Long-term Use Of Metformin Research Articles

CASE STUDY: ORAL HYPOGLYCEMIC DRUGS OVERDOSE INDUCED GENERALISED TONICCLONIC SEIZURES

Metformin is an oral hypoglycemic agent of the biguanide class, and glimepiride is an oral hypoglycemic agent of the sulfonylurea class frequently used to treat Type-II diabetes mellitus. Under certain conditions, overdose or long-term use of metformin and glimepiride can cause lactic acidosis and hypoglycemia. Metformin overdose can cause severe hypoglycemia in the absence of other anti-diabetic drugs. Potential mechanisms of metformin-induced hypoglycemia include decreased hepatic glucose production, decreased glucose absorption, and low oral intake. Hypoglycemia, in turn, leads to loss of consciousness, headache, confusion, and neurological symptoms such as insomnia, delirium, and in rare conditions may lead to coma, seizures, and death. Here, this case study is of 23-years-old female patient and non-diabetic presented with alleged consumption of metformin (8 g), glimepiride (32 mg) with three-episodes of generalized tonic-clonic seizures (GTCS), fever with chills, and loss of consciousness. In general, diabetic patient’s hypoglycemia condition can be more often due to drug overdosage or dietary restrictions. However, in non-diabetic patients, hypoglycemia is considered a jeopardy situation because it may lead to several fatal effects.

Frequency of Vitamin B12 Deficiency in Type 2 Diabetic Patients Taking Metformin.

IntroductionType 2 diabetes mellitus (DM) is a prevalent global health problem and is on a constant rise, especially in middle- and low-income countries. Vitamin B12 malabsorption is one of the reported side effects of metformin. Our study aims to assess the correlation of B12 deficiency in type 2 diabetics using metformin for their treatment.MethodsThis case-control study was conducted in a tertiary care hospital in Pakistan from February 2021 to December 2021. Patients (n=100) with a documented diagnosis of type 2 DM on metformin monotherapy for a minimum of six months were enrolled via consecutive convenient non-probability sampling. Another 100 patients without a history of diabetes were included in the study as a control group for comparison.ResultsSerum vitamin B-12 levels were higher in the non-diabetic participants as compared to the diabetic group (301.71 ± 72.12 vs. 189.25 ± 31.22; p-value: <0.0001). Hypovitaminosis was more significant in the diabetic group (p-value: 0.0000). Serum vitamin B12 levels were found to be declining with the increasing duration of metformin use (p-value: <0.0001).ConclusionOur study found a significant effect of vitamin B12 deficiency in metformin-treated patients. Therefore, it is prudent to recognize B12 deficiency as a potential side effect of long-term use of metformin. A periodic screening of B12 in such patients and subsequent supplementation of vitamin B12 is an effective and safe means of prevention of development or worsening of peripheral nerve damage and other clinical manifestations.

Long Term Use of Metformin and its Effect on Serum Vitamin B12 with its Oral Manifestations: A Review

Metformin is the most frequently prescribed first line therapy for Type 2 Diabetes Mellitus (T2DM) and it is one of the fewer antihyperglycaemics associated with improvements in the morbidity and mortality of cardiovascular disease associated with T2DM. Although there are major beneficial effects but it is shown to have disadvantages with long-term use of metformin. Recent studies have shown that metformin induces malabsorption of Vitamin B12, which may increase the risk of developing Vitamin B 12 deficiency. Vitamin B12 is one of the integral nutritional components that affect the oral health with individuals with decreased levels exhibit various oral manifestations such as glossitis, glossodynia, recurrent ulcers, angular cheilitis, dysgeusia, lingual paraesthesia, burning sensations and pruritis. Most of the vitamin B12 deficiencies are associated with malabsorption syndrome, gastrectomy cases, and elderly people. The prevalence of oral manifestations with regard to metformin induced Vitamin B12 has to be considered as new paradigm in routine diagnosis and investigations. This review likewise centers around the mechanism involved in metformin induced vitamin B12 deficiency and possible implications in the diagnosis and management of oro-mucosal lesions associated with such deficiency.

Long-Term Use of Metformin Is Associated With Reduced Risk of Cognitive Impairment With Alleviation of Cerebral Small Vessel Disease Burden in Patients With Type 2 Diabetes.

Objective: Type 2 diabetes (T2D) is a risk factor for cognitive impairment and cerebral small vessel disease (CSVD). The relation of metformin use and cognitive impairment or CSVD is not clear. The objective of this study was to investigate the cross-sectional effects of long-term use of metformin on total CSVD burden and cognitive function in patients with T2D.Methods: A total of 234 participants with T2D from the memory clinic in Hebei General Hospital were enrolled in this retrospective study. Duration of metformin use and dosage were recorded. Along with cerebral magnetic resonance imaging (MRI) examination, Mini-Mental State Examination (MMSE) was also performed to assess their cognitive status. We determined the validated total CSVD score (ranging from 0–4) by combining four markers of CSVD that were visually rated. We used binary logistic regression analysis, ordinal logistic regression analysis and mediation analysis to assess the relation of long-term use of metformin with CSVD burden and cognitive function.Results: Binary logistic regression analysis showed long-term use of metformin was associated with reducing the risk of cognitive impairment (OR: 0.446; 95% Confidence Interval (CI): 0.249 to 0.800; P = 0.007), after adjustment of potential confounders, such as total CSVD burden score, age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Ordinal logistic regression analysis suggested that long-term use of metformin was associated with alleviation of total CSVD burden score (OR: 0.583; 95% CI: 0.359 to 0.943; P = 0.027), after adjusting for age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Mediation analysis showed significant mediation by the presence of severe CSVD burden score for long-term use of metformin in relation to cognitive impairment.Conclusion: Long-term use of metformin was associated with lower rates of cognitive impairment and lower total CSVD burden score in patients with T2D. A proportion of the relation between long-term use of metformin and cognitive impairment may be attributable to alleviation of CSVD burden.

The use of metformin in the treatment of gastrointestinal cancer

Type 2 diabetes mellitus and malignancies have several common risk factors, such as obesity, metabolic syndrome, hyperinsulinemia, and chronic inflammation. Currently these factors are considered as possible mechanisms that increase the risk of the development of malignanttumors, including gastrointestinal cancer. Epidemiological studies and meta-analyses indicate that patients with diabetes have a higher incidence and mortality from malignancies. Metformin is well-known oral hypoglycemic drug that belongs to the biguanide class and is being used to treat diabetes mellitus for almost a century. It has been established that in patients with diabetes mellitus, long-term use of metformin reduces the incidence of tumors and mortality from various cancers. The results of recent studies suggest that metformin may have direct pleiotropic anticancer activity against many tumor cells and their microenvironment. Its potential mechanisms include both insulin-dependent and insulin-independent. Moreover, metformin promotes antitumor immunosuppressive metabolic control of T lymphocytes and cancer cells, it is able to modulate the intestinal microbiota and renders a systemic effect on a body metabolism. The article presents data that reveal possible mechanisms of anticancer action of metformin and justify the use of metformin as a drug that may be useful for the treatment of gastrointestinal cancer. Although most of the clinical trials have retrospective design, they are often limited in time and patient bias, recent data from preclinical studies on the antitumor effects of metformin suggest that its effects on carcinogenesis and gastrointestinal cancer progression need to be further investigated. Future studies should consider the diabetic status, prognostic biomarkers, disease stage, and treatment regimens. Given that metformin is a safe and widely available drug with low cost, the feasibility of further study of its anti-cancer effects is beyond doubt.

Prevalence of Vitamin B12 deficiency in Type II diabetic patients using metformin.

Objectives: To determine the prevalence of Vitamin B12 deficiency in type II diabetic patients using metformin. Study Design: Cross Sectional study. Setting: Endocrinology Unit Shalamar Hospital Lahore. Period: July to September 2017. Material &amp; Methods: All of our patients were having previously diagnosed type II diabetes and using metformin for more than six months. Using strict exclusion criteria, vitamin B12 levels of patients were measured and analyzed. Results: It was evident from the present study that 27.33% of type II diabetic patients using metformin were having vitamin B12 levels less than 150pg/ml. Furthermore, our study showed that smokers are more liable to develop vitamin B12 deficiency than the nonsmokers. Also, use of multivitamins (containing vitamin B12) had a protective role against vitamin B12 deficiency. Conclusions: Long term use of metformin in type II diabetic patients is strongly associated with Vitamin B12 deficiency, therefore endocrinologists and physicians should take into consideration this significant adverse effect of metformin and screen for vitamin B12 deficiency in diabetic population before starting metformin therapy.

Metformin use and the risk of anal intraepithelial neoplasia in type II diabetic patients.

Emerging evidence has suggested that metformin may be protective against the development of human-papillomavirus-related cancers. Anal intraepithelial neoplasia (AIN) is highly associated with human papillomavirus infection and a precancerous status of anal cancer. The aim of this study was to investigate the relationship between metformin usage and the development of AIN in a large national sample. The IBM MarketScan dataset was used to design a nested case-control study from 2010 to 2017. Patients aged 18-65years with type 2 diabetes mellitus (DM) were evaluated, and cases of AIN were identified. Four controls were randomly selected in the risk set of each case by using incidence density sampling. The association between metformin usage and AIN was assessed using multivariate logistic regression modelling. A total of 258 patients with type 2 DM were diagnosed with AIN during the study interval, and these were matched to 1032 control patients without a diagnosis of AIN. Patients who developed AIN had 38% lower odds of prior metformin use compared to those without a history of AIN (P<0.01) and this finding remained robust after adjusting for age, sex, human immunodeficiency virus infection and DM complications (P=0.02). Patients with AIN had 56% lower odds of long-term metformin use compared to control patients (P=0.01). An AIN diagnosis in patients with DM is associated with 56% lower likelihood of prior metformin use. This relationship suggests that metformin could potentially play a protective role against AIN. Prospective studies in non-diabetic patients are warranted to examine these findings further.

Potential mechanisms of metformin-induced memory impairment.

Metformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus. In addition to its ability to lower glucose levels, it has recently been reported to be potentially useful for the treatment of other conditions because of its anticancer activity, cardiovascular protective effect, neuroprotective effect, and efficacy in the treatment of polycystic ovary syndrome. However, long-term use of metformin may lead to side-effects such as memory impairment. Here, we critically review the effect of metformin on memory impairment and the potential molecular mechanisms of memory dysfunction to provide a reference for researchers and a better understanding of the side-effects of metformin.

Recent Perspective of Metformin

Metformin has been used clinically more than 60 years in type 2 diabetes as the first-line drug for treatment. Metformin has been prescribed in more than 80% of Korean patients with diabetes. Despite long-term use and wide prescription of metformin in patients with type 2 diabetes, many questions remain. Recent advances have revealed a new mechanism of action and new benefits of metformin. In this article, we review recent advances regarding metformin treatment. Keywords: Cardiovascular diseases; Delayed-action preparations; Diabetes mellitus; type 2; Metformin

1013-P: Long-Term Metformin Use and Risk of Death and CV-Renal Outcomes in Type 2 Diabetes with Chronic Kidney Disease (Stage 1-4)

Introduction: The overall evidence for the long-term exposure of metformin on cardiovascular-renal (CV) outcomes in patients with type 2 diabetes (T2D) at different stages of chronic kidney disease (CKD) remains controversial. Methods: We conducted a prospective analysis of 14,766 Chinese patients with T2D enrolled between 2000 and 2016 observed until 31 December 2019. We compared all-cause mortality and incidence of major adverse CV events (MACE) and end-stage kidney disease (ESKD) in prevalent and new metformin users versus other glucose lowering drugs (GLDs) users stratified by CKD stage. Results: During a mean follow-up of 9.6 years (141,310 person-years), we identified 1,798 deaths in metformin users (n=13,967) and 352 deaths in other-GLDs users (n=799). The mean daily dosage of metformin was 1,450 mg and duration of exposure was 7.8 years in CKD stage 1-2 (n=12,375). The respective figures were 1000 mg and 5.7 years in CKD stage 3-4 (n=1,592). Compared with other-GLDs, metformin exposure was associated with reduced risk of all-cause mortality (All: HR=0.48, 95% CI: 0.43-0.54; CKD stage 1-2: HR=0.38, 0.33-0.44; stage 3A: HR=0.53, 0.41-0.69); MACE (All: HR=0.85, 0.72-0.99; stage 1-2: HR=0.80, 0.65-0.99; stage 3-4: HR=0.97, 0.74-1.27) and ESKD (All: HR=0.65, 0.54-0.80; stage 1-2: HR=0.53, 0.33-0.85; stage 3-4: HR=0.80, 0.63-1.02). New users of metformin (n=4,013) had reduced risk of all-cause mortality across all CKD stages; MACE in stage 1-2 and ESKD in stage 1, 2 and 3 compared with users of other oral-GLDs (n=536). Increasing duration and dosage of metformin (up to 1500 mg/day) was associated with reduced or neutral risk of MACE, ESKD and all-cause mortality. The rate of metformin-associated lactic acidosis (MALA) was 5.39 per 100,000 patient-years in CKD stage 3-4. Conclusion: Long-term metformin use was associated with reduced or neutral risk of all-cause mortality, MACE and ESKD among Chinese patients with T2D at CKD stage 1-3 with low risk of MALA. Disclosure A. Yang: None. E. S. H. Lau: None. H. Wu: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. A. W. Fu: Research Support; Self; Merck KGaA. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Funding Asia Diabetes Foundation; Merck Pharmaceutical (HK) Limited; Chinese University of Hong Kong (to A.Y.)

Long-term metformin use and risk of pneumonia and related death in type 2 diabetes: a registry-based cohort study.

The long-term effects of metformin in individuals with type 2 diabetes who are at increased risk of severe respiratory infections are unknown. This study aimed to evaluate the effects of metformin use on the risk of first pneumonia hospitalisation and pneumonia-related death in a cohort of Chinese individuals with type 2 diabetes. We performed a retrospective analysis of a consecutive cohort of 22,638 individuals with type 2 diabetes in the Hong Kong Diabetes Register enrolled between 2001 and 2018, with follow-up until 31 December 2019. Overlap propensity-score weighting was performed to balance baseline characteristics. Of 22,638 individuals with type 2 diabetes, after excluding those who had not been prescribed any glucose-lowering drugs (GLDs) and/or with eGFR ≤30mlmin-1 [1.73m]-2 or treated by dialysis and/or treated with insulin at baseline, we identified 15,784 either prevalent or incident metformin users and 917 users of other GLDs during a mean follow-up period of 7.5years. Overlap-weighted analysis showed an HR of 0.63 (95% CI 0.52, 0.77) for first pneumonia hospitalisation and 0.49 (95% CI 0.33, 0.73) for pneumonia-related death in metformin users vs users of other GLDs; similar observations resulted following stratification by sex and kidney function. There was also a negative association between metformin exposure over time (proportion of duration of metformin prescriptions during the total follow-up time) and pneumonia events using the penalised spline analysis. Metformin users had a lower neutrophil/lymphocyte ratio at first pneumonia hospitalisation vs non-metformin users (mean [95% CI]: 12.8 [12.1, 13.5] vs 14.8 [12.3, 17.3], p = 0.032). The rate of metformin-associated lactic acidosis was 2.5 per 100,000 person-years. The lower risk of pneumonia events was also observed among incident metformin users vs other GLD users. Long-term use of metformin was associated with reduced risk of pneumonia and pneumonia-related death among Chinese individuals with diabetes. The relevance of these results to other respiratory infections merits further investigation.

A prospective study of type 2 diabetes, metformin use, and risk of breast cancer

Type 2 diabetes (T2D) has been associated with increased breast cancer risk, but commonly prescribed antidiabetic medications such as metformin may reduce risk. Few studies have investigated T2D and medications together in relation to breast cancer. Data came from 44541 Sister Study participants aged 35 to 74 years at enrollment (2003-2009) who satisfied eligibility criteria, followed through 15 September 2017. Information on time-varying, self-reported, physician-diagnosed, prevalent and incident T2D, use of antidiabetic medications, and covariates was obtained from baseline and follow-up questionnaires. Incident breast cancers were confirmed with medical records. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. During follow-up (median, 8.6 years), 2678 breast cancers were diagnosed at least 1 year after enrollment. There were 3227 women (7.2%) with prevalent and 2389 (5.3%) with incident T2D, among whom 61% (n= 3386) were ever treated with metformin. There was no overall association between T2D and breast cancer risk (HR 0.99; 95% CI, 0.87-1.13). However, T2D was associated with increased risk of triple-negative breast cancer (HR 1.40; 95% CI, 0.90-2.16). Compared with not having T2D, T2D with metformin use was not associated with overall breast cancer risk (HR 0.98; 95% CI, 0.83-1.15), but it was associated with decreased risk of estrogen receptor (ER)-positive breast cancer (HR 0.86; 95% CI 0.70-1.05) and increased risk of ER-negative (HR 1.25; 95% CI, 0.84-1.88) and triple-negative breast cancer (HR 1.74; 95% CI, 1.06-2.83). The inverse association with ER-positive cancer was stronger for longer duration (≥10 year) metformin use (HR 0.62; 95% CI, 0.38-1.01; P for trend= 0.09). Results were supported by sensitivity analyses. Our findings suggest that associations between T2D and breast cancer may differ by hormone receptor status and that associations between T2D and ER-positive breast cancer may be reduced by long-term metformin use.

Impact of metformin on survival outcome in ovarian cancer: a nationwide population-based cohort study.

ObjectiveInvestigation of new drugs (INDs) is a tremendously inefficient process in terms of time and cost. Drug repositioning is another method used to investigate potential new agents in well-known drugs. This study assessed the survival impact of metformin medication on ovarian cancer.MethodsA national sample cohort of the Korean National Health Insurance Service Data was analyzed. Cox proportional hazards regression was used to analyzing hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for underlying diseases and medications as confounding factors for overall survival (OS) and cancer-specific survival (CSS).ResultsA total of 866 eligible patients were included from among 1,025,340 cohort participants. Among them, 101 (11.7%) were metformin users. No difference in OS was observed between non-users and users. No difference in OS was observed according to age and Charlson Comorbidity Index. Long-term metformin use (≥720 days) was associated with better OS (adjusted HR=0.244; 95% CI=0.090–0.664; p=0.006). A multivariate Cox proportional hazards model showed that long-term metformin use was an independent favorable prognostic factor for OS (HR=0.193; 95% CI=0.070–0.528; p=0.001) but not for CSS (HR=0.599; 95% CI=0.178–2.017; p=0.408).ConclusionLong-term metformin use reduced all-cause mortality, but not CSS in ovarian cancer. Whether metformin itself reduces deaths because of ovarian cancer requires further investigation.

Metformin prevents brain injury after cardiopulmonary resuscitation by inhibiting the endoplasmic reticulum stress response and activating AMPK-mediated autophagy.

The neurological damage caused by cardiac arrest (CA) can seriously affect quality of life. We investigated the effect of metformin pretreatment on brain injury and survival in a rat CA/cardiopulmonary resuscitation (CPR) model. After 14 days of pretreatment with metformin, rats underwent 9 minutes of asphyxia CA/CPR. Survival was evaluated 7 days after restoration of spontaneous circulation; neurological deficit scale (NDS) score was evaluated at days 1, 3, and 7. Proteins related to the endoplasmic reticulum (ER) stress response and autophagy were measured using immunoblotting. Seven-day survival was significantly improved and NDS score was significantly improved in rats pretreated with metformin. Metformin enhanced AMPK-induced autophagy activation. AMPK and autophagy inhibitors removed the metformin neuroprotective effect. Although metformin inhibited the ER stress response, its inhibitory effect was weaker than 4-PBA. In a CA/CPR rat model, 14-day pretreatment with metformin has a neuroprotective effect. This effect is closely related to the activation of AMPK-induced autophagy and inhibition of the ER stress response. Long-term use of metformin can reduce brain damage following CA/CPR.

THU032 - Evolution of hepatic fibrosis and steatosis during long-term use of metformin in patients with type 2 diabetes

THU032 - Evolution of hepatic fibrosis and steatosis during long-term use of metformin in patients with type 2 diabetes

Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.

Metformin may protect against hepatocellular carcinoma and mortality among patients with type 2 diabetes. To investigate whether long-term use of metformin improves survival and reduces liver-related outcomes among patients with type 2 diabetes and non-alcoholic steatohepatitis. A total of 191 diabetic patients with biopsy-proven non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis were retrospectively identified at Indiana University Medical Center between October 2004 and January 2016. Of them, 110 were users and 81 never-users of metformin. Primary outcomes were transplant-free survival, development of hepatocellular carcinoma or a first event of hepatic decompensation. Cirrhosis was present in 85% of metformin users and 88% of nonusers. Metformin dose was greater than or equal to 1g/d in 104 out of 110 users and its median duration of use was 6 (95% CI: 4.4-7.9) years. The mean follow-up was 6.92 and 6.80years for metformin users and non-users, respectively. During follow-up, 28 patients developed hepatocellular carcinoma (metformin users: 7, nonusers: 21), and 52 died (metformin users: 7, nonusers: 24) or were transplanted (metformin users: 13, non-users: 13). Metformin use was associated with lower risk of overall mortality or transplant (HR: 0.42; 95% CI: 0.24-0.74, P=0.003) and hepatocellular carcinoma (sHR: 0.25; 95% CI: 0.11-0.58, P=0.001), and remained independently associated with both outcomes after propensity-score and covariate-adjusted analyses. No instances of hepatotoxicity or lactic acidosis were observed. Our study demonstrated an association between long-term metformin use and reduced the risk of all-cause mortality/transplant and hepatocellular carcinoma in diabetics with non-alcoholic steatohepatitis and advanced fibrosis.

Monitoring Vitamin B12 in Women Treated with Metformin for Primary Prevention of Breast Cancer and Age-Related Chronic Diseases.

Metformin (MET) is currently being used in several trials for cancer prevention or treatment in non-diabetics. However, long-term MET use in diabetics is associated with lower serum levels of total vitamin B12. In a pilot randomized controlled trial of the Mediterranean diet (MedDiet) and MET, whose participants were characterized by different components of metabolic syndrome, we tested the effect of MET on serum levels of B12, holo transcobalamin II (holo-TC-II), and methylmalonic acid (MMA). The study was conducted on 165 women receiving MET or placebo for three years. Results of the study indicate a significant overall reduction in both serum total B12 and holo-TC-II levels according with MET-treatment. In particular, in the MET group 26 of 81 patients and 10 of the 84 placebo-treated subjects had B12 below the normal threshold (<221 pmol/L) at the end of the study. Considering jointly all B12, Holo-TC-II, and MMA, 13 of the 165 subjects (10 MET and 3 placebo-treated) had at least two deficits in the biochemical parameters at the end of the study, without reporting clinical signs. Although our results do not affect whether women remain in the trial, B12 monitoring for MET-treated individuals should be implemented.

SAT-148 Vitamin B12 Deficiency Among Patients with Metformin and Diabetic Neuropathy.

Introduction: Vitamin B12 deficiency due to metformin use has been demonstrated in multiple studies with variable prevalence. There are no studies in our population that demonstrate the prevalence of vitamin B12 deficiency in patients with metformin and diabetic neuropathy. The objective of this study is to describe its prevalence and the characteristics of the patients who present vitamin B12 deficiency. Methodology: Cross sectional study. 162 patients were included. The level of vitamin B12 was considered low, less than 200 pg / ml and borderline, 201 to 300 pg / ml. The level of vitamin B12 was analized according to age, sex, metformin dose, metformin time of use, time from the diagnosis of diabetes or prediabetes and the presence of diabetic neuropathy. A linear regression model was used to evaluate the variables that correlate with vitamin B12 levels. Results: 162 patients were collected. An altered level of vitamin B12 was found in 29% (CI95%: 22% to 36%) and a low level of vitamin B12 in 7.3% (CI 95%: 4.0% to 12%). In patients with diabetic neuropathy the prevalence of altered B12 levels was 64% (95% CI 47-78%), while in patients without diabetic neuropathy it was 17% (95% CI 10-26%). Patients with diabetic neuropathy had lower levels of vitamin B12 compared with patients without neuropathy (coefficient -110.8, CI 95%: -165.8 to -59.7). A higher dose of metformin showed correlation with lower levels of vitamin B12 (coef -0.061 CI 95%: - 0.09 to -0.024). Female patients had higher levels of vitamin B12 compared to men (coef 49.1 CI 95%: 2.3 to 95). Conclusions: Vitamin B12 deficiency is frequent in our population of patients treated with metformin, with prevalences higher than those described in other populations. Patients with diabetic neuropathy have much higher prevalence of vitamin B12 deficiency. Male patients with higher doses of metformin and patients with diabetic neuropathy have the lowest levels of vitamin B12. More studies are needed to establish an association between vitamin b12 deficiency and diabetic neuropathy. Bibliography Berchtold P, Bolli P, Arbenz U, Keiser G. Disturbance of intestinal absorption following metformin therapy (observations on the mode of action of biguanides) [in German]. Diabetologia. 1969;5:405- 412. Aroda VR, Edelstein SL, Goldberg RB. Diabetes Prevention Program Research Group. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J ClinEndocrinolMetab. 2016 Apr; 101(4): 1754-1761. Reinstatler L, Qi YP, Williamson RS, et al. Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006.Diabetes Care. 2012 Feb;35(2):327-33.1. Roy RP, Ghosh K, Ghosh M; et al. Study of vitamin B12 deficiency and peripheral neuropathy in metformin treated early Type 2 diabetes mellitus. Indian J EndocrinolMetab. 2016; 20(6): 895.

Pleiotropic Repositioning of Metformin as a Potential Pluripotent Drug

Metformin repositioning is a hot interesting topic and valuable substitute to molecular target based drug discovery as therapeutic switching using off-target strategy. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The author performed a Scopus database literature review of articles published on repositioning of metformin with special consideration of all details published on 2016, 2017 and 2018 as the latest updated literature that described concisely metformin as a potential pleiotropic multi-therapeutic agent. The repositioning of already a marketed anti-diabetic drug saves the high cost of the time-consuming normal drug development process for the other mentioned pharmacological activities. Metformin inhibits dyskinesia in Parkinson's disease, cancer recurrence, neuroendocrine tumors, colorectal carcinoma, prostate cancer, breast cancer, pancreatic cancer, cholangiocarcinoma, fibrosarcoma and even enhancing the healing process for liver injury, cardiovascular disease and Fragile X syndrome. Metformin is beneficial for neurodegenerative diseases especially Alzheimer disease. And it up regulates neurotrophic factor and prevents dopaminergic neuron death in Parkinson's model. As one of the most frequently used oral antidiabetic drugs, it also improves serum lipid profiles, positively influences hemostasis, cognitive impairment and possesses anti-inflammatory properties. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other antidiabetic drugs. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetics.

Use and preventive value of metformin in geriatric women with polycystic ovary syndrome

Objective: To establish the effects of long-term use and preventive value of metformin in geriatric women with PCOS. Methods: A search of published review articles was carried out in sites such as NCBI, ScienceDirect, Elsevier, Springer, Wolters Kluwer, among others, using the key words: “polycystic ovary syndrome”, “PCOS”, “Polycystic ovary syndrome and metformin”, “effects of metformin and PCOS“,” insulin resistance and metformin “and” long-term sequelae of polycystic ovarian syndrome“. Results: We retrospectively analyzed data specific to the randomized clinical trial of Pedersen et al. 2017, to determine the impact that treatment had for twelve months with metformin in three specific variables: weight, total cholesterol and HDL. The study was conducted in 40 Caucasian women from 18 to 39 years of age, with a fixed dose of metformin (2 g / day for 12 months), who met the Rotterdam criteria for PCOS in their genetic variant MATE1 with SOP7. Conclusions: It was confirmed that the establishment of twelve-month treatment with metformin in the randomized clinical trial of Pedersen et al. 2017 had a significant effect on the three specific variables: weight, total cholesterol and HDL.