomes for different types of surgery (23, 36, 37, 39), there were 24 groups of postoperative death data. Because the death outcomes of insulin-treated diabetes and non-insulin-treated diabetes in one study were both zero events (37), the data from this study could not be combined with data from other studies. Finally, 22 sets of data (19 studies, 206,736 participants) were pooled. Among these 22 sets, five were the adjusted OR, and the remaining 17 were the crude RR. A random-effects model was used to pool all the data, and a significant difference was found (RR, 1.305; 95% CI, 1.127–1.511; p < 0.001; Figure 2), suggesting that insulin-treated diabetes had a higher risk of 30-day mortality compared to non-insulin-treated diabetes. The quality of evidence was rated as very low. The details of the GRADE summary of the findings are shown in Supplementary Digital Content 3 (see Table, Supplementary Digital Content 3, which demonstrates GRADE).

FIGURE 2

Figure 2. Forest plot for risk of 30-day mortality.

We conducted subgroup analyses by the age of participants, type of surgery, RR/OR type, and comparability score of NOS (Supplemental Digital Content 4). In the subgroups of aged ≥ 60 years, orthopedic surgery, general surgery, upper extremity surgery, crude RR, adjusted OR, comparability score of 0-point, 1-point and 2-point, the results showed a higher risk of 30-day mortality of insulin-treated diabetes compared to non-insulin-treated diabetes. In the subgroups of aged <60 years, vascular surgery, ventral hernia repair, bariatric surgery, emergency abdominal surgery, tonsillectomy, major non-cardiac surgery, the results showed a similar 30-day mortality between insulin-treated diabetes and non-insulin-treated diabetes.

The details of the subgroup analysis are presented in Table 3.

TABLE 3

Table 3. Results of subgroup and sensitivity analyses for risk of 30-day mortality.

We also conducted sensitivity analysis. Limiting the analysis to studies with a NOS score ≥ 7, the results were consistent with the original analysis (RR, 1.182; 95% CI, 1.002–1.393; p = 0.047). Limiting the analysis to the studies that controlled for complications and comorbidities of patients with diabetes based on the design or analysis, the results were consistent with the original analysis (RR, 1.157; 95% CI, 1.042–1.286; p = 0.006). The included studies were excluded one by one, and no single study had a noticeable influence on the total combined effect size (see Text document, Supplementary Digital Content 4, which demonstrates sensitivity analysis).

The publication bias was evaluated. The funnel plot appeared asymmetrical (see Text document, Supplementary Digital Content 5, which demonstrates funnel plot). Significant publication bias was detected using Egger's test (bias = 0.88; 95% CI, 0.31–1.44; p = 0.004). After using the trim-and-fill method, the new pooled effect size from the random-effects model was similar to the primary result (RR, 1.260; 95% CI, 1.076–1.476; p = 0.004). A new funnel plot after adding seven simulated missing studies is presented in Supplementary Digital Content 6 (see Text document, Supplementary Digital Content 6, which demonstrates new funnel plot).

3.3. Hospital mortality

Two included studies provided information on the outcome of hospital mortality. A random-effects model was used to pool the data, and no significant difference was found (RR, 0.970; 95% CI, 0.584–1.611; p = 0.905; Figure 3) between insulin-treated diabetes and non-insulin-treated diabetes, suggesting that the two groups had a similar hospital mortality. The quality of evidence was rated as very low. The details of the GRADE summary of the findings are shown in Supplementary Digital Content 3 (see Table, Supplementary Digital Content 3, which demonstrates GRADE).

FIGURE 3

Figure 3. Forest plot for risk of in-hospital mortality.

As only two studies were included in the outcome, we did not conduct subgroup analysis, sensitivity analysis or evaluate publication bias.

4. Discussion

Our study demonstrated that compared with non-insulin-treated diabetes, insulin-treated diabetes was associated with a higher risk of 30-day mortality, but a similar risk of in-hospital mortality after surgery. The quality of the evidence was rated as very low.

4.1. Comparison with the published literature

Our findings are consistent with two previously published systematic reviews of cardiac surgery that found that insulin-treated diabetes had a significantly higher risk of short-term mortality (<1 year) after percutaneous coronary intervention (18) and a significantly higher risk of short-term mortality (≤ 30 days) after coronary artery bypass surgery compared with non-insulin-treated diabetes (17).

Although all the included studies provided postoperative death outcomes for insulin-treated diabetes and non-insulin-treated diabetes, only seven studies specifically compared postoperative mortality outcomes between insulin-treated and non-insulin-treated diabetes (19, 22, 23, 33, 36, 38, 47). Only one study found that insulin-treated diabetes was associated with increased postoperative mortality compared to non-insulin-treated diabetes (19). However, in this study, the relationship only held for insulin-only diabetes, and did not include diabetes treated both with and without insulin.

It has also been reported that neither diabetes nor insulin exposure is an independent risk factor for death at 30 days after non-cardiac surgery in 65-year-old patients with coronary artery disease or heart failure (24). Among studies with longer follow-up times after non-cardiac surgery, some studies found insulin-treated diabetes to be an independent risk factor for postoperative death compared with non-insulin-treated diabetes (50, 51), while one study found no association (52). One study found that oral hypoglycemic therapy, but not insulin therapy, was associated with non-cardiac mortality at 2 years in patients at coronary risk (25).

4.2. Strengths

Our study had several strengths. First, to our knowledge, it is the first systematic review comparing short-term postoperative mortality between insulin-treated diabetes and non-insulin-treated diabetes in non-cardiac surgery. Second, we screened 17,265 articles and finally included 22 studies that comprised 208,214 patients with diabetes; thus, our study comprised a notably large number of patients. Third, no significant heterogeneity was found in our study (I²= 22.5%, p = 0.159). Although there was significant publication bias, the new pooled result was only slightly changed after adding the simulated missing study using the trim-and-fill method, suggesting that the effect of publication bias on the result might be small. Fourth, of the studies we included, only two included type 2 diabetes (19, 35). The remaining 21 studies did not clarify the type of diabetes. The patients were grouped based on prehospital hypoglycemic regimens. This shows that our conclusions are practical.

4.3. Implications for clinicians, policy, and research

Our study showed that insulin-treated diabetes and non-insulin-treated diabetes had a similar risk of in-hospital mortality after surgery. However, only two studies were included in the outcome, thus, the findings may be not reliable. Our study also showed that in non-cardiac surgery, the 30-day mortality of insulin-treated patients with diabetes was higher than that of non-insulin-treated diabetes patients. This suggests that prehospital hypoglycemic regimens might be one of the bases for the preoperative risk stratification of patients with diabetes. However, it must be noted that because of the generally low quality of the originally included studies, this conclusion may be unreliable. In particular, only three studies controlled the bias of comorbidities and complications of patients with diabetes in the study design or data analysis. Only one of the originally included studies found that type 2 diabetes treated with insulin alone was an independent risk factor for short-term postoperative death compared with diabetes treated with oral hypoglycemic agents alone. However, the results of the study might be explained by its inclusion of more patients with a history of myocardial infarction, more patients with a history of coronary artery bypass graft, more patients with a history of heart failure, and a higher ASA grade in the insulin-only group. Surprisingly, insulin-treated diabetes was still associated with increased postoperative mortality but with a reduced effect size in our sensitivity analyses that included only studies that controlled for comorbidities and complications and only high-quality studies. This suggests on the one hand that confounders caused an overestimation of the effect size, and on the other hand, long-term prehospital hypoglycemic regimens might indeed influence short-term postoperative mortality. This might be related to the long-term cardiovascular protective effects of oral hypoglycemic agents (53–55).

In published models predicting postoperative cardiac complications for non-cardiac surgery, the Revised Cardiac Risk Index included preoperative treatment with insulin as a risk factor (20), while the Geriatric-Sensitive Perioperative Cardiac Risk Index included diabetes as a risk factor (56). Although it is still not clear whether the hypoglycemic regimen or the severity of the patient's condition leads to increased short-term postoperative mortality, our current results still tended to stratify diabetes patients according to prehospital hypoglycemic regimens and assign insulin-treated diabetes with a higher risk level.

Sensitivity and subgroup analyses with adjusted effect sizes showed that insulin-treated diabetes was an independent risk factor. However, in the subgroup analysis of surgical types, only the subgroup of orthopedic surgery and vascular surgery could be further analyzed, while the number of studies on other surgical types was too small to be further analyzed. In the vascular surgery subgroup, insulin-treated diabetes was not associated with increased 30-day mortality. This suggests that there is a need to further distinguish the risks of long-term hypoglycemic regimens between different surgical types. There was no association between insulin-treated diabetes and 30-day mortality in the subgroup of age <60 years. This indicates that our results may not be applicable to all populations. It is also possible that the severity of diabetes might be similar in patients undergoing vascular surgery or in patients aged <60 years. However, our current research was unable to answer this question; thus, well-designed and high-quality research are required to answer these questions in the future.

5. Limitation

The most notable limitation of our study is that the quality of most of the originally included studies was not high. Of the 22 studies, only two were rated as high-quality studies. Diabetes-related complications and comorbidities were independent risk factors for non-cardiac postoperative 30-day mortality (26). Age and ASA grade were also listed as risk factors for major adverse cardiovascular events and mortality within 30 days after surgery (56–58). Therefore, we regarded diabetes-related complications and comorbidities as the most important confounding factors, while age and ASA grade were the second most important confounding factors. Of the 22 studies included, only three controlled for diabetes-related complications and comorbidities, and only three controlled for age and ASA classification. The evidence quality rating was very low. This showed that the results obtained are uncertain.

In the subgroup analysis, the results of the vascular surgery and age <60 subgroups were not consistent with the original analysis. Thus, our study conclusions may not be applicable to all surgery types and populations.

6. Conclusion

Our study showed that insulin-treated diabetes was associated with an increased risk of 30-day mortality after non-cardiac surgery compared with non-insulin-treated diabetes. The quality of the evidence was rated as very low. As it is difficult to rule out the influence of confounding factors, we believe that the results obtained are not reliable. Well-designed, high-quality studies that controls for important confounding factors is needed to investigate the impact of prehospital hypoglycemic regimens on short-term mortality after non-cardiac surgery.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

JJ and SW: methodology and writing—original draft preparation. RS and SL: data curation and writing—review and editing. YZ and ZZ: methodology and writing—editing. JB: data curation and funding acquisition. AL: funding acquisition and supervision. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by China National Key R&D (Program No. 2020YFC2009002) and grants from the National Natural Science Foundation of China (Grant Nos. 81771159 and 81974160 to AL, 82001161 to JB).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2023.1142490/full#supplementary-material

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