Table 1.

Critical appraisal of the included observational studies

Author; year	Study design	Validity				Importance		Applicability		LOEb,c,d,e
		IR	Fa	OB	A	Outcome [adjusted variables]	Estimates [95% CI]	Indirect.	Import.
Cheng X; 2020 [14]	Retrospective cohort	✓	✓	✓	✓	Mortality [2–6, 8–10]	HR 1.65 [0.71–3.86] Severe: 1.56 [0.63–3.85]	✓	✓	IVf
						Acidosis [2–6, 8–10]	HR 2.73 [1.04–7.13] Severe: HR 3.82 [1.27–11.50]	✓	✓	IVg,h
						AHI [2–6, 8–10]	HR 1.02 [0.62–1.66] Mild: HR 1.62 [0.54–4.91] Severe: HR 0.81 [0.48–1.38]	✓	✓	IVf
						AKI [2–6, 8–10]	HR 0.65 [0.19–2.24] Severe: HR 0.47 [0.11–2.00]	✓	✗	IVf
						ARDS [2–6, 8–10]	HR 0.85 [0.61–1.17] Mild: HR 0.42 [0.04–4.65] Severe: HR 0.81 [0.57–1.16]	✓	✓	IVf
						DIC [2–6, 8–10]	HR 1.68 [0.26–10.90] Severe: HR 0.91 [0.10–7.98]	✓	✗	Vg
						HF [2–6, 8–10]	HR 0.59 [0.41–0.83] Mild: HR 0.57 [0.27–1.19] Severe: HR 0.63 [0.42–0.96]	✓	✓	III
						Lactic acidosis [2–6, 8–10]	HR 4.46 [1.11–18.00] Severe: HR 5.65 [1.06–30.10]	✓	✓	IVg,h
Dashti H; 2020 [11]	Case-series	✓	?	✓	✗	Mortality	OR 1.87 [1.32–2.67]i,j	✓	✗	Vk
						Severity	OR 1.88 [1.54–2.28]i,j	✓	✗	Vk
						Hospitalization	OR 4.45 [3.84–5.17]i,j	✓	✗	Vk
Gao Y; 2020 [12]	Case-control	✓	✗	✓	✓	Severity [2, 3, 11, 12]	OR 3.96 [1.03–15.19]	✓	✓	Vg,h
Goodall JW; 2020 [19]	Retrospective cohort	✓	✗	✓	✓	Mortality	HR 0.97 [0.75–1.25]i	✓	✗	IVl
Izzi-Engbeaya C; 2020 [20]	Retrospective cohort	✓	✗	✓	✓	ICU or Mortality [2–4, 7, 13–18]	OR 0.94 [0.16–5.67]	✓	✓	Vg
Mirsoleymani S; 2020 [21]	Retrospective cohort	✓	?	✗	✗	Mortality	RR 2.13 [0.95–4.77]i,j	✗	✗	Vf,l,m
Pérez-Belmonte LM; 2020 [13]	Retrospective cohort	✓	?	✓	✓	Mortality [1]	OR 1.16 [0.78–1.72] Metformin + DPP4i: OR 0.72 [0.39–1.27]	✓	✓	III
						Severity [1]	OR 1.05 [0.73–1.52] Metformin + DPP4i: OR 0.84 [0.49–1.41]	✓	✓	III
						In-hospital complications [1]	OR 1.17 [0.81–1.70] Metformin + DPP4i: OR 0.86 [0.50–1.47]	✓	✓	III
						Prolonged hospitalization [1]	OR 1.49 [0.96–2.33] Metformin + DPP4i: OR 1.17 [0.62–2.19]	✓	✓	III
Wang B; 2020 [22]	Retrospective cohort	✓	?	✓	✗	Mortality	OR 0.35 [0.01–3.08]i	✗	✗	Vf,k,l
						Hospitalization	OR 5.85 [0.69–278.29]i	✗	✗	Vg,k,l

^aWhen adequacy of follow-up was not explicitly stated, limitations on the validity of follow-up domain were judged as serious when the loss to follow up rate was > 10%. ^bLOE of evidence may be upgraded by one level due to large effect size (RR > 2 or RR < 0.5) or by two levels due to very large effect size (RR > 5 or RR < 0.2). ^cLOE may be downgraded by one level each due to imprecision (wide CI: upper limit – lower limit of 95% CI > 1 [for increased risks] or > 0.8 [for decreased risks]), indirectness (study PICO not applicable to question’s PICO), and poor study quality (validity score < 3). ^dLOE may be downgraded by two levels each due to very serious imprecision (very wide CI: upper limit – lower limit of 95% CI > 5 [for increased risks] or > 0.5 [for decreased risks]) or very poor study quality (validity score < 2). ^eLOE assessment starts with level III for cohort studies and level IV for case-series and case-control studies. ^fDowngraded by one level due to imprecision. ^gDowngraded by two levels due to imprecision. ^hUpgraded by one level due to large effect size. ⁱEstimates were not adjusted for confounders. ^jCalculated from binary data. ^kDowngraded by one level due to poor study quality (validity score < 3). ^lDowngraded by one level due to indirectness. ^mDowngraded by two levels due to poor study quality (validity score < 2)

¹Matched by PSM, ²Age, ³Sex, ⁴C-reactive protein, ⁵Aspartate transaminase, ⁶Urea, ⁷Red blood cells, ⁸Creatinine, ⁹Hospital site, ¹⁰Blood glucose, ¹¹Lactate dehydrogenase, ¹²Ethnicity, ¹³Comorbidities (e.g., type 1 diabetes mellitus, active foot disease, stroke, ischemic heart disease, hypercholesterolemia, heart failure, hypertension, chronic obstructive pulmonary disease, cancer), ¹⁴Other medications (e.g., insulin, GLP-1 mimetic, sulphonylurea, DPP4 inhibitor, number of anti-diabetic drugs, statin, ACE inhibitor, angiotensin receptor blocker), ¹⁵Other laboratory parameters (viz., white cell count, hemoglobin, platelet count, neutrophil, lymphocytes, serum sodium) ¹⁶On-diagnosis parameters (viz., eGFR, capillary blood glucose, respiratory rate, heart rate, NEWS score, oxygen saturation requirement), ¹⁷Temperature, ¹⁸Systolic and diastolic blood pressure

IR, inception and representative cohort; F, sufficient follow-up; OB, objective or blind outcome ascertainment; A, appropriate adjustment for important prognostic factors; ACE, angiotensin-converting enzyme; AHI, acute heart injury; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; CI, confidence interval; DIC, disseminated intravascular coagulation; DPP4i, dipeptyl peptidase 4 inhibitor; eGFR, estimated glomerulus filtration rate; GLP-1, glucagon-like peptide-1; ICU, intensive care unit; Import., importance; Indirect., indirectness of population; HF, heart failure; HR, hazard ratio; LOE, level of evidence; NEWS, National Early Warning Score; OR, odds ratio; RR, relative risk