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Forest plots for each outcome. (A) Pooled analysis in change in HbA1c. (B) Pooled analysis in PBS. (C) Pooled analysis in FPG. (D) Pooled analysis in any adverse event. (E) Pooled analysis in severe adverse event. (F) Pooled analysis in adverse effect leading to discontinuation. (G) Pooled analysis in any gastrointestinal adverse event. (H) Pooled analysis in vomiting. (I) Pooled analysis in diarrhea. (J) Pooled analysis of flatulence. (K) Pooled analysis of nausea. (L) Pooled analysis of abdominal pain. (M) Pooled analysis of any cause of death. Abbreviations: HbA1c, hemoglobin A1C; PBS, postprandial blood glucose; FPG, fasting plasma glucose.
Source publication
Background: Metformin, a commonly used antidiabetic medication, is available in both an immediate-release (IR) formulation and a long-acting formulation (metformin extended-release; XR).
Objective: We performed a systematic review to compare the effectiveness, safety, and patient compliance and satisfaction between the metformin IR and XR formulati...
Citations
... To mitigate the risk of GI side effects, it is advisable to administer metformin with meals. Extended-release (ER) metformin, formulated for once-daily intake, usually commences at 500 mg for a single day, with the highest allowable dose of 2000-2500 mg [28,29]. ...
This extensive review delves into the complex relationship between prolonged use of metformin and the possible emergence of vitamin B12 deficiency (VB12D) in diabetic patients. Metformin, a pivotal element in diabetes management, is constantly linked with decreased absorption of vitamin B12, prompting concerns about the enduring consequences of this interaction. The review systematically amalgamates current evidence, elucidating the prevalence, mechanisms, and clinical ramifications of VB12D induced by consistent consumption of metformin. Exploring the different pathways through which metformin might disrupt the absorption of Vitamin B12, the review encompasses interference with the calcium-dependent membrane activity and alterations of the microbiota present in the gut. A meticulous analysis of experimental studies and human trials is undertaken, accentuating the prevalence of variable VB12D among individuals on long-duration treatment of metformin across diverse populations and age groups. Clinical indications of cobalamin deficiency, spanning haematological abnormalities to neurological complications, are systematically examined. Furthermore, the review delves into the potential implications of cobalamin deficiency associated with metformin on diabetes-related complications and overall patient health. This review offers a comprehensive overview of the intricate interplay between the use of metformin and deficiency of vitamin B12 in diabetic patients, emphasizing the importance that lies in routine monitoring, early detection, and personalized interventions to optimize the long-period safety and efficiency of metformin in the treatment of diabetes. It also proposes future research directions to refine clinical guidelines and enhance the understanding regarding the correlation between diabetes, metformin, and vitamin B12.
... ameliorated by using a long-acting preparation, strong evidence for a favourable side effect profile is lacking, although compliance certainly improves with the long-acting preparation. 72 Taken together, it appears that in the short term, metformin reduces insulin requirements, improves cardiometabolic markers without a clear effect on HbA1c. However, the limited data suggest that the beneficial effects of metformin are not sustained long term. ...
Glycaemic therapy in type 1 diabetes (T1D) is focused on insulin, with the majority of studies investigating different insulin preparations, delivery devices and dosing accuracy methods. While insulin deficiency is the key mechanism for hyperglycaemia in T1D, individuals with this condition can also develop insulin resistance (IR), making optimisation of glycaemia more challenging. Importantly, IR in T1D increases the risk of both microvascular and macrovascular complications; yet, it is rarely targeted in routine clinical care. In this narrative review, we briefly discuss the mechanistic pathways for diabetes complications in individuals with T1D, emphasising the adverse role of IR. We subsequently cover the use of adjunctive glycaemic therapies for improving the metabolic profile in T1D, focusing on therapies that have possible or definite cardiovascular or renal protective properties in individuals with type 2 diabetes. These include metformin and agents in the thiazolidinedione, Sodium‐Glucose Cotransporter‐2 inhibitor (SGLT2i) and Glucagon‐Like Peptide‐1 Receptor Agonists (GLP‐1RA) groups. In addition to reviewing the role of these agents in improving metabolic parameters, we address their potential vascular and renal protective effects in individuals with T1D. We suggest a pragmatic approach for using these agents in T1D, based on current knowledge of their benefits and risks, while also highlighting gaps in knowledge and areas that require further research. It is hoped that the review raises awareness of the role of adjunctive therapies in T1D and offers healthcare professionals simple guidance on using such agents for the management of high‐risk individuals with T1D.
... This issue poses a challenge in ensuring optimal patient adherence and therapeutic outcomes. Metformin HCl, being a hydrophilic biguanide, exhibits poor bioavailability and solubility, which may contribute to its adverse effects on the gastrointestinal tract 3 . The gastric irritation associated with metformin intake often manifests as symptoms such as nausea, vomiting, and abdominal discomfort, leading to suboptimal patient compliance and, consequently, hindered glycemic control. ...
This study focuses on developing and characterizing metformin microspheres using spray drying with hydroxypropyl methylcellulose (HPMC) as a polymer, aiming to enhance gastrointestinal drug delivery, reduce gastric irritation, and lower dosage requirements for type 2 diabetes management. Metformin hydrochloride and HPMC concentrations are varied to generate microspheres with1 to1000µm diameter. These biodegradable polymers were selected because of their efficacy and compatibility with drugs. The thermal analysis and compatibility of the excipients used in microsphere tablet compression are assessed using differential scanning calorimetry and Fourier transform infrared spectroscopy. In-vitro drug release behaviour is evaluated over an 8-hour period using a Copley dissolution tester in 0.1 N HCl at 37 ± 0.5°C, with drug release monitored by UV spectroscopy at 228 nm. Results show that metformin release from microspheres is sustained for the first 6 hours, with a decrease noted at the 8-hour mark. The Higuchi model suggested diffusion-controlled release, while the Korsmeyer-Peppas model indicated non-Fickian diffusion. Some other drug release kinetic models, such as zero-order and first-order kinetic models are used to study the drug release mechanism.
... Despite the very widespread clinical use of metformin, there is a lack of systematic evidence regarding the risk of GI AE of the drug, with the exception of our recent meta-analysis of RCTs where we compared metformin to other glucose-lowering drugs or placebo [17] and other meta-analyses, and systematic reviews comparing different metformin formulations [16,18] and network meta-analyses that focused mainly on drugs other than metformin [19,20]. ...
... There are many studies, among them our recent metaanalysis [17], which indicate that XR metformin may be a better option for patients who have GI intolerance using the IR formulation, while still achieving glycemic control [54,55]. Another meta-analysis did not confirm reduced GI AE with metformin XR, however, it led to improvement in compliance [18]. ...
Introduction
Metformin is the most prescribed medication for type 2 diabetes mellitus (T2DM); there is a well-established link with the elevated incidence of gastrointestinal (GI) adverse events (AE) limiting its administration or intensification.
Objectives
The objective of this systematic review and meta-analysis of observational studies was to evaluate the pooled incidence of GI AE related to metformin use in patients with T2DM.
Materials and methods
PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 29.07.2024 for observational studies in English describing the frequency of GI AE in patients with T2DM treated with metformin. Random-effects meta-analyses were used to derive effect sizes: event rates.
Results
From 7019 publications, we identified 211 potentially eligible full-text articles. Ultimately, 21 observational studies were included in the meta-analysis. The prevalence of GI AE was as follows: diarrhea 6.9% (95% CI: 0.038–0.123), bloating 6,2% (95% CI: 0.020–0.177), abdominal pain 5,3% (95% CI: 0.003–0.529), vomiting 2.4% (95%: CI 0.007–0.075), constipation 1.1% (95%: CI 0.001–0.100). The incidence of bloating (coefficient -4.46; p < 0.001), diarrhea (coefficient -1.17; p = 0.0951) abdominal pain (coefficient -2.80; p = 0.001), constipation (coefficient -5.78; p = 0.0014) and vomiting (coefficient -2.47; p < 0.001) were lower for extended release (XR) metformin than metformin immediate release (IR) formulation.
Conclusions
This study highlights the prevalence of GI AE in patients receiving metformin, with a diarrhea predominance, followed by bloating, diarrhea, abdominal pain, constipation, and vomiting. The incidence is lower in patients administered with XR metformin.
Trial registration
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975, identifier CRD42021289975.
... It is available in both immediate-release and extended-release tablets [2]. Metformin HCl extended-release tablet versus immediate-release tablet is associated with improved patient compliance due to the preference for once-daily administration [3]. Furthermore, extended-release formulations may enhance tolerability and reduce adverse effects such as dyspepsia [4]. ...
Metformin HCl is the first-line therapy for type 2 diabetes. It is available in both immediate-release and extended-release tablet forms, with the extended-release tablet being more beneficial. In this study, 34 formulations using five sustained-release agents, alone or in combination, were evaluated. The granular flowability, angle of repose, bulk Density, tapped Density, compressibility index, and Hausner ratio were assessed. Furthermore, the compressed tablets were tested for appearance, hardness, friability, and in-vitro drug release. Eleven formulations were evaluated for dissolution profiles according to the standards specified in the United States Pharmacopeia. After calculating the similarity factor (f1) and difference factor (f2), eight formulations were identified for further investigation. The combination of xanthan gum and hypromellose (HPMC K100) demonstrated superior results regarding the sustained-release agent amount and tablet appearance. This noteworthy finding led to continuing the study to explore further formulations with different amounts of xanthan gum and Hypromellose K100. As a result, formulation F34 was identified as the optimal choice because of its higher drug-to-polymer ratio. In conclusion, the final formulation is a rapid, cost-effective, and straightforward method due to the less time required for drying, the amount of sustained-release agents, and the number of components.
... Especially for patients who are overweight, metformin is the first-line medication for lowering elevated levels of blood sugar in adolescents and children with type 2 diabetes. 10 Metformin is used to lower the concentration of glucose absorbed from the intestines, raise insulin sensitivity, and decrease the amount of glucose generated in the liver. The main issue with its safety is gastrointestinal intolerance, which includes nausea, diarrhea, and pain in the abdomen. ...
Objective: To assess the safety and efficacy of liraglutide versus metformin in patients with type 2 diabetes in the pediatric age group Methods: This was an open-label, 24-week randomized controlled experiment. Three to sixteen-year-old Children with type 2 diabetes were randomized to receive either metformin or liraglutide. The main outcome was the variation in HbA1c at week 24. The research was completed by 150 subjects in all, and analysis was done on this cohort. Results: At week 24, the metformin group had a decrease in HbA1c (p value = 0.001), going from 8.0 ± 0.7% to 7.2 ± 0.8% (53 ± 2 mmol/mol), and in the liraglutide group (p = 0.001), going from 7.7 ± 0.7% to 7.1 ± 0.6% (52 ± 2 mmol/mol). However, the group comprised liraglutide grasped maximum decline more quickly as compared to metformin group. The incidence of hypoglycemia and other parameters studied did not differ significantly across the groups. Conclusion: During a 24-week period, individuals with T2DM treated with liraglutide and metformin alone had comparable reductions in HbA1c, with no discernible differences in other metrics.
... Contrarily, increased risks of bloating and diarrhea have been identified for MIR compared to MXR [11]. Tan et al., Aiken et al., and Tarry-Adkins et al. also conducted meta-analyses that compared different forms of metformin in terms of the risk of GI side effects [58][59][60]. Tan et al. found no differences in safety between MXR and MIR [58]. In turn, Tarry-Adkins et al. and Aiken et al. observed a significant reduction in GI side effects in patients taking delayed-release formulation of metformin (MDR) compared to MIR [59,60]. ...
... Tan et al., Aiken et al., and Tarry-Adkins et al. also conducted meta-analyses that compared different forms of metformin in terms of the risk of GI side effects [58][59][60]. Tan et al. found no differences in safety between MXR and MIR [58]. In turn, Tarry-Adkins et al. and Aiken et al. observed a significant reduction in GI side effects in patients taking delayed-release formulation of metformin (MDR) compared to MIR [59,60]. ...
Metformin, one of the most frequently used oral glucose-lowering drugs (GLDs), is associated with the occurrence of gastrointestinal (GI) adverse events in approximately 20% of users. These unwanted actions result in non-compliance or even discontinuation of metformin therapy. The aim of the presented meta-analysis was to determine whether adding a drug from the group of sulfonylureas, glitazones, DPP-IV inhibitors, or probiotics to metformin monotherapy may affect the risk of GI side effects. The material for this meta-analysis comprised data from 26 randomized controlled clinical trials (RCTs) published in English. This meta-analysis included 41,048 patients. The PubMed, Cochrane Library, and Clinical Trials databases were thoroughly searched to find relevant RCTs. The Population, Intervention, Comparison, Outcomes, and Study Type (PICOT) structure was used to formulate study selection criteria and the research question. Cochrane Review Manager Software 5.4 was used to carry out analysis of collected data. The results were presented as relative risk (RR) and 95% confidence interval (95% CI) for each group, and p < 0.05 was considered as statistically significant. As expected from clinical practice, metformin was associated with a markedly increased risk of abdominal pain, nausea, and vomiting compared to placebo. In comparison to other GLDs, taking metformin was related to an elevated risk of diarrhea and abdominal pain and to a lowered risk of vomiting and bloating. In turn, adding other GLDs to metformin treatment was associated with an elevated risk of nausea and vomiting than treatment with metformin in monotherapy. However, adding probiotics to metformin therapy was related to a decreased risk of diarrhea, bloating, and constipation. The obtained results demonstrate that the combination of metformin with other GLDs may elevate the risk of nausea and vomiting, whereas combination with probiotics decreases the risk of diarrhea, bloating, and constipation. Thus, the results of our meta-analysis suggest that probiotics may reduce the risk of some GI side effects in people with type 2 diabetes mellitus (T2DM) who started treatment with metformin.
... A study based on a randomized clinical trial has shown that extended-release formulations have better outcomes in terms of glycemic control, lipid, and certain inflammatory markers levels [45]. Furthermore, in a systematic review study, better adherence to treatment for extended-release metformin formulations was reported [46]. ...
Diabetes mellitus is a complex, multifactorial, progressive condition with a variety of approved therapeutic options. The purpose of this study was to offer an overview of the authorized antidiabetic medicines (excluding insulin) compared with marketed products in seven European countries. Data were obtained from primary sources, including the websites of national authorities and directly from specialists in the countries of interest. The range of marketed medicines compared with the authorized group was assessed in terms of active pharmaceutical ingredients (>60% in Bulgaria, France, Serbia), brand names (>70% in Bulgaria, the Czech Republic, Romania, Serbia, Spain), pharmaceutical forms (>60% in all countries), strengths (>60% in Bulgaria, the Czech Republic, Romania, Serbia, Spain), marketing authorization holder (≥50% in all countries) and the status of medicine. Spain was found to have the highest number of products based on most of these attributes. Over 90% of authorized medicines had a pharmacy price in Serbia. Regarding the newer class of GLP-1 receptor agonists, a retail price for all approved substances was available in Bulgaria, Romania, Serbia, and Spain. Only one brand name with one concentration was found available for some agents, being susceptible to drug shortages: glibenclamide (Romania, Serbia, Spain), glipizide (the Czech Republic, Poland, Romania, Spain), glisentide (Spain), acarbose (the Czech Republic), sitagliptin (Bulgaria, Poland), vildagliptin (the Czech Republic, Poland) and saxagliptin (the Czech Republic, France, Romania, Serbia). An overview of the national and international therapeutic options may allow competent authorities and health professionals to take rapid measures in case of supply problems or health crises.
... In the current study, the mean age of controls was 53.89 years, whereas it was 54.39 years in T2DM patients without complications, and it was 56.3 years in T2DM patients with diabetic complications. A systematic review compiled by Tan et al. (2021) also reported a mean age of 54.39 years in T2DM patients [15]. In T2DM patients without complications, urban background, higher BMI levels, alcohol consumption, smoking, family history of diabetes, and menopausal stage (in females) showed a significant association with the disease as well as its complications. ...
... In the current study, the mean age of controls was 53.89 years, whereas it was 54.39 years in T2DM patients without complications, and it was 56.3 years in T2DM patients with diabetic complications. A systematic review compiled by Tan et al. (2021) also reported a mean age of 54.39 years in T2DM patients [15]. In T2DM patients without complications, urban background, higher BMI levels, alcohol consumption, smoking, family history of diabetes, and menopausal stage (in females) showed a significant association with the disease as well as its complications. ...
Prolonged hyperglycemic conditions in type 2 diabetes mellitus (T2DM) cause pathological and functional damage to many organs and tissues, including the kidneys, retina, skin, and neuronal tissues, resulting in the development of microvascular diabetic complications. The altered renin angiotensin aldosterone system (RAAS) pathway has been reported to play an important role in the development of insulin resistance in T2DM and associated complications. The current study was carried out to evaluate the association of risk factors and altered expression of RAAS genes in T2DM patients without complications and T2DM patients with complications (retinopathy, nephropathy, and neuropathy). Four hundred and twenty subjects including 140 healthy controls, 140 T2DM patients with diabetic complications, and 140 T2DM patients without diabetic complications were included in the study. Risk factors associated with the development of T2DM and diabetic complications were evaluated. Further, expression analysis of RAAS genes (AGT, ACE, ACE2, and AGT1R) was carried out using qRTPCR in healthy controls, T2DM patients with complications, and T2DM patients without complications. Various risk factors like urban background, higher BMI, alcoholism, smoking, and family history of diabetes among others were found to be associated with the development of T2DM as well as diabetic complications. The expression level of AGT, ACE, and AGT1R was found to be upregulated whereas ACE2 was found to be downregulated in T2DM patients with complications and T2DM patients without complications as compared to controls. Altered expression of the studied genes of RAAS pathway is associated with the development of microvascular diabetic complications.
... One of these is the extended-release (XR) form, which was developed to replace immediate-release (IR) tablets and thus facilitate a once-daily dosing regimen. 12 The glycemic control efficacy offered by metformin XR is comparable to that of metformin IR, [13][14][15][16][17][18][19] while the reduced dosing also enhances compliance. 13,16 The research indicates a correlation between metformin XR and a reduction in the number of adverse gastrointestinal (GI) events, 14,15 although a randomized trial conducted internationally in 2017 suggested that both the XR and IR formulations share a similar safety profile. ...
... First, a literature review was performed to construct the basis for a structured questionnaire [14][15][16][17][18][19]22 (Supplemental). Certain parts of the questionnaire were modified to make it more appropriate to the UAE context while retaining the main research points. ...
... Earlier randomized controlled trials and methodical reviews reported that the XR formulation improves drug adherence by 10% because of its non-complicated use. [16][17][18][19] However, as regards practice of metformin XR, the pharmacists obviously neglected this advantage by choosing the medication in patients that prefer not to administer multiple doses daily, and prescribing the medication mostly due to patients' preference rather than efficacy and safety of the drug. This indicates a potential lack of direction in adapting international evidence to prescribing settings in the UAE with respect to metformin XR, indicating a weak localization of international standards as implied in a previous report. ...
Background
There is a little knowledge on the extent to which healthcare providers understand and accept the professional recommendations and appropriate dosing strategy regarding metformin XR.
Objectives
To evaluate UAE community pharmacists’ knowledge, attitude, and practices (KAP) concerning metformin XR.
Methods
This is a cross-sectional research study conducted amongst licensed community pharmacists. The survey took place via a questionnaire and physical interviews were held. The survey used in this study included questions on demographics and questions on the participants’ attitudes, knowledge and practices concerning metformin XR. The factors influencing KAP regarding metformin XR were examined via simple logistic regression analysis.
Results
Threehundred fifty-three (n = 353) participants were recruited in the study. Independent pharmacies constituted 57.5% of this study sample and 42.5% were chain pharmacies. The average knowledge score about metformin XR tablets was 42.5% with a confidence interval (CI) of 95% [37.3%, 47.4]. Better knowledge scores on metformin XR tablets was observed in respondents aged ⩾40 years (OR 2.97, 95% CI 1.63-5.4), having greater than 10 years in terms of experience (OR 2.28; 95% CI 1.25-4.16) and pharmacist graduated from Regional or international universities (OR 2.08; 95% CI 1.34-3.24). About 78% (n = 275) of the participants believed that metformin XR tablets have better efficacy and 63.2% (n = 233) indicated that metformin IR was associated with greater adverse effects.
Conclusion
This study demonstrated a distinct gap in knowledge, attitude and practice pertaining to metformin XR among community pharmacists in the UAE. The community pharmacists need to enhance their practice by receiving accurate and reliable data to support their decision-making on the prescribing of metformin XR. The implementation of novel guidelines and evidence dissemination strategies may help bridge this gap.
