Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years.

Diabetes medications may modify the risk of certain cancers. We systematically searched MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from 2011 to March 2021 for studies evaluating associations between diabetes medications and the risk of breast, lung, colorectal, prostate, liver, and pancreatic cancers. A total of 92 studies (3 randomized controlled trials, 64 cohort studies, and 25 case-control studies) were identified in the systematic review, involving 171 million participants. Inverse relationships with colorectal (n = 18; RR = 0.85; 95% CI = 0.78-0.92) and liver cancers (n = 10; RR = 0.55; 95% CI = 0.46-0.66) were observed in biguanide users. Thiazolidinediones were associated with lower risks of breast (n = 6; RR = 0.87; 95% CI = 0.80-0.95), lung (n = 6; RR = 0.77; 95% CI = 0.61-0.96) and liver (n = 8; RR = 0.83; 95% CI = 0.72-0.95) cancers. Insulins were negatively associated with breast (n = 15; RR = 0.90; 95% CI = 0.82-0.98) and prostate cancer risks (n = 7; RR = 0.74; 95% CI = 0.56-0.98). Positive associations were found between insulin secretagogues and pancreatic cancer (n = 5; RR = 1.26; 95% CI = 1.01-1.57), and between insulins and liver (n = 7; RR = 1.74; 95% CI = 1.08-2.80) and pancreatic cancers (n = 8; RR = 2.41; 95% CI = 1.08-5.36). Overall, biguanide and thiazolidinedione use carried no risk, or potentially lower risk of some cancers, while insulin secretagogue and insulin use were associated with increased pancreatic cancer risk.

Hip and vertebral fracture risk after initiating antidiabetic drugs in Japanese elderly: a nationwide study.

INTRODUCTION: We aimed to clarify the risks of initiating antidiabetic drugs for fractures using a nationwide health insurance claims database (NDBJ). MATERIALS AND METHODS: Patients aged ≥ 65 years initiating antidiabetic drugs at the outpatient department were enrolled after a 180-day period without prescribed antidiabetic drugs and followed with during 2012-2018 using NDBJ. The adjusted hazard risks (HRs) of each antidiabetic drug (thiazolidine, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, glinide, and insulin) for fractures compared with biguanide were obtained adjusting for age, gender, polypharmacy, dementia, and the other antidiabetic drugs. RESULTS: The DPP-4 inhibitor was the most often prescribed antidiabetic drug followed by biguanide with prescribed proportions of 71.7% and 12.9%. A total of 4,304 hip fractures and 9,388 vertebral fractures were identified among the 966,700 outpatient participants. Compared with biguanide, insulin, alpha-glucosidase inhibitor, and DPP-4 inhibitor were related to increased hip fracture risks. Vertebral fracture risk was higher in outpatients prescribed with insulin, thiazolidine, and DPP-4 inhibitor compared with biguanide. Patients prescribed insulin for hip and vertebral fractures' adjusted HRs were 2.17 (95% CI 1.77-2.66) and 1.45 (95% CI 1.24-1.70), respectively. Those prescribed DPP-4 inhibitor for hip and vertebral fractures' adjusted HRs were 1.27 (95% CI 1.15-1.40) and 1.20 (95% CI 1.12-1.28), respectively. CONCLUSIONS: Initiating insulin increased the risk of not only hip fractures but also vertebral fractures. Patients initiating antidiabetic drugs had increased risks of hip and vertebral fractures compared with those initiating biguanide independently for age, gender, polypharmacy, and dementia in the Japanese elderly.

Cardiac Dysfunction Due to Thiamine Deficiency after Hemodialysis for Biguanide-related Lactic Acidosis.

Biguanide is an ideal drug for the treatment of type 2 diabetes mellitus. When used appropriately, the incidence of lactic acidosis is reported to be very low. Risk factors associated with biguanide-related lactic acidosis include chronic kidney disease, congestive heart failure, alcohol use, severe dehydration, shock, hypoxic states, sepsis, and advanced age. We herein report a case of cardiac dysfunction due to thiamine deficiency after hemodialysis in a patient with suspected biguanide-related lactic acidosis. Patients who develop severe lactic acidosis while taking biguanides should be given a large dose of thiamine without delay, given the possibility of thiamine deficiency as a complication.

Safety and tolerability of topical polyhexamethylene biguanide: a randomised clinical trial in healthy adult volunteers.

BACKGROUND AND AIMS: Polyhexamethyl biguanide (PHMB), a widely used topical treatment for Acanthamoeba keratitis (AK), is unlicensed with no formal safety assessment. This study evaluated its safety and tolerability. METHODS: A prospective, randomised, double-masked controlled trial in 90 healthy volunteers. Subjects were treated with topical 0.04%, 0.06%, 0.08% PHMB or placebo (vehicle) 12× daily for 7 days, then 6× daily for 7 days. The rates of dose-limiting adverse events (DLAEs) leading to interruption of dosing, mild adverse events (AEs) (not dose limiting) and incidental AEs (unrelated to treatment) were compared. The primary outcome was the difference between treatments for DLAE rates. RESULTS: 5/90 subjects developed DLAE within <1-4 days of starting treatment; 2/5 using PHMB 0.06% and 3/5 PHMB 0.08%. These resolved within 1-15 days. There were no significant differences in DLAE between treatment groups. Mild AEs occurred in 48/90 subjects (including placebo). There was no trend for an increased incidence of any AE with increasing concentrations of PHMB, except for corneal punctate keratopathy with PHMB 0.08%, which fully resolved within 7-14 days. CONCLUSION: These findings are reassuring for PHMB 0.02% users. They also suggest that higher PHMB concentrations may show acceptable levels of tolerance and toxicity in AK subjects, whose susceptibility to AE may be greater than for the normal eyes in this study. Given the potential benefits of higher PHMB concentrations for treating deep stromal invasion in AK, we think that the use of PHMB 0.08% is justified in treatment trials. TRIAL REGISTRATION NUMBER: NCT02506257.

Insight into the Reaction of Alexidine with Sodium Hypochlorite: A Potential Error in Endodontic Treatment.

Therapeutic success in endodontic treatment depends on successful infection control. Alexidine dihydrochloride (ALX) was recently proposed as a potential alternative to 2% chlorhexidine (CHX) as it possesses similar antimicrobial properties, expresses substantivity and does not produce p-chloroaniline (PCA) when mixed with sodium hypochlorite (NaOCl). However, the products released in this reaction have not been described to date. The aim of this study was to identify detected chemical compounds formed in the reaction of ALX and NaOCl with the ultra-high-performance liquid chromatography-mass spectrophotometry (UHPLC-MS) method and assess whether precipitates and PCA are formed in this reaction. Solutions of ALX were mixed with the equivalent volume of 2% and 5.25% (w/v) NaOCl solutions. As control, 2% (w/v) CHX was mixed with 2% and 5.25% (w/v) NaOCl. Samples were subjected to the UHPLC-MS analysis. The mixture of ALX and NaOCl resulted in a yellowish precipitate formation, the amount of which depended on NaOCl concentration. Interaction of ALX and NaOCl resulted in the production of aliphatic amines. No PCA was formed when NaOCl was mixed with ALX. However, for the first time, we identified the possible products of the interaction. The interaction between NaOCl and ALX results in the formation of aliphatic amines; therefore, these compounds should not be mixed during endodontic treatment.

Contact allergy to polyhexamethylene biguanide (polyaminopropyl biguanide).

BACKGROUND: Polyaminopropyl biguanide (INCI name) and polyhexamethylene biguanide (PHMB) are polymeric biguanides. PHMB is a broad-spectrum antimicrobial substance used as a preservative in many products. Due to our limited knowledge on PHMB contact allergy frequency and the fact that cases of allergic contact dermatitis to PHMB might be missed, we have included PHMB as a screening allergen since 2016. OBJECTIVE: To report the prevalence of positive patch test reactions to PHMB as a screening allergen in patients with suspected allergic contact dermatitis. METHODS: A retrospective analysis of 1760 patch tested patients from July 2016 to December 2018 was performed. Polyaminopropyl biguanide 2.0% aqua was included in the extended Malmö baseline series during the study period. RESULTS: Of all patients, 1204 (68.4%) were female. Positive patch test reactions were reported in 19 patients (1.1%). The most common sites of lesions were face, head, and neck (52.6%). There was a significant correlation between concomitant reactions to PHMB and other cosmetic-related allergens. CONCLUSION: The prevalence of positive reactions to PHMB was higher than that previously reported. Patch testing with PHMB should be performed in patients with dermatitis who have lesions on the face, head, and neck.

Safety Assessment of Polyaminopropyl Biguanide (Polyhexamethylene Biguanide Hydrochloride) as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of Polyaminopropyl Biguanide (polyhexamethylene biguanide hydrochloride), which functions as a preservative in cosmetic products. The Panel reviewed relevant data relating to the safety of this ingredient and concluded that Polyaminopropyl Biguanide is safe in cosmetics in the present practices of use and concentration described in the safety assessment, when formulated to be nonirritating and nonsensitizing, which may be based on a quantitative risk assessment or other accepted methodologies. The Panel also concluded that the data are insufficient to determine the safety of Polyaminopropyl Biguanide in products that may be incidentally inhaled.

Tolerability and safety of urotainer® polihexanide 0.02% in catheterized patients: a prospective cohort study.

BACKGROUND: In patients with indwelling bladder catheters for > 2 weeks, bacterial colonization is inevitable, leading to urinary tract infections or encrustations with subsequent catheter blockage. Currently, bladder irrigations are the most frequently used prophylactic means, but the best solution remains yet to be determined. In vitro studies demonstrate that polihexanide is a promising option for catheter irrigation, but no data about safety and tolerability exist. METHODS: In a prospective observational study in patients with indwelling bladder catheter for > 2 weeks, a 0.02% polihexanide solution was used to rinse the catheter on five consecutive days. Adverse events, tolerability and vital signs were assessed before, during, after and at the end of the treatment period. RESULTS: There was no serious adverse event in the study. A total of 28 adverse events (AEs) in 15 (46.88%) participants were experienced. Absolute changes in pain scores were not clinically relevant. No incidences of either flushing or sweating were found during instillation. Bladder spasms during instillation were reported in two cases during a single instillation. Mean pulse rates did not change by more than 3 beats per minute. Mean changes in body temperature did not exceed 0.12 °C. Clinically relevant changes in blood pressure were recorded for 3 patients. CONCLUSIONS: This is the first study to demonstrate that a 0.02% polihexanide solution can safely be used for catheter irrigation. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02157415 ), June 6th, 2014.

Antidiabetics and antihypertensive medications use in Morocco: A pharmacoepidemiological descriptive study.

 Background: In Morocco, and many other African countries, there is a paucity of antihypertensive and antidiabetics use amongst the general population. AIM: To investigate the epidemiological profile of antihypertensive and antidiabetics use and analysis their adverse reactions. SETTING: This study was conducted in the prefecture of Figuig, Morocco. METHODS: A cross-sectional descriptive study. Data was collected using semi-structured questionnaire about their pharmacological treatment and presented using descriptive statistical analysis. RESULTS: Sample of 244 subjects, predominantly women 58.15% (p 0.03) composed of diabetic patients 56.96% (n = 139) and hypertensive patients 43.03% (n = 105). After adjustments, 60.24% of all patients were under monotherapy. The diabetics were being treated using the Biguanide class (26.92%), insulin (20.0%) and sulfonylureas (10.0%) while hypertensive patients were treated by Calcium Channel Blockers (27.36%), Angiotensin Converting Enzyme Inhibitors (21.05%), Angiotensin T-Blockers (16.84%), Diuretics (7.36%) and ß-adrenergic receptors blockers (3.15%). In total, 23.00% of all subjects have experienced negative side-effects, mostly, reported (90.38%) to health professionals and 23.52% of them have interrupted temporarily or try to change their treatment. Gastro-intestinal problems were the most adverse reactions reported (11.11%) followed by headache, dizziness and tinnitus (6.66%) and asthenia, feeling sick and feeling of faintness (5.33%). CONCLUSION: Managing diabetes and hypertension entails a lot of public challenges and requires more focus and interest, especially amongst the illiterate population in remote areas. Some of the suggested ways to help face the problem include the introduction of new innovative measures, systems of fellow-up and adverse reactions.

A case of allergic contact dermatitis caused by Olanedine solution-A diagnostic patch-testing method involving dried filter paper.

BACKGROUND: Olanedine solution is a new antiseptic, and several cases of allergic contact dermatitis caused by the agent were reported in 2018; however, these cases were diagnosed based on positive results in 2-day closed patch testing of Olanedine solution "as is." OBJECTIVES: To present another case of Olanedine-induced allergic contact dermatitis and to analyze the optimal patch-testing method for this condition. METHODS: A 34-year-old Japanese female patient and 25 healthy control subjects were patch tested using wet filter paper, which had been treated with 15 µL Olanedine solution, and dried filter paper, which had been treated with 15 µL Olanedine solution and then dried. RESULTS: The patient and all of the control subjects exhibited false-positive reactions due to irritation in the 2-day closed patch tests with wet filter paper containing Olanedine solution "as is." The tests with dried filter paper produced a positive reaction on day 7 in the patient, and negative reactions in all control subjects. CONCLUSIONS: It is preferable to perform 2-day closed patch tests using filter paper with the test solution "as is," which had been dried before application in order to correctly diagnose antiseptic-induced allergic contact dermatitis.

Micropore Particle Technology Promotes Wound Healing, Whereas Polyhexamethylene Biguanide Causes Tissue Degeneration: A Case Report.

CASE REPORT: A 72-year-old woman with a nontraumatic spinal cord injury developed eschar on her lower right back. An underlying abscess was identified, which upon surgical debridement left a large wound extending down to the hip bone. In addition, the hip suffered from chronic osteomyelitis and was exposed at the bottom of the wound. The wound was initially treated for 5 weeks with Manuka honey but deteriorated further. Next, micropore particle technology (MPPT) was used. It cleared the wound of necrotic tissue based on autolytic debridement and removed the soft tissue infection; over a 3-month period, the wound reduced 50% in volume. Treatment approach was changed to polyhexamethylene biguanide (PHMB) and was applied as a gel once every second day to the wound. After 6 days, it was observed to cause tissue degeneration, disruption of the structure of the exposed bone, and the appearance of froth coming through the hip bone. A pain syndrome developed and the use of PHMB was terminated on day 10. After a wash-out period, the use of MPPT was reinitiated. Over the following 8 months, MPPT continued to control the infectious debris coming from the hip bone and promote healing without affecting the bone or causing side effects. CONCLUSIONS: It is generally assumed that the cytotoxic properties of antiseptics seen in cell culture experiments do not occur on wounds. The present case shows these cytotoxic properties are expressed on wounds, and they do disrupt tissues and tissue regeneration.

Cardiovascular risks associated with dipeptidyl peptidase-4 inhibitors monotherapy compared with other antidiabetes drugs in the Japanese population: A nationwide cohort study.

PURPOSE: We evaluated the cardiovascular risk associated with dipeptidyl peptidase-4 inhibitors (DPP-4Is) as monotherapy compared with other antidiabetic drugs in Japan. METHODS: We conducted a nationwide cohort study involving 2 716 000 diabetes patients in Japan. New users of any antidiabetic drug as monotherapy between 1 April 2010 and 31 October 2014 were identified. Occurrences of myocardial infarction (MI), heart failure (HF), and stroke requiring hospitalization associated with DPP-4Is were compared with those associated with biguanides (BGs), sulfonylureas (SUs), or α-glucosidase inhibitors (α-GIs). Adjusted hazard ratios (aHRs) for these outcomes were estimated by Cox proportional hazards model. Propensity score standardization was used to control for confounding. RESULTS: We identified 1 105 103 patients using DPP-4Is, 278 280 patients using BGs, 273 449 patients using SUs, and 217 026 patients using α-GIs. The risks of MI and HF for DPP-4I users were significantly higher than those for BG users (MI: aHR, 1.48 [95%CI, 1.20-1.82], HF: aHR, 1.46 [95%CI, 1.31-1.62]), while significantly lower than those for SU users (MI: aHR, 0.84 [95%CI, 0.72-0.98], HF: aHR, 0.86 [95%CI, 0.81-0.92]). The risk of MI for DPP-4I users was similar to that for α-GI users, while the risk of HF for DPP-4I users was slightly higher than for α-GI users (MI: aHR, 0.98 [95%CI, 0.82-1.17], HF: aHR, 1.12[95%CI, 1.04-1.21]). CONCLUSIONS: Risk of MI and HF requiring hospitalization associated with DPP-4Is as monotherapy was significantly higher than BGs, significantly lower than SUs, and similar to α-GIs.

Acidosis láctica asociada a metformina, ¿un fantasma o un asesino? / Metformin-associated lactic acidosis, a ghost or a murderer?

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Review of Biguanide (Metformin) Toxicity.

In the 1920s, guanidine, the active component of Galega officinalis, was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B12 deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.

Intraoperative wound irrigation to prevent surgical site infection after laparotomy (IOWISI): study protocol for a randomized controlled trial.

BACKGROUND: Postoperative surgical site infection (SSI) is one of the most common hospital infections and contributes substantially to postoperative morbidity and mortality. In addition, SSIs dramatically increase the treatment cost and length of hospital stay. Following visceral surgery by laparotomy, SSI rates are especially high (14-25%). Therefore, measures to prevent SSI in this field are urgently needed. Prophylactic intraoperative wound irrigation (IOWI) of the subcutaneous soft tissue before skin closure hypothetically represents an easy and economical option to reduce SSI rates and is already frequently used in clinical practice. However, there are currently no definite recommendations on the use of IOWI since high-level evidence supporting its use is lacking. Consequently, clinical practice varies widely. Antiseptic polyhexanide (PHX)-based solutions are approved for soft-tissue wound irrigation in surgery but have not been specifically evaluated in randomized clinical trials for the prevention of SSI following laparotomy for visceral surgery. METHODS/DESIGN: The IOWISI trial is a multicentre, randomized, observer- and patient-blinded clinical trial with three parallel treatment groups, comparing IOWI with a 0.04% PHX solution to no irrigation (test 1) or saline (test 2) before skin closure after laparotomy for visceral surgery (contamination level II-IV). The primary endpoint of the trial is the SSI rate within 30 days postoperatively. Statistical analysis of the primary endpoint measure will be based on the intention-to-treat population. The global level of significance is set at 2.5% for test 1 and 5% for test 2 and the sample size (n = 540) is determined to assure a power of 94% (test 1) and 85% (test 2). DISCUSSION: The IOWISI trial will provide high-level evidence as a basis for clinical recommendations regarding the use of IOWI with PHX or saline and will potentially impact on future clinical guidelines and practice. The pragmatic trial design guarantees high external validity. TRIAL REGISTRATION: Registered at the German Clinical Trials Register, DRKS00012251 . Registered on 3 July 2017.