Insulin Treatment Is Associated with Increased Mortality in Patients with COVID-19 and Type 2 Diabetes

A total of 689 consecutive patients with T2D who died or discharged from a cohort of 3,305 hospitalized patients with confirmed COVID-19 from Tongji Hospital, Wuhan, China, were included in this study (Figure 1). Among the patients with T2D, 364 patients (52.8%) were male and 325 (47.2%) were female (Table 1). The median age was 66 (IQR 55–73) years. A total of 346 of these patients received insulin alone or with other anti-diabetic medications for at least 3 days (Insulin group). The remaining 343 patients were treated with (or without) other antidiabetic drugs but without insulin (Non-insulin group). The median ages in the Insulin group and the Non-insulin group were 67 (IQR 58–75) and 65 (IQR 56–71) years (p = 0.019), respectively. Male patients were 187 (54.0%) in the Insulin group and 177 (51.6%) in the Non-insulin group (p = 0.521). There were no significant differences between the two subgroups in other underlying diseases, including hypertension (p = 0.087), coronary heart disease (p = 0.298), COPD (p = 0.727), and chronic kidney disease (p = 0.990). There were no significant differences in major symptoms at baseline between the two groups either (Table 1).

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Figure 1. The Flowchart of Study Design

The baseline laboratory test results of all patients and the propensity score-matched subpopulations between the two groups were presented in Table 2. In the overall population, the patients from the Insulin group had higher levels of white cell count, neutrophil count, aspartate aminotransferase, total bilirubin, lactate dehydrogenase, blood urea nitrogen, NT-ProBNP, cTnI, international normalized ratio, D-dimer, C-reactive protein, IL-6, IL-10, IL-8, IL-2R, and TNF-α compared with the Non-insulin group patients (p < 0.05). In contrast, the levels of lymphocyte count, platelet count, and albumin were lower in patients from the Insulin group than the Non-insulin group (p < 0.05). Furthermore, baseline levels of fasting blood glucose and HbA1c were also significantly different between the two groups at admission (p < 0.05). However, no differences in hemoglobin (p = 0.764), alanine aminotransferase (p = 0.132), creatinine (p = 0.675), APTT (p = 0.839), and IL-1β (p = 0.114) levels were observed between the two groups. After propensity score matching, the baseline characteristics for the matched subpopulations of patients were comparable between the Insulin group and the Non-insulin group (almost all p > 0.05).

All patients received standard treatments for COVID-19 symptoms, according to the Clinical Guideline for COVID-19 Diagnosis and Treatment published by the National Health Commission of China (National Health Commission of the People’s Republic of China, 2020). However, as shown in Table 3, significant differences in certain treatments were noted between Insulin and Non-insulin groups, including the types of antidiabetic drugs (26.3% versus 38.5% of metformin, p < 0.05; 9.2% versus 22.4% of sulfonylureas, p < 0.05), antibacterial treatment (77.2% versus 65.6%, p < 0.05), glucocorticoids (52.6% versus 24.5%, p < 0.05), and oxygen therapy (86.4% versus 73.2%, p < 0.05). There were no differences in the application of glucosidase inhibitors (p = 0.271), dipeptidyl peptidase-4 (DPP-4) inhibitors (p = 0.536), insulin-sensitizing agents (p = 0.065), and antiviral treatment (p = 0.657) between Insulin and Non-insulin groups.

Among the entire cohort of 689 patients with COVID-19 and T2D, a total of 106 patients died (mortality 15.4%), including 94 out of 346 in the Insulin group (27.2%) and 12 out of 343 in the Non-insulin group (3.5%, chi-square test, p < 0.001). The median hospital stay durations were 22 days for the Insulin group and 20 days for the Non-insulin group (p = 0.431) (Table 4). However, for discharged patients, median hospitalization time was significantly longer for the insulin-treated patients than the non-insulin-treated patients (26 versus 20 days, p < 0.001).

The Kaplan-Meier survival analysis showed a significantly poorer survival in patients with T2D treated with insulin compared with patients with T2D without insulin treatment (log-rank, p < 0.001) (Figure 2A). According to Schoenfeld’s global test, the insulin treatment groups did not violate the proportional hazard assumption in all Cox regression models. Thus, the proportional Cox regression method was used to analyze the influence of insulin treatment on death as the primary outcome. The results from Cox regression showed the risk of all-cause mortality was higher in the insulin-treated group (crude HR, 7.70; 95% CI, 4.22–14.05; p < 0.001). After further adjustments for age; gender; histories of hypertension, coronary heart disease, COPD, and chronic kidney disease; the baseline levels of SpO2, respiratory rate, pulse, glucose, lymphocyte, albumin, NT-proBNP, HbA1c, CRP, and IL-6; and poorly controlled glucose (glucose > 10 mmol/L on admission), patients treated with insulin still had a significantly lower survival rate than those without insulin treatment (adjusted HR, 5.38; 95% CI, 2.75–10.54; p < 0.001). In the propensity score-matched subcohorts, the use of insulin was associated with a 3.21-fold higher risk for all-cause mortality after adjustment for systolic blood pressure, white cell count, blood urea nitrogen, NT-ProBNP, D-dimer, and IL-6. In addition, in the propensity-matched cohorts, the deleterious effect of insulin manifested from day 7 after admission based on survival curve. This result suggests that long-term use of insulin (>7 days) might be harmful to patients with COVID-19 and T2D (Figure 2B). Furthermore, we compared the differences between groups with or without episodes of hypoglycemia in order to evaluate the effect of hypoglycemia on the observed higher mortality associated with insulin treatment. Among the patients with T2D without episodes of hypoglycemia during hospitalization, insulin treatment was still associated with higher mortality (25.66% [68/265] versus 3.53% [12/340], p < 0.001), with an adjusted HR at 6.85 (95% CI 1.22–38.45; p = 0.029). Furthermore, we performed a multivariable Cox regression analysis in all patients with T2D who had reported episodes of hypoglycemia. The result showed that insulin treatment was associated with a higher mortality compared to non-insulin treatment (adjusted HR, 5.19; 95% CI, 2.69–10.01; p < 0.001). All these results suggest that insulin treatment could increase the risk of patients with T2D independently from the onset of hypoglycemia. Indeed, in the propensity score-matched population, the use of insulin was still significantly associated with a worse clinical outcome (in-hospital mortality, 16.9% in the Insulin group versus 4.9% in the Non-insulin group; HR, 3.21; 95% CI, 1.37–7.54; p = 0.007) (Figure 2B).

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Figure 2. Kaplan-Meier Survival Curve for Patients with COVID-19 and T2D with and without Insulin Treatment

(A) Kaplan-Meier survival curve for all 689 patients with COVID-19 and T2D.

(B) Kaplan-Meier survival curve for patients with COVID-19 and T2D in the propensity score-matched subpopulation.

(C) Kaplan-Meier survival curve for critically ill patients with COVID-19 with T2D. Log-rank; p < 0.05 indicated statistical significance.

In order to evaluate the impact of insulin treatment on patients with COVID-19 with different disease severity, we analyzed a subcohort of 201 patients with COVID-19 and T2D who were critically ill based on the criteria set by the Chinese clinical guideline for diagnosis and treatment of COVID-19 (National Health Commission of the People’s Republic of China, 2020). Among them, 145 received insulin treatment after becoming critically ill and 56 received no insulin treatment. In this subcohort of critically ill patients with COVID-19 and T2D, mortality was also markedly higher in patients treated with insulin than patients receiving no insulin treatment (57.24% [83/145] versus 21.43% [12/56], p < 0.001) (Figure 2C) (crude HR, 2.77; 95% CI, 1.51–5.09; p < 0.001; adjusted HR, 2.45; 95% CI, 1.25–4.81; p = 0.009). This conclusion remained valid even when the observation started from the date of admission (Figure S1). Therefore, insulin treatment was associated with significantly higher mortality in patients with COVID-19 and T2D, independent of COVID-19 severity. Furthermore, the associations of insulin treatment with the incidences of secondary outcomes were also explored. Except for acute liver injury, the incidences of all other secondary outcomes, including acute cardiac injury, acute kidney injury, invasive mechanical ventilation, transferring to intensive care unit, and episodes of hypoglycemia, were all higher in the patients treated with insulin compared with those without insulin treatment. In propensity score-matched subcohorts, the statistical differences were still significant for acute kidney injury, invasive mechanical ventilation, admission to intensive care unit, and hypoglycemia, but not for acute liver injury and acute cardiac injury (Table 5).

In patients with well-controlled glucose (≤10 mmol/L), the mortalities for the Insulin group versus the Non-insulin group were 31.55% (59/187) versus 2.69% (7/260) (p < 0.001), with a crude HR 11.52 (95% CI, 5.26–25.22; p < 0.001) and an adjusted HR 8.50 (95% CI, 3.04–23.75; p < 0.001) (Figure 3A). In patients with poorly controlled glucose (>10 mmol/L), the mortalities for the Insulin group versus the Non-insulin group were 22.00% (33/150) versus 5.71% (4/70) (p = 0.005), with a crude HR 3.93 (95% CI, 1.40–11.08, p = 0.010) and an adjusted HR 13.16 (95% CI, 1.49–116.44; p = 0.010) (Figure 3B). In patients with well-controlled HbA1c (<6.5%), the mortalities for the Insulin group versus the Non-insulin group were 35.71% (10/28) versus 2.86% (1/35) (p < 0.001), with a crude HR 18.50 (95% CI, 2.36–145.07; p = 0.006) and an adjusted HR 20.20 (95% CI, 2.52–159.19; p = 0.005) (Figure 3C), and again, in patients with poorly controlled HbA1c (≥6.5%), mortalities were 18.39% (16/87) versus 5.80% (4/69) (p = 0.038),with a crude HR 3.00 (95% CI, 1.01–9.00), p = 0.049 and an adjusted HR 3.26 (95% CI, 1.09–9.81; p = 0.035) (Figure 3D). In patients with normal lymphocyte count at admission (≥1.1 × 10⁹ /L), the mortalities for the Insulin group versus the Non-insulin group were 11.57% (14/121) versus 0.56% (1/178), with an adjusted HR 18.06 (95% CI, 2.14–152.34; p = 0.008) (Figure 3E), while in patients with low lymphocyte count at admission (<1.1 × 10⁹/L), the mortalities were 36.84% (77/209) versus 5.52% (8/145), with an adjusted HR 6.84 (95% CI, 3.12–14.99; p < 0.001) (Figure 3F). In patients with normal plasma albumin level on admission (≥35 g/L), the mortalities for the Insulin group versus the Non-insulin group were 11.61% (13/112) versus 1.60% (3/187), with an adjusted HR 4.38 (95% CI, 1.16–16.48; p = 0.029) (Figure 3G), and in patients with low albumin level (<35 g/L), the mortalities were 35.32% (77/218) versus 5.44% (8/147), with an adjusted HR 6.42 (95% CI, 2.94–14.03; p < 0.001) (Figure 3H). In patients with high NT-proBNP (>285 pg/mL) at admission, the mortalities for the Insulin group versus the Non-insulin group were 43.33% (65/150) versus 10.00% (8/80) (p < 0.001), with a crude HR 4.77 (95% CI, 2.29–9.95, p < 0.001) and an adjusted HR 4.37 (95% CI, 1.97–9.68; p < 0.001) (Figure 3I), while in patients with normal NT-proBNP at admission (≤285 pg/mL), the mortalities were 16.81% (19/113) versus 1.60% (3/188) (p < 0.001), with a crude HR 9.87 (95% CI, 2.92–33.42; p < 0.001) and an adjusted HR 13.59 (95% CI, 3.30–55.11; p < 0.001) (Figure 3J). In patients with high C-reactive protein (>10 mg/L) and high IL-6 (>7 pg/mL), the Kaplan-Meier survival curves also showed a lower survival rate in patients treated with insulin compared to the non-insulin treated (Figures 3K and 3L).

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Figure 3. Kaplan-Meier Survival Curve for Patients with COVID-19 and T2D with and without Insulin Treatment in Different Subgroups

(A) Kaplan-Meier survival curve for patients with COVID-19 and T2D with well-controlled glucose (≤10 mmol/L).

(B) Kaplan-Meier survival curve for patients with COVID-19 and T2D with poorly controlled glucose (>10 mmol/L).

(C) Kaplan-Meier survival curve for patients with COVID-19 and T2D with well-controlled HbA1c (<6.5%).

(D) Kaplan-Meier survival curve for patients with COVID-19 and T2D with poorly controlled HbA1c (≥6.5%).

(E) Kaplan-Meier survival curve for patients with COVID-19 and T2D with normal lymphocyte count on admission (≥1.1 × 10⁹/L).

(F) Kaplan-Meier survival curve for patients with COVID-19 and T2D with low lymphocyte count on admission (<1.1 × 10⁹/L).

(G) Kaplan-Meier survival curve for patients with COVID-19 and T2D with normal albumin on admission (≥35 g/L).

(H) Kaplan-Meier survival curve for patients with COVID-19 and T2D with low albumin on admission (<35 g/L).

(I) Kaplan-Meier survival curve for patients with COVID-19 and T2D with high NT-proBNP on admission (>285 pg/mL).

(J) Kaplan-Meier survival curve for patients with COVID-19 and T2D with low NT-proBNP on admission (≤285 pg/mL).

(K) Kaplan-Meier survival curve for patients with COVID-19 and T2D with high C-reactive protein on admission (>10 mg/L).

(L) Kaplan-Meier survival curve for patients with COVID-19 and T2D with high IL-6 (>7 pg/mL) on admission.

(M) Kaplan-Meier survival curve for patients with COVID-19 and newly diagnosed T2D.

(N) Kaplan-Meier survival curve for patients with COVID-19 and T2D less than 5 years.

(O) Kaplan-Meier survival curve for patients with COVID-19 and T2D more than 5 years. Log-rank; p < 0.05 indicated statistical significance.

Finally, we performed direct comparisons on mortalities in patients receiving insulin treatment versus patients receiving other anti-diabetic treatments either in the entire T2D cohort or in propensity score-matched subcohorts (Figures 4 and S3). The baseline characteristics were shown in Tables S7–S10. In the entire T2D cohort, we observed a consistently higher mortality in insulin-treated patients than patients receiving other anti-diabetic treatments, including metformin, α-glucosidase inhibitors, sulfonylureas, and DPP-4 inhibitors. More importantly, in the subcohort of patients after propensity score matching with comparable baseline characteristics, the results showed insulin treatment was still significantly associated with a higher mortality in comparison with all other anti-diabetic treatments (Figure 4). These results implicate a specific adverse effect of insulin treatment among current anti-diabetic therapies for patients with COVID-19 and T2D.

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Figure 4. Kaplan-Meier Survival Curve for Patients with COVID-19 and T2D with Insulin and Other Anti-diabetic Drugs after PSM

(A) Kaplan-Meier survival analysis of patients treated with insulin or metformin.

(B) Kaplan-Meier survival analysis of patients treated with insulin or α-glucosidase inhibitors.

(C) Kaplan-Meier survival analysis of patients treated with insulin or sulfonylureas.

(D) Kaplan-Meier survival analysis of patients treated with insulin or DPP-4 inhibitors.

PSM, propensity score matching. Log-rank; p < 0.05 indicated statistical significance.

To evaluate the temporal pattern of clinical manifestation following the administration of insulin, the dynamic profiles of vital signs (pulse, respiratory rate, systolic blood pressure, and diastolic blood pressure) and indicators of systemic inflammation and organ injuries (plasma levels of albumin, lymphocyte, NT-proBNP, hs-cTnI, hs-CRP, IL-6, and D-dimer) were analyzed and compared from day 2 to day 20 after admission at 4-day intervals. In the entire study cohort, patients in the Insulin group had higher rates of heartbeat and respiration than patients in the Non-insulin group at almost all time points during hospitalization. For instance, at the 12th day, median pulse rate was 80 beats/min (70–90 beats/min) for the Insulin group and 78 beats/min (69–85 beats/min) for the Non-insulin group (p = 0.009), while respiratory rate at the 12th day was 19 times/min (18–20 breaths/min) for the Insulin group and 20 times/min (18–21 breaths/min) for the Non-insulin group (p < 0.001). However, there were no significant differences in systolic blood pressure between the two groups, although at some points (8th and 20th day) the level of diastolic blood pressure for the Insulin group was lower than the Non-insulin group (p < 0.05). Additionally, most patients in the Insulin group showed abnormal levels of lymphocyte counts (indicator of immune system reaction), NT-proBNP (indicator of heart failure), albumin (indicator of liver dysfunction), hs-cTnI (indicator of myocardial injury), hs-CRP (indicator of inflammation), IL-6 (indicator of cytokine storm), and D-dimer (indicator of coagulation) throughout their hospitalization. In contrast, these indices were within normal ranges for most patients in the Non-insulin group. The dynamic changes of these parameters showed significant differences between the Insulin and Non-insulin groups (p < 0.05) as depicted in Figure 5. Interestingly, the NT-proBNP and hs-cTnI levels in the insulin-treated patients were elevated gradually during hospitalization and reached the highest levels around the 12th day after the beginning of insulin treatment (p < 0.05), indicating a potential association between insulin treatment and myocardial injury (Figures 5E and 5F). A similar temporal pattern of gradual induction was also observed for D-dimer levels in the Insulin group following the inception of insulin treatment during hospitalization (Figure 5I). Furthermore, in the propensity score-matched subcohorts, the baseline characteristics were comparable (Tables 1 and 2) and there were no differences in all vital signs or indicators of systemic inflammation and organ injuries at the onset of observation. However, following insulin treatment, the levels of NT-ProBNP, hs-cTnI, IL-6, and D-dimer were elevated gradually in the Insulin subgroup, while these indicators were reduced in the Non-insulin subgroup (p < 0.05) (Figure S5). These results support the hypothesis that insulin treatment may exacerbate inflammatory induction and aggravate injuries to vital organs during COVID-19 pathogenesis, and ultimately lead to increased mortality.

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Figure 5. Dynamic Profile of Vital Signs and Laboratory Parameters in All 689 Patients with COVID-19 and T2D with and without Insulin Treatment

(A) Dynamic change of pulse rates.

(B) Dynamic change of diastolic blood pressure.

(C) Dynamic change of albumin; the dashed line in black shows the upper normal limit of albumin (35 g/L).

(D) Dynamic change of lymphocyte count; the dashed line in black shows the lower normal limit of lymphocyte count (1.1 × 10⁹/L).

(E) Dynamic change of NT-proBNP; the dashed line in black shows the lower limit of the adjudication of heart failure (125 pg/mL).

(F) Dynamic change of hs-cTnI; the dashed line in black shows the lower limit of the adjudication of myocardial injury for female (15.6 pg/mL).

(G) Dynamic change of hs-CRP; the dashed line in black shows the lower limit of the adjudication of inflammation (10 pg/mL).

(H) Dynamic change of IL-6; the dashed line in black shows the upper normal limit (7 pg/mL).

(I) Dynamic change of D-dimer; the dashed line in black shows the upper normal limit (0.5 mg/mL). ^∗p < 0.05.