Metformin and pancreatic neuroendocrine tumors: A systematic review and meta-analysis

Table 1 Characteristics of studies included in systematic review: Type 2 diabetes mellitus as risk factor

Ref.	Country	Period	Design	n	Controls	Male (%)	Mean age (yr)	Outcome measure	95%CI	NOS
Diagnosis
Hassan et al[27], 2008	United States	2000-2006	Retro	160	924	55	54	OR	2.8 (1.5–5.2)	7
Halfdanarson et al[28], 2014	United States	2000-2011	Retro	273	602	54	59	OR	1.9 (1.3-2.9)	8
Valente et al[29], 2017	Europe	2013-2015	Retro	201	603	51	60	OR	2.1 (1.3-3.5)1	8
Giraldi et al[30], 2021	Italy	2014-2017	Retro	100	248	46	NA	OR	3.0 (1.2-7.9)	8
Feola et al[31], 2022	Italy	NA	Retro	75	210	NA	NA	OR	2.6 (1.3-5.2)	6
Treatment (PFS)
Pusceddu et al[32], 2018	Italy	1999-2015	Retro	445	-	53	59	HR	1.0 (0.6-1.5)	8
Pusceddu et al[33], 2021	Italy	2006-2013	Pros	204	-	52	62	HR	1.6 (1.0- 2.8)	9
Treatment (TFS)
de Mestier et al[34], 2020	France	2003-2018	Retro	268	-	40	55	HR	2.4 (1.2-4.5)	8
Sandini et al[35], 2020	Germany	2001-2017	Retro	417	-	56	58	HR	2.3 (1.3-4.2)	8
Fan et al[17], 2020	China	2006-2018	Retro	299	-	40	NA	HR	1.0 (0.6-1.8)	8
Tan et al[36], 2022	China	2009-2019	Retro	190	-	48	NA	HR	4.5 (1.2-10.3)	8
Treatment (OS)
Fan et al[17], 2020	China	2006-2018	Retro	299	-	40	NA	HR	1.2 (0.5-2.7)	8
Awwad et al[37], 2022	Germany	1999-2009	Retro	120	-	NA	58	HR	3.2 (1.2-10.3)2	8
Zhang et al[38], 2022	China	2008-2020	Retro	335	-	43	NA	HR	2.7 (1.3-5.3)	8

¹No recent onset.

²Only patients with metabolic syndrome (n = 32).

NOS: Newcastle–Ottawa Score; OR: Odds ratio; NA: Not available; HR: Hazard ratio; PFS: Progression-free survival; TFS: Tumor-free survival; OS: Overall survival.

Table 2 Characteristics of studies included in systematic review: Metformin as risk factor

Ref.	Country	Period	Design	n	Controls	Male (%)	Mean age (yr)	Outcome measure	95%CI	NOS
Diagnosis
Hassan et al[27], 2008	United States	2000-2006	Retro	160	924	55	54	OR	0.8 (0.3-2.5)	7
Valente et al[29], 2017	Europe	2013-2015	Retro	201	603	51	60	OR	1.4 (0.7-2.7)1 1.5 (0.7-3.4)2	8
Treatment (PFS)
Pusceddu et al[32], 2018	Italy	1999-2015	Retro	445	-	53	59	HR	0.5 (0.3-0.8)	8
Treatment (TFS)
Fan et al[17], 2020	China	2006-2018	Retro	299	-	40	NA	HR	0.8 (0.4-1.6)3 1.3 (0.6-3.0)3	8
Treatment (OS)
Fan et al[17], 2020	China	2006-2018	Retro	299	-	40	NA	HR	0.7 (0.2-2.6)4 0.4 (0.1-2.8)4	8
Awwad et al[37], 2022	Germany	1999-2009	Retro	120	-	NA	58	HR	2.6 (0.7-7.0)5	8

¹No insulin.

²Metformin and insulin.

³Only with metastases.

⁴No metastases

⁵Only patients with metabolic syndrome (n = 32).

NOS: Newcastle–Ottawa Score; OR: Odds ratio; NA: Not available; HR: Hazard ratio; PFS: Progression-free survival; TFS: Tumor-free survival; OS: Overall survival.