Table 1.
The effects of antidiabetic drugs in HCC can be evaluated at two main levels: Chemoprevention and treatment.
| Study | Phase/type | Identifier | Number of patients | Study drug | Diabetes mellitus | Number centres/countries | Year | Primary endpoint | Conclusions | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|
| Chemoprevention | ||||||||||
| Evans JM et al. | Retrospective case-control study | n.a. | Cases (983) – Controls (1,846) | Metformin | T2D | Population databases/Tayside-Scotland | 2005 | Odds ratio | Metformin may reduce the risk of cancer in patients with T2D. The unadjusted odds ratio was 0.86 (95% CI 0.73 to 1.02). The unadjusted odds ratio for any exposure to metformin since 1993 was 0.79 (0.67 to 0.93). | 146 |
| ADOPT | III | NCT00279045 | Rosiglitazone (1,456) vs. metformin (1,454) vs. glyburide/glibenclamide (1,441) | Metformin, TZD, sulfonylurea | T2D | 490 centres/US, Europe/hospital based | 2006 | Monotherapy failure | Post hoc analysis of occurrence of HCC in patients enrolled in OADM monotherapy trial. HCC total: 4. HR metformin vs. rosiglitazone: 0.92 (95% CI 0.63–1.35); metformin vs. glibenclamide: 0.78 (95% CI 0.53–1.14) | 147 |
| RECORD | III | NCT00379769 | Rosiglitazone (2,220) vs. Metformin (1,122) vs. Sulfonylurea (1,105) | Metformin, TZD, sulfonylurea | T2D | 447 centres/US, Australia/hospital based | 2007 | Cardiac outcomes, regulation of glycaemia | Post hoc analysis of HCC incidence in cardiovascular outcomes study of OADM, with addition of another “rescue” OADM as needed for glycaemic control. HCC total: 4. On background of sulfonylurea: metformin vs. rosiglitazone HR 1.22 (95% CI 0.86–1.74). On background of metformin: sulfonylurea vs. rosiglitazone HR 1.33 (95% CI 0.94–1.88) | 100 |
| Donadon V et al. | Retrospective case-control study | n.a. | HCC cases (610) - matched liver cirrhosis (618) - controls (1,696) | Metformin | T2D | 1 centre/Italy | 2010 | To explore the relationships among T2D, antidiabetic therapy and HCC risk. | T2D is an independent risk factor for HCC and pre-exists to HCC occurrence. Metformin was associated with a significant reduction of risk for HCC vs. controls vs. cirrhosis cases when compared with sulfonylurea and insulin therapy (OR 0.15; CI 0.04–0.50; p = 0.005 and OR 0.16; CI 0.06–0.46; p = 0.0006 respectively) | 148 |
| Chang CH et al. | Retrospective case-control study | n.a. | T2D (606,583). A total of 10,741 liver cancer cases, 7,200 colorectal cancer cases, and 70,559 diabetic controls were included. | TZD | T2D | Population databases/Taiwan | 2012 | To assess the association between TZDs (both pioglitazone and rosiglitazone) and the occurrences of liver, colorectal, lung, and urinary bladder cancers. | The use of pioglitazone and rosiglitazone is associated with a decreased liver cancer incidence in diabetic patients. A significantly lower risk of liver cancer incidence was found for any use of rosiglitazone (OR 0.73, 95% CI 0.65-0.81) or pioglitazone (OR 0.83, 95% CI 0.72-0.95), respectively. | 136 |
| Singh S et al. | Meta-analysis | n.a. | Ten studies reporting 22,650 cases of HCC in 334,307 patients | Metformin, TZD, sulfonylurea, insulin | T2D | Multicentre | 2013 | Risk of incident HCC | Meta-analysis of observational studies showed a 50% reduction in HCC incidence with metformin use, but an increase in HCC incidence with sulfonylurea or insulin use. TZD did not modify the risk of HCC. | 128 |
| Zhang H et al. | Meta-analysis | n.a. | Seven studies reporting 562 cases of HCC in 16,549 patients | Metformin | T2D | Population databases/China | 2013 | To determine the association between metformin use and HCC among diabetic patients. | Metformin treatment was associated with reduced risk of HCC in diabetic patients (RR 0.24, 95% CI 0.13–0.46, p <0.001). | 129 |
| Lai SW et al. | Retrospective cohort study | n.a. | Controls diabetics on TZD treatment (23,580)/case diabetics on TZD treatment (23,580) | TZD | T2D | Taiwan | 2020 | Risk of incident HCC | There was a negative association in a duration-dependent manner between the risk of HCC and TZD use among T2D patients who had risk factors for HCC | 137 |
| Vilar-Gomez E et al. | Cohort | n.a. | No T2D (87) vs. T2D (212) | Metformin, sulfonylurea, insulin | T2D and NASH cirrhosis | Six centres/Europe, Asia, Australia, Cuba | 2021 | To determine the influence of T2D, hyperglycaemia, and ADMs on outcomes of HCC, liver decompensation, and death | Metformin significantly reduced the risk of hepatic decompensation and HCC only in subjects with HbA1c levels greater than 7.0% (Ahr 0.97; 95% CI 0.95–0.99 and aHR 0.67; 95% CI 0.43–0.94, respectively) | 149 |
| Kaplan DE et al. | Retrospective cohort study | n.a. | 74 984 diabetics; 40,368 with T2D before cirrhosis. 11 114 had active utilization of metformin. | Metformin | T2D | Population databases/US | 2021 | To investigate the impact of metformin exposure on mortality, hepatic decompensation, and HCC in individuals diagnosed with cirrhosis with a pre-existing diagnosis of diabetes mellitus | Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure. | 150 |
| Yen FS et al. | Observational case-control study | n.a. | 2,828 paired propensity score matched DPP-4 inhibitor users and nonusers T2D with compensated liver cirrhosis | DPP-4 inhibitors | T2D | Population databases/Taiwan | 2021 | To assess the outcomes of all-cause mortality, HCC, major adverse cardiovascular events, decompensated cirrhosis, and hepatic failure. | DPP-4 inhibitor users were associated with higher risks of decompensated cirrhosis and hepatic failure than did non-users among patients with T2D and compensated liver cirrhosis. Risk of all-cause mortality, HCC, and major cardiovascular events between DPP-4 inhibitor users and nonusers were not statistically different. | 151 |
| Li Q et al. | Meta-analysis | n.a. | Seven studies reporting 562 cases of HCC in 16,549 patients | Metformin | T2D | Multicentre | 2022 | To evaluate the relationship between metformin therapy and HCC survival and risk. | Metformin in T2D patients is significantly associated with reduced risk and all-cause mortality of HCC (OR/RR 0.59, 95% CI 0.51–0.68, I2 = 96.5%, p <0.001). | 130 |
| Kramer JR et al. | Cohort | n.a. | T2D and NAFLD (85,963) | Metformin, sulfonylurea, insulin | T2D and NAFLD | 130 centres/US | 2022 | Risk of incident HCC | Use of metformin was associated with a reduced risk of HCC compared with no medication, 22% lower risk of HCC (HR 0.77; 95% CI 0.65–0.90; p = 0.001), whereas use of combination therapy was associated with increased risk (HR for insulin and metformin, 1.53; 95% CI 1.26–1.86; p <0.0001; HR for insulin, metformin, and sulfonylureas, 1.71; 95% CI 1.41–2.08; p <0.0001). | 152 |
| Hendryx M et al. | Retrospective cohort study | n.a. | 3,185 patients with HCC and pre-existing diabetes, 137 (4.3%) patients used SGLT2 inhibitors. | Sodium-glucose cotransporter 2 (SGLT2) inhibitors | T2D | SEER-Medicare dataset/US | 2022 | aHRs for mortality | SGLT2 inhibitor initiation was associated with improved overall survival of patients with HCC and pre-existing type 2 diabetes compared with no SGLT2 inhibitor use (HR 0.68, 95% CI 0.54–0.86). | 139 |
| Treatment HCC | ||||||||||
| Chen TM et al. | Retrospective cohort study | n.a. | No T2D RFA (82)/T2D RFA with metformin (21)/T2D without metformin (32) | Metformin, sulfonylurea, insulin | T2D 32.3% | 1 centre/Taiwan | 2011 | OS | Metformin users among patients with T2D and HCC undergoing RFA had favourable OS compared to patients with T2D not receiving metformin treatment. | 153 |
| Bhat M et al. | Retrospective cohort study | n.a. | No T2D (438)/T2D not on metformin (207)/T2D on metformin (56) | Metformin | T2D 37.5% | 1 centre (part Bridge cohort) | 2014 | OS | This study demonstrates no survival benefit with metformin in patients with T2D and HCC. | 154 |
| Jang WI et al. | Retrospective cohort study | n.a. | SBRT without T2D (169)/SBRT T2D not on metformin (29)/SBRT T2D on metformin (19) | Metformin | T2D 22% | Four centres/Korea | 2015 | OS | The use of metformin in patients with HCC receiving radiotherapy was associated with higher OS. In the propensity score-matched cohort (n = 76), the OS rate of the metformin group was higher than that of the non-metformin group (2-year, 76% vs. 37%, p = 0.022). | 155 |
| Seo YS et al. | Retrospective cohort study | n.a. | Curative resection T2D on metformin (533)/curative resection T2D not on metformin (218) | Metformin | T2D | National database (NHIS and KKRC)/Korea | 2016 | OS | In patients treated with curative hepatic resection, metformin use was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events. | 156 |
| Casadei Gardini A et al. | Retrospective cohort study | n.a. | Sorafenib (51) vs. sorafenib+metformin (31) vs. sorafenib+insulin (11) | Multiple kinase inhibitor, metformin, insulin | T2D 42.5% | 1 centre/Italy | 2015 | PFS, OS | The result of greater tumour aggressiveness is described and resistance to sorafenib in patients treated with metformin. | 132 |
| Casadei Gardini A et al. | Prospective cohort study | n.a. | Sorafenib (193) vs. sorafenib+metformin (52) vs. sorafenib+insulin (34) | Multiple kinase inhibitor, metformin, insulin | T2D 30.0% | 1 centre/Italy | 2017 | PFS, OS | In patients with HCC undergoing chronic treatment with metformin, the use of sorafenib was associated with poor PFS and OS (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without T2D and 8.4 months and 16.6 months, respectively, for patients on insulin (p <0.0001). | 131 |
| Chung YK et al. | Retrospective case-control study | n.a. | Recurrence after LR: sorafenib+metformin (40)/sorafenib+insulin (23)/sorafenib control (241); propensity score matching control (40) Recurrence after LT: sorafenib+metformin (14)/sorafenib+insulin (17)/sorafenib control (43); propensity score matching (28) |
Multiple kinase inhibitor, metformin, insulin | T2D | 1 centre/Korea | 2018 | OS | Absence of synergistic antitumor effects of metformin. | 133 |
| Schulte L et al. | Retrospective case-control study | n.a. | 5,093 patients with HCC, 1,917 patients (37.6%) were diagnosed with T2D, of whom 338 (17.6%) received treatment with metformin | Metformin | T2D (37.6%) | 3 centres/Germany, Austria | 2019 | OS | In the matched cohorts, mOS remained significantly longer in metformin-treated patients (22 vs. 16 months, p = 0.021). Co-treatment of metformin and sorafenib was associated with a survival disadvantage. | 127 |
| El Shorbagy S et al. | RCT | n.a. | Sorafenib+metformin (40) vs. sorafenib (40) | Multiple kinase inhibitor, metformin | T2D 60% | 2 centres/Egypt | 2021 | OS, TDP, Safety | No superior efficacy of adding metformin to sorafenib in HCC treatment. | 134 |
| Cho YY et al. | Retrospective cohort study | n.a. | 1,566 patients with unresectable HCC who received sorafenib. Long-term survivor group (survival more than 2 years, n = 257) or a control group (n = 1,309). | Multiple kinase inhibitor | Presence T2D analysed but percentage by groups not reported | 9 centres/Korea | 2021 | Clinical characteristics of long-term survivors after sorafenib treatment. | The prognostic factors predicting long-term survival were metformin use (aHR 3.464; p <0.001), hand-foot skin reaction (aHR 1.688; p = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR 2.766; p <0.001). | 135 |
| Systemic therapy for HCC | ||||||||||
| First-line | ||||||||||
| SHARP | III | NCT00105443 | Sorafenib (299) vs. placebo (303) | Multiple kinase inhibitor: VEGFR, KIT, RET, FLT-3, PDGFR-β, RET/PTC, MAPK | Not specified | 178 centres/23 countries | 2008 | OS | Sorafenib improves survival compared with placebo | 118 |
| Asia-Pacific | III | NCT00492752 | Sorafenib (149) vs. placebo (75) | Multiple kinase inhibitor: VEGFR, KIT, RET, FLT-3, PDGFR-β, RET/PTC, MAPK | Not specified | 23 centres/China, South Korea and Taiwan | 2009 | OS | Sorafenib improves survival compared with placebo | 157 |
| REFLECT | III | NCT01761266 | Lenvatinib (478) vs. sorafenib (476) | Multiple kinase inhibitor: VEGFR 1-3, FGFR 1–4, PDGFR α, RET, KIT | Not specified | 154 centres/24 countries | 2018 | OS | Lenvatinib is non-inferior compared with sorafenib | 119 |
| IMbrave 150 | III | NCT03434379 | Atezolizumab + bevacizumab (336) vs. sorafenib (165) | Checkpoint inhibitor + Antiangiogenic: Anti-PD-L1 antibody + Anti VEGFA antibody | Not specified∗ | 111 centres/17 countries | 2020 | OS, PFS (co-primary) | Atezolizumab plus bevacizumab improve overall survival compared with sorafenib | 120 |
| HIMALAYA | III | NCT03298451 | Durvalumab + tremelimumab (Stride 393) vs. sorafenib (389) | Checkpoint inhibitor + checkpoint inhibitor: Anti-PD-1 antibody + Anti-CTLA-4 antibody | Not specified | 181 centres/16 countries | 2022 | OS | Durvalumab plus tremelimumab improve overall survival compared with sorafenib | 158 |
| COSMIC-312 | III | NCT03755791 | Atezolizumab + cabozantinib (432) vs. sorafenib (217) | Checkpoint inhibitor + multiple kinase inhibitor: Anti-PD-L1 antibody + VEGFR, MET, TAM family receptors (TYRO3, AXL, MER | Not specified∗ | 178 centres/32 countries | 2022 | PFS, OS (dual) | Atezolizumab plus cabozantinib improve progression-free survival compared with sorafenib | 159 |
| CheckMate 459 | III | NCT02576509 | Nivolumab (371) vs. sorafenib (372) | Checkpoint inhibitor: Anti-PD-1 antibody | Not specified∗ | 22 countries | 2022 | OS | Nivolumab does not improve survival compared with sorafenib | 160 |
| Second-line | ||||||||||
| RESORCE | III | NCT01774344 | Regorafenib (379) vs. placebo (194) | Protein kinase inhibitor: RAF-1, RET, BRAFV600E, VEGFR, TIE-2, PDGFR, FGFR, EGFR, CSF1R, c-kit | Not specified. NASH: 25 (7%) vs. 13 (7%) |
152 centres/21 countries | 2017 | OS | Regorafenib improves survival compared with placebo | 121 |
| CELESTIAL | III | NCT01908426 | Cabozantinib (470) vs. placebo (237) | Multiple kinase inhibitor: VEGFR, MET, TAM family receptors (TYRO3, AXL, MER) | Not specified. NASH: 43 (9%) vs. 23 (10%) |
95 centres/19 countries | 2018 | OS | Cabozantinib improves survival compared with placebo | 122 |
| REACH-2 | III | NCT02435433 | Ramucirumab (197) vs. placebo (95) | Monoclonal antibody: Anti VEGFR-2 | Not specified. NASH: 19 (10%) vs. 4 (4%) |
92 centres/22 countries | 2019 | OS | Ramucirumab improves survival compared to placebo with AFP ≥400 ng/ml | 123 |
| KEYNOTE-224 | II | NCT02702414 | Pembrolizumab (104) | Checkpoint inhibitor: Anti-PD-1 antibody | Not specified∗ | 47 centres/10 countries | 2018 | ORR | Pembrolizumab approved by the US FDA | 161 |
| CheckMate-040 | I/II | NCT01658878 | Nivolumab + ipilimumab (140) | Checkpoint inhibitor + checkpoint inhibitor: Anti-PD-1 antibody + Anti-CTLA-4 antibody | Not specified∗ | 31 centres/10 countries | 2020 | Safety, tolerability, ORR | Nivolumab and ipilimumab approved by the FDA | 162 |
| KEYNOTE-240 | III | NCT02702401 | Pembrolizmab (278) vs. placebo (135) | Checkpoint inhibitor: Anti-PD-1 antibody | Not specified∗ | 119 centres/29 countries | 2020 | PFS, OS (co-primary | Pembrolizumab does not improve survival and progression-free survival compared with placebo | 163 |
| KEYNOTE-394 | III | NCT03062358 | Pembrolizumab (300) vs. placebo (153) | Checkpoint inhibitor: Anti-PD-1 antibody | Not specified | Asia | 2022 | OS | Pembrolizumab improves survival compared with placebo in Asia | 164 |
Information on the presence of diabetes mellitus in clinical trials for the treatment of advanced HCC is very scarce. AFP, alpha-fetoprotein; CTLA-4, cytotoxic T-Lymphocyte antigen 4; ICI, immune checkpoint inhibitors; LR, liver resection; LT, liver transplantation; n.a., not applicable; OADM, oral antidiabetic medications; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death 1; PFS, progression-free survival; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy; T2D, type 2 diabetes; TDP, time to disease progression; TKI, tyrosine kinase inhibitors.
∗
Patients with controlled type 1 diabetes mellitus who are on an insulin regimen were eligible for the study.