Background: Until now, it is uncertain whether lifestyle interventions during pregnancy can prevent gestational diabetes mellites (GDM) in high-risk pregnant women. Objective: This study aims at investigating the effectiveness of dietary interventions and/or exercise interventions during pregnancy for preventing GDM in high-risk pregnant women. Materials and Methods: Eligible randomized controlled trials (RCTs) were selected after a search in CENTRAL, Scopus, and PubMed. Synthesis was performed for the outcome of GDM in women with any identified GDM risk factor. Separate meta-analyses (MA) were performed to assess the efficacy of either nutrition or physical activity (PA) interventions or both combined compared with standard prenatal care for preventing GDM. Subgroup and sensitivity analyses, as well as meta-regressions against OR, were performed to assess potentional heterogeneity. Overall quality, the quality of RCTs, and publication bias were also evaluated. Results: A total of 13,524 participants comprising high-risk pregnant women in 41 eligible RCTs were analyzed for GDM. Women receiving only a nutrition intervention during pregnancy were less likely to experience GDM compared with women following standard prenatal care. Among 3109 high-risk pregnant women undergoing only dietary intervention for preventing GDM, 553 (17.8%) developed GDM; however, the result of the MA was marginally not significant (OR 0.73, 95%CI 0.51, 1.03; p-value 0.07), (Q 21.29, p-value 0.01; I² 58% (95%CI 10, 78%)). Subgroup analyses demonstrated an effect for studies that were conducted in Great Britain (OR 0.65, 95%CI 0.49, 0.81; p-value 0.003), and in Spain (OR 0.50, 95%CI 0.27, 0.94; p-value 0.03), for studies with forms of the Mediterranean diet as the intervention’s component (OR 0.61; 95%CI 0.46, 0.81; p-value 0.0005), and for studies including a motivation arm in the intervention (OR 0.71, 95%CI 0.58, 0.87; p-value 0.0008). Among 2742 high-risk pregnant women being analyzed for GDM outcome after receiving only an exercise intervention, 461 (16.8%) were diagnosed with GDM. Women after receiving PA intervention were less likely to develop GDM (OR 0.64, 95%CI 0.51, 0.80; p-value < 0.0001), (Q 11.27, p-value 0.51; I² 0% (95%CI 0, 99%)). Finally, 1308 (17%) cases of GDM were diagnosed among 7673 high-risk pregnant women undergoing both diet and PA intervention. Women in the group of mixed lifestyle intervention had a significant reduction in incidence of GDM (OR 0.70, 95%CI 0.55, 0.90; p-value 0.005), (Q 50.32, p-value < 0.0001, I² 66%, (95% CI 44, 79%)). Conclusions: The results of this study support the efficacy of lifestyle interventions during pregnancy for preventing GDM in high-risk women if an exercise component is included in the intervention arm, either alone, or combined with diet. A combined lifestyle intervention including physical exercise and a Mediterranean diet accompanied by motivation support may be considered the most effective way to prevent GDM among high-risk women during pregnancy. Future research is needed to strengthen these findings.

Metformin, the most widely prescribed oral antihyperglycemic agent, is established as the first-line therapy for type 2 diabetes mellitus (T2DM) owing to its efficacy, affordability, and safety. Increasing evidence indicates that its benefits extend beyond glycemic control, encompassing cardiovascular protection and diabetes prevention in individuals at elevated cardiometabolic risk. Mechanistic studies demonstrate that metformin exerts pleiotropic effects through activation of AMP-activated protein kinase, modulation of the gut microbiota, inhibition of pro-inflammatory and oxidative stress pathways, and improvements in endothelial function, lipid metabolism, and insulin sensitivity. These actions address core drivers of atherosclerosis and metabolic dysfunction, many of which occur independently of glucose lowering. In patients with T2DM, the cardiovascular benefits of metformin are well recognized, including reductions in all-cause mortality and cardiovascular events. In individuals without diabetes but at high cardiovascular risk—such as those with prediabetes, obesity, or metabolic syndrome—evidence is more limited, as most data are derived from subgroup analyses or trials with surrogate endpoints. Nonetheless, consistent signals suggest that metformin may delay the progression from prediabetes to overt diabetes and potentially confer vascular protection, particularly in carefully selected high-risk populations. Clinical trials and meta-analyses have demonstrated that metformin reduces incident diabetes by approximately one quarter in high-risk adults, with stronger effects observed in younger, overweight individuals, women with prior gestational diabetes, and those treated for longer durations. However, uncertainties remain regarding its long-term cost-effectiveness, optimal dosing strategies, and cardiovascular benefits in non-diabetic populations. The ongoing VA-IMPACT trial (NCT02915198) is expected to clarify whether metformin reduces major cardiovascular events in prediabetic patients with atherosclerotic disease. Taken together, metformin represents more than an antidiabetic drug. Its pleiotropic mechanisms, favorable safety profile, and low cost support its potential integration into broader cardiometabolic prevention strategies, including primary prevention. Expanding its role beyond diabetes management may offer a cost-effective, widely accessible intervention with significant public health impact.

Objective: This study is a Narrative Review that aims at investigating the implications of obesity, excessive gestational weight gain (GWG) and gestational diabetes mellitus (GDM). Additionally, this Review seeks to explore the effectiveness of nutrition, and/or exercise interventions during pregnancy on reducing GWG and preventing GDM. Materials and Methods: The search in literature included studies that identified obesity, GWG, GDM and associated risks during pregnancy. Also, SR and MA focusing on interventions including diet, or physical activity (PA), or combined (i.e., lifestyle interventions) and their impact on metabolic risk during pregnancy, were identified through searches in PubMed, Cochrane Database of Systematic Reviews (CDSRs), and Scopus. Results: The study findings suggest that lifestyle interventions during pregnancy may be effective in reducing excessive GWG. Regarding the prevention of GDM, results from studies evaluating lifestyle interventions vary. However, significant and less controversial results were reported from studies assessing the efficacy of exercise interventions, particularly in high-risk pregnant women. Conclusions: Lifestyle interventions during pregnancy may reduce excessive GWG. Exercise during pregnancy may prevent GDM, especially in high-risk pregnant women. Future research is warranted to tailor lifestyle interventions for optimal effectiveness during pregnancy.

Background: The effectiveness of metformin in preventing Type-2 Diabetes Mellitus (T2DM) is examined. There are new available data. Currently, there are no available analyses classifying its effectiveness compared to placebo, standard care, or lifestyle interventions, and there is limited evidence on the combined action of metformin and lifestyle interventions in preventing T2DM. Objective: To calculate the updated overall effectiveness of metformin in preventing T2DM using all available and most recent data, and to explore the effectiveness of metformin and lifestyle interventions in preventing T2DM. Materials and Methods: A search was performed in PubMed and the Cochrane Library Central Register of Controlled Trials (CENTRAL) (from inception to 24 May 2025). A systematic review (SR) and meta-analysis (MA) of randomized controlled trials (RCTs) was carried out, including metformin-naïve adults with any identified diabetes risk factors. The overall effectiveness of metformin was estimated by combining studies that compare metformin against placebo, metformin and standard care against standard care, and metformin plus lifestyle interventions and the same lifestyle interventions. The combined action of metformin and lifestyle interventions was evaluated against standard care. We performed a GRADE assessment of the overall evidence. Results: Overall, metformin may reduce the incidence of T2DM by 23% in high-risk adults (OR 0.77, 95% CI 0.67, 0.88, p-value 0.0001) and 25% in patients with prediabetes (OR 0.75, 95%CI 0.66, 0.86, p-value < 0.0001). It is also effective in both obese and normal-weight patients, in Caucasians, in studies with female predominance, in studies with a mean age over 60 years, at 1700 mg daily, and after 18 months of administration. Effectiveness weakens after interruption of administration. Metformin is more effective compared to placebo and when combined with standard care than standard care alone, but not when combined with lifestyle interventions against lifestyle interventions alone. Metformin and lifestyle interventions reduce the incidence of diabetes in patients with prediabetes by 52% compared to standard care (OR 0.48, 95% CI 0.30, 0.77; p-value 0.002). There are effectiveness concerns in studies with more men than women, Asian Indians and Pakistanis, a mean age below 60 years, 500 mg of metformin daily, and after six months. The effect is reduced during post-intervention. Finally, metformin alone is more effective than standard care (OR 0.56, 95% CI 0.34, 0.90, p-value 0.02). The quality of evidence was moderate for the overall effectiveness of metformin and metformin combined with lifestyle interventions, and low for metformin against standard care. Conclusions: A 1700 mg dose of metformin daily is effective in preventing T2DM, especially in Caucasians, in women over 60 years, in prediabetes, and independent of obesity. Lifestyle interventions and 500 mg of metformin daily may prevent T2DM in patients with prediabetes, especially in men and Asian Indians or Pakistanis under 60 years. The effectiveness of complex interventions is more pronounced than that of metformin alone in patients with prediabetes. Further research is needed for post-intervention effectiveness, patients with any diabetes risk factors, patients from different regions, and women in complex interventions.

Introduction: There are conflicting results and limited data regarding the individual effectiveness of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors and their combined action in preventing type 2 diabetes mellitus (T2DM) in high-risk adults. An updated investigation is warranted. We aimed to explore their effectiveness in preventing T2DM in high-risk patients and assess changes in body weight/body mass index (BMI), glycemic parameters, and safety. Materials and methods: PubMed, Cochrane Library Central Register of Controlled Trials, and Scopus were searched for eligible randomized controlled trials (RCTs), and a systematic review (SR) and meta-analysis (MA) were conducted. GRADE assessment was conducted for rating the overall certainty of evidence. Results: All 24,157 participants in 10 GLP-1 RA RCTs were overweight/obese. Compared to placebo, GLP-1 RAs reduced T2DM incidence (OR 0.51; 95% CI 0.28, 0.94; P -value 0.03), and 2.4 mg of semaglutide was overall effective (OR 0.38; 95% CI 0.16, 0.94; P -value < 0.0001). Subgroup analysis indicated effectiveness in patients more than 50 years across the world, in cardiovascular disease, after 100 weeks, and during the post-intervention period. Liraglutide was not overall effective. However, subgroup analyses demonstrated effectiveness for studies that were performed worldwide, for women more than 40 years, at 3.0 mg daily, after 55 weeks of administration, and only during intervention. Exenatide was not effective. Heterogeneity was large (Q 54.56, P -value < 0.0001; I ² 84%, 95% CI 74%, 89%), and MA was performed using the random-effects model. Heterogeneity was explained by countries’ performance in semaglutide- and liraglutide-based RCTs and participants’ mean age, dosage, duration, and post-intervention evaluation in liraglutide-based RCTs. Sensitivity analyses considering studies with post-intervention assessment and studies with the largest sample size and dropout rate more than 5% in semaglutide-based RCTs explain further heterogeneity. The quality of evidence was low. Compared to placebo, GLP-1 RAs reduced weight (kg) and BMI (kg/m²) (mean difference –6.35, P -value < 0.00001 and –2.46, P -value < 0.00001, respectively). Finally, GLP-1 RAs were safe (OR for adverse events 1.01; P -value 0.95). Conclusions: GLP-1 RAs may prevent diabetes in high-risk adults and ameliorate body and glycemic factors. Their effectiveness should be considered carefully due to the low quality of evidence. No safety issues were identified. Future investigation is necessary to provide consistency of estimations. Systematic Review Registration: OSF Registration, identifier DOI 10.17605/OSF.IO/8XH4