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

Abstract

COVID-19 caused by SARS-COV-2 infection can lead to multi-organ injuries and significant mortality in severe and critical patients, especially among those individuals with type 2 diabetes (T2D) as a comorbidity. While attenuated mortality was observed with aggressive glucose control, it was unclear whether therapeutic regimens including insulin treatment were beneficial for patients with COVID-19 and T2D. This retrospective study investigated 689 patients with COVID-19 and T2D from a cohort of 3,305 cases from Wuhan, China. Unexpectedly, we found that insulin treatment for patients with COVID-19 and T2D was associated with a significant increase in mortality (27.2% versus 3.5%; adjusted HR, 5.38 [2.75-10.54]). Further analysis showed that insulin treatment was associated with enhanced systemic inflammation and aggravated injuries of vital organs. Therefore, insulin treatment for patients with COVID-19 and T2D should be used with caution.

Keywords: COVID-19; antidiabetic treatment; glycemic control; inflammation; insulin; mortality; type 2 diabetes.

Graphical abstract

Figure 1

The Flowchart of Study Design

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.

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.

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.

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.