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Journal of Endocrinology & Metabolism

Review

Volume 12, Number 6, December 2022, pages 161-167

Protective Effect of Metformin on Venous Thrombosis in Diabetic Patients: Findings From a Systematic Review

Vascular disease including venous thromboembolism (VTE) is a common cause of death among patients with comorbid conditions such as diabetes mellitus [1, 2]. VTE results in a range of events from symptomless distal venous thrombus of deep veins to threatening deep venous thrombus and fatal pulmonary embolism [3]. The likelihood of VTE and its associated complications are higher in older patients than younger ones and the risk becomes two-fold with every decade of aging [4]. This risk also varies by the sex of the patients with males being affected more by the second episode than females. The yearly incidence of VTE is between 1.5 and 3.0 cases per 1,000 individuals. The incidence of VTE is even higher among diabetic patients. For example, the data suggest the annual rate of VTE among diabetic patients was 432 per 100,000 population [2]. VTE is considered as the third most common cause of cardiovascular disease following stroke and myocardial infarction [3, 5].

It seems that metformin being an antihyperglycemic drug prevents cardiovascular disease beyond glycemic control [6]. However, despite the effects of metformin on glycemic control, its effects on venous thrombosis may be different. Overall, there is limited evidence supporting such beneficial effects with scarce evidence from well-conducted trials. Few epidemiological studies have shown that hypoglycemic agents such as metformin may have a direct effect on VTE [7]. However, such evidence is not qualitatively synthesized both from observational and intervention studies, thereby limiting our understanding of the role of metformin in preventing VTE. Thus, we carried out a systematic review of the epidemiological studies assessing the role of metformin in preventing VTE. The findings of this review will help clinicians and researchers to plan further studies and make evidence-based clinical and policy decisions to treat the patients appropriately and reduce the burden of VTE and its associated morbidity and mortality.

The updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was employed to carry out this systematic review on assessing the role of metformin in preventing VTE [8]. A systematic search of three main electronic databases including Embase, PubMed, and EBSCO was undertaken. Additionally, using two techniques such as snowballing and pearl growing methods, relevant articles were also searched and reviewed [9, 10]. All relevant published articles from January 2001 to December 2021 were included and we limited the search to articles published in the English language due to translation issues in other languages. Search restrictions with filters were employed on the language (English), publication period, and age category to include eligible studies in the search.

Using different combinations of keywords and after conducting a deep literature search by using the following search terms: “Metformin AND venous thrombus AND Diabetes”, “Metformin AND thrombus formation AND Diabetes”, “Metformin AND thromboembolism AND Diabetes Mellitus”, metformin AND deep vein thrombosis AND prediabetes”, and “Metformin AND thromboembolism OR thrombus AND Diabetes Mellitus”. In addition, the most prevalent concepts were employed including metformin AND venous thrombus. Then these major concepts were combined using combinations (AND, OR) relevant to the research question. An example of a complete search strategy included: “Metformin AND thromboembolism OR thrombus AND Diabetes Mellitus OR Type 2 Diabetes Mellitus” ((“metformin”/exp OR metformin) AND (“thromboembolism”/exp OR thromboembolism) OR “thrombus”/exp OR thrombus) AND (“diabetes mellitus”/exp OR “diabetes mellitus” OR ((“diabetes”/exp OR diabetes) AND mellitus)). Further, truncation (*) with a similar root word was employed to identify more germane articles.

Any study that focused on the role of metformin in preventing VTE in patients diagnosed with type 2 diabetes mellitus was considered eligible to be included in the review. We considered both observational and interventional studies that had assessed the beneficial role of metformin in preventing VTE formation among diabetic patients. However, grey literature, review articles, qualitative studies, letters to the editor, secondary data, and case reports were excluded from this review. The main outcome of interest was VTE in diabetic patients and to include the maximum literature on this topic, we considered both descriptive and analytical observational studies.

Data extraction was carried out independently. Initially, all appropriate research studies were imported into the reference manager software, where an individual study was reviewed, and all duplicate studies were discarded. As a first step, the chosen articles were screened by titles, then by abstracts, and finally, a full-text articles evaluation was carried out. The following information was extracted in the chosen observational studies: research author, reference of the study, year of publication, country, total sample size, gender of the study participants, age group, key findings, and main conclusion of the studies. The abstracts that did not explicitly explore the study objective were not reviewed further and this was followed by retrieving and reviewing the full-text articles of the appropriate. A standardized proforma was used to abstract and summarize the articles that met the required eligibility criteria. In addition, the references of all relevant studies were also assessed to evade missing any useful studies.

A total of 8,879 records were identified in three databases (Embase, PubMed, and EBSCO). After removing 4,578 duplicates, the remaining 4,301 unique studies were left whose titles and abstracts were screened. During this process of reviewing abstracts, 186 articles did not meet the eligibility criteria based on the abstract reading, and 34 articles were not considered potentially eligible after reviewing full documents. Following a comprehensive review of the research articles based on the eligibility criteria, six articles were incorporated in the review as shown in Figure 1.

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Figure 1. Flow chart summarizing the identification and selection of relevant papers.

Studies were conducted in different countries across the world such as Taiwan, Saudi Arabia, Sudan, and Turkey (Table 1 [11-16]). Overall, the sample size of the included studies was reasonable ranging from 24 to 907,277 diabetic patients. Regarding the gender distribution of the -participants, the findings revealed that both males and females equally participated in the respective studies. Almost all of the studies were observational studies except one randomized controlled trial and majority of the studies mentioned their outcome, which was mainly VTE or thrombus formation or mortality in diabetic patients.

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Table 1. Characteristics of the Included Studies in the Systematic Review (n = 6)

Overall, the results revealed a favorable effect of metformin against deep venous thrombosis, meaning that metformin may play a vital role in preventing deep venous thrombosis among patients (Table 2). For example, a non-randomized, pair-matched cohort study was undertaken in Taiwan in 2014 on 14,945 diabetic patients [14]. Of these 7,167 patients were taking metformin and the remaining 7,778 were in the control group. The cohort of diabetic patients was followed for 3.74 years and it was found that out of 7,167 patients given metformin, 0.21% developed deep venous thrombosis while 0.56% from the control group [14]. Patients who received metformin were 58% less likely to develop venous thrombosis than those who did not receive metformin with significant results (hazard ratio (HR): 0.42, 95% confidence interval (CI): 0.240 - 0.758) [14]. One more prospective cohort study was conducted in Saudi Arabia on 277 patients diagnosed with venous thrombosis [12]. After the average time of follow-up of 1 year, it was found that metformin reduced the risk of thrombosis by 84% (HR: 0.78, 95% CI: 0.65 - 0.95) among elderly patients after adjusting for other variables in the model [12]. Likewise, a cross-sectional study was conducted in Khartum-Sudan on 96 diabetic patients. These patients were either given metformin or glimperide and effects were seen on platelet indices such as mean platelet volume, platelet large cell ratio, and platelet distribution width [11]. The findings revealed that both types of treatments were found to reduce the platelet indices with insignificant results for glimperide [11]. Both metformin and glimperide were shown to have a favorable prognostic effect on pro-thrombotic state. However, metformin was found to have a much better effect on platelet indices than glimperide [11].

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Table 2. Summary of Findings From the Included Studies in the Systematic Review (n = 6)

A large nationwide prospective cohort study was conducted in Taiwan using the data of 907,277 patients with the age up to 104 years [13]. The subjects were followed for about 10.4 years and various risk and protective factors were identified for the retinal vein occlusion. The study findings demonstrated that metformin was found to be protective against retinal vein occlusion among diabetic patients [13]. More precisely, it reduced the risk of retinal vein occlusion by 54% after adjusting for demographic and clinical factors (HR: 0.46, 95% CI: 0.30 - 0.71) [13]. These findings are consistent with a national primary care database study conducted in London in 2019 [17]. Likewise, a prospective open-labeled study was conducted in diabetic patients; however, the sample size was only 24. The study findings showed that metformin reduced the formation of plasminogen activator inhibitors and vascular endothelial growth factors [16]. After 4 weeks of follow-up, metformin was found to improve endothelial function and prevent thrombus formation. However, there was no effect on chronic subclinical vascular formation among obese insulin-resistant diabetic individuals [16]. Likewise, a study was conducted to examine the effects of metformin in 38 patients diagnosed with type 2 diabetes mellitus in a double-blinded randomized controlled trial. Patients were followed for about 6 weeks after being randomized to metformin and placebo [15]. Among those who were treated with metformin, basal and post-venous occlusion plasminogen activator inhibitor fell after 3 weeks without any change in these concentrations in the placebo group. After 3 weeks, post venous occlusion for plasminogen activator activity increased in the metformin group [15].

This review was undertaken to summarize the evidence regarding the protective effect of metformin on VTE in diabetic patients. Overall the findings of the review demonstrated a protective effect of metformin among diabetic patients in terms of reducing venous thrombus formation. Though, limited evidence exists and perhaps there is a need to conduct more randomized controlled trials, the available evidence is suggestive of beneficial effects of metformin against VTE. This can be further confirmed by undertaking large intervention studies to endorse the findings.

According to the current guidelines of the American Diabetes Association/European Association, metformin should be considered as either as a monotherapy or in combination for patients diagnosed with type 2 diabetes mellitus. This is even more beneficial for patients who are at risk of thrombus formation. Metformin being an insulin sensitizer can improve the function of vessels and related vascular abnormalities with few side effects in patients with type 2 diabetes mellitus [18]. The potential mechanisms by which metformin may prevent venous thrombosis are by inhibiting platelet activation in vivo and in vitro [19]. The evidence suggests that platelets are involved in several biological processes such as clotting, vascular lesions, and activation of other platelets [20]. This activity of platelets is markedly suppressed in the presence of metformin and it is mainly by suppression of platelet prothrombinase activity and by reducing extracellular mitochondrial release [1, 19].

This is consistent with the reduced platelet adhesive function after administering metformin. The animal studies suggest that metformin significantly suppressed aggregation of platelets and prevent both arterial and venous thrombosis in rat models [19]. And thrombus formation deteriorated in the rats treated with metformin [19]. Besides, it has been found that metformin reduces the size and weight of arterial and venous thrombi and subsequently reduces the incidence of pulmonary embolism [19]. Also, metformin reduces markers of endothelial activation such as Von Willebrand factor and it also decreases the inflammation and levels of plasminogen activator inhibitor 1 [19, 21-23]. These potential mechanisms contribute to the protective effect of metformin in reducing thrombus formation and associated mortality in diabetic patients.

This is a unique review as it is the first of its type that synthesized the findings of the role of metformin in preventing thromboembolism or associated mortality in diabetic individuals. The findings of this review can provide a framework to clinicians, endocrinologists, and policymakers to use metformin among diabetic patients who are at risk of developing thrombus formation to reduce morbidity and mortality mainly in the elderly. We also used an updated PRISMA checklist to conduct this review and most of the studies were large enough to be adequately powered to detect the protective effect of metformin on VTE. Besides, we included studies mainly from high-middle income countries, therefore, findings may not be generalizable to resource poor-settings with differences in the prevalence of causal partners or other factors that may interact with metformin differently in different settings.

Despite these strengths, the findings of the current review should be interpreted with caution due to some caveats associated with the individual studies. Since most all of the studies were observational epidemiological studies, one cannot establish causality between metformin and the outcome under investigation. Since the observational studies suffer from issues of unmeasured confounding, therefore, the researchers could not collect data on all confounders or covariates in their individual studies. Hence, the effect of metformin cannot be independent of all the factors. To address this issue, it is recommended to undertake randomized controlled trials in the future to prove the preventive effect of metformin independent of other factors. In addition, due to the overall dearth of literature on this area, studies from low-middle income countries were almost negligible, which warrant conducting more such studies in resource-poor settings. Also, the overall sample size of the review was small due to the scarcity of research in this area. Despite performing a deep literature search, we could not find more articles relevant to the study objective, which implies undertaking more research in this area before making any firm conclusions. Lastly, the included studies were of varying sample sizes, which is unavoidable but almost all of the studies were able to detect the desired effect size of metformin against VTE. However, overall, the included studies were very few as the literature is scarce on this topic mainly in human beings and most of the evidence is from animal or laboratory studies. These warrants conducting more epidemiological studies in human beings before making any robust conclusions about the role of metformin against thrombus formation in diabetic patients.

Overall, the existing studies included in this review demonstrate that metformin may be found protective against VTE, mainly in diabetic patients. Based on the available findings, metformin may be safely used in diabetic patients at risk of thromboembolism; however, we would recommend conducting more epidemiological studies particularly randomized controlled trials to assess the effect of metformin on VTE before making any definitive conclusions about the same. Considering the limited sample size of this review, more studies and their respective reviews are required to confirm these findings and these studies need to be undertaken both in developing and developed countries to confirm these findings and recommend the use of metformin on a broader scale for the prevention of thromboembolism in diabetic patients.

Acknowledgments

None to declare.

Financial Disclosure

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest

The authors declare no conflict of interest.

Informed Consent

Not applicable.

Author Contributions

Both authors contributed equally to conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; software; supervision; validation; visualization; roles/writing process. Both authors involve in the writing of the original draft; review and editing processes.

Data Availability

The data used to support the findings of this study are included within the article.

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