Metformin Intake Research Articles

Association of metformin intake with bladder cancer risk and oncologic outcomes in type 2 diabetes mellitus patients: A systematic review and meta-analysis.

Recent clinical trials indicated that metformin intake might play a protective role in the incidence and oncologic outcomes of various cancers. However, its protective effect on bladder cancer remains uncertain. We performed a meta-analysis to investigate the association between metformin intake and bladder cancer risk as well as oncologic outcomes in diabetes mellitus (DM) patients. A comprehensive literature search was performed using PubMed, Embase, and the Cochrane Central Search Library in December 2017. Hazard ratio (HR) with 95% confidence interval (CI) was pooled. A total of 9 retrospective cohort studies with 1,270,179 patients were included. A meta-analysis revealed that metformin intake was associated with an increased recurrence-free survival (HR = 0.55, 95% confidence interval [CI] = 0.35-0.88; P = .01; I = 64%), improved progression-free survival (HR = 0.70, 95% CI = 0.51-0.96; P = .03; I = 33%), and prolonged cancer-specific survival (HR = 0.57, 95% CI = 0.40-0.81; P = .002; I = 0%). However, results demonstrated that metformin intake was not associated with a decreased incidence of bladder cancer (HR = 0.82, 95% CI = 0.61-1.09; P = .17; I = 85%) or an increased overall survival in bladder cancer patients (HR = 0.83, 95% CI = 0.47-1.44; P = .50; I = 64%). The present meta-analysis indicated that metformin intake could improve the prognosis of bladder cancer patients. Further prospective cohort studies and mechanistic studies are still required to determine the precise role of metformin in the initiation and progression of bladder cancer.

Metformin Use Is Not Associated With B12 Deficiency or Neuropathy in Patients With Type 2 Diabetes Mellitus in Qatar.

Metformin may lead to B12 deficiency and neuropathy. There are no published data on the prevalence of Metformin-related B12 deficiency and neuropathy in the Arabian Gulf. Determine whether Metformin intake is associated with B12 deficiency and whether B12 deficiency is associated with diabetic peripheral neuropathy (DPN) and painful diabetic neuropathy. Patients with type 2 diabetes mellitus (T2DM) (n = 362) attending outpatient clinics at HMC underwent assessment of B12 levels, the DN4 questionnaire, and vibration perception threshold (VPT). Comparing Metformin to non-Metformin users there were no differences in B12 levels, VPT, or DN4. The prevalence of B12 deficiency (B12 <133 pmol/l) was lower (P < 0.01) in Metformin (8%) compared to non-Metformin (19%) users. Patients with B12 deficiency had a comparable prevalence and severity of sensory neuropathy and painful neuropathy to patients without B12 deficiency. Serum B12 levels were comparable between Metformin and non-Metformin users with T2DM in Qatar. T2DM patients on Metformin had a lower prevalence of B12 deficiency. Furthermore, the prevalence and severity of neuropathy and painful diabetic neuropathy were comparable between patients with and without B12 deficiency.

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues

Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P= .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Range of therapeutic metformin concentrations in clinical blood samples and comparison to a forensic case with death due to lactic acidosis

Due to a lack of reference values for blood concentration of metformin in the literature, the forensic evaluation of metformin findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested metformin amounts are often vague. Furthermore, post mortem evaluation of death due to lactic acidosis because of metformin is difficult since renal performance or lactate concentrations can not always reliably be determined after death.To describe a concentration range in clinical samples after chronic use of metformin, metformin serum concentrations were determined in serum samples of 95 diabetic patients receiving daily doses of 500mg–3000mg of metformin. The analyses of metformin was carried out using a validated high performance liquid chromatograph coupled to triple quadrupole mass spectrometry (LC–QQQ-MS).On average, metformin concentrations were 1846ng/mL (<LoQ—5560ng/mL) and independent of the prescribed daily dose. There was no correlation between plasma concentration and glomerular filtration rate except for the 1700mg daily dose collective (R2=0.707). Results of the herein presented study are useful for the interpretation of analytical metformin findings in forensic toxicology. The utility of the described concentration range is demonstrated by discussing a death case involving a fatal lactate acidosis after metformin intake and renal failure. Usefulness of the parameters metformin blood concentration, lactate concentration and glomerular filtration rate in post mortem cases of lactic acidosis due to metformin intoxication are discussed.

Comparative Efficacy of Antihypertensive Agents in Salt-Sensitive Hypertensive Patients: A Network Meta-Analysis.

Salt-sensitive hypertension (SSH) is an intermediate inherited phenotype of essential hypertension as well as being an independent risk factor for cardiovascular disease. However, effective medications for the treatment of SSH have not been clarified. This study was to compare the efficacious of different classes of antihypertensive agents combined with salt intake on the reduction of blood pressure (BP) in patients with SSH. We used sources as PubMed, EMBASE, Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), CNKI, and WANFANG database from inception to November 2016. Studies that compared the efficacy of 2 or more antihypertensive agents or placebos in adult salt-sensitive hypertensive patients were included. The outcomes included variations in mean arterial blood pressure, systolic and diastolic blood pressure. Twenty-five studies were involved in this meta-analysis. A calcium channel blocker (CCB) with hydrochlorothiazide and moderate salt intake was significantly the most efficacious in comparison with placebo (standardized mean differences (SMD), 95% credibility intervals (CI): 26.66, 12.60 to 40.16), angiotensin receptor blockers (ARBs) (SMD, 95% CI: 22.94, 5.26 to 40.51), and the other interventions for patients with SSH and no concomitant diseases. For SSH patients who were obese, CCB with metformin and moderate salt intake would decrease blood pressure with 17.90 mm Hg. For SSH patients with no concomitant diseases, CCB combined with hydrochlorothiazide and moderate salt intake was optimal in reducing BP, while CCB combined with metformin and moderate salt intake was the most efficacious at reducing BP in SSH patients with coexisting obesity.

Factors Determining Blood and Urine Concentrations of Metformin among Patients with Type 2 Diabetes: A Cross Sectional Study

Background: Diabetes Mellitus (DM) is a chronic medical condition characterized by high levels of blood glucose due to a dysfunction in the amount or the function of the hormone insulin. Among the oral hypoglycaemic drugs used to treat DM, metformin is considered the first line treatment and is available in the Lebanese market in both its regular and extended release formulations. Metformin is prescribed at standard doses for all diabetic patients without taking into account variables such as gender, age, other medications, lifestyle differences, creatinine levels, etc. Methods: A cross sectional study was conducted to find the association between the ingested dose of metformin (extended release formulation) and its concentration in the blood and urine, and investigate the different factors that affect this relation, such as gender, weight, other medications (drug-drug interaction), Kidney function (measured by creatinine level and eGFR), timing of metformin intake, dosage, duration since metformin intake, HBA1C, smoking and alcohol intake. The HPLC technique was used to detect the levels of metformin in 95 samples, collected from diabetic patients visiting the Saint Georges Hospital laboratory in Beirut. Results: No correlation was found between the levels of metformin in blood or urine and the following variables: age, creatinine, GFR, years on metformin, HbA1c level, glucose level, and gender. Two linear correlations were obtained from the study; daily dose of metformin vs. urine (Spearman r=0.6 and p<0.001); and daily dose of metformin vs. weight (p=0.044). Conclusion: The drug is administered and totally excreted from the body. The correlation “dose-metformin concentration in urine” could be used as a clinical purpose to check patient compliance to the treatment.

Preconception Optimization of Glucose and Insulin Metabolism in Women Wanting to Conceive - High Rate of Spontaneous Conception Prior to Planned Assisted Reproduction.

Background A hyperglycemic metabolic status with insulin resistance can have a negative effect on fertility and pregnancy outcomes. The aim of this retrospective study was to investigate disorders of glucose and insulin metabolism in women wanting to conceive who conceived spontaneously prior to planned assisted reproduction (ART). Associated risk factors of patients in terms of live births and miscarriages were also analyzed. Method Out of total study population of 589 pregnancies, the pregnancies of 129 women wishing to have children who conceived spontaneously prior to planned ART were analyzed in more detail. A 75 g OGTT (OGTT: oral glucose tolerance test) was carried out prior to conception and after determination of pregnancy, including glucose measurement and testing of insulin resistance. If anomalies or risk factors for gestational diabetes (GDM) were detected, patients received metformin therapy prior to conception (off-label use). The course and outcome of pregnancies in the defined cohort were recorded. Results The rate of spontaneous conception before planned ART after treatment for disorders of glucose/insulin metabolism was 21.9% (n = 129/589). 66.7% of the 129 pregnancies resulted in a live birth, 32 patients had a miscarriage. 76.0% of patients were treated with metformin (off-label use) for polycystic ovary syndrome (PCOS), positive risk profile for GDM, or abnormal glucose/insulin metabolism prior to conception. 55.8% of the cohort developed GDM. The insulin requirements of patients with GDM differed significantly depending on their metformin intake. 24.6% of GDM patients receiving metformin treatment developed GDM requiring insulin treatment compared to 53.8% who did not receive metformin medication. The PCOS rate in the study population who had live births was significantly higher (57.0%) than in the group who had miscarriages (31.3%). There were no significant differences with regard to rate of live births and rate of miscarriages with/without metformin treatment and GDM and metformin intake. Conclusion The high rate of spontaneous conceptions in the cohort of women wishing to conceive emphasizes the importance of optimizing glucose/insulin metabolism prior to conception. The high rate of GDM in a cohort of pregnant women with a history of sterility also emphasizes the importance of expanding diagnostic testing for sterility to include the investigation of glucose metabolism and testing for insulin resistance. It is possible that PCOS patients in particular could benefit from treatment with metformin prior to conception, and this could explain the high rate of live births in this patient cohort.

Effect of metformin on maternal and neonatal outcomes in pregnant obese non-diabetic women: A meta-analysis

Metformin reduces maternal and neonatal weight gain in gestational diabetes mellitus; however, this effect is poorly investigated in non-diabetic women. We performed this meta-analysis to investigate the effect of metformin intake during pregnancy on maternal and neonatal outcomes in obese non-diabetic women. We searched Medline, EMBASE, and Cochrane CENTRAL for eligible randomized controlled trials addressing the efficacy of metformin in pregnant obese non-diabetic women. Data were extracted and analyzed using RevMan software (Version 5.3). Neonatal birth weight was the key outcome. Secondary outcomes included maternal weight gain, the incidence of preeclampsia, and neonatal adverse effects (miscarriage, stillbirth and congenital anomalies). Pooled data from two RCTs (n=843) showed that metformin caused a significant reduction in maternal gestational weight gain (MD-1.35, 95% CI: [2.08, -0.630]), compared to placebo. The summary effect-estimate did not favor either of the two groups in terms of reduction of neonatal birth weight Z score (MD-0.09, 95% CI: [0.23, 0.06]). Metformin was associated with 41% reduction in the risk of preeclampsia; however, this reduction was not statistically significant [RR 0.59, 95% CI: [0.03, 11.46]). None of the neonatal adverse events including stillbirth [RR 1.14, 95% CI: 0.42, 3.10]) and congenital anomalies (RR= 1.36, 95% CI: [0.58, 3.21]) differed significantly between the two groups. For obese pregnant women, metformin could decrease gestational weight gain with no significant reduction in neonatal birth weight. In light of the current evidence, metformin should not be used to prevent poor pregnancy outcomes in obese non-diabetic women.

Immediate reduction of serum citrulline but no change of steroid profile after initiation of metformin in individuals with type 2 diabetes

Metformin is the most important first-line treatment for type 2 diabetes mellitus (T2DM) but its exact mode of action remains unknown. In this study, we used targeted metabolomics to gain new insights into the metabolic effects of metformin in humans with T2DM. We also examined changes in the serum steroid hormone profile. We quantified 167 serum metabolites and 19 steroid hormones using liquid chromatography-tandem mass spectrometry at three time points in individuals with previously untreated T2DM: before the start of metformin therapy (time point A), after the first dose (B) and after short-term therapy for 4–6 weeks (C). For metabolite analysis, we split the study cohort into a discovery and a replication study of 88 and 45 subjects, respectively. The statistical analysis was done using linear mixed-effects models. Among the metabolites quantified, citrulline showed the most pronounced changes. Compared to its baseline serum concentration, citrulline was reduced by 17% after the first dose of metformin (p=1.34E-07) and by 24% after short-term therapy (p=2.84E-08) in the discovery study. These results were confirmed in the replication study. The only other metabolite significantly changed after correction for multiple testing was PC ae C36:4 between baseline and 4–6 weeks. The serum steroid hormone profile showed no significant changes after metformin intake. In summary, we observed an immediate and sustained reduction of serum citrulline by metformin in humans. This may be relevant for some of the wanted or unwanted effects of the drug.

Metformin intake associates with better cognitive function in patients with Huntington's disease.

Huntington’s disease (HD) is an inherited, dominant neurodegenerative disorder caused by an abnormal expansion of CAG triplets in the huntingtin gene (htt). Despite extensive efforts to modify the progression of HD thus far only symptomatic treatment is available. Recent work suggests that treating invertebrate and mice HD models with metformin, a well-known AMPK activator which is used worldwide to treat type 2-diabetes, reduces mutant huntingtin from cells and alleviates many of the phenotypes associated to HD. Herein we report statistical analyses of a sample population of participants in the Enroll-HD database, a world-wide observational study on HD, to assess the effect of metformin intake in HD patients respect to cognitive status using linear models. This cross-sectional study shows for the first time that the use of metformin associates with better cognitive function in HD patients.

Prognostic significance of anti-diabetic medications in pancreatic cancer: A meta-analysis.

The role of anti-diabetic medications in pancreatic cancer remains conflicting. We carried out a systematic search of Pubmed and Embase databases for studies published before August 2016, which assessed the associations between anti-diabetic medications (metformin, sulfonylureas, thiazolidinediones and insulin) intake and pancreatic cancer prognosis. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using the random-effects model. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS). Fourteen studies enrolling 94778 participants were eligible for inclusion, with 12 cohort studies and 2 randomized controlled trials (RCTs). Significant association between metformin (adjusted HR=0.77, 95% CI=0.68-0.87) use and OS was found in cohort studies, whereas no significant association between metformin use and PFS (HR=1.22; 95% CI=0.76-1.95) or OS (HR=1.20, 95% CI=0.84-1.72) in RCTs. No significant survival benefits were identified for insulin (HR=1.18, 95% CI=0.83-1.69), sulfonylureas (HR=1.03, 95% CI=0.81-1.30), or thiazolidinediones (HR=0.84, 95% CI=0.58-1.22). The trim-and-fill method and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. Our findings provide strong evidence that metformin is associated with improved OS in pancreatic cancer patients in cohort studies. However, the effect of other anti-diabetic medications should be interpreted with caution owing to the limited number of studies.

Prognostic role of metformin intake in diabetic patients with colorectal cancer: An updated qualitative evidence of cohort studies.

Several observational studies have shown that metformin can modify the risk and survival of colorectal cancer (CRC) in patients with diabetes mellitus, although the magnitude of this relationship has not been determined. We conducted an updated systematic review and meta-analysis to analyze the association between metformin and CRC mortality and searched relevant databases up to July 2016. The primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CS) and disease-free survival (DFS). Summary hazard ratios (HRs) were calculated using a random-effects model. Seventeen studies enrolling 269,417 participants were eligible for inclusion. Comparing with non-metformin users in diabetic CRC patients, the summary HRs for OS in metformin users were 0.69 (95% CI, 0.61-0.77). Subgroup analyses stratified by the study characteristics and sensitivity analysis by the trim-and-fill method (adjusted HR 0.77, 95% CI, 0.67-0.87) confirmed the robustness of the results. However, significant OS benefit was noted in patients with stage II and III disease. Five studies reported the CRC prognosis for CS and three for DFS; metformin intake was significantly associated with patient CS (HR 0.75, 95% CI, 0.59-0.94), but not DFS (HR 0.38, 95% CI, 0.13-1.17). Our findings suggest that metformin intake is associated with improved survival outcomes in terms of OS and CS in CRC patients with diabetes, particular for OS in stage II and stage III patients. Further studies should be conducted to determine CRC survival between metformin use and patient specific clinical and molecular profiles.

COMPARISON OF OPPORTUNITIES FROM TWO THERAPEUTICAL COMPLEXES FOR CORRECTION OF VASCULAR HEMOSTASIS IN HYPERTENSIVES WITH METABOLIC SYNDROME

Though there is a progress in medical science and practice, hypertension remains widely prevalent in economically developed countries, and is comorbid with metabolic syndrome. This leads to weakening of vascular wall functioning in these patients and developing conditions for the formation of intravascular thrombi of various location. Aim. Comparative assessment of hemostatic function correction of vessel wall in hypertensives with metabolic syndrome (MS) with the complex of valsartan and losartan together with metformin and nonmedication treatments. Material and methods. Under follow-up, there were 47 hypertensives, of 1-2 grade, risk 4, middle age. Controls were 25 healthy persons of the same age. The assessment of biochemical and hematological parameters was performed. For blood pressure correction, 24 patients were prescribed valsartan 160 mg daily, 23 patients — losartan 100 mg daily. For metabolism optimization all patients were prescribed metformin 500 mg b.i.d., hypocaloric diet and regular physical activity of tolerable intensity. Results. The application of a complex with valsartan leads to normalization in hypertensives with MS the function of vascular wall in 4 months. Further non-strict adherence to the prescribed nonmedication part of the complex retains positive effect by the end of follow-up (12 months). Usage of losartan improves, but does not normalize vessel wall function in 4 months. Further non-strict adherence of non-medication part of treatment, regardless the continuation of losartan and metformin intake, decreases the achieved effect of treatment. Conclusion. Usage of treatment complex of hypocaloric diet, physical exercise and metformin helps to influence positively vascular hemostasis in hypertensives with MS in case of valsartan inclusion, and is less effective if replaced by losartan.

Chondrocyte-Specific Ablation of AMPKα1 Does Not Affect Bone Development or Pathogenesis of Osteoarthritis in Mice.

AMP-activated protein kinase (AMPK) acts as an intracellular sensor that modulates the energy balance within the cell. AMPKα1 is the dominant catalytic isoform expressed in the bone, but the significance of AMPKα1 in articular cartilage has not been well studied. In this study, we aimed to assess the in vivo function of AMPKα1 in chondrocytes. We created chondrocyte-specific AMPKα1 conditional knockout (KO) mice using Col2α1-Cre and analyzed and compared growth characteristics, HE staining, and AMPKα gene expression between wild-type (WT) mice and AMPKα1 conditional KO mice under normal physiological conditions or following activation of AMPK by metformin intake or treadmill exercise. Microcomputed tomography and safranin O-fast green staining were compared between WT and KO mice after induction of experimental osteoarthritis (OA). Our data showed that there was no somatic difference between WT mice and KO mice of the same age. Metformin intake and treadmill exercise did not alter the phenotype of KO mice, and no difference in cartilage degradation was observed in WT mice or in KO mice after induction of traumatic arthritis. We thought that chondrocyte-specific ablation of AMPKα1 had no effect on bone growth or on pathogenesis of OA in mice, probably because the feedback overexpression of AMPKα2 compensated for loss of AMPKα1 and maintained the combination of AMPKα subunits.

Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice

Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin’s effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control (C), high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation.

Influence of metformin intake on the risk of bladder cancer in type 2 diabetes patients.

The aim of this study was to look at the influence of metformin intake and duration, on urinary bladder cancer (UBC) risk, with sulfonylurea (SU) only users as control using a new user design (inception cohort). We conducted a retrospective cohort study using data from the UK Clinical Practice Research Datalink (CPRD) including all patients with at least one prescription of oral anti-diabetic drugs (ADD) and/or insulin. The risk of UBC in different groups of ADD users (metformin alone (one), metformin in combination (two) with other ADD medication (glinides, glitazones, DPP-4-inhibitors, SUs, insulin or more than one combination), all metformin users (1 + 2) was compared with SU only users using Cox proportional hazards models. The estimates were adjusted for age, gender, smoking status, BMI and diabetes duration. The inception cohort included 165,398 participants of whom 132,960 were metformin users and 32,438 were SU only users. During a mean follow-up time of more than 5 years 693 patients developed UBC, 124 of the control group and 461 of the all metformin users. There was no association between metformin use and UBC risk (HR = 1.12, 95% CI 0.90, 1.40) compared with SU only users, even after adjustment for diabetes duration (HR = 1.13, 95% CI 0.90, 1.40). We found a pattern of decreasing risk of UBC with increasing duration of metformin intake, which was statistically not significant. Metformin has no influence on the risk of UBC compared with SU in type 2 diabetes patients using a new user design.

Influence of metformin intake on the risk of bladder cancer in type 2 diabetes patients

Influence of metformin intake on the risk of bladder cancer in type 2 diabetes patients

Quantitative Proteome Analysis Reveals Increased Content of Basement Membrane Proteins in Arteries From Patients With Type 2 Diabetes Mellitus and Lower Levels Among Metformin Users.

The increased risk of cardiovascular diseases in type 2 diabetes mellitus has been extensively documented, but the origins of the association remain largely unknown. We sought to determine changes in protein expressions in arterial tissue from patients with type 2 diabetes mellitus and moreover hypothesized that metformin intake influences the protein composition. We analyzed nonatherosclerotic repair arteries gathered at coronary bypass operations from 30 patients with type 2 diabetes mellitus and from 30 age- and sex-matched nondiabetic individuals. Quantitative proteome analysis was performed by isobaric tag for relative and absolute quantitation-labeling and liquid chromatography-mass spectrometry, tandem mass spectrometry analysis on individual arterial samples. The amounts of the basement membrane components, α1-type IV collagen and α2-type IV collagen, γ1-laminin and β2-laminin, were significantly increased in patients with diabetes mellitus. Moreover, the expressions of basement membrane components and other vascular proteins were significantly lower among metformin users when compared with nonusers. Patients treated with or without metformin had similar levels of hemoglobin A1c, cholesterol, and blood pressure. In addition, quantitative histomorphometry showed increased area fractions of collagen-stainable material in tunica intima and media among patients with diabetes mellitus. The distinct accumulation of arterial basement membrane proteins in type 2 diabetes mellitus discloses a similarity between the diabetic macroangiopathy and microangiopathy and suggests a molecular explanation behind the alterations in vascular remodeling, biomechanical properties, and aneurysm formation described in diabetes mellitus. The lower amounts of basement membrane components in metformin-treated individuals are compatible with the hypothesis of direct beneficial drug effects on the matrix composition in the vasculature.

Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.

Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.

Association between Metformin Therapy and Breast Cancer Incidence and Mortality: Evidence from a Meta-Analysis

PurposeMetformin may be associated with a decreased risk of breast cancer. We performed a meta-analysis to assess the effect of metformin intake on breast cancer risk and mortality.MethodsWe performed a PubMed and EMbase search for all available studies that described the risk of breast cancer and all-cause mortality in relation to the use of metformin among patients with type 2 diabetes mellitus. Pooled relative risks (RRs) were determined using a random effects model to assess the strength of association between metformin and the risk of breast cancer.ResultsFifteen articles from PubMed satisfied the inclusion criteria, including a total of 838,333 participants. Compared with the control group, metformin use was not related to a reduced incidence of breast cancer (RR, 0.964; 95% confidence interval [CI], 0.761-1.221; p=0.761). However, metformin therapy was associated with decreased all-cause mortality (RR, 0.652; 95% CI, 0.488-0.873; p=0.004). No obvious publication bias was detected (incidence: pBegg=0.755, pEgger=0.008; mortality: pBegg=0.072, pEgger=0.185).ConclusionThe present study suggested that metformin therapy may decrease the all-cause mortality of patients affected by breast cancer. However, this finding should be considered carefully and confirmed with further studies.