Dipeptidyl peptidase 4 inhibitors in COVID-19: Beyond glycemic control

Table 1 Observation studies assessing coronavirus disease 2019 outcomes and dipeptidyl peptidase-4 inhibitors therapy

Sl no	Ref.	Design, location	Population	Findings
Studies with neutral outcomes with the use of DPP-4i
1	Fadini et al[38], 2020	RO, Italy	Registry based DM patients with and without COVID-19. Subgroup analysis of proportion of DPP-4i users	Diabetic COVID-19 patients who were on DPP-4i had a similar disease outcome as those who were not
2	Chen et al[39], 2020	RO, China	Single centre hospitalised COVID-19 patients with DM; DPP-4i users (n = 20) compared with nonusers (n = 100)	Mortality OR 1.48, 95%CI 0.4-5.53, P = 0. 56
3	Pérez-Belmonte et al[40], 2020	RO, Spain	Registry based COVID-19 patients with DM. DPP-4i users (n = 105) compared with nonusers (n = 105)	Composite outcome of ICU admission, mechanical ventilation, or in-hospital death: OR 1.12, 95%CI 0.65-1.95, P = 0.675
4	Silverii et al[41], 2021	RO, Italy	Registry based all deaths due to COVID-19 infection; Subgroup analysis of DPP-4i users (n = 13) vs nonusers (n = 146) in DM patients	Mortality risk in COVID-19 infection. HR 1.0, 95%CI 0.5-2.1, P = 0.56
5	Kim et al[42], 2020	RO, Korea	Single centre hospitalised COVID-19 patients with and without DM; Subgroup analysis of DM patients using DPP-4i (n = 85) and others (n = 235)	Mortality OR 1.47, 95%CI 0.45-4.78, P = 0.52; Severe disease OR 1.05, 95%CI 0.44-2.49, P = 0.92
6	Noh et al[43], 2021	PO, South Korea	Registry based COVID-19 patients with DM; Mortality in DPP-4i users (n = 453) compared with nonusers (n = 133)	All-cause mortality: HR 0.74, 95%CI 0.43-1.26; Severe disease HR 0.83, 95%CI 0.45-1.53
7	Zhou et al[44], 2020	RO, China	Multi-centre, hospitalised COVID-19 patients with DM; Subgroup analysis of DPP-4i users (n = 142) vs nonusers (n = 1257)	28-d mortality: aHR = 0.44, 95%CI: 0.09-2.11, P = 0.31); Secondary outcomes such as septic shock, acute respiratory distress syndrome, organ (kidney, liver, and cardiac) injuries, were also comparable between the two groups
8	Yan et al[47], 2020	RO, China	Hospitalised COVID-19 patients; Subgroup analysis of DPP-4i use in patients with severe illness	No significant association between use of DPP-4i and COVID-19 severity after adjustment for age, sex, and BMI (OR 0.32, 95%CI 0.02-2.18, P = 0.31)
9	Izzi-Engbeaya et al[45], 2021	RO, United Kingdom	Registry based COVID-19 patients with DM admitted to 3 hospitals (n = 337); DPP-4i users (n = 93)	Admission to ICU or death OR 1.27 (0.79-2.05)
10	Israelsen et al[46], 2021	RO, Denmark	Registry based COVID-19 patients with DM; DPP-4i users (n = 284) compared with SGLT2i users (n = 342)	DPP-4i users- 30-d mortality aRR 2.42 (95%CI 0.99-5.89) when compared with SGLT-2i users. DPP-4i use was not associated with decreased risk of hospital admission
Studies with positive outcomes with the use of DPP-4i
1	Mirani et al[48], 2020	RO, Italy	Single centre hospitalised COVID-19 patients with DM; DPP-4i users (n=11) compared with nonusers (n=79)	DPP-4i users had lower risk of mortality (aHR 0.13, 95%CI 0.02-0.92; P = 0.042)
2	Solerte et al[49], 2020	RO case control, Italy	Hospitalised COVID-19 patients with DM; Case sitagliptin + Standard care (n = 169) Controls – age sex matched patients with Standard care (n = 338)	Mortality: HR 0.44, 95%CI 0.29–0.66, P = 0.0001); Admission to ICU: HR: 0.51, 95%CI 0.27-0.95, P = 0.03; Mechanical ventilation HR: 0.27, 95% CI 0.11-0.62, P = 0.03; Hospital discharges 120 vs 89, P < 0.01
3	Rhee et al[50], 2021	RO, South Korea	Registry based COVID-19 patients with DM; DPP-4i users (n = 263) vs non users (n = 832); Assessed for severity of disease	OR for severe disease was 0.303 (95%CI 0.135-0.682) among DPP-4i users
4	Nafakhi et al[51], 2020	RO, Iraq	Newly diagnosed COVID-19 pneumonia; Subgroup analysis to assess predictors for adverse outcomes	DPP-4i users had decreased length of ICU stay. (OR 0.3, 95%CI 0.2-3, P = 0.04)
5	Wargny et al[52], 2021	PO, France	Registry based COVID-19 patients with DM. Subgroup analysis of DPP-4i use in patients succumbing to death within 28 d	The need for mechanical ventilation and death within seven days were similar in DPP-4i users compared to nonusers. (OR 0.83, 95%CI 0.65-1.05, P = 0.12). Discharge at day 28: OR 1.22, 95%CI 1.02-1.47, P = 0.03)
6	Wong et al[53], 2021	RO, China	Registry based COVID-19 patients with DM (n = 1214); DPP-4i users (n = 107) compared with others (n = 1107)	DPP4i users were associated with lower odds of clinical deterioration (OR 0.71, 95%CI 0.54-0.93, P = 0.013), hyperinflammatory syndrome (OR = 0.56, 95%CI 0.45-0.69, P < 0.001), invasive mechanical ventilation (OR = 0.30, 95%CI 0.21-0.42, P < 0.001), reduced length of hospitalization (-4.82 days, 95%CI -6.80 to -2.84, P < 0.001). No difference seen in mortality
Studies with negative outcomes with the use of DPP-4i
1	Dalan et al[54], 2021	RO, Singapore	Single centre hospitalised COVID-19 patients with and without DM; Subgroup analysis of DM patients using DPP-4i (n = 27) and others (n = 49)	DPP-4i were at higher risk of ICU admission (aRR 4.07, 95%CI 1.42-11.66) and mechanical ventilation (aRR 2.54, 95%CI 0.43-14.99)
2	Khunti et al[55], 2021	RO, United Kingdom	Registry based Nationwide cohort data; HR of COVID-19-related mortality assessed in patients with diabetes on DPP-4i	HR 1.07 (1.01-1.13)

COVID-19: Coronavirus disease 2019; DPP-4i: Dipeptidyl peptidase-4 inhibitors; CI: Confidence interval; HR: Hazard ratio; ICU: Intensive care unit; n: Number of patients on DPP-4i; N: Number of patients with diabetes; OR: Odds ratio; PO: Prospective observational; RO: Retrospective observational; RR: Relative risk;

Table 2 Randomized controlled trials assessing coronavirus disease 2019 outcomes and dipeptidyl peptidase-4 inhibitors therapy

Sl no	Ref.	Design, location	Comparators	Age (mean ± SD)	% male	Primary outcomes	Secondary outcomes	Results
1	Abuhasira et al[63]	Open-label, prospective, multi-centre trial, Germany	Linagliptin 5 mg + standard therapy (n = 32); Standard therapy (n = 32)	65.5 ± 16; 68.4 ± 11.5	65.6%; 53.1%	Time to clinical improvement	Proportion of patients with 2- point clinical improvement at 28 d, mortality at 28 d, length of hospitalization, ICU admissions, and MV	Time to clinical improvement (HR 1.22; 95%CI, 0.70-2.15; P = 0.49); In-hospital mortality; (OR 0.56; 95%CI, 0.16-1.93). No difference in secondary outcomes
2	Guardado-Mendoza et al[64]	Parallel double blind single centre trial, Mexico	LI group (n = 35) I group (n = 38)	57 ± 2; 60 ± 2	51%; 76%	Need for assisted MV and mortality	Glucose levels and insulin requirements, pulmonary parameters and clinical progression	Reduced risk of assisted MV; (HR 0.258, 95%CI 0.1-0.7, P = 0.009), improved blood glucose levels, lower insulin requirements in LI group

HR: Hazard risk, I: Insulin, LI: Linaglitin plus insulin, MV: Mechanical ventilation, OR: Odds ratio, RR: Relative risk, SD: Standard deviation.