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Metformin as adjuvant in standard therapy in patients with diffuse large B-cell lymphoma: A systematic review and meta-analysis
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Received: ,
Accepted: ,
How to cite this article: Ramadhan MB, Hakim MH, Suskhan MN, Cahyanur R. Metformin as adjuvant in standard therapy in patients with diffuse large B-cell Lymphoma: A systematic review and meta-analysis. South Asian J Cancer. 2026;15:143-50. doi: 10.25259/SAJC_11_2025
Abstract
Background:
Diffuse large B-cell lymphoma (DLBCL) is the leading form of adult non-Hodgkin lymphoma (NHL), accounting for 4–5% of new cancer diagnoses and 3–4% of cancer-related mortalities. Preliminary studies on the addition of metformin to chemotherapy have resulted in higher survival and response rates, but the results found still vary. Since no meta-analysis has been published examining this topic, our study investigates the efficacy of metformin as an adjuvant in DLBCL by measuring Overall Survival (OS), Event-Free Survival (EFS), and Objective Response Rate (ORR).
Material and Methods:
Literature retrieval included searches in four main databases, including PubMed, Scopus, Cochrane, and ClinicalTrials.gov, from all publication years. The search keywords included “Metformin,” “DLBCL,” “Adjuvant therapy,” and “Diabetes Mellitus”. PRISMA checklist was used to select articles to ensure a comprehensive review. The quality of each article was critically reviewed using the Cochrane RoB 2 tools for RCTs or ROBINS-I for non-randomised studies.
Results:
From the search results, 7 studies were identified (n = 1344). OS and EFS were found to be significantly better in the metformin group compared to the control group, with a hazard ratio (HR) of 0.54 [0.34–0.87] and 0.54 [0.36–0.82], respectively; while ORR was found to be non-significant (RR: 1.16 [0.98–1.38]). Subgroup analysis for studies with diabetic populations showed similar significant effects on OS and EFS, with HR of 0.54 [0.33–0.88] and 0.56 [0.40–0.77], respectively. Meta-regression results indicate greater therapeutic effect (lower OS and EFS hazard ratio) in lower risk patients (International Prognostic Index (IPI) score 0–2).
Conclusion:
Metformin as adjuvant therapy in DLBCL patients has demonstrated a trend in reducing mortality and disease progression, more effectively in lower-risk patients (IPI score 0–2). To further elaborate on the beneficial effects of metformin, a prospective, randomised, double-blinded study with a larger population is warranted, specifically targeting the low-risk DLBCL patients.
Keywords
Adjuvant therapy
DLBCL
Metformin
Meta analysis
Systematic review
INTRODUCTION
Non-Hodgkin lymphoma (NHL) is the seventh most common cancer, accounts for 4–5% of new cancer diagnoses and 3–4% of cancer-related deaths in the world, with Diffuse large B-cell lymphoma (DLBCL) as the most prevalent form.[1]
Although chemotherapy regimens have been developed,[2] ongoing research continues to improve clinical outcomes, particularly with metformin, which is effective as adjuvant therapy for many types of cancer.[2] Metformin inhibits tumour growth and metastasis by decreasing blood glucose levels, reducing inflammation, and improving the tumour microenvironment.[3] Studies have indicated that the addition of metformin to front-line chemotherapy for DLBCL is associated with superior clinical outcomes, manifesting as higher response rates and extended event-free and/or overall survival, but the results found still vary.[4–10] However, comprehensive meta-analyses of these studies remain limited.Therefore,this study aims to assess metformin usage as an adjuvant in DLBCL chemo-immunotherapy. By systematically reviewing metformin effects throughout similar studies, our work will help clinicians to decide on DLBCL treatment.
MATERIAL AND METHODS
Study design, search strategy, and inclusion criteria
This systematic review and meta-analysis is registered in PROSPERO under the registration ID CRD1060867 and was conducted in adherence to the 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [Supplementary Table 1 -PRISMA 2020 Checklist].[11]
The study utilised PubMed, Scopus, ProQuest, and ClinicalTrials.gov as sources for relevant studies published up to December 2024. The search keywords included “Metformin,” “DLBCL,” “Adjuvant therapy,” and “Diabetes Mellitus”. The inclusion criteria encompassed patients with DLBCL undergoing chemotherapy with a standard regimen, and studies designed as clinical trials or observational studies, while the exclusion criterion was an inaccessible full text.
Data extraction and statistical analysis
Three writers extracted outcomes from Kaplan-Meier graphs of overall survival (OS) and event-free survival (EFS) using WebPlotDigitizer, and objective response rate (ORR) as categorical variables. The Kaplan-Meier data is converted to individual patients using the “IPDfromKM” package in R to gain effect sizes in logHR and standard error.[12]
OS is defined as the patient's life condition before mortality, while EFS is defined as the patient's stable condition without the occurrence of certain events, including disease progression, re-treatment after initial management, or death from any cause. ORR is calculated based on the number of patients who successfully experience partial remission (PR) or complete remission (CR) after therapy is given.
Risk of bias assessments were performed using the Risk of Bias (RoB) 2 tool for randomised clinical trials (RCTs) and the ROBINS-I tool for non-randomised studies.[13,14]
The risk-of-bias visualisation (robvis) tool is used to visualise the results of risk of bias assessment.[15]
Each included study was independently assessed by two reviewers. Discrepancies were resolved by consensus. Statistical meta-analysis conducted using RStudio software with the “meta” package. A random-effects model was applied to account for expected variability across studies, and heterogeneity was assessed using I2 statistics. A meta-regression was conducted to compare cancer characteristics, including cancer stage, IPI score, and cancer type, to solve any heterogeneity.
RESULTS
Based on the literature search, 7 double-armed clinical studies (n = 1344, male = 704, with 1 RCT and 6 non-RCTs) were identified according to the inclusion and exclusion criteria [Figure 1].[4-10] The included studies were conducted in patients with diabetes (5 studies),[5–9] nondiabetes (1 study)[4], or unknown status (1 study).[10]
As an adjuvant therapy, metformin was combined with rituximab-based therapy, usually R-CHOP. Metformin dosage used varied from 500mg/day to 1000 mg x 2/day (diabetic population) or 1000mg x 2/21 day (nondiabetic population). The age of the patients ranged from 15.5 to 87.2 years, with a follow-up period of 0.2 to 185 months. Regarding cancer characteristics, the included patients consisted of 467 (34.7%) patients with low cancer stage (I or II) and 877 (65.3%) patients with high cancer stage (III or IV); 633 (56%) patients with low International Prognostic Index (IPI) score (0–2) and 498 (44%) patients with high IPI score (3–5); and 514 (48.5%) patients with germinal centre B-cell (GCB) cancer type and 546 (51.5%) patients with NonGCB cancer type. All baseline characteristics of the patients in each study are presented in Table 1.
| No | Author (Year) | Study design | Study location | Study interval | Population subject | Cancer characteristics | Study group | Total patients | Male | Age (year) [Mean ± SD /median*] | Follow-up (Months, mean/median*) | OS log (HR) ± SE | EFS log (HR) ± SE | ORR (Events/total) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Hegazy et al. (2024)[4] | RCT phase 2 | Egypt | January 2021 to January 2023 | Non-diabetic DLBCL patients | Stage I-II/III-IV (29%/71%)IPI Low/High (78%/22%)GCB/Non-GCB (79%/21%) | Metformin (1000mg x2/21 days) + R-CHOP | 50 | 18 | 51.18 ± 12.64 | 15.9* | -1,652 ± 0,636 | -1,591 ± 0,457 | 46/50 |
| R-CHOP | 50 | 30 | 51.59 ± 15.45 | 37/50 | ||||||||||
| 2 | Zhou et al. (2022)[5] | Retro-spective cohort | China | January 2010 to June 2020 | Hyper- glycemic DLBCL patients | Stage I-II/III-IV (33.6%/66.4%)IPI low/high (52.3%/47.7%)GCB/Non-GCB (43.2%/56.8%) | Metformin + R-CHOP/CHOP with/without other hypoglycemic agents | 146 | 369 | 64.38 ± 12.45 | 35.8 ± 33.4 | −0.385 ± 0.169 | −0.369 ± 0.172 | N/A |
| Other hypo- glicemic agents + R-CHOP/CHOP | 586 | N/A | ||||||||||||
| 3 | Jiang et al. (2021)[6] | Clinical trial | China | N/A | Diabetic DLBCL patients | Stage I-II/III-IV (38%/62%)IPI Low/High (60%/40%)GCB/Non-GCB (34%/66%) | Metformin + R-CHOP | 50 | 32 | 60 (31 – 85)* | 34* | -0.879 ± 0.27 | -0.853 ± 0.249 | 44/50 |
| Other hypo- glicemic agents + R-CHOP | 50 | 28 | 59 (26 – 86)* | 34/50 | ||||||||||
| 4 | Singh et al. (2020)[7] | Retro-spective cohort | N/A | 1997 -2013 | Diabetic DLBCL patients | Stage I-II/III-IV (30.6%/69.4%)IPI Low/High (59.2%/40.8%)GCB/Non-GCB (45.5%/54.5%) | Metformin + R-CHOP/R-EPOCH | 28 | 15 | 63.5* | N/A | -1.28 ± 0.436 | -0.875 ± 0.417 | N/A |
| R-CHOP/R-EPOCH | 21 | 15 | 73* | N/A | ||||||||||
| 5 | Wang et al. (2019)[8] | Pro-spective cohort | USA | March 2002 to June 2015 | Diabetic DLBCL patients | Stage I-II/III-IV (31.4%/68.6%)IPI Low/High (52%/48%)GCB/Non-GCB (69.6%/30.4%) | Metformin (500mg /day–1000mgx2/day) + R-CHOP | 48 | 29 | N/A | 83 (0.2 –179)* | 0.105 ± 0.245 | -0.171 ± 0.258 | N/A |
| R-CHOP | 54 | 31 | N/A | N/A | ||||||||||
| 6 | AlKhatib et al. (2017)[9] | Retro-spective case control | USA | January 2000 and Dece- mber 2014 | Diabetic DLBCL patients | Stage I-II/III-IV (35,4%/64,6%)IPI Low/High (62,5%/37,5%)GCB/Non-GCB (84,6%/15,4%) | Metformin (mostly 1000mgx2/day) + R-CHOP | 24 | 15 | 65* | 52 (3–185)* | -1.047 ± 0.452 | -1.079 ± 0.388 | 22/24 |
| R-CHOP | 24 | 14 | 66.5* | 53 (2 –184)* | 17/24 | |||||||||
| 7 | Xuan et al. (2011)[10] | Retro- spective clinical study | Singa- pore | January 2006 to March 2009 | DLBCL patients | Stage I-II/III-IV (42,3%/57,7%)IPI Low/High (N/A%/N/A%)GCB/Non-GCB (N/A%/N/A%) | Metformin + R-CHOP/Rituximab-based | 31 | 14 | 62.2 (41.9–81)* | 16.6* | 0.172 ± 0.412 | 0.177 ± 0.303 | 25/31 |
| R-CHOP/Rituximab-based | 182 | 94 | 58 (15.5–87.2)* | 160/182 |
Notes: Age and follow-up time are expressed as mean ± SD or range. If these values were not available, a (*) symbol was used to indicate the median. OS and EFS are presented as log(HR) ± SE. N/A: Not available. RCT: Randomised controlled trials, DLBCL: Diffuse large B-cell lymphoma, GCB: Germinal center B-cell, IPI: International prognostic index, R-CHOP: Rituximab, C: Cyclophosphamide, H: Hydroxydaunorubicin (doxorubicin), O: Oncovin (vincristine), P: Prednisone. OS: Overall survival, EFS: Event free survival, HR: Hazard ratio, SE: Standard error.
Risk of bias assessment
A comprehensive risk of bias assessment was conducted for all included studies using the Risk of Bias (RoB) 2 tool for RCTs and ROBINS-I tool for non-randomised studies, as shown in Figure 2. The study by Alkhatib et al. (2016)[9] has a very high risk of bias due to the significant number of unexplained missing subjects and unknown information about baseline analysis. The moderate criteria were found in the Jiang et al. (2021)[6]study because the outcome analysis plan and response rate measurement were not explained adequately, and the Koo et al.(2011)[10]study due to no explanation regarding the measurement/standard of the response rate. Other studies have a low risk of bias. Supplementary Table 2 - Complete Risk of Bias Assessment, shows a complete risk of bias assessment.
Primary outcomes
After follow-up, patients with adjuvant metformin therapy had better OS and EFS with lower death incidence (HR: 0.54, 95% CI: 0.34–0.87) and events/progressions (HR: 0.54, 95% CI: 0.36–0.82) at any given time compared to the control group. In the subgroup analysis for the diabetic population, similar (significant) results were found in the metformin group compared to the control group for OS (HR: 0.54, 95% CI: 0.33–0.88) and EPF (HR: 0.56, 95% CI: 0.40–0.77). However, compared with the control group, patients with adjuvant metformin therapy had a statistically insignificant ORR (RR: 1.16, 95% CI: 0.98–1.38). All primary outcomes are shown in Figure 3.
Meta regression
Meta-regression analysis in Figure 4 showed the IPI score as the only significant moderator of metformin's therapeutic effect (OS p = 0.0004 and EFS p = 0.0014), specifically causing greater efficacy in patients with a lower IPI score (lower-risk populations). In contrast, neither cancer stage nor cancer type was significantly associated with the treatment outcomes. Notably, these covariates successfully explained all between-study variability, as the residual heterogeneity (I2) was reduced to 0.00% in all results.
![Meta-regression results of outcomes (Overall survival [OS]; Event free survival [EFS]) to cancer characteristics, including cancer stage (stadiumLowPercent), cancer type (GCBPercent), and IPI score (IPLowPercent). (a) Overall survival, (b) Event-free survival, (c) OS to stadium Low, and (d) EFS to stadium Low analysis.(GCBPercent), and IPI score (IPLowPercent). (a) Overall survival, (b) Event-free survival, (c) OS to stadiumLow, and (d) EFS to stadiumLow analysis. GCB: Germinal center B-cells, IPI: International Prognostic Index.](/content/199/2026/15/1/img/SAJC-15-143-g004.png)
DISCUSSION
This meta-analysis compared the included studies based on prognostic outcomes of OS, EFS, and ORR. Analysis of all studies and subgroups for the diabetes population showed that metformin as an adjuvant therapy for DLBCL demonstrated a trend to reduce mortality and events/progressions, with insignificant effect on the response rate of treatment. Meta-regression analysis revealed that the protective effect of metformin against mortality and disease progression was significantly associated with lower-risk patients (low IPI score), but not with cancer stage and type. This association is likely attributable to the more favourable prognosis and overall survival inherent to patients with a low IPI score.[16] These results suggest the long-term protective effects of metformin against death and disease progression, although it did not significantly increase the number of remissions.
The aforementioned protective effects of metformin can occur through the antitumor mechanism of metformin, which increases apoptosis and inhibits cancer cell growth through modulation of AMPK signalling, reducing mTOR activity, decreasing ATP production, and inhibiting HMGCS1 enzyme and membrane synthesis.[7,17–21] Regarding the therapeutic response (ORR), most studies showed the effectiveness of metformin in increasing the treatment response, except for the study by Koo et al (2011).[10] This ineffectiveness may happen due to confounding comorbidities in diabetic patients or the masking effect from standard DLBCL therapy.[10,22] In general, the effectiveness of metformin as an adjuvant therapy has been proven in acute and chronic myeloid leukaemia; breast, ovarian, endometrial, prostate, and head and neck cancer.[23–28] Despite its benefits, metformin is one of the safest antidiabetic drugs with only a significantly higher incidence of nausea in DLBCL patients.[4,29,30] In addition, other studies related to the effect of metformin as adjuvant therapy for various cancer types were found to have no significant difference in serious side effects compared to the control group.[31,32]
This study is the first meta-analysis discussing the effects of metformin as adjuvant therapy in DLBCL patients. With quite high heterogeneity, the results of this study are expected to apply to the general population to prove the benefit of using metformin in improving clinical outcomes. Despite having good results, most studies in this review are non-RCTs, and some of those had a moderate to very high risk of bias. Therefore, further studies involving randomised, double-blind, and larger diabetic and nondiabetic populations are needed to ensure the effects of metformin as an adjuvant therapy for DLBCL patients.
TAKE HOME MESSAGE
Metformin as adjuvant therapy in DLBCL patients has demonstrated a trend in reducing mortality and disease progression. The protective effect is more pronounced in lower-risk patients (IPI score 0–2). However, considering most of the studies included are non-RCTs and some of those had a moderate to high risk of bias, further research focusing on the beneficial effects of metformin with a design of prospective, randomised, double-blinded, and larger diabetic and nondiabetic populations is warranted, specifically targeting the low-risk DLBCL patients.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial Intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using the AI.
Financial support and sponsorship: Nil.
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