The Effectiveness of Metformin in Diabetes Prevention: A Systematic Review and Meta-Analysis

Diabetes mellitus is a growing global health concern, and prevention strategies play a crucial role in reducing its burden. Metformin has been widely studied as a potential intervention for diabetes prevention, but its overall effectiveness and impact on various populations remain unclear. This study aims to provide a comprehensive synthesis of the available evidence on the effectiveness of metformin in diabetes prevention. A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar for articles published from inception to June 2023. The reference lists of the included studies were also searched to retrieve possible additional studies. Any quantitative data were analyzed using Review Manager 5.4. A P-value of 0.05 was adopted as the significance threshold. Our analysis included 17 studies with a total sample size of 30,474. Our meta-analysis included two key analyses. First, the meta-analysis evaluating the effects of metformin on prediabetes demonstrated a significant reduction in the risk of progressing to type 2 diabetes mellitus (T2DM). The pooled odds ratio (OR) was 0.65 (95% confidence interval [CI] 0.53-0.80), indicating a 35% lower odds of developing T2DM among individuals with prediabetes who received metformin interventions compared to control groups. Secondly, the meta-analysis assessing the efficacy of metformin interventions in preventing T2DM yielded a significant reduction in the risk of developing the disease. The pooled risk ratio was 0.58 (95% CI 0.44-0.77), indicating a 42% lower risk of developing T2DM in individuals receiving metformin interventions compared to those in non-metformin intervention groups. These findings provide strong evidence for the effectiveness of metformin in preventing the progression of prediabetes to T2DM and reducing the overall incidence of the disease. The review demonstrated that metformin is effective in reducing the risk of developing diabetes mellitus among individuals at risk for the disease. The findings highlight the potential of metformin as a valuable intervention for diabetes prevention, particularly in high-risk populations.


Introduction And Background
Diabetes mellitus is a long-term metabolic condition characterized by high blood glucose levels [1].It is a worldwide public health issue, affecting an estimated 463 million persons globally in 2019.This number is expected to rise to 578 million by 2030 and 700 million by 2045 [2].Type 2 diabetes mellitus (T2DM), in particular, accounts for the vast majority of diabetes cases and is strongly linked to lifestyle variables such as obesity, sedentary activity, and poor eating habits.The concept of pre-disease, or at least its terminology, is relatively recent.The awareness that the top limits of normal measurements of blood glucose may pose a health concern and may be a warning that a patient is going toward diabetes is referred to as pre-disease [1].
Prediabetes is defined as a state of intermediate glucose dysregulation between normal glucose tolerance and overt diabetes [3].Individuals with prediabetes have higher-than-normal blood glucose levels but have not yet reached the diabetes diagnosis threshold [3,4].Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are terms used to describe prediabetes.In 2021, 464 million and 298 million adults aged between 20 and 79 years were estimated to have IGT and IFG, respectively [5].This is expected to increase to 638 million for IGT cases and 414 million for IFG cases by 2045 [5].Prediabetes has been associated with the development of certain pathologies.Wen et al. reported on an 11-year follow-up of 36,000 people in 2005 that those with IFG (fasting glucose levels between 6.1 and 6.9 mmol/L) had a significantly higher risk of mortality from cardiovascular diseases (CVDs) and diabetes than those with blood glucose levels below 6 mmol/L [6].Unwin et al. determined in a careful study of the matter that IFG and IGT (glucose 7.8 and 11.1 mmol/L, two hours after consumption of a 75-g oral glucose load) were strongly linked with CVD [7].IGT was found to be more significantly linked to CVD than IFG [7].Importantly, prediabetes increases the chance of developing T2DM, CVD, and other problems [1,[6][7][8][9][10].Identifying effective therapies to prevent or delay the transition from prediabetes to diabetes is, therefore, critical.
Adopting a balanced diet, increased physical exercise, and obtaining and maintaining a healthy weight are all considered the cornerstones of diabetes prevention.Lifestyle therapies have been shown in large-scale clinical trials, such as the Diabetes Prevention Program (DPP), to reduce the risk of developing diabetes by 58% in those with prediabetes [11].Nonetheless, despite the established benefits of lifestyle changes, their execution and long-term adherence remain difficult for many people [11].Pharmacological therapies have been examined as a viable method for diabetes prevention.Metformin, an oral antidiabetic drug, has emerged as a promising alternative among the numerous treatments investigated.Metformin is a biguanide derivative that reduces hepatic glucose synthesis, improves insulin sensitivity, and improves peripheral glucose uptake [12][13][14].
Metformin has been tested in various clinical trials for diabetes prevention, providing vital evidence of its efficacy and safety.The landmark DPP in the United States tested the efficacy of metformin, lifestyle changes, and placebo in people with prediabetes [11].Over a two-year and eight-month average follow-up period, metformin lowered the chance of getting diabetes by 31% compared to a placebo group.Furthermore, a 10-year follow-up trial called the DPP outcomes trial (DPPOS) investigated the long-term benefits of metformin and found a persistent reduction in the incidence of diabetes.Metformin lowered the risk of acquiring diabetes by 18% over 10 years [15].The objective of this systematic review and meta-analysis is to offer complete evidence on metformin's efficacy, safety, and long-term results by only using randomized controlled trials (RCTs).

Review Methodology
This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines [16].Three databases (PubMed, Scopus, and ScienceDirect) were searched for articles comprehensively.The search was performed from the inception of the database to the present date.There was no restriction on the publication language, and non-English articles were translated.The articles had to present information on the effectiveness of metformin in diabetes prevention.PubMed was the primary database considered to represent internationally indexed articles across the globe.

Search Strategy
The search strategy for PubMed featured a combination of free keyword searches and controlled the Medical Subject Headings (MeSH) terms.The keyword search featured an all-text analysis to broaden the sensitivity of the search strategy.The search strategies used for Scopus and ScienceDirect were slight modifications of PubMed's strategy.Table 1 represents the selection of primary keywords considered for PubMed search.
In addition to the search conducted on the three databases, a direct search was done using the Google Scholar database.To allow the presentation of the most relevant results on the first pages, keywords representing our research objective (metformin, diabetes prevention, prediabetes, T2DM, glucose metabolism, insulin resistance, and glycemic control) were included in the search.The reference lists of the included studies were also searched for any relevant additional articles.

Study Selection and Eligibility Criteria
To ensure the inclusion of reliable and robust evidence, only RCTs were chosen.The selected studies specifically involved the administration of metformin intending to delay or prevent the onset of T2DM.The participants in these studies were individuals with IGT or IFG, either in the entire sample or a subset.A crucial requirement was that the development of diabetes was measured as an outcome.Furthermore, the studies included in the review had a minimum follow-up period of six months.
Studies that satisfied the following criteria were excluded, studies that did not directly address the research question or did not meet the inclusion criteria defined in the review, non-primary studies, and studies with inadequate follow-up.
Potentially eligible studies were individually screened using Zotero (Corporation for Digital Scholarship, Fairfax, VA).The selection featured a rigorous screening of titles, abstracts, and full texts.The full-text screening featured a focus on the presentation of any form of data on the effectiveness of metformin in diabetes prevention.After the selection of articles for inclusion, data were extracted into a predefined data descriptor table with fields such as author, year of publication, study design, patients' characteristics, treatment group, control group, and outcome of the interest.

Quality Assessment and Statistical Analysis
The methodological quality of the included studies was assessed using the risk of bias (RoB) using the Cochrane tool for RCTs.For each study, we assessed the overall RoB score and categorized it based on the number of criteria for high RoB met.If a study fulfilled more than two criteria for some concerns of bias, we assigned it a high rating.If a study met one to two criteria for high RoB, we assigned it a rating of some concerns.Finally, if a study did not meet any criteria for a high RoB, we assigned it a rating of low RoB.
We employed random-effects meta-analysis models to consider the variability among studies.In cases where trials reported zero events in one of the study arms, we applied a continuity correction of 0.5.Our analysis involved estimating the combined relative risk (RR) for diabetes achieved after active intervention of medication trials.Additionally, we calculated the measure of association (odds ratio) between the intervention and the outcomes.To explore the effects of interventions after treatment withdrawal, we estimated the aggregate RR for diabetes at the end of active intervention, as well as at the end of the washout period for medication trials or the end of the follow-up period for lifestyle modification (LSM) trials.
We assessed heterogeneity across studies by calculating I2, where a value greater than 75% indicated significant heterogeneity.For quantitative data analysis, we utilized Review Manager 5.4 software.A P-value of 0.05 was adopted as the significance threshold.

Results
Initially, a total of 2,250 articles were retrieved through the search process.After removing 23 duplicates, 2,357 articles were excluded based on the eligibility criteria during the title and abstract screening.The remaining 58 articles underwent a full-text review.Among them, 41 articles were excluded as they did not fully meet the eligibility criteria.It's important to note that some articles were excluded for multiple reasons.The specific reasons for exclusion are outlined in the PRISMA flowchart (Figure 1).Ultimately, only 17 articles met all the inclusion criteria and were included in the review paper.A visual representation of the study selection process is shown in Figure 1.

Study Characteristics
We included a total of 17 RCTs.The studies encompassed a sample size of 30,474 patients, with a mean age of 46.67 years.Among the participants, 14,628 (48.0%) were men, and the baseline body mass index averaged 30.8 (calculated as weight in kilograms divided by height in meters squared).The included articles involved participants from Asian, North American, and European regions.Among the included articles, five studies were not included in the meta-analysis for various reasons.Some studies did not report the number of participants who developed diabetes at the end of the study, while others did not provide the number of individuals at risk for diabetes at baseline in each arm (n = 1).On the other hand, 11 articles provided sufficient data for meta-analyses, and based on quality assessment, it was deemed appropriate to pool the data from these studies.The included studies had varying lengths of follow-up, with 13 studies ranging from 0.5 to 6.3 years.Notably, the US DPP studies reported a follow-up period of 10 years since randomization.Study characteristics and findings are summarized in Table 2.

Results of Included Studies
In the study conducted by Li et al., a total of 90 participants were enrolled, with 45 assigned to each group.However, in their primary analysis, the authors excluded patients from both groups if they did not adhere to the treatment (metformin or placebo), were lost to follow-up, or experienced gastrointestinal side effects [19].Consequently, only 70 patients were included in the primary analysis: 33 in the metformin group and 37 in the placebo group.Although the authors performed an intention-to-treat analysis, they still excluded five participants (three from the metformin group and two from the placebo group) who were lost to followup.The authors provided follow-up outcomes for those excluded due to non-compliance and side effects, but not for those lost to follow-up.In our report, we focused on the primary analysis of the 70 participants as reported by Li et al. [19].However, we also conducted an intention-to-treat analysis, which included the five participants lost to follow-up.
In the study conducted by Ramachandran et al., a total of 531 participants were enrolled and randomly assigned to four different groups [18].For our comparison, we focused on the metformin-only group and the usual care (control) group.Notably, the control group did not utilize a placebo, making it impossible to blind the patients to their respective treatments.Out of the 129 participants enrolled in the control group and 136 in the metformin group, only 128 and 133 participants, respectively, were available for follow-up and subsequent analysis.
The study conducted by Knowler et al., as part of the DPP Research Group, enrolled a total of 3,234 individuals who were randomly assigned to one of three groups [17].In our analysis, we specifically compared the placebo-controlled group, consisting of 1,082 participants, with the metformin group, which comprised 1,073 participants.This study was notable for its well-executed design, comprehensive reporting, and notably larger sample size compared to other studies.The authors conducted an intention-to-treat analysis, which involved including all participants enrolled in the study when assessing the outcomes.Unfortunately, the authors did not provide the actual number of participants lost to follow-up in each group.However, they did report that 99.6% of the full study population was alive at the end of the follow-up period.Assuming this percentage was equally distributed across both groups, we used it to estimate the number of individuals lost to follow-up in each group.
One meta-analysis was performed.Figures 2-3 show the results of the meta-analysis that includes the findings from the three studies as the authors reported them.with IGT in a specific region [22].The study found that the addition of medication did not yield any notable improvements.As a result, the researchers recommended the incorporation of lifestyle advice and follow-up as essential components of primary healthcare to address this issue effectively.
O'Brien et al. conducted a study to compare the effectiveness of intensive lifestyle intervention and metformin in individuals participating in the DPP, considering their level of education [27].The researchers concluded that both intensive lifestyle intervention and metformin demonstrated higher efficacy among individuals with a higher level of education.Orchard et al. conducted a study to assess the prevalence of MetS at the start of the DPP and to examine how intensive lifestyle intervention and metformin therapy influenced the occurrence and resolution of the syndrome [28].The study concluded that both the lifestyle intervention and metformin therapy contributed to a reduction in the development of MetS among the remaining participants.Ratner et al. conducted a study aiming to identify individuals who had IGT and intervene to prevent or delay the onset of diabetes [29].The study findings indicated that both intensive lifestyle intervention and metformin were highly successful in postponing or preventing diabetes in women with IGT and a history of gestational diabetes mellitus (GDM).Sussman et al. conducted a study to investigate whether certain participants in the DPP would derive greater or lesser benefits from either metformin or a structured LSM program [30].The study findings revealed that the benefit of metformin was predominantly observed in patients belonging to the highest quarter of diabetes risk.Conversely, no significant benefits were observed in the lowest-risk quarter.Participants in the highest-risk quarter experienced an average absolute risk reduction of 21.4% over three years, with a number needed to treat of 4.6.
Weber et al. conducted a study to evaluate the efficacy of expert guidelines for preventing diabetes, specifically focusing on lifestyle intervention and the addition of metformin as needed for individuals with prediabetes [21].The study concluded that a majority of the participants required the inclusion of metformin in addition to lifestyle intervention.Zinman et al. conducted a study to examine the impact of low-dose combination therapy on the development of T2DM [31].The study findings indicated that low-dose combination therapy involving rosiglitazone and metformin proved to be highly effective in preventing the onset of T2DM in patients with IGT.Additionally, the study noted minimal influence on the clinically significant adverse events associated with these two drugs.
The DPP research group conducted an RCT study in 2003 [24].The study findings revealed that the primary analysis of the DPP demonstrated a 31% reduction in the risk of diabetes with the use of metformin.Another study by the DPP research group conducted in 2012 reported that the use of metformin for diabetes prevention is both safe and well-tolerated [32].They also noted that weight loss is associated with adherence to metformin and remains consistent over a treatment period of at least 10 years.The DPP research group conducted a study in 2009, which revealed that over 10 years since the randomization of the DPP, the incidence of diabetes was reduced by 34% (with a range of 24%-42%) in the lifestyle intervention group and by 18% (with a range of 7%-28%) in the metformin group when compared to the placebo group [15].In 2015, the DPP research group conducted a study to examine the lasting effects of lifestyle intervention and metformin in preventing diabetes, as initially demonstrated in the three-year DPP [20].The study also aimed to determine if these interventions had a positive impact on diabetes-related microvascular complications.The findings of the study indicated that both lifestyle intervention and metformin significantly reduced the development of diabetes over 15 years.

Efficacy of Medication Interventions
The results of the meta-analysis indicate that the use of metformin medication interventions is associated with a significant reduction in the risk of developing diabetes.The risk ratio of 0.58 suggests that individuals receiving metformin had a 42% lower risk of developing diabetes compared to those in the control group.This finding highlights the efficacy of metformin as a preventive measure for diabetes.The 95% confidence interval (CI) of 0.44 to 0.77 indicates a high level of confidence that the true risk ratio falls within this range.These results suggest that metformin shows promise in reducing the risk of diabetes and could be considered an effective intervention in preventing the onset of the disease.
In the analysis, the heterogeneity statistic, represented by I², was calculated to be 82%.This meant that approximately 82% of the total variation in the study results could be attributed to factors other than random chance.In simpler terms, there is a substantial amount of diversity among the studies included in the meta-analysis.Additionally, the P-value associated with the heterogeneity test was 0.0002.The P-value indicated the statistical significance of the observed heterogeneity.In this case, the low P-value suggested that the observed heterogeneity is unlikely to have occurred by chance alone.Therefore, the differences among the study results are considered statistically significant.

RoB in Included Studies
The majority of the studies were determined to have a low RoB due to deviations from the intended intervention, bias in outcome measurement, and bias in the selection of reported results.On the other hand, several studies were identified to have some concerns regarding the RoB related to the randomization process.The traffic light plot and summary plot were generated as shown in Figures 6-7, respectively.

Discussion
The prevention of diabetes is of paramount importance in addressing the global burden of this chronic disease.Metformin, a widely prescribed oral medication for the treatment of T2DM, has gained significant attention for its potential role in diabetes prevention.In this systematic review and meta-analysis, we sought to evaluate the effectiveness of metformin in preventing the onset of diabetes in individuals at high risk.By synthesizing the available evidence from RCTs, our study provides valuable insights into the efficacy of metformin as a preventive intervention.
Our systematic review and meta-analysis encompassed a range of studies evaluating the effectiveness of metformin in diabetes prevention.The study conducted by Li et al. demonstrated that metformin reduced the risk of developing diabetes, as evidenced by the primary analysis of 70 participants [19].Similarly, Ramachandran et al. found that metformin, compared to usual care, showed a potential for diabetes prevention, although the availability of participants for follow-up analysis was slightly limited [18].Of particular note was the study conducted by Knowler et al., which encompassed a larger sample size and employed a robust design [17].Their findings indicated a reduction in diabetes incidence by 18% to 34% in the metformin and lifestyle intervention groups, respectively, compared to the placebo group over 10 years.These results provide compelling evidence for the effectiveness of metformin in preventing diabetes in highrisk individuals.Furthermore, our analysis revealed consistent findings across multiple studies.Andreadis et al. reported that metformin significantly reduced the likelihood of developing T2DM in overweight and obese individuals without diabetes while also improving the profile of CVD risk factors [23].Florez et al. highlighted the beneficial impact of interventions, including metformin, on reducing the occurrence of diabetes [25].Conversely, Iqbal Hydrie et al. emphasized the significance of lifestyle intervention in preventing diabetes among individuals with IGT, suggesting that medication alone did not yield notable improvements [22].In line with these findings, studies conducted by the DPP research group consistently demonstrated the effectiveness and long-term benefits of metformin in diabetes prevention.Their research showed a 31% reduction in diabetes risk with metformin use, as well as the safety and tolerability of metformin over an extended treatment period.Moreover, the group's studies showcased the lasting effects of lifestyle intervention and metformin, leading to significant reductions in diabetes development over 15 years, as well as potential positive impacts on diabetes-related microvascular complications.
Our meta-analysis revealed compelling evidence supporting the effectiveness of metformin in reducing the risk of developing diabetes.The analysis demonstrated a significant reduction in the risk of diabetes among individuals receiving metformin medication interventions, as indicated by the risk ratio of 0.58.This finding suggests that individuals receiving metformin had a 42% lower risk of developing diabetes compared to those in the control group.Collectively, these findings from various studies provide robust evidence supporting the effectiveness of metformin in preventing the onset of diabetes, particularly in high-risk individuals.The results highlight the potential of metformin as a valuable preventive intervention in the global efforts to combat the growing burden of diabetes.
Our findings are supported by several other studies investigating the effectiveness of metformin in diabetes prevention.Maruthur et al. conducted a systematic review and meta-analysis, which showed that metformin, was effective in reducing the incidence of diabetes in individuals with IGT, MetS, and polycystic ovary syndrome [33].These findings support the broad applicability of metformin in various high-risk populations.Moreover, the Diabetes Prevention Program Outcomes Study (DPPOS) conducted by the DPP research group in 2009 demonstrated the long-term efficacy of metformin in reducing the risk of diabetes, with the benefits persisting over 10 years.Gebrie et al. conducted a network meta-analysis comparing various interventions and found that metformin was among the most effective interventions in reducing the incidence of diabetes [34].This aligns with our results, indicating the efficacy of metformin in preventing T2D.Furthermore, Abbasi et al. conducted research focusing on the effects of metformin on CVDs in patients with diabetes [35].Their analysis revealed that metformin use was associated with a reduced risk of CVD events and mortality in diabetic patients.Although our focus is on diabetes prevention, these findings suggest that metformin may provide additional benefits by reducing CVD risk factors in individuals with diabetes.Another systematic review and meta-analysis by Vella et al. analyzed the effects of metformin in preventing diabetes in individuals at high risk [36].Their findings supported the notion that metformin significantly reduced the risk of diabetes compared to placebo or no treatment.This concurs with our results, reinforcing the role of metformin as an effective intervention for diabetes prevention.Furthermore, a study by Rena et al. explored the mechanisms of action of metformin and its role in preventing diabetes [37].Their findings indicated that metformin improved insulin sensitivity, reduced hepatic glucose production, and decreased intestinal glucose absorption, all of which contribute to its preventive effects on diabetes.These mechanisms align with our findings; supporting the notion that metformin exerts its beneficial effects through multiple pathways.
This review has several limitations that should be considered.First, heterogeneity among the included studies, such as variations in participant characteristics, interventions, and outcome measures, may limit the ability to conduct a pooled analysis and draw definitive conclusions across all studies.However, we addressed these limitations by conducting a comprehensive search strategy across multiple databases and implementing strict inclusion criteria to minimize the risk of missing relevant studies and ensure the selection of high-quality research.Furthermore, our review included a meta-analysis, allowing for a quantitative synthesis of the data, and enhancing the statistical power of our analysis.Overall, the comprehensive search strategy, rigorous study selection, and meta-analysis were key strengths of our review, providing a solid foundation for the findings and contributing to the reliability and validity of our conclusions.

Conclusions
This systematic review and meta-analysis provides strong evidence supporting the effectiveness of metformin in the prevention of diabetes mellitus.The findings from our analysis, along with the alignment with other relevant studies, consistently demonstrate that metformin supplementation reduces the likelihood of developing T2DM, particularly in overweight and obese individuals without diabetes.The combination of metformin and lifestyle intervention shows synergistic effects, emphasizing the importance of comprehensive approaches in diabetes prevention strategies.The consistent evidence from our review supports the consideration of metformin as a valuable intervention in diabetes prevention efforts, especially in high-risk populations.Further research should continue to explore the specific subgroups and factors that may influence the effectiveness of metformin, as well as long-term outcomes and potential adverse effects.
Ultimately, the findings from our review contribute to the growing body of evidence, highlighting the important role of metformin in reducing the burden of T2DM and informing healthcare practitioners and policymakers in making informed decisions regarding diabetes prevention strategies.

FIGURE 1 :
FIGURE 1: PRISMA flowchart.PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

FIGURE 3 :
FIGURE 3: Funnel plot.OR, odds ratio; SE, standard error Forest and funnel plots for the efficacy of medication interventions are shown in Figures 4-5, respectively.

FIGURE 4 :
FIGURE 4: Forest plot for efficacy of medication intervention.CI, confidence interval

FIGURE 5 :
FIGURE 5: Funnel plot for the efficacy of medication intervention.RR, relative risk; SE, standard error