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In this month's article, George Winter discusses the role of metformin in treating diabetes, as well as a range of other conditions [ABSTRACT FROM AUTHOR]

Purpose: Glucophage Ⓡ (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in guidelines as first-line treatment of type 2 diabetes mellitus and increasingly in related insulin-resistant conditions, such as prediabetes and polycystic ovary syndrome. The GelShield Ⓡ sustained-release formulation tablet of Glucophage Ⓡ has been improved from the historic version marketed in 2000. Bioequivalence has been demonstrated stepwise along this evolution; however, a head-to-head evaluation between the initial and the current version is missing. This analysis aims to close this gap and to determine bioequivalence between related originator GelShield Ⓡ sustained-release formulations of metformin, Glucophage Ⓡ (GXR 500 mg), from Europe and the United States., Methods: Data from seven randomized crossover bioequivalence studies in 361 healthy participants of Asian and non-Asian ethnicity from Europe, the United States, and Asia were considered. All evaluated a single oral dose of 500 mg of the test and reference formulation in healthy male and female participants in fed and fasted state. Bioequivalence was evaluated by means of a combined bridging analysis of available data on the current round tablet from Europe (rGXR EU) and the historic oblong tablet from the United States (oGXR US) in healthy Asian and non-Asian participants under fed and fasting conditions. Bioequivalence between the two formulations was assessed statistically with a mixed effects model for AUC 0-t , C max , and AUC 0-inf ., Findings: In all studies, bioequivalence between the respective test and reference formulations of GXR was shown. Statistical analysis of pooled pharmacokinetic data of 2 (primary pooling set) or 3 studies (secondary pooling set) demonstrated bioequivalence between rGXR EU and oGXR US via bridging with oGXR EU. The 90% CI for the geometric mean ratio of all pharmacokinetic parameters was within the bioequivalence range of 0.80 to 1.25. In the primary pooling set, geometric least squares mean ratios in the fed group ranged from 0.9931 (90% CI, 0.9151-1.0778) for AUC 0-inf to 1.1344 (90% CI, 1.0711-1.2014) for C max ; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings., Implications: Bioequivalence was determined between sustained-release formulations of Glucophage Ⓡ from Europe and the United States under fasted and fed conditions in healthy men and women, including different ethnicities. The efficacy and safety of Glucophage Ⓡ XR can be claimed along the evolution from oGXR US, via oGXR EU to rGXR EU, and in several ethnicities and production sites., Competing Interests: Declaration of competing interest All authors, i.e., Axel Krebs-Brown, Kerstin Brand, Marco Nogueira Filho, Sumedh Gaikwad and Yvonne Schnaars, are employees of Merck Healthcare KGaA, Darmstadt, Germany, which holds marketing authorizations of the product in scope of this publication, i.e., Glucophage(Ⓡ) XR., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Type 2 diabetes and its associated comorbidities are growing more prevalent, and the complexity of optimising glycaemic control is increasing, especially on the frontlines of patient care. In many countries, most patients with type 2 diabetes are managed in a primary care setting. However, primary healthcare professionals face the challenge of the growing plethora of available treatment options for managing hyperglycaemia, leading to difficultly in making treatment decisions and contributing to therapeutic inertia. This position statement offers a simple and patient-centred clinical decision-making model with practical treatment recommendations that can be widely implemented by primary care clinicians worldwide through shared-decision conversations with their patients. It highlights the importance of managing cardiovascular disease and elevated cardiovascular risk in people with type 2 diabetes and aims to provide innovative risk stratification and treatment strategies that connect patients with the most effective care. [ABSTRACT FROM AUTHOR]

Aim: To assess the long‐term clinical benefits of early combination treatment with vildagliptin‐metformin vs. standard‐of‐care, metformin monotherapy in the ongoing VERIFY study. Methods: We randomized 2001 participants with multi‐ethnic background, aged 18–70 years, having HbA1c levels 48–58 mmol/mol (6.5–7.5%) and BMI 22–40 kg/m2. Baseline data included HbA1c, fasting plasma glucose and homeostasis model β‐cell and insulin sensitivity. Standardized meal‐tests, insulin secretion rate relative to glucose, and oral glucose insulin sensitivity were assessed in a subpopulation. Results: Out of 4524 screened, data were collected from the 2001 eligible participants (53% women) across Europe (52.4%), Latin America (26.8%), Asia (17.2%), South Africa (3.1%) and Australia (0.5%). The median (interquartile range) disease duration was 3.4 (0.9, 10.2) months; mean (±SD) age 54.3±9.4 years; weight 85.5±17.5 kg and BMI 31.1±4.7 kg/m2. Baseline HbA1c was 52±3 mmol/mol (6.9±0.3%), fasting plasma glucose 7.5±1.5 mmol/l and the median (interquartile range) of fasting insulin was 109 (75–160) mU/l. Homeostasis model β‐cell and insulin sensitivity values were 84% (60, 116) and 46% (31, 68), respectively. In those undertaking meal‐tests, insulin secretion rate relative to glucose was 28±12 pmol/min/m2/mmol/l and oral glucose insulin sensitivity was 353±57 ml/min/m2. Conclusions: Our current, multi‐ethnic, newly diagnosed VERIFY population reflects a characteristic presence of early insulin resistance in participants with increased demand for insulin associated with obesity. The VERIFY study will provide unique evidence in characterizing therapeutic intervention in a diverse population with hyperglycaemia, focusing on durability of early glycaemic control. What's new?: The VERIFY study is the first study to assess the long‐term clinical benefits of early combination treatment with a dipeptidyl peptidase‐4 inhibitor (vildagliptin)‐metformin vs. standard‐of‐care metformin monotherapy in people newly diagnosed with Type 2 diabetes.This report describes the baseline characteristics of a newly diagnosed population with Type 2 diabetes from a diverse geographical and ethnic background, demonstrating a classic profile of presence of early insulin resistance associated with elevated BMI as a surrogate for obesity.The study anticipates generating unique evidence on the progression of β‐cell function, insulin resistance, early complications of diabetes, and effect on health status upon treatment with early vildagliptin‐metformin combination. [ABSTRACT FROM AUTHOR]

Objective: To compare recent diabetes guideline updates from the American Diabetes Association-European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists-American College of Endocrinology (AACE/ACE).Summary: The ADA/EASD guideline continues to advocate a stepwise approach to glycemic control that initiates with metformin and intensifies treatment incrementally to dual and triple therapy at 3-month intervals until the patient is at their individualized goal. The AACE/ACE guideline provides a broader choice of first-line medications, with a suggested hierarchy of use, and it encourages initial dual and triple therapy if the glycated hemoglobin (A1C) level is high enough at diagnosis (7.5%-9.0% and >9.0%, respectively). Target A1C levels are higher in the ADA/EASD guideline (≤7.0%) compared with the AACE/ACE guideline (≤6.5%), although both statements indicate that targets should be adjusted to specific clinical scenarios based on safety. Both guidelines now include the new sodium-glucose cotransporter-2 inhibitors among their choices of acceptable glucose-lowering medications and endorse the overall cardiovascular and pancreatic safety of incretin therapies, and the safety of pioglitazone vis-a-vis bladder cancer.Conclusion: In practice, the ADA/EASD guidelines tend to be more user-friendly for general practitioners because of the simple stepwise intensification regimen, whereas the AACE/ACE guidelines are more commonly followed by specialists (endocrinologists) because of the more aggressive A1C targets. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1 in 3500-6000 male births. Despite broad research aiming to improve muscle function as well as heart and brain function, sufficient therapeutic efficacy has not yet been achieved and current therapeutic management is still supportive. In a recent pilot trial, oral treatment with L-arginine and metformin showed consistent changes of muscular metabolism both in vitro and in vivo by raising NO levels and expression of mitochondrial proteins in the skeletal muscle tissue of patients with DMD. This randomised, double-blind, placebo-controlled trial aims to demonstrate the superiority of L-citrulline and metformin therapy over placebo in DMD patients with regard to the Motor Function Measure (MFM) D1 subscore (primary endpoint) as well as additional clinical and subclinical tests.Methods/design: A total of 40-50 ambulant patients with DMD will be recruited at the outpatient department of the University of Basel Children's Hospital (Switzerland), as well as from the DMD patient registries of Switzerland, Germany and Austria. Patients will be randomly allocated to one of the two arms of the study and will receive either a combination of L-citrulline and metformin or placebo for 26 weeks. Co-medication with glucocorticoids is allowed. The primary endpoint is the change of the MFM D1 subscore from baseline to week 26 under L-citrulline and metformin therapy. Secondary endpoints will include the motor function measure (MFM) and its items and subscores, the 6-minute walking test, timed function tests and quantitative muscle testing. Furthermore, quantitative muscle MRI assessment to evaluate the muscle fat fraction as well as safety and biomarker laboratory analyses from blood will be included. For comparison, muscle metabolism and mitochondrial function will be analysed in 10-20 healthy age-matched male children.Discussion: The aim of this study is to test if a 6-month treatment of a combination of L-citrulline and metformin is more effective than placebo in preventing loss of motor function and muscle degeneration in DMD. The MFM D1 subscore is used as a clinical outcome measure and a quantitative muscle MRI assessment as the surrogate outcome measure of fatty muscle degeneration.Trial Registration: ClinicalTrials.gov: NCT01995032 . Registered on 20 November 2013. [ABSTRACT FROM AUTHOR]

Unlabelled: Glucose lowering medication use among patients with type 2 diabetes and advanced renal disease (eGFR<60) in a large multinational outcome trial (TREAT) is assessed. We demonstrate statistically significant differences regionally in use of metformin at lower eGFR and increasing reliance upon insulin with/without other medications at low eGFR.Introduction: As renal disease advances, most of the oral anti-diabetic agents requiring renal clearance must be reduced or discontinued. The potential for prolonged hypoglycemia, fluid/volume overload and congestive heart failure may complicate medication choices. In order to evaluate patterns of glycemia management we describe glucose lowering medication use among patients with advanced renal disease and type 2 diabetes in a large multinational outcome trial designed to focus on patients with eGFR<60 in order to commence a dialog on best practices. We felt that analysis of this data would be able to describe regional variations in treatment within a multinational trial in order to understand potential outcome differences attributed to complications.Results: The patients entering this study had moderate glycemic control. Insulin therapy either alone (32%) or in combination with other agents (17%) reflected a shift towards insulin use in those subjects with decreased renal function when compared with standard populations with normal kidney function. The use of multiple oral agents, or oral agents plus insulin was quite common. While gender did not appear to play a role in medication choices, there were significant regional variations. For example, oral agents were used more in North America compared with other regions (Latin America, Australia/Western Europe, Russia/Eastern Europe). Patients enrolled at more advanced ages were less likely to be on a regimen of rapid-acting insulin alone consistent with recommendations that suggest a preference for longer-acting preparations in the geriatric population (1). Higher degrees of obesity were associated more complex treatment regimens. Despite this population being at high risk for cardiovascular events, the use of beta blockers (50%), statins (64%) and aspirin (48%) were relatively low, especially in the group that did not require medications to achieve adequate glycemic control.Conclusions: Current attempts to compare strategies for diabetes therapy must control for baseline demographic group differences influencing treatment choice. Future recommendations for glycemic control in patients with Grade 3 or higher chronic kidney disease require additional studies, with matched populations. We suggest that evaluation of studies similar to TREAT will assist in determining the optimal therapeutic regimens for populations with moderate to severe renal dysfunction, a condition in which repeated hospitalizations for fluid overload/heart failure add to the high cost of diabetes care. [ABSTRACT FROM AUTHOR]

Aims: Investigate efficacy and tolerability of intensifying diabetes treatment with once- or twice-daily biphasic insulin aspart 30 (BIAsp 30) added to sitagliptin, and twice-daily BIAsp 30 without sitagliptin in patients with type 2 diabetes (T2D) inadequately controlled on sitagliptin.Methods: Open-label, three-arm, 24-week trial; 582 insulin-naïve patients were randomized to twice-daily BIAsp 30+sitagliptin (BIAsp BID+Sit), once-daily BIAsp 30+sitagliptin (BIAsp QD+Sit) or twice-daily BIAsp 30 without sitagliptin (BIAsp BID), all with metformin.Results: After 24 weeks, HbA1c reduction (%) was superior with BIAsp BID+Sit vs. BIAsp QD+Sit (BIAsp BID+Sit minus BIAsp QD+Sit difference: -0.36 [95% CI -0.54; -0.17], P<0.001) and BIAsp BID (BIAsp BID minus BIAsp BID+Sit difference: 0.24 [0.06; 0.43], P=0.01). Observed final HbA1c values were 6.9%, 7.2% and 7.1% (baseline 8.4%), and 59.8%, 46.5% and 49.7% of patients achieved HbA1c <7.0%, respectively. Confirmed hypoglycaemia was lower with BIAsp QD+Sit vs. BIAsp BID (P=0.015); rate: 1.17 (BIAsp QD+Sit), 1.50 (BIAsp BID+Sit) and 2.24 (BIAsp BID) episodes/patient-year. Difference in bodyweight change favoured BIAsp QD+Sit vs. both BID groups (P<0.001).Conclusions: Adding BIAsp 30 to patients with T2D poorly controlled with sitagliptin and metformin is efficacious and well tolerated; however, while BIAsp BID+Sit showed superior glycaemic control, BIAsp QD+Sit had a lower rate of hypoglycaemia and showed no weight gain. [ABSTRACT FROM AUTHOR]

Aims The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, linagliptin, added to ongoing metformin therapy, were assessed in patients with Type 2 diabeteswho had inadequate glycaemic control (HbA1c⩾ 7.5 to ⩽ 10%; ⩾58.5 to ⩽85.8mmol / mol) with metformin alone. Methods Patients (n = 333)were randomized to receive double-blind linagliptin (1,5 or10 mg oncedaily)or placeboor openlabel glimepiride (1-3 mg once daily). The primary outcome measure was the change from baseline in HbA1c at week 12 in patients receiving combination therapy compared with metformin alone. Results Twelve weeks of treatment resulted in a mean (sem) placebo-corrected lowering in HbA1c levels of 0.40% (± 0.14); 4.4 mmol / mol (± 1.5) for 1 mg linagliptin, 0.73% (± 0.14); 8.0 mmol/ mol (± 1.5) for 5 mg, and 0.67% (± 0.14); 7.3 mmol / mol (± 1.5) for 10 mg. Differences between linagliptin and placebo were statistically significant for all doses (1 mg, P = 0.01; 5 mg and 10 mg, P < 0.0001). The change in mean (sem) placebo-corrected HbA1c from baseline was )0.90% (± 0.13);)9.8mmol / mol (± 1.4) for glimepiride. Adjusted and placebo-correctedmean changes in fasting plasma glucosewere )1.1 mmol/ l for linagliptin 1 mg (P = 0.002), )1.9 mmol / l for 5 mg and )1.6 mmol / l for 10 mg (both P < 0.0001). One hundred and six (43.1%) patients reported adverse events; the incidence was similar across all five groups. There were no hypoglycaemic events for linagliptin or placebo, whereas three patients (5%) receiving glimepiride experienced hypoglycaemia. Conclusions The addition of linagliptin to ongoing metformin treatment in patients with Type 2 diabetes was well tolerated and resulted in significant and clinically relevant improvements in glycaemic control, with 5 mg linagliptin being the most effective dose. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is the commonest cause of end-stage renal failure in both Australia and New Zealand. In addition, the burden of diabetes is prominent in those with chronic kidney disease who have not yet reached the requirement for renal replacement therapy. While diabetes is associated with a higher incidence of mortality and morbidity in all populations studied with kidney disease, little is known about optimal treatment strategies for hyperglycaemia and the effects of glycaemic treatment in this large group of patients. Metformin is recommended as the drug of first choice in patients diagnosed with type 2 diabetes in the USA, Europe and Australia. There are potential survival benefits associated with the use of metformin in additional to recent studies suggesting benefits in respect to cardiovascular outcomes and metabolic parameters. The use of metformin has been limited in patients with renal disease because of the perceived risk of lactic acidosis; however, it is likely that use of this drug would be beneficial in many with chronic kidney disease. Thus the potential benefits and harms of metformin are outlined in this review with suggestions for its clinical use in those with kidney disease. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to assess glycaemic control as well as changes in glycaemic control over time in patients with type 2 diabetes mellitus (T2DM) who added a sulphonylurea (SU) or thiazolidinedione (TZD) to their metformin monotherapy in typical treatment settings within seven European countries. Methods: An observational, cross-sectional multicentre study with retrospective medical chart review was conducted in Finland, France, Germany, Norway, Poland, Spain and UK. T2DM patients who added a SU or a TZD to metformin monotherapy between January 2001 and January 2006 (i.e. index date) and who had ≥1 haemoglobin A1C (HbA1C) measurement within 12 months before the visit date, which occurred from June 2006 to February 2007, were included in the study. Demographic and clinical data were collected from medical records. The main study outcome measure was the proportion of patients with adequate glycaemic control (defined according to the International Diabetes Federation as HbA1C < 6.5%) using the most recent HbA1C measurement before the visit date. In addition, patients were grouped based upon the interval from the index date to the most recent HbA1C measurement to evaluate goal attainment and treatment changes over time. Findings: In this European cohort of 2023 T2DM patients on metformin and either an SU or a TZD (mean age = 60.4 years), 25.5% of patients had adequate glycaemic control. The average HbA1C level was 7.2% after a mean of 2.6 years of treatment with combination oral antihyperglycaemic agent (AHA) therapy. Among the patients (n = 227) with most recent HbA1C measurement within 1 year after first adding an SU or a TZD, 27% had adequate glycaemic control (HbA1C < 6.5%), with a mean (s.d.) HbA1C of 7.1% (1.0); 1.3% of these patients were using some type of insulin therapy. Among the patients (n = 176) with most recent HbA1C measurement occurring ≥5 years after adding an SU or a TZD, 20% had adequate glycaemic control, with a mean (s.d.) HbA1C of 7.4% (1.17), and 29.6% of these patients were using insulin. Overall, patients with (vs. without) adequate glycaemic control had significantly (p < 0.05) lower HbA1C levels (7.6 vs. 8.2%) at the time of adding an SU or a TZD to ongoing metformin monotherapy, were less likely to report a history of macrovascular complications (20 vs. 26%) and were more often engaged in physical activity three to five times a week (29 vs. 23%). Conclusions: Approximately one quarter of European out-patients with T2DM had adequate glycaemic control after a mean of 2.6 years following initiation of combination AHA therapy. Overall glycaemic control modestly declined over time, even though more patients were being treated with insulin. These findings highlight the progressive nature of the disease and need for more effective disease management/therapeutic alternatives. [ABSTRACT FROM AUTHOR]

A short term (6-month) cost-effectiveness model has been developed to simulate current medical practice and disease progression in patients with type 2 (non-insulin-dependent) diabetes mellitus uncontrolled by diet and exercise. The model is based on decision-analytical techniques and includes probabilities of switching between treatments, the reason for the switch and the most common switch options. Effectiveness and economic measures are the 2 main outcomes. In order to assess effectiveness, we use symptom-free days with acceptable control (SFDACs), which represent each day of treatment without adverse events or symptoms, and with acceptable control of glucose and lipids. For the economic evaluation, only incremental costs incurred directly by a health insurance system are considered. This model should prove useful in the evaluation of new oral antidiabetic agents, since the short term aim of antidiabetic therapy is to provide adequate control in the absence of adverse effects and symptoms (a prerequisite for successful long term treatment). Furthermore, short term analysis provides data for comparing initial investment in drug therapy with potential savings over a longer treatment period. [ABSTRACT FROM AUTHOR]

The article offers analysis on the clinical trial of woman with polycystic ovary syndrome treating with metformin and clomiphene in Europe. The overall results of a clinical trial show different ovulation rates, pregnancy rates or spontaneous abortion. It illustrates that pregnancy rates are the same if using metformin and clomiphene alone or, both drug combined. These results are beneficial in lowering risk of diabetes and heart diseases.

Metformin represents a striking example of a "historical nemesis" of a drug. About 40 years after its marketing in Europe, once demonstrated its efficacy and safety, metformin was registered also in the U.S. A few years later, it has become a mainstay in T2DM treatment, according to all international Scientific Societies guidelines. Today, despite the advent of new innovative drugs, metformin still persists as a first-choice drug in T2DM. This success is largely justified. In fact, over the years, also positive effects on health increased. In particular, evidence has been accumulated on a beneficial impact against many other aging-related morbidities (obesity, metabolic syndrome, cardiovascular disease, cancer, cognitive decline and mortality). This literature review describes preclinical and clinical evidence favoring the "anti-aging" therapeutic potential of metformin outside of T2DM. The rationale to the use of metformin as part of a combined therapy in a variety of clinical settings, allowing for a reduction of the chemotherapy dose in cancer patients, has also been discussed. In particular, the focus was on metformin action on RAS/RAF/MAPK pathway. In the end, the real challenge for metformin could be to fully demonstrate beneficial effects on health even in non-diabetic subjects. [ABSTRACT FROM AUTHOR]

This study was designed to characterize the spatial distribution of metformin medication used as first-line monotherapy for prevention of T2DM in relationship with the socioeconomic status (level of deprivation) and T2DM mortality at district level in a nationwide cross-sectional ecological study for the first time in a European country, Hungary. Risk analysis was used to estimate the relationships between socioeconomic status, characterized by tertiles of deprivation index, and mortality caused by diabetes, and metformin medication (both prescription and redemption) for the years of 2018 and 2019 at the district level. The spatial distribution of districts with a higher relative frequency of metformin prescriptions and redemptions showed a positive correlation with socio-economic deprivation. Significant association between the relatively high T2DM mortality and the highest level of deprivation could also be detected, but less-deprived regions with high T2DM mortality and low metformin utilization could also be identified. Although the statistical associations detected in this ecological study do not indicate a causal relationship, it is reasonable to suppose that the underuse of metformin medication may contribute to the unfavourable T2DM mortality in certain regions. Our findings underline the need for more effective preventive services including metformin medication to decrease T2DM morbidity and mortality burden.

A GC-MS/MS method with EI ionization was developed and validated to detect and quantify N -nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5-9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.

Objective: At present, there are many studies on metformin and the risk of colorectal cancer in patients with diabetes, but the conclusions are contradictory. Our aim is to comprehensively collect the published literature and systematically evaluate the relationship between metformin and the risk of colorectal cancer in patients with diabetes., Methods: We systematically searched the MEDLINE, EMBASE, and CENTRAL databases up to March 2020. We adopted adjusted estimates and their 95% confidence intervals (CI) to calculate summary effect estimates using either a fixed-effects or a random-effects model., Results: A total of 17 articles were included in this study, with a total of 1,092,074 patients with diabetes. Meta-analysis of observational studies showed that metformin treatment could significantly reduce the incidence of colorectal cancer in diabetic patients (adjusted RR = 0.884, 95%CI = 0.829-0.943), and there was heterogeneity between studies (p = 0.013, I 2 = 47.9%). Subgroup analysis showed that metformin treatment was significantly associated with a significantly reduced risk of colorectal cancer in diabetics in America and Europe (adjusted RR = 0.852, 95%CI = 0.786-0.924; adjusted RR = 0.900, 95%CI = 0.845-0.958). Patients with diabetes treated with metformin had a significantly lower risk of colorectal cancer compared with patients who had never been treated with metformin or sulfonamide monotherapy (adjusted RR = 0.863, 95%CI = 0.776-0.960; adjusted RR = 0.911, 95%CI = 0.882-0.941)., Conclusions: Metformin therapy is associated with a significantly reduced risk of colorectal disease in patients with diabetes, and it is necessary to conduct larger, more standardized clinical studies to verify this conclusion.

Context: To date, established risk factors for prostate cancer (PCa) are limited to age, race, family history, and certain genetic polymorphisms. Despite great research efforts, available evidence on potentially modifiable risk factors is conflicting. Moreover, most studies on PCa risk factors did not consider the impact of prostate-specific antigen (PSA) testing on PCa diagnosis., Objective: To provide a detailed overview of the latest evidence on the role of metabolic diseases, drugs, and dietary factors for risk of PCa incidence, recurrence, and survival in men exposed to PSA testing., Evidence Acquisition: A systematic review of the English-language literature was performed using the MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations. Randomized, case-control, or cohort studies published during the periods 2008-2017 (on drugs and metabolic diseases) and 2003-2017 (on dietary factors), with extensive follow-up (≥8-10yr for studies on PCa risk; ≥2-5yr for studies on PCa recurrence, progression, and survival, depending on the review subtopic) and adjusting of the analyses, beyond established risk factors, for either rate of PSA testing (for risk analyses) or PCa stage and primary treatment (for survival analyses), were eligible for inclusion., Evidence Synthesis: Overall, 39 reports from 22 observational studies were included. Studies were heterogeneous regarding definitions of exposure or outcomes, length of follow-up, risk of bias, and confounding. For some risk factors, evidence was insufficient to assess potential effects, while for others there was no evidence of an effect. For selected risk factors, namely metformin, aspirin and statin use, diabetes, obesity, and specific dietary intakes, there was low-quality evidence of modest effects on PCa risk., Conclusions: Current evidence from long-term observational studies evaluating the effect of drugs, metabolic diseases, and dietary factors for PCa risk considering the impact of PSA testing is still not conclusive. Future research is needed to confirm the associations suggested by our review, exploring their potential biological explanations and selecting those risk factors most likely to trigger effective public health interventions., Patient Summary: We reviewed the available studies published in the recent literature on the potential role of drugs, metabolic diseases, and food and dietary factors for the risk of prostate cancer, considering the impact of prostate-specific antigen testing on prostate cancer diagnosis. We found that for some factors data are currently insufficient to make definitive conclusions, while for others available studies seem to indicate an effect on the risk of prostate cancer., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Metformin (MET), CAS 1115-70-4 (Metformin hydrochloride), is an antidiabetic drug with high usage in North America and Europe and has become the subject of regulatory interest. A pharmaceutical industry working group investigated environmental risks of MET. Environmental fate and chronic effects data were collated across the industry for the present risk assessment. Predicted environmental concentrations (PECs) for MET were modeled for the USA and Europe using the PhATE and GREAT-ER models, respectively. PECs were compared with measured environmental concentrations (MECs) for the USA and Europe. A predicted no effect concentration (PNEC) of 1 mg/L for MET was derived by deterministic procedures, applying an assessment factor of 10 to the lowest no observed effect concentration (i.e., 10 mg/L) from multiple chronic studies with algae, daphnids and fish. The PEC/PNEC and MEC/PNEC risk characterization ratios were <1, indicating no significant risk for MET with high Margins of Safety (MOS) of >868. MET is known to degrade during wastewater treatment to guanylurea (GUU, CAS 141-83-3), which we have shown to further degrade. There are no GUU toxicity data in the literature; hence, chronic studies for GUU were conducted to derive a PNEC of 0.16 mg/L. PECs were derived for GUU as for MET, plus MECs were retrieved from the literature. The PEC/PNEC and MEC/PNEC risk characterization ratios for GUU were also <1, with an MOS of >6.5. Based on standard risk assessment procedures for both MET and its transformation product GUU, there is no significant risk to aquatic life., (Copyright © 2018. Published by Elsevier Ltd.)

This review discusses the occurrence, impact, analysis and treatment of metformin and guanylurea in coastal aquatic environments of Canada, USA and Europe. Metformin, a biguanide in chemical classification, is widely used as one of the most effective first-line oral drugs for type 2 diabetes. It is difficult to be metabolized by the human body and exists in both urine and faeces samples in these regions. Guanylurea is metformin's biotransformation product. Consequently, significant concentrations of metformin and guanylurea have been reported in wastewater treatment plants (WWTPs) and coastal aquatic environments. The maximum concentrations of metformin and guanylurea in surface water samples were as high as 59,000 and 4502ngL -1 , respectively. Metformin can be absorbed in non-target organisms by plants and in Atlantic salmon (Salmo salar). Guanylurea has a confirmed mitotic activity in plant cells. Analysis methods of metformin are currently developed based on high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The removal of metformin from aquatic environments in the target regions is summarized. The review helps to fill a knowledge gap and provides insights for regulatory considerations. The potential options for managing these emerging pollutants are outlined too., (© 2018 Elsevier Ltd All rights reserved.)

The article compares the efficacy of the drugs dulaglutide and liraglutide to metformin treated patients suffering from type-2 diabetes to reduce hemoglobin (Hb) A [1c] levels. It states the exclusion criteria of the study including pancreatitis, higher calcitonin level in serum and cardiovascular (CV) event. It concludes that weekly intake of dulaglutide did not show greater efficacy as compared to daily intake of liraglutide.

Aims: To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination., Methods: In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1:1:1:1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight., Results: Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (-0.52 vs. -0.30%, p = 0.0106 and -0.65% vs. -0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of <7%. Efficacy outcomes for dapagliflozin twice daily were numerically similar to those for dapagliflozin once daily. Dapagliflozin twice daily was well tolerated., Conclusions: Dapagliflozin 2.5 or 5 mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone. This study supports the development of a fixed-dose combination regimen., (© 2014 John Wiley & Sons Ltd.)