Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients.

Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m2 or better before restarting metformin.

Impact of Initial Treatment Policies on Long-term Complications and Costs in Japanese Patients with Type 2 Diabetes: A Real-World Database Study.

INTRODUCTION: Type 2 diabetes (T2D) represents a remarkable disease burden in Japan, and the cost-effectiveness of pharmacotherapy is an important consideration. In this study, we compared the long-term effects of the type of initial medication, as well as the initial frequency of clinic visits, on the occurrence of T2D-related complications. Additionally, we compared the medical costs associated with each treatment pattern. METHODS: We analyzed electronic health record data collected from multiple primary care clinics in Japan. Patients were selected based on being primarily prescribed either biguanides (BG) or DPP-4 inhibitors (DPP-4i) during a 3-month baseline period, both of which are commonly used as first-choice medications in Japan. We then followed the onset of T2D-related complications and conducted survival analyses. Additionally, we calculated the accumulated medical costs up to the onset of an event or loss to follow-up, and summarized the annual costs per patient for each treatment pattern. RESULTS: A total of 416 Japanese patients with T2D who initiated treatment between January 2015 and September 2021 were included. The median follow-up period was 2.69 years. The survival analysis showed that the use of DPP-4is and frequent visits from the beginning of treatment did not offer a benefit in suppressing the onset of complications later on. On the other hand, it was found that the annual medical costs for the group using DPP-4i with frequent visits were about 1.9 times higher than for the group using BGs with less frequent visits. CONCLUSIONS: The results suggest that for Japanese patients with T2D, the use of BGs along with relatively long follow-up intervals in the beginning of treatment can remarkably reduce medical costs while providing a level of complication suppression equivalent to that of the use of DPP-4is or frequent visits.

Effect of Water and Chlorhexidine with Different Pressures of Oral Irrigation Device on the Surface Roughness and Topography of Giomer

Abstract Objective: To evaluate the effect of different pressures of an oral irrigation device (OID) and the irrigation solution type on the surface roughness of the giomer restorative material. Material and Methods: In this in vitro study, disk-shaped giomer samples were fabricated and assigned to 5 groups (n=23): Group 1, storage in distilled water (control); Group 2, OID #7 pressure/ water; Group 3, OID #10 pressure/ water; Group 4, OID #7 pressure/ 0.05% CHX; Group 5, OID #10 pressure/ 0.05% CHX. The samples' treatment simulated a one-year application of OID. Surface roughness (Ra) and topography of the giomer were evaluated using profilometry and scanning electron microscopy. The data were analyzed with Paired t-test, Tukey, and ANOVA tests (α=0.05). Results: The Ra of the samples increased significantly after treatment with OID (p<0.001). The roughness increase in groups with a pressure of 10 was higher than those with a pressure of 7 (p<0.001). The effect of pressure on surface changes was significant (p<0.001). However, the solution type and the cumulative effect of these two factors were insignificant (p=0.08 and p=0.43, respectively). Conclusion: Oral irrigation device with both solutions significantly increased the surface roughness and topographic changes of the giomer. The severity of these changes was related to the device's pressure.

Insights from insulin resistance pathways: Therapeutic approaches against Alzheimer associated diabetes mellitus.

Alzheimer Associated Diabetes Mellitus, commonly known as Type 3 Diabetes Mellitus (T3DM) is a distinct subtype of diabetes with a pronounced association with Alzheimer's disease (AD). Insulin resistance serves as a pivotal link between these two conditions, leading to diminished insulin sensitivity, hyperglycemia, and impaired glucose uptake. The brain, a vital organ in AD context, is also significantly impacted by insulin resistance, resulting in energy deficits and neuronal damage, which are hallmark features of the neurodegenerative disorder. To pave the way for potential therapeutic interventions targeting the insulin resistance pathway, it is crucial to comprehend the intricate pathophysiology of T3DM and identify the overlapped features between diabetes and AD. This comprehensive review article aims to explore various pathway such as AMPK, PPARγ, cAMP and P13K/Akt pathway as potential target for management of T3DM. Through the analysis of these complex mechanisms, our goal is to reveal their interdependencies and support the discovery of innovative therapeutic strategies. The review extensively discusses several promising pharmaceutical candidates that have demonstrated dual drug action mechanisms, addressing both peripheral and cerebral insulin resistance observed in T3DM. These candidates hold significant promise for restoring insulin function and mitigating the detrimental effects of insulin resistance on the brain. The exploration of these therapeutic options contributes to the development of innovative interventions that alleviate the burden of T3DM and enhance patient care.

Risk of Lactic Acidosis in Hospitalized Diabetic Patients Prescribed Biguanides in Japan: A Retrospective Total-Population Cohort Study.

Patient data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) are used to assess the effect of biguanide administration on rates of lactic acidosis (LA) in hospitalized diabetes mellitus (DM) patients. In this retrospective cohort study (from April 2013 to March 2016), we compare DM inpatients prescribed biguanides to DM inpatients who were not prescribed biguanides to quantify the association between biguanides and incidence of LA. In total, 8,111,848 DM patient records are retrieved from the NDB. Of the 528,768 inpatients prescribed biguanides, 782 develop LA. Of the 1,967,982 inpatients not prescribed biguanides, 1310 develop LA. The rate ratio of inpatients who develop LA and are administered biguanides to those who developed LA without receiving biguanides is 1.44 (95% CI, 1.32-1.58). Incidence rates and rate ratios for both sexes are elevated in the group prescribed biguanides for patients aged 70 years and older, markedly in those 80 years and older: 40.12 and 6.31 (95% CI, 4.75-8.39), respectively, for men and 34.96 and 5.40 (95% CI, 3.91-7.46), respectively, for women. Biguanides should be used conservatively in patients older than 70 years, particularly for those with comorbidities, and with caution in patients 80 years and older.

Identification of CYP3A4 inhibitors as potential anti-cancer agents using pharmacoinformatics approach.

Biguanide derivatives exhibit a wide variety of therapeutic applications, including anti-cancer effects. Metformin is an effective anti-cancer agent against breast cancer, lung cancer, and prostate cancer. In the crystal structure (PDB ID: 5G5J), it was found that metformin is found in the active site of CYP3A4, and the associated anti-cancer effect was explored. Taking clues from this work, pharmacoinformatics research has been carried out on a series of known and virtual biguanide, guanylthiourea (GTU), and nitreone derivatives. This exercise led to the identification of more than 100 species that exhibit greater binding affinity toward CYP3A4 in comparison to that of metformin. Selected six molecules were subjected to molecular dynamics simulations, and the results are presented in this work.

Extended-release metformin improves cognitive impairment in frail older women with hypertension and diabetes: preliminary results from the LEOPARDESS Study.

BACKGROUND: Women have a high risk of frailty independently of age and menopause state. Diabetes and hypertension increase the risk of frailty and cognitive impairment. Metformin has been employed in post-menopausal women and some reports have shown encouraging effects in terms of attenuated frailty. However, the impact on cognitive performance of a recently introduced extended-release formulation of metformin has never been explored. METHODS: We studied consecutive frail hypertensive and diabetic older women presenting at the ASL (local health authority of the Italian Ministry of Health) Avellino, Italy, from June 2021 to August 2022, who were treated or not with extended-release metformin. We included a control group of frail older males with diabetes and hypertension treated with extended-release metformin and a control group of frail older women with diabetes and hypertension treated with regular metformin. RESULTS: A total of 145 patients successfully completed the study. At the end of the 6-month follow-up, we observed a significantly different cognitive performance compared to baseline in the group of frail women treated with extended-release metformin (p: 0.007). Then, we compared the follow-up groups and we observed significant differences between frail women treated vs. untreated (p: 0.041), between treated frail women and treated frail men (p: 0.016), and between women treated with extended-release metformin vs. women treated with regular metformin (p: 0.048). We confirmed the crucial role of extended-release metformin applying a multivariable logistic analysis to adjust for potential confounders. CONCLUSIONS: We evidenced, for the first time to the best of our knowledge, the favorable effects on cognitive impairment of extended-release metformin in frail women with diabetes and hypertension.

[Evolution of the non-insulin therapeutic strategy in type 2 diabetes]. / Évolution de la stratégie thérapeutique hors insuline dans le diabète de type 2.

While the prevalence of diabetes continues to rise worldwide, with 537 million adults aged 20-79-years-old having diabetes in 2021, the development of new therapeutic classes improving not only glycemic control but also kidney function and cardiovascular prevention has revolutionized patient care. Today, the treatment of diabetes is no longer just the treatment of blood sugar level. In this context, the individualized therapeutic strategy has been completely reviewed, with in particular sulfamides indicated much later in the therapeutic strategy, while SGLT2 inhibitors are indicated very early in patients with kidney disease and/or with ischemic heart disease or chronic heart failure, and GLP-1 analogues in obese patients and/or in primary or secondary cardiovascular prevention. As for lifestyle rules and metformin, they remain the cornerstone of treatment. Knowledge of antidiabetic effects in terms of efficacy and hypoglycemic risk, of cardiovascular, nephroprotective and weight effects is essential to optimize the management of diabetic patients today.

Metformin May Alter the Metabolic Reprogramming in Cancer Cells by Disrupting the L-Arginine Metabolism: A Preliminary Computational Study.

Metabolic reprogramming in cancer is considered to be one of the most important hallmarks to drive proliferation, angiogenesis, and invasion. AMP-activated protein kinase activation is one of the established mechanisms for metformin's anti-cancer actions. However, it has been suggested that metformin may exert antitumoral effects by the modulation of other master regulators of cellular energy. Here, based on structural and physicochemical criteria, we tested the hypothesis that metformin may act as an antagonist of L-arginine metabolism and other related metabolic pathways. First, we created a database containing different L-arginine-related metabolites and biguanides. After that, comparisons of structural and physicochemical properties were performed employing different cheminformatic tools. Finally, we performed molecular docking simulations using AutoDock 4.2 to compare the affinities and binding modes of biguanides and L-arginine-related metabolites against their corresponding targets. Our results showed that biguanides, especially metformin and buformin, exhibited a moderate-to-high similarity to the metabolites belonging to the urea cycle, polyamine metabolism, and creatine biosynthesis. The predicted affinities and binding modes for biguanides displayed good concordance with those obtained for some L-arginine-related metabolites, including L-arginine and creatine. In conclusion, metabolic reprogramming in cancer cells by metformin and biguanides may be also driven by metabolic disruption of L-arginine and structurally related compounds.

Effect of Pre-Meal Metformin With or Without an Acute Exercise Bout on Postprandial Lipemic and Glycemic Responses in Metabolic Syndrome Patients: A Randomized, Open Label, Crossover Study.

INTRODUCTION: Both exercise and pre-meal metformin could lower postprandial glucose and lipid profiles. AIMS: To explore whether pre-meal metformin administration is superior to metformin administration with the meal in reducing postprandial lipid and glucose metabolism, and whether its combination with exercise confer superior benefits in metabolic syndrome patients. MATERIALS AND METHODS: In a randomized crossover design, 15 metabolic syndrome patients were assigned to 6 sequences including 3 experimental conditions: metformin administration with a test meal (met-meal), metformin administration 30 min prior to a test meal (pre-meal-met) with or without an exercise bout designed to expend 700 Kcal at 60% VO2 peak performed the evening just before pre-meal-met condition. Only 13 participants (3 males, 10 females; age: 46 ± 9.86, HbA1c: 6.23 ± 0.36) were included in the final analysis. RESULTS: Postprandial triglyceridemia was unaffected by any condition (all P > .05). However, both pre-meal-met (-7.1%, P = .009) and pre-meal-metx (-8.2%, P = .013) significantly reduced total cholesterol AUC with no significant differences between the two latter condition (P = .616). Similarly, LDL-cholesterol levels were significantly lower during both pre-meal-met (-10.1%, P = .013) and pre-meal-metx (-10.7%, P = .021) compared to met-meal with no difference between latter conditions (P = .822). Plasma glucose AUC was significantly reduced by pre-meal-metx compared to both pre-meal-met (-7.5%, P = .045) and met-meal (-8%, P = .03). Insulin AUC was significantly lower during pre-meal-metx compared to met-meal (-36.4%, P = .044). CONCLUSIONS: Metformin administration 30 minutes prior to meal seems to exert favorable effects on postprandial TC and LDL-Cholesterol levels compared to its administration with meal. Addition of one exercise bout only improved postprandial glycemia and insulinemia. TRIAL REGISTRY: Pan African clinical trial registry, Identifier PACTR202203690920424.

Metformin: new applications for an old drug.

Metformin is a biguanide, evolved as one of the most widely used medicines. The applications of this component include but are not limited to reducing blood glucose, weight loss, and polycystic ovary syndrome. Studies about other probable indications have emerged, indicating that this agent can also be utilized for other purposes. In this review, applications of metformin are noticed based on the current evidence. Metformin commonly is used as an off-label drug in non-alcoholic fatty liver disease (NAFLD), but it worsens inflammation and should not be used for this purpose, according to the latest research. Metformin decreased the risk of death in patients with liver cirrhosis. It is an effective agent in the prevention and improvement of survival in patients suffering hepatocellular carcinoma. There is evidence of the beneficial effects of metformin in colorectal cancer, early-stage prostate cancer, breast cancer, urothelial cancer, blood cancer, melanoma, and bone cancer, suggesting metformin as a potent anti-tumor agent. Metformin shows neuroprotective effects and provides a potential therapeutic benefit for mild cognitive impairment and Alzheimer's disease (AD). It also has been shown to improve mental function and reduce the incidence of dementia. Another condition that metformin has been shown to slow the progression of is Duchenne muscular dystrophy. Regarding infectious diseases, tuberculosis (TB) and coronavirus disease (COVID-19) are among the conditions suggested to be affected by metformin. The beneficial effects of metformin in cardiovascular diseases were also reported in the literature. Concerning renal function, studies showed that daily oral administration of metformin could ameliorate kidney fibrosis and normalize kidney structure and function. This study reviewed the clinical and preclinical evidence about the possible benefits of metformin based on recent studies. Numerous questions like whether these probable indications of metformin can be observed in non-diabetics, need to be described by future basic experiments and clinical studies.

Entering the Sugar Rush Era: Revisiting the Antihyperglycemic Activities of Biguanides after a Century of Metformin Discovery.

The development of clinically viable metformin analogs is a challenge largely to be overcome. Despite being an extremely efficient drug for the treatment of type 2 diabetes mellitus, multiple studies were conducted seeking to improve its hypoglycemic activity or to ameliorate aspects such as low oral absorption and the incidence of gastrointestinal side effects. Furthermore, efforts have been made to attribute new activities, or even to expand the pre-existing ones, that could enhance its effects on diabetes, such as pancreas-protective, antioxidant, and anti-inflammatory activities. In this paper, we describe the analogs of metformin developed in the last three decades, highlighting the lack of computationally based rational approaches to guide their development. We also discuss this is probably a consequence of how unclear the mechanism of action of the parent drug is and highlight the recent advances towards the establishment of the main molecular target(s) for metformin. We also explored the binding of metformin, buformin and phenformin to the mitochondrial respiratory chain complex I through molecular docking analyses and reviewed the prospects of applying computational tools to improve the success in the development of such analogs. Therefore, it becomes evident that the wide range of molecular targets and the multiple activities displayed by metformin make this drug a promising prototype for developing novel entities, particularly for treating type 2 diabetes mellitus.

Three Cases of Lactic Acidosis Caused by Biguanides.

Biguanides may cause lactic acidosis (LA) in elderly patients. We report three cases of LA after the administration of biguanides. Case 1 was an 85-year-old man with no hepatic dysfunction who was discharged, case 2 was a 67-year-old man with no hepatic dysfunction who was discharged, and case 3 was a 77-year-old woman with hepatic dysfunction who died. Therefore, caution should be exercised in administering biguanides to elderly patients with hepatic dysfunction.

B- and Al-Doped Porous 2D Covalent Organic Frameworks as Nanocarriers for Biguanides and Metformin Drugs.

Nanostructures such as nanosheets, nanotubes, nanocages, and fullerenes have been extensively studied as potential candidates in various fields since the advancement of nanoscience. Herein, the interaction between biguanides (BGN) and metformin (MET) on the modified covalent organic framework (COF), COF-B, and COF-Al was investigated using density functional theory at the ωB97XD/6-311+G (d, p) level of computation to explore a new drug delivery system. The electronic properties evaluation reveals that the studied surfaces are suited for the delivery of both drug molecules. The calculated adsorption energies and basis set superposition errors (BSSE) ranged between -21.20 and -65.86 kJ/mol. The negative values obtained are an indication of excellent interaction between the drug molecules and the COF surfaces. Moreover, BGN is better adsorbed on COF-B with Eads of -65.86 kJ/mol, while MET is better adsorbed on COF-Al with Eads = -47.30 kJ/mol. The analysis of the quantum theory of atom in molecules (QTAIM) explained the nature and strength of intermolecular interaction existing between the drug molecules BGN and MET with the adsorbing surfaces. The analysis of noncovalent interaction (NCI) shows a weak hydrogen-bond interaction. Other properties such as quantum chemical descriptors and natural bond orbital (NBO) analysis also agree with the potential of COF surfaces as drug delivery systems. The electron localization function (ELF) is discussed, and it confirms the transitions occurring in the NBO analysis of the complexes. In conclusion, COF-B and COF-Al are suitable candidates for the effective delivery of BGN and MET.

Pharmacotherapy of type 2 diabetes: An update and future directions.

Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.

Sulfonylureas or biguanides is associated with a lower risk of rheumatoid arthritis in patients with diabetes: A nationwide cohort study.

Objective: Diabetes mellitus (DM) is associated with immune dysregulation, while sulfonylureas or biguanides have been linked to anti-inflammatory mechanisms. In this study, we aimed to examine the occurrence rate of rheumatoid arthritis (RA) among DM patients and its incidence rate between different treatments. Methods: This cohort study used the Taiwan National Health Insurance Research Database between 1997 and 2013 to evaluate the primary outcomes of the preventive role of sulfonylureas or biguanides in the development of RA. We used the Chi-square test for categorical variables and Cox proportional hazard regression and log-rank test to explore the time for development of RA in DM patients. Logistic regression was adopted to estimate the odds ratio of RA in different dosages of medication exposure. Results: Our cohort study included 94,141 DM cases. The risk of RA development of non-sulfonylureas/biguanides users among the DM group in each analysis was set as the reference, and the adjusted hazard ratio of RA in DM patients who were using sulfonylureas or biguanides was 0.73 (95% confidence interval 0.60-0.90). Within 1 year before the index date, compared with no-biguanides users, patients with more than 180 days of prescription of biguanides had a significantly lower RA risk. Similarly, the significantly lower risk of RA was still observed in DM patients who had more than 365 days of prescription of sulfonylurea within 2 or 3 years before the index date of first RA visit (all p < 0.05). Conclusion: Our data suggest that sulfonylureas or biguanides are associated with a lower rate of RA development in patients with DM; the effect of biguanides appeared more rapid than that of sulfonylureas, but the sulfonylureas might have a longer effect on lowering RA development incidence.

Metformin: When Should We Fear Lactic Acidosis?

Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world. Over the sixty years during which it has been used, many benefits have been described, which are not limited to the treatment of diabetes mellitus. However, since metformin is similar to other members of the same drug family, there is still much concern regarding the risk of lactic acidosis. This article aims to highlight the correlation between the use of metformin and the onset of renal damage or lactic acidosis. Metformin-associated lactic acidosis exists; however, it is rare. The appropriate use of the drug, under safe conditions, induces benefits without risks.

The Mechanism of Action of Biguanides: New Answers to a Complex Question.

Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this "complex" model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.

Metformin use is not associated with reduced risk of older onset inflammatory bowel disease: a Danish nationwide population-based study.

BACKGROUND: Metformin has pleiotropic effects including anti-inflammatory properties and effects on the gut microbiome. It is primarily used in the older population, where the occurrence of inflammatory bowel disease (IBD) is increasing. The aim of this study was to examine whether metformin protects against development of IBD. METHODS: In the setting of a Danish nationwide population-based cohort, we conducted a nested case-control study using a new-user active comparator design. For each patient with IBD, we selected 10 IBD-free individuals matched on age, sex, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) of IBD. Adjustment included educational level, other immune-mediated inflammatory diseases, and use of dipeptidyl peptidase (DPP)-4 inhibitors and statins. RESULTS: Among 302,863 IBD-free new users of oral glucose-lowering drugs, we identified 1271 patients who developed IBD and 12,676 matched IBD-free individuals. Mean age at IBD diagnosis was 66 (SD, 11) years. We found no association between ever use of metformin and risk of IBD, Crohn's disease or ulcerative colitis, adjusted OR 0.95 (95% CI 0.78-1.15), 0.87 (95% CI 0.60-1.26), and 1.04 (95% CI 0.83-1.31), respectively. Neither was the cumulative dose of metformin or the treatment duration with metformin associated with risk of IBD. CONCLUSIONS: In this population-based study, we report that despite anti-inflammatory effects and a notable impact on the gut microbiome, metformin use is not associated with reduced risk of older onset IBD.

Structural Comparison of Sulfonamide-Based Derivatives That Can Improve Anti-Coagulation Properties of Metformin.

Due to its high efficiency, good safety profile, and potential cardio-protective properties, metformin, a dimethyl biguanide, is the first-line medication in antihyperglycemic treatment for type 2 diabetic patients. The aim of our present study was to assess the effects of eight new sulfonamide-based derivatives of metformin on selected plasma parameters and vascular hemostasis, as well as on endothelial and smooth muscle cell function. The compounds with an alkyl chain (1-3), trifluoromethyl substituent (4), or acetyl group (5) significantly elevated glucose utilization in human umbilical endothelial cells (HUVECs), similarly to metformin. Our novel findings showed that metformin analogues 1-3 presented the most beneficial properties because of their greatest safety profile in the WST-1 cell viability assay, which was also proved in the further HUVEC integrity studies using RTCA DP. Compounds 1-3 did not affect either HUVEC or aortal smooth muscle cell (AoSMC) viability up to 3.0 mM. Importantly, these compounds beneficially affected some of the coagulation parameters, including factor X and antithrombin III activity. In contrast to the above-mentioned metformin analogues, derivatives 4 and 5 exerted more profound anticoagulation effects; however, they were also more cytotoxic towards HUVECs, as IC50 values were 1.0-1.5 mM. In conclusion, the chemical modification of a metformin scaffold into sulfonamides possessing alkyl substituents results in the formation of novel derivatives with potential bi-directional activity including anti-hyperglycemic properties and highly desirable anti-coagulant activity.