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Frontiers in Endocrinology 2020Metformin is a widely used biguanide drug due to its safety and low cost. It has been used for over 60 years to treat type 2 diabetes at the early stages because of its... (Review)
Review
Metformin is a widely used biguanide drug due to its safety and low cost. It has been used for over 60 years to treat type 2 diabetes at the early stages because of its outstanding ability to decrease plasma glucose levels. Over time, different uses of metformin were discovered, and the benefits of metformin for various diseases and even aging were verified. These diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, liver diseases, cardiovascular disease, and renal diseases. Metformin exerts different effects through different signaling pathways. However, the underlying mechanisms of these different benefits remain to be elucidated. The aim of this review is to provide a brief summary of the benefits of metformin and to discuss the possible underlying mechanisms.
Topics: Aging; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Metformin; Neoplasms; Signal Transduction
PubMed: 32425881
DOI: 10.3389/fendo.2020.00191 -
JAMA May 2019Metformin is the first-line pharmacologic treatment for type 2 diabetes and the most commonly prescribed drug for this condition worldwide, either alone or in... (Review)
Review
Metformin is the first-line pharmacologic treatment for type 2 diabetes and the most commonly prescribed drug for this condition worldwide, either alone or in combination with insulin or other glucose-lowering therapies. Metformin is a biguanide, a drug class of herbal origin that has been widely used to treat diabetes since the 1950s. Two other biguanides were withdrawn from clinical use because they caused lactic acidosis. Metformin was also taken off the US market due to concerns over lactic acidosis, but it subsequently has been proven safe and effective in lowering glucose levels and was reintroduced in 1995. Optimal metformin use requires clear understanding of its effects, dosing, safety, and alternatives.
Topics: Contraindications, Drug; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Practice Guidelines as Topic
PubMed: 31009043
DOI: 10.1001/jama.2019.3805 -
Diabetologia Sep 2017Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these... (Review)
Review
Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes.
Topics: AMP-Activated Protein Kinases; Animals; Biguanides; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin
PubMed: 28776086
DOI: 10.1007/s00125-017-4342-z -
Metabolism: Clinical and Experimental Feb 2016Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis.... (Review)
Review
Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.
Topics: Acidosis, Lactic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Risk Factors
PubMed: 26773926
DOI: 10.1016/j.metabol.2015.10.014 -
International Journal of Antimicrobial... Sep 2020Using antiseptics in wound care can promote healing by preventing and treating infection. However, using antiseptics can present many challenges, including issues with... (Review)
Review
OBJECTIVES
Using antiseptics in wound care can promote healing by preventing and treating infection. However, using antiseptics can present many challenges, including issues with tolerability, inactivation by organic matter and the emergence of antimicrobial resistance/cross-resistance. This review discussed the key challenges in antisepsis, focusing on povidone-iodine (PVP-I) antiseptic.
METHODS
Literature searches were conducted in PubMed, in January 2019, with a filter for the previous 5 years. Searches were based on the antimicrobial efficacy, antiseptic resistance, wound healing properties, and skin tolerability for the commonly used antiseptics PVP-I, chlorhexidine gluconate (CHG), polyhexanide (PHMB), and octenidine (OCT). Additional papers were identified based on author expertise.
RESULTS
When compared with CHG, PHMB and OCT, PVP-I had a broader spectrum of antimicrobial activity against Gram-negative bacteria, actinobacteria, bacterial spores, fungi and viruses, and a similar and broad spectrum of activity against Gram-positive bacteria. PVP-I was also highly effective at eradicating bacterial biofilms, which is a vitally important consideration for wound care and infection control. Despite a long history of extensive use, no resistance or cross-resistance to PVP-I has been recorded, which is in contrast with other antiseptics. Despite previous misconceptions, it has been shown that PVP-I has low allergenic properties, low cytotoxicity and can promote wound healing through increased expression of transforming growth factor beta.
CONCLUSION
With increased understanding of the importance of tackling antimicrobial resistance and bacterial biofilms in acute and chronic wound care, alongside improved understanding of the challenges of antiseptic use, PVP-I remains a promising agent for the management of antisepsis.
Topics: Anti-Infective Agents, Local; Bacteria; Bacterial Infections; Biguanides; Biofilms; Chlorhexidine; Humans; Imines; Povidone-Iodine; Pyridines; Wound Healing
PubMed: 32599228
DOI: 10.1016/j.ijantimicag.2020.106064 -
Clinical Science (London, England :... Mar 2012Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent... (Review)
Review
Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent now recommended as the first-line oral therapy for T2D (Type 2 diabetes). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The demonstration that respiratory chain complex I, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin has been reported to restore ovarian function in PCOS (polycystic ovary syndrome), reduce fatty liver, and to lower microvascular and macrovascular complications associated with T2D. Its use has also recently been suggested as an adjuvant treatment for cancer or gestational diabetes and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.
Topics: Animals; Cardiovascular System; Circadian Clocks; Diabetic Nephropathies; Female; Humans; Hypoglycemic Agents; Metformin; Neoplasms; Polycystic Ovary Syndrome
PubMed: 22117616
DOI: 10.1042/CS20110386 -
The Cochrane Database of Systematic... Mar 2021Leg ulcers are open skin wounds that occur below the knee but above the foot. The majority of leg ulcers are venous in origin, occurring as a result of venous... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Leg ulcers are open skin wounds that occur below the knee but above the foot. The majority of leg ulcers are venous in origin, occurring as a result of venous insufficiency, where the flow of blood through the veins is impaired; they commonly arise due to blood clots and varicose veins. Compression therapy, using bandages or stockings, is the primary treatment for venous leg ulcers. Wound cleansing can be used to remove surface contaminants, bacteria, dead tissue and excess wound fluid from the wound bed and surrounding skin, however, there is uncertainty regarding the effectiveness of cleansing and the best method or solution to use.
OBJECTIVES
To assess the effects of wound cleansing, wound cleansing solutions and wound cleansing techniques for treating venous leg ulcers.
SEARCH METHODS
In September 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting.
SELECTION CRITERIA
We considered randomised controlled trials (RCTs) comparing wound cleansing with no wound cleansing, or RCTs comparing different wound cleansing solutions, or different wound cleansing techniques.
DATA COLLECTION AND ANALYSIS
We screened studies for their appropriateness for inclusion, assessed their risk of bias using the Cochrane 'Risk of bias' tool, and used GRADE methodology to determine the certainty of evidence. Two review authors undertook these tasks independently, using predetermined criteria. We contacted study authors for missing data where possible.
MAIN RESULTS
We included four studies with a total of 254 participants. All studies included comparisons between different types of cleansing solutions, and three of these reported our primary outcomes of complete wound healing or change in ulcer size over time, or both. Two studies reported the secondary outcome, pain. One study (27 participants), which compared polyhexamethylene biguanide (PHMB) solution with saline solution for cleansing venous leg ulcers, did not report any of the review's primary or secondary outcomes. We did not identify any studies that compared cleansing with no cleansing, or that explored comparisons between different cleansing techniques. One study (61 participants) compared aqueous oxygen peroxide with sterile water. We are uncertain whether aqueous oxygen peroxide makes any difference to the number of wounds completely healed after 12 months of follow-up (risk ratio (RR) 1.88, 95% confidence interval (CI) 1.10 to 3.20). Similarly, we are uncertain whether aqueous oxygen peroxide makes any difference to change in ulcer size after eight weeks of follow-up (mean difference (MD) -1.38 cm, 95% CI -4.35 to 1.59 cm). Finally, we are uncertain whether aqueous oxygen peroxide makes any difference to pain reduction, assessed after eight weeks of follow-up using a 0 to 100 pain rating, (MD 3.80, 95% CI -10.83 to 18.43). The evidence for these outcomes is of very low certainty (we downgraded for study limitations and imprecision; for the pain outcome we also downgraded for indirectness). Another study (40 participants) compared propyl betaine and polihexanide with a saline solution. The authors did not present the raw data in the study report so we were unable to conduct independent statistical analysis of the data. We are uncertain whether propyl betaine and polihexanide make any difference to the number of wounds completely healed, change in ulcer size over time, or wound pain reduction. The evidence is of very low certainty (we downgraded for study limitations and imprecision). The final study (126 participants) compared octenidine dihydrochloride/phenoxyethanol (OHP) with Ringer's solution. We are uncertain whether OHP makes any difference to the number of wounds healed (RR 0.96, 95% CI 0.53 to 1.72) or to the change in ulcer size over time (we were unable to conduct independent statistical analysis of available data). The evidence is of very low certainty (we downgraded for study limitations and imprecision). None of the studies reported patient preference, ease of use of the method of cleansing, cost or health-related quality of life. In one study comparing propyl betaine and polihexanide with saline solution the authors do not report any adverse events occurring. We are uncertain whether OHP makes any difference to the number of adverse events compared with Ringer's solution (RR 0.58, 95% CI 0.29 to 1.14). The evidence is of very low certainty (we downgraded for study limitations and imprecision).
AUTHORS' CONCLUSIONS
There is currently a lack of RCT evidence to guide decision making about the effectiveness of wound cleansing compared with no cleansing and the optimal approaches to cleansing of venous leg ulcers. From the four studies identified, there is insufficient evidence to demonstrate whether the use of PHMB solution compared with saline solution; aqueous oxygen peroxide compared with sterile water; propyl betaine and polihexanide compared with a saline solution; or OHP compared with Ringer's solution makes any difference in the treatment of venous leg ulcers. Evidence from three of the studies is of very low certainty, due to study limitations and imprecision. One study did not present data for the primary or secondary outcomes. Further well-designed studies that address important clinical, quality of life and economic outcomes may be important, based on the clinical and patient priority of this uncertainty.
Topics: Aged; Anti-Infective Agents, Local; Betaine; Bias; Biguanides; Confidence Intervals; Detergents; Disinfectants; Ethylene Glycols; Female; Humans; Hydrogen Peroxide; Imines; Male; Middle Aged; Pain Measurement; Pyridines; Randomized Controlled Trials as Topic; Ringer's Solution; Saline Solution; Varicose Ulcer; Wound Healing
PubMed: 33734426
DOI: 10.1002/14651858.CD011675.pub2 -
Cell Mar 2013The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases...
The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans cocultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy-and also to its side effects, which include folate deficiency and gastrointestinal upset.
Topics: Adenylate Kinase; Aging; Animals; Biguanides; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Caloric Restriction; DNA-Binding Proteins; Diabetes Mellitus, Type 2; Escherichia coli; Folic Acid; Humans; Hypoglycemic Agents; Longevity; Metagenome; Metformin; Methionine; Transcription Factors
PubMed: 23540700
DOI: 10.1016/j.cell.2013.02.035 -
The Lancet. Microbe Oct 2022Surgical site infection (SSI) is the most common postoperative complication and substantially increases health-care costs. Published meta-analyses and international... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Surgical site infection (SSI) is the most common postoperative complication and substantially increases health-care costs. Published meta-analyses and international guidelines differ with regard to which preoperative skin antiseptic solution and concentration has the highest efficacy. We aimed to compare the efficacy of different skin preparation solutions and concentrations for the prevention of SSIs, and to provide an overview of current guidelines.
METHODS
This systematic review and network meta-analysis compared different preoperative skin antiseptics in the prevention of SSIs in adult patients undergoing surgery of any wound classification. We searched for randomised controlled trials (RCTs) in MEDLINE, Embase, and Cochrane CENTRAL, published up to Nov 23, 2021, that directly compared two or more antiseptic agents (ie, chlorhexidine, iodine, or olanexidine) or concentrations in aqueous and alcohol-based solutions. We excluded paediatric, animal, and non-randomised studies, and studies not providing standard preoperative intravenous antibiotic prophylaxis. Studies with no SSIs in both groups were excluded from the quantitative analysis. Two reviewers screened and reviewed eligible full texts and extracted data. The primary outcome was the occurrence of SSI (ie, superficial, deep, and organ space). We conducted a frequentist random effects network meta-analysis to estimate the network effects of the skin preparation solutions on the prevention of SSIs. A risk-of-bias and Grading of Recommendations, Assessment, Development, and Evaluation assessment were done to determine the certainty of the evidence. This study is registered with PROSPERO, CRD42021293554.
FINDINGS
Overall, 2326 articles were identified, 33 studies were eligible for the systematic review, and 27 studies with 17 735 patients reporting 2144 SSIs (overall incidence of 12·1%) were included in the quantitative analysis. Only 2·0-2·5% chlorhexidine in alcohol (relative risk 0·75, 95% CI 0·61-0·92) and 1·5% olanexidine (0·49, 0·26-0·92) significantly reduced the rate of SSIs compared with aqueous iodine. For clean surgery, we found no difference in efficacy between different concentrations of chlorhexidine in alcohol. Seven RCTs were at high risk of bias, 24 had some concerns, and two had low risk of bias. Heterogeneity across the studies was moderate (I=27·5%), and netsplitting did not show inconsistencies between direct and indirect comparisons. Five of ten studies that mentioned adverse events related to the skin preparation solutions reported no adverse events, and five reported a total of 56 mild events (mainly erythema, pruritus, dermatitis, skin irritation, or mild allergic symptoms); none reported a substantial difference in adverse events between groups.
INTERPRETATION
For adult patients undergoing a surgical procedure of any wound classification, skin preparation using either 2·0-2·5% chlorhexidine in alcohol or 1·5% olanexidine is most effective in the prevention of SSIs. For clean surgery, no specific concentration of chlorhexidine in alcohol can be recommended. The efficacy of olanexidine was established by a single randomised trial and further investigation is needed.
FUNDING
Dutch Association for Quality Funds Medical Specialists.
Topics: Anti-Infective Agents, Local; Biguanides; Chlorhexidine; Ethanol; GRADE Approach; Humans; Incidence; Iodine; Network Meta-Analysis; Povidone-Iodine; Surgical Wound Infection
PubMed: 35985350
DOI: 10.1016/S2666-5247(22)00187-2 -
Dermatology (Basel, Switzerland) 2017Psoriasis is a common chronic inflammatory skin disease that manifests as scaly erythematous plaques as a consequence of keratinocyte hyperproliferation and... (Review)
Review
Psoriasis is a common chronic inflammatory skin disease that manifests as scaly erythematous plaques as a consequence of keratinocyte hyperproliferation and inflammation. It is commonly associated with diabetes, obesity, and the metabolic syndrome. While there are numerous approved treatment options available, they have limitations including availability, toxicities such as immunosuppression, and high cost. There is increasing evidence to suggest that several hypoglycemic agents used in the treatment of type 2 diabetes, including glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones and biguanides, exert beneficial effects in psoriasis. In this review, we summarize the growing evidence supporting the therapeutic role of hypoglycemic agents in psoriasis and discuss the potential underlying mechanisms. We suggest that dermatologists consider the use of hypoglycemic agents in psoriasis especially in cases with coexisting diabetes and in cases in which immunosuppression is contraindicated. Earlier referral to endocrinology in patients with concomitant diabetes may be appropriate.
Topics: Biguanides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Psoriasis; Thiazolidinediones; Venoms
PubMed: 28538228
DOI: 10.1159/000472149