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Bell DSH. All That Glistens Is not Gold: Neuropathy in Diabetic Patients May not Be Exclusively due to Diabetes. Endocr Pract 2025; 31:266-267. [PMID: 39222845 DOI: 10.1016/j.eprac.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024]
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Atkinson M, Gharti P, Min T. Metformin Use and Vitamin B12 Deficiency in People with Type 2 Diabetes. What Are the Risk Factors? A Mini-systematic Review. TOUCHREVIEWS IN ENDOCRINOLOGY 2024; 20:42-53. [PMID: 39526048 PMCID: PMC11548349 DOI: 10.17925/ee.2024.20.2.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/04/2024] [Indexed: 11/16/2024]
Abstract
Background and Aim: Metformin is recommended as the first-line agent for the management of type 2 diabetes following lifestyle and dietary changes. The long-term use of metformin has been associated with vitamin B12 deficiency. The aim of this review is to investigate the effect of metformin on vitamin B12 levels and identify any risk factors. Method: A literature search was conducted using MEDLINE, PubMed and ProQuest Central. Selected articles were peer-reviewed articles, written in English and published from 2015 and onwards. Excluded articles were case reports, reviews or meta-analyses, as well as those with no access to full text. Results: In total, 21 articles were included. There was a significant association between metformin use and vitamin B12 levels in 17 studies, while 4 studies found no such association. The risk factors examined were metformin dose, treatment duration, patient age and patient ethnicity. Conclusion: In summary, metformin use was associated with lower vitamin B12 concentrations, and higher doses and longer durations of treatment increase the risk of vitamin B12 deficiency. Routine vitamin B12 screening is recommended, prioritizing higher-risk patients. Further research is needed to identify when to initiate monitoring.
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Affiliation(s)
- Michael Atkinson
- Department of Diabetes and Endocrinology, Morriston Hospital, Swansea Bay University Health Board, Swansea, UK
| | - Prashamsa Gharti
- Diabetes Research Group, Swansea University Medical School, Swansea, UK
| | - Thinzar Min
- Diabetes Research Group, Swansea University Medical School, Swansea, UK
- Department of Diabetes and Endocrinology, Neath Port Talbot Hospital, Swansea Bay University Health Board, Swansea, UK
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Ramzan NUH, Shahjahan K, Dhillon RA, Khan NTA, Hashmat MB, Anwer MU, Ahmed D, Afzal F, Tahir MM, Muzaffar A. Vitamin B12 Deficiency in Patients Taking Metformin: Pathogenesis and Recommendations. Cureus 2024; 16:e68550. [PMID: 39233729 PMCID: PMC11374140 DOI: 10.7759/cureus.68550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 09/03/2024] [Indexed: 09/06/2024] Open
Abstract
Metformin is a cornerstone therapy for type 2 diabetes mellitus due to its glucose-lowering efficacy and additional benefits such as reducing cardiovascular mortality. However, accumulating evidence suggests an association between long-term metformin use and vitamin B12 deficiency, which can lead to serious clinical consequences. This review aims to synthesize current knowledge on the pathogenesis, prevalence, clinical implications, and management of metformin-induced vitamin B12 deficiency. Given the significant clinical implications, it is crucial to monitor and manage vitamin B12 levels in patients using metformin. This review emphasizes the importance of early detection and supplementation to prevent adverse outcomes. By analyzing the current evidence, the review aims to inform healthcare professionals about best practices for managing vitamin B12 deficiency in patients on metformin, offering insights to guide future clinical practices and research directions.
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Affiliation(s)
| | | | | | | | | | | | - Dawood Ahmed
- Medicine, Faisalabad Medical University, Faisalabad, PAK
| | - Fazila Afzal
- Medicine, Faisalabad Medical University, Faisalabad, PAK
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Yazidi M, Kammoun E, Oueslati I, Chihaoui M. Metformin-Induced Vitamin B12 Deficiency in Patients with Type 2 Diabetes: A Narrative Review with a Practical Approach for Screening, Diagnosing, and Managing Vitamin B12 Deficiency. Korean J Fam Med 2024; 45:189-198. [PMID: 39054838 PMCID: PMC11273170 DOI: 10.4082/kjfm.24.0090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/27/2024] [Accepted: 06/12/2024] [Indexed: 07/27/2024] Open
Abstract
Metformin is the most widely used antihyperglycemic drug in patients with type 2 diabetes (T2D). Over the past 2 decades, several studies have highlighted a substantial increase in the risk of vitamin B12 deficiency in patients with T2D on metformin therapy. This can lead to several complications and induce or exacerbate peripheral neuropathy. Despite these data, there are no definite guidelines for screening, diagnosing, and treating vitamin B12 deficiency in patients with T2D on metformin therapy. Therefore, in this narrative review, we aimed to suggest a practical diagnostic and therapeutic strategy to address vitamin B12 deficiency in patients with T2D receiving metformin treatment. Clinical evidence supporting an increased risk of vitamin B12 deficiency in patients with T2D on metformin therapy and its risk factors and potential complications are also discussed.
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Affiliation(s)
- Meriem Yazidi
- Department of Endocrinology, La Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Elyes Kammoun
- Department of Endocrinology, La Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Ibtissem Oueslati
- Department of Endocrinology, La Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Melika Chihaoui
- Department of Endocrinology, La Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
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Bell DSH. The Consequences of Lowering Vitamin B12 With Chronic Metformin Therapy. Endocr Pract 2023; 29:928-929. [PMID: 37625545 DOI: 10.1016/j.eprac.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/27/2023]
Affiliation(s)
- David S H Bell
- Southside Endocrinology, 1900 Crestwood Boulevard, Suite 201, Irondale, AL 35210.
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Tiwari A, Kumar Singh R, Satone PD, Meshram RJ. Metformin-Induced Vitamin B12 Deficiency in Patients With Type-2 Diabetes Mellitus. Cureus 2023; 15:e47771. [PMID: 38034222 PMCID: PMC10688235 DOI: 10.7759/cureus.47771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/26/2023] [Indexed: 12/02/2023] Open
Abstract
Diabetes mellitus (DM) is the most common metabolic disease worldwide. Hence, the prevalence of the disease continues to increase across the globe. Metformin is used as a first-line oral hypoglycemic drug to keep control of type-2 DM (T2DM) in adults. Diabetic patients on metformin have been largely seen to be suffering from a deficiency of vitamin B12. It is a water-soluble vitamin mainly obtained from animal food like meat. At the basic cell level, it acts as a cofactor for enzymes essential for DNA synthesis and neuroprotection. As a result, vitamin B12 deficiency can show clinical effects such as progressive demyelination, peripheral neuropathy and haematological abnormalities (such as macrocytic anaemia and neutrophil hypersegmentation). Various studies also show a relation between vitamin B12 insufficiency and metformin-treated T2DM patients as decreased absorption of vitamin B12. There could be a severe complication of vitamin B12 deficiency in T2DM patients. The use of proton pump inhibitors, gastric bypass surgery, older patients and patients with a higher red blood cell turnover are factors that hasten the depletion of vitamin B12 reserves in the liver. Methylmalonic acid and homocysteine levels can be measured to identify vitamin B12 insufficiency at its early stage if blood vitamin B12 levels are borderline. The action of metformin on vitamin B12 absorption and its potential mechanisms of inhibition will be the main topics of discussion in this review. The review will also discuss how vitamin B12 deficiencies in T2DM patients using metformin affect their clinical results.
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Affiliation(s)
- Aakriti Tiwari
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Rakshit Kumar Singh
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Prasiddhi D Satone
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Revat J Meshram
- Paediatrics, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Vargas-Uricoechea H, Nogueira JP, Pinzón-Fernández MV, Agredo-Delgado V, Vargas-Sierra HD. Population Status of Vitamin B12 Values in the General Population and in Individuals with Type 2 Diabetes, in Southwestern Colombia. Nutrients 2023; 15:2357. [PMID: 37242240 PMCID: PMC10221874 DOI: 10.3390/nu15102357] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Vitamin B12 (B12) is necessary for the proper functioning of the central and peripheral nervous systems. Although there is no exact definition for B12 levels, a value of 200 pg/mL is compatible with deficiency, 200-299 pg/mL is considered borderline, and 300 pg/mL is considered normal. In population studies, the prevalence of B12 deficiency ranges between 2.9% and 35%. Furthermore, many medications, such as metformin [for type 2 diabetes mellitus (T2DM)], can cause B12 deficiency. The objectives of this study were to determine the population status of B12 in southwestern Colombia (and the status of B12 in subjects with T2DM). In the total population (participants with and without T2DM), the prevalence of B12 deficiency was 17.8%; that of borderline was 19.3%; and that of normal levels was 62.9%. The prevalence of deficiency increased with age and was significantly higher in those aged ≥60 years (p = 0.000). In T2DM subjects, the prevalence of deficiency was significantly higher concerning those without T2DM (p = 0.002) and was significantly higher in those who received >1 gm/day of metformin (p = 0.001). Thus, the prevalence of deficiency and borderline levels of B12 in our population was high, particularly in those >60 years of age. B12 deficiency was significantly higher in individuals with T2DM than in individuals without T2DM, especially among those receiving high doses of metformin.
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Affiliation(s)
- Hernando Vargas-Uricoechea
- Metabolic Diseases Study Group, Department of Internal Medicine, Universidad del Cauca, Popayan 190003, Colombia
| | - Juan Patricio Nogueira
- Centro de Investigación en Endocrinología, Nutrición y Metabolismo (CIENM), Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa 3600, Argentina
| | - María V. Pinzón-Fernández
- Health Research Group, Department of Internal Medicine, Universidad del Cauca, Popayan 190003, Colombia
| | - Valentina Agredo-Delgado
- Fellowship in Clinical Endocrinology and Metabolism, Universidad de Antioquia, Medellin 050010, Colombia
| | - Hernando David Vargas-Sierra
- Metabolic Diseases Study Group, Department of Internal Medicine, Universidad del Cauca, Popayan 190003, Colombia
- Fellowship in Endocrinology, Diabetes and Metabolism, Universidad Pontificia Bolivariana, Medellin 050031, Colombia
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Bell DSH. Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes. Diabetes Obes Metab 2022; 24:1423-1428. [PMID: 35491956 DOI: 10.1111/dom.14734] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/15/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022]
Abstract
Metformin blocks the absorption of vitamin B12 through a mechanism that has not been established but could be because of interference with the calcium-dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum. The subsequent deficiency of vitamin B12 may cause or accelerate distal symmetrical and autonomic neuropathy in the patient with diabetes. Several observational studies and meta-analyses have reported a significant association between metformin utilization and vitamin B12 deficiency. Prospective studies have shown that not only do metformin utilizers have lower vitamin B12 levels but they also have higher frequencies of distal symmetrical polyneuropathy and autonomic neuropathy (including cardiac denervation, which is associated with increased incidences of cardiac arrhythmias, cardiac events and mortality). Therefore, periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin, particularly if metformin has been used for over 5 years at which stage hepatic stores of vitamin B12 would probably be depleted. Factors that accelerate the loss of hepatic vitamin B12 stores are proton pump inhibitors, bariatric surgery, being elderly and having an increased turnover of red blood cells. If serum vitamin B12 levels are borderline, measurement of methylmalonic acid and homocysteine levels can detect vitamin B12 deficiency at its earliest stage. Therapies include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy and regular monitoring of vitamin B12 levels and vitamin B12 supplements if metformin continues to be utilized. With adequate vitamin B12 replacement, while symptoms of neuropathy may or may not improve, objective findings of neuropathy stabilize but do not improve.
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Metformin Is a Pyridoxal-5'-phosphate (PLP)-Competitive Inhibitor of SHMT2. Cancers (Basel) 2021; 13:cancers13164009. [PMID: 34439169 PMCID: PMC8393646 DOI: 10.3390/cancers13164009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/18/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The mitochondrial enzyme serine hydroxymethyltransferase (SHMT2), which converts serine into glycine and generates 1C units for cell growth, is one of the most consistently overexpressed metabolic enzymes in cancer. Here, we reveal that the anti-diabetic biguanide metformin operates as a novel class of non-catalytic SHMT2 inhibitor that disrupts the pyridoxal-5′-phosphate (PLP)-dependent SHMT2 oligomerization process and ultimately SHMT2 activity. As SHMT2 inhibitors have not yet reached the clinic, these findings may aid the rational design of PLP-competitive SHMT2 inhibitors based on the biguanide skeleton of metformin. Abstract The anticancer actions of the biguanide metformin involve the functioning of the serine/glycine one-carbon metabolic network. We report that metformin directly and specifically targets the enzymatic activity of mitochondrial serine hydroxymethyltransferase (SHMT2). In vitro competitive binding assays with human recombinant SHMT1 and SHMT2 isoforms revealed that metformin preferentially inhibits SHMT2 activity by a non-catalytic mechanism. Computational docking coupled with molecular dynamics simulation predicted that metformin could occupy the cofactor pyridoxal-5′-phosphate (PLP) cavity and destabilize the formation of catalytically active SHMT2 oligomers. Differential scanning fluorimetry-based biophysical screening confirmed that metformin diminishes the capacity of PLP to promote the conversion of SHMT2 from an inactive, open state to a highly ordered, catalytically competent closed state. CRISPR/Cas9-based disruption of SHMT2, but not of SHMT1, prevented metformin from inhibiting total SHMT activity in cancer cell lines. Isotope tracing studies in SHMT1 knock-out cells confirmed that metformin decreased the SHMT2-channeled serine-to-formate flux and restricted the formate utilization in thymidylate synthesis upon overexpression of the metformin-unresponsive yeast equivalent of mitochondrial complex I (mCI). While maintaining its capacity to inhibit mitochondrial oxidative phosphorylation, metformin lost its cytotoxic and antiproliferative activity in SHMT2-null cancer cells unable to produce energy-rich NADH or FADH2 molecules from tricarboxylic acid cycle (TCA) metabolites. As currently available SHMT2 inhibitors have not yet reached the clinic, our current data establishing the structural and mechanistic bases of metformin as a small-molecule, PLP-competitive inhibitor of the SHMT2 activating oligomerization should benefit future discovery of biguanide skeleton-based novel SHMT2 inhibitors in cancer prevention and treatment.
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Infante M, Leoni M, Caprio M, Fabbri A. Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind. World J Diabetes 2021; 12:916-931. [PMID: 34326945 PMCID: PMC8311483 DOI: 10.4239/wjd.v12.i7.916] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/21/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
To date, metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile. Indeed, metformin is the most widely used oral insulin-sensitizing agent, being prescribed to more than 100 million people worldwide, including patients with prediabetes, insulin resistance, and polycystic ovary syndrome. However, over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency. Of note, evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status. Vitamin B12 (also referred to as cobalamin) is a water-soluble vitamin that is mainly obtained from animal-sourced foods. At the cellular level, vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection. Thus, vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities (e.g., megaloblastic anemia and formation of hypersegmented neutrophils), progressive axonal demyelination and peripheral neuropathy. Nevertheless, no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy, and vitamin B12 deficiency remains frequently unrecognized in such individuals. Therefore, in this "field of vision" article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients, which could serve as a practical guide for identifying individuals at high risk for this condition. Moreover, we discuss additional relevant topics related to this field, including: (1) The lack of consensus about the exact definition of vitamin B12 deficiency; (2) The definition of reliable biomarkers of vitamin B12 status; (3) Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis; and (4) Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency. Finally, we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency, particularly when this condition is induced by metformin.
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Affiliation(s)
- Marco Infante
- UniCamillus, Saint Camillus International University of Health Sciences, Rome 00131, Italy
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Alesini Hospital, Department of Systems Medicine, University of Rome Tor Vergata, Rome 00145, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Rome 00145, Italy
| | - Martina Leoni
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Alesini Hospital, Department of Systems Medicine, University of Rome Tor Vergata, Rome 00145, Italy
| | - Massimiliano Caprio
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome 00166, Italy
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome 00166, Italy
| | - Andrea Fabbri
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Alesini Hospital, Department of Systems Medicine, University of Rome Tor Vergata, Rome 00145, Italy
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Interaction between Metformin, Folate and Vitamin B 12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. Int J Mol Sci 2021; 22:ijms22115759. [PMID: 34071182 PMCID: PMC8198407 DOI: 10.3390/ijms22115759] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/15/2022] Open
Abstract
Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity. Vitamin B12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.
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Knychala MA, Garrote-Filho MDS, Batista da Silva B, Neves de Oliveira S, Yasminy Luz S, Marques Rodrigues MO, Penha-Silva N. Red cell distribution width and erythrocyte osmotic stability in type 2 diabetes mellitus. J Cell Mol Med 2021; 25:2505-2516. [PMID: 33591627 PMCID: PMC7933938 DOI: 10.1111/jcmm.16184] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/30/2020] [Accepted: 11/07/2020] [Indexed: 12/15/2022] Open
Abstract
This study aimed to investigate the relationship between red cell distribution width (RDW) and erythrocyte osmotic stability in non‐diabetic and diabetic individuals in both sexes. The study sample (N = 122) was constituted by 53 type 2 diabetics (DM) and 69 non‐diabetics (ND), being 21 and 22 men in each group, respectively. The osmotic stability of erythrocytes was obtained by the variation in saline concentration (dX) capable of determining hypoosmotic lysis. Higher RDW values and lower serum iron concentrations were found in the diabetic group when compared to the non‐diabetic volunteers. In the group of diabetic women, RDW was positively correlated with the reticulocyte index, and both RDW and dX were negatively correlated with iron, haemoglobin, transferrin saturation index, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration. In all the groups studied, RDW was positively correlated with dX, especially in the diabetic group, where the correlation was the strongest. RDW elevation in both women and men with type 2 diabetes mellitus was associated with decreased serum iron indicators. Furthermore, RDW has a similar meaning to dX, as small erythrocytes have less haemoglobin, resulting in both an increase of RDW and dX.
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Affiliation(s)
| | | | | | | | - Sarah Yasminy Luz
- Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, Brazil
| | | | - Nilson Penha-Silva
- Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, Brazil
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Demaré S, Kothari A, Calcutt NA, Fernyhough P. Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system. Expert Rev Neurother 2020; 21:45-63. [PMID: 33161784 PMCID: PMC9482886 DOI: 10.1080/14737175.2021.1847645] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Metformin is currently first line therapy for type 2 diabetes (T2D). The mechanism of action of metformin involves activation of AMP-activated protein kinase (AMPK) to enhance mitochondrial function (for example, biogenesis, refurbishment and dynamics) and autophagy. Many neurodegenerative diseases of the central and peripheral nervous systems arise from metabolic failure and toxic protein aggregation where activated AMPK could prove protective. Areas covered: The authors review literature on metformin treatment in Parkinson’s disease, Huntington’s disease and other neurological diseases of the CNS along with neuroprotective effects of AMPK activation and suppression of the mammalian target of rapamycin (mTOR) pathway on peripheral neuropathy and neuropathic pain. The authors compare the efficacy of metformin with the actions of resveratrol. Expert opinion: Metformin, through activation of AMPK and autophagy, can enhance neuronal bioenergetics, promote nerve repair and reduce toxic protein aggregates in neurological diseases. A long history of safe use in humans should encourage development of metformin and other AMPK activators in preclinical and clinical research. Future studies in animal models of neurological disease should strive to further dissect in a mechanistic manner the pathways downstream from metformin-dependent AMPK activation, and to further investigate mTOR dependent and independent signaling pathways driving neuroprotection.
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Affiliation(s)
- Sarah Demaré
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre , Winnipeg, MB, Canada.,Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, MB, Canada
| | - Asha Kothari
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre , Winnipeg, MB, Canada.,Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, MB, Canada
| | - Nigel A Calcutt
- Department of Pathology, University of California San Diego , La Jolla, CA, USA
| | - Paul Fernyhough
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre , Winnipeg, MB, Canada.,Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, MB, Canada
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Wakeman M, Archer DT. Metformin and Micronutrient Status in Type 2 Diabetes: Does Polypharmacy Involving Acid-Suppressing Medications Affect Vitamin B12 Levels? Diabetes Metab Syndr Obes 2020; 13:2093-2108. [PMID: 32606868 PMCID: PMC7308123 DOI: 10.2147/dmso.s237454] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 02/27/2020] [Indexed: 12/13/2022] Open
Abstract
Metformin is the first-choice drug in uncomplicated type 2 diabetes (T2DM) and is effective in improving glycaemic control. It is the most widely prescribed oral antidiabetic medicine and has a good safety profile. However, there is an abundance of evidence that metformin use is associated with decreased Vitamin B12 status, though the clinical implications of this in terms of increased risk of diabetic peripheral neuropathy are debated. There is growing evidence that other B vitamins, vitamin D and magnesium may also be impacted by metformin use in addition to alterations to the composition of the microbiome, depending on the dose and duration of therapy. Patients using metformin for prolonged periods may, therefore, need initial screening with intermittent follow-up, particularly since vitamin B12 deficiency has similar symptoms to diabetic neuropathy which itself affects 40-50% of patients with T2DM at some stage. Among patients with T2DM, 40% are reported to experience symptomatic gastroesophageal reflux disease (GORD), of whom 70% use oral antidiabetic medications. The most common medications used to treat GORD are proton pump inhibitors (PPIs) and antagonists of histamine selective H2 receptors (H2RAs), both of which independently affect vitamin B12 and magnesium status. Research indicates that co-prescribing metformin with either PPIs or H2RAs can have further deleterious effects on vitamin B12 status. Vitamin B12 deficiency related to metformin and polypharmacy is likely to contribute to the symptoms of diabetic neuropathy which may frequently be under-recognised. This review explores current knowledge surrounding these issues and suggests treatment strategies such as supplementation.
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Affiliation(s)
- Michael Wakeman
- Faculty of Health and Wellbeing, Sciences Complex, University of Sunderland, SunderlandSR1, UK
- Correspondence: Michael Wakeman Faculty of Health and Wellbeing, Sciences Complex, University of Sunderland, SunderlandSR1 3SD, UKTel +44 191 5153381 Email
| | - David T Archer
- Faculty of Health and Wellbeing, Sciences Complex, University of Sunderland, SunderlandSR1, UK
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Pathak M, Sharma D, Sharma N, Sharma M. Spectroscopic and thermodynamic studies of the binding mechanism of metformin to pepsin. J Mol Struct 2018. [DOI: 10.1016/j.molstruc.2018.04.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Mohn ES, Kern HJ, Saltzman E, Mitmesser SH, McKay DL. Evidence of Drug-Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018; 10:E36. [PMID: 29558445 PMCID: PMC5874849 DOI: 10.3390/pharmaceutics10010036] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/13/2018] [Accepted: 03/16/2018] [Indexed: 12/18/2022] Open
Abstract
The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug-nutrient interactions is quite limited. A comprehensive, updated review of the potential drug-nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care.
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Affiliation(s)
- Emily S Mohn
- Jean Mayer USDA Human Nutrition Research Center on Aging, and Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
| | - Hua J Kern
- Nutrition & Scientific Affairs, Nature's Bounty Co., Ronkonkoma, NY 11779, USA.
| | - Edward Saltzman
- Jean Mayer USDA Human Nutrition Research Center on Aging, and Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
| | - Susan H Mitmesser
- Nutrition & Scientific Affairs, Nature's Bounty Co., Ronkonkoma, NY 11779, USA.
| | - Diane L McKay
- Jean Mayer USDA Human Nutrition Research Center on Aging, and Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
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Intestinal Absorption of Water-Soluble Vitamins: Cellular and Molecular Mechanisms. PHYSIOLOGY OF THE GASTROINTESTINAL TRACT 2018. [DOI: 10.1016/b978-0-12-809954-4.00054-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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18
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Tian S, Han J, Huang R, Sun J, Cai R, Shen Y, Wang S. Increased Plasma Homocysteine Level is Associated with Executive Dysfunction in Type 2 Diabetic Patients with Mild Cognitive Impairment. J Alzheimers Dis 2017; 58:1163-1173. [PMID: 28550262 DOI: 10.3233/jad-170162] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Sai Tian
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, PR China
- Medical School of Southeast University, Nanjing, PR China
| | - Jing Han
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, PR China
| | - Rong Huang
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, PR China
| | - Jie Sun
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, PR China
| | - Rongrong Cai
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, PR China
| | - Yanjue Shen
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, PR China
| | - Shaohua Wang
- Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, Nanjing, PR China
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Damião CP, Rodrigues AO, Pinheiro MFMC, Cruz RAD, Cardoso GP, Taboada GF, Lima GAB. Prevalence of vitamin B12 deficiency in type 2 diabetic patients using metformin: a cross-sectional study. SAO PAULO MED J 2016; 134:473-479. [PMID: 28076635 PMCID: PMC11448733 DOI: 10.1590/1516-3180.2015.01382111] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 11/21/2015] [Indexed: 01/01/2023] Open
Abstract
CONTEXT AND OBJECTIVE: The prevalence of vitamin B12 deficiency varies from 5.8% to 30% among patients undergoing long-term treatment with metformin. Because of the paucity of data on Brazilian patients, this study aimed to determine the frequency of B12 deficiency and related factors among Brazilian patients with type 2 diabetes mellitus (T2DM) using metformin. DESIGN AND SETTING: Cross-sectional study at a public university hospital. METHODS: Patients with T2DM and a control group of non-diabetics were included. Serum B12 levels were measured and biochemical B12 deficiency was defined as serum levels < 180 pg/ml. Associations between B12 deficiency and age, duration of T2DM, duration of use and dosage of metformin, and use of proton pump inhibitors (PPIs) or histamine H2 antagonists were determined. RESULTS: 231 T2DM patients using metformin (T2DM-met) and 231 controls were included. No difference in the frequency of PPI or H2-antagonist use was seen between the groups. B12 deficiency was more frequent in the T2DM-met group (22.5% versus 7.4%) and this difference persisted after excluding PPI/H2-antagonist users (17.9% versus 5.6%). The factors that interfered with serum B12 levels were PPI/H2-antagonist use and duration of metformin use ≥ 10 years. Use of PPI/H2-antagonists was associated with B12 deficiency, with an odds ratio of 2.60 (95% confidence interval, 1.34-5.04). CONCLUSIONS: Among T2DM patients, treatment with metformin and concomitant use of PPI/H2-antagonists are associated with a higher chance of developing B12 deficiency than among non-diabetics.
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Affiliation(s)
- Charbel Pereira Damião
- MD. Master's Student, Department of Internal Medicine, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
| | - Amannda Oliveira Rodrigues
- MD. Attending Physician, Department of Internal Medicine, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
| | | | - Rubens Antunes da Cruz
- MD, PhD. Associate Professor, Department of Internal Medicine, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
| | - Gilberto Peres Cardoso
- MD, PhD. Associate Professor, Department of Internal Medicine, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
| | - Giselle Fernandes Taboada
- MD, PhD. Adjunct Professor, Department of Internal Medicine, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
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20
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Roy RP, Ghosh K, Ghosh M, Acharyya A, Bhattacharya A, Pal M, Chakraborty S, Sengupta N. Study of Vitamin B 12 deficiency and peripheral neuropathy in metformin-treated early Type 2 diabetes mellitus. Indian J Endocrinol Metab 2016; 20:631-637. [PMID: 27730072 PMCID: PMC5040042 DOI: 10.4103/2230-8210.190542] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Long-term therapy with metformin was shown to decrease the Vitamin B12 level and manifested as peripheral neuropathy. AIM The aim of this study is to define the prevalence of Vitamin B12 deficiency in early Type 2 diabetic patients (duration ≤5 years or drug treatment ≤3 years) and the relationship among metformin exposure and levels of cobalamin (Cbl), folic acid, and homocysteine (Hcy) with severity of peripheral neuropathy. METHODOLOGY This is a cross-sectional study involving randomly selected ninety patients (male 56, female 34) between age groups of 35 and 70 years, comparing those who had received >6 months of metformin (Group A) (n = 35) with those without metformin (Group B) (n = 35) and patients taking metformin with other oral hypoglycemic agent (Group C) (n = 20). Comparisons were made clinically, biochemically (serum Cbl, fasting Hcy, and folic acid), and with electrophysiological measures (nerve conduction studies of all four limbs). Comorbidities contributing to neuropathy were excluded from the study. RESULTS Group A patients (54.28%) were prone to develop peripheral neuropathy comparing Group B (28.57%) and Group C (35%). There was significantly low plasma level of Cbl in Group A (mean 306.314 pg/ml) than in Group B (mean 627.543 pg/ml) and Group C (mean 419.920 pg/ml). There was insignificant low-level plasma folic acid in Group A (16.47 ng/ml) than in Group B (16.81 ng/ml) and Group C (22.50 ng/ml). There was significantly high level of Hcy in Group A (mean 17.35 µmol/L) and Group C (mean 16.99 µmol/L) than in Group B (mean 13.22 µmol/L). Metformin users even for 2 years showed evidence of neuropathy on nerve conduction velocity though their body mass index and postprandial blood sugar were maintained. There was significant difference in between groups regarding plasma Cbl, folic acid, and Hcy level as significance level <0.05 in all three groups (F [2, 87] = 28.1, P = 0.000), (F [2, 87] = 7.43, P = 0.001), (F [2, 87] = 9.76, P = 0.000). Post hoc study shows significant (P < 0.05) lowering of Cbl and Hcy level in Group A (mean = 306.314, standard deviation [SD] = 176.7) than in Group C (mean = 419.92, SD = 208.23) and Group B (mean = 627.543, SD = 168.33). DISCUSSION Even short-term treatment with metformin causes a decrease in serum Cbl folic acid and increase in Hcy, which leads to peripheral neuropathy in Type 2 diabetes patients. A multicenter study with heterogeneous population would have increased the power of the study. We suggest prophylactic Vitamin B12 and folic acid supplementation or periodical assay in metformin user.
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Affiliation(s)
- Rudra Prasad Roy
- Department of Medicine, Vivekananda Hospital, Durgapur, West Bengal, India
| | - Kaushik Ghosh
- Department of Medicine, Murshidabad Medical College, Berhampore, West Bengal, India
| | - Manas Ghosh
- Department of Medicine, Murshidabad Medical College, Berhampore, West Bengal, India
| | - Amitava Acharyya
- Independent Public Health Consultant, Howrah, West Bengal, India
| | | | - Mrinal Pal
- Department of Biochemistry, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
| | - Sisir Chakraborty
- Department of Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata, West Bengal, India
| | - Nilanjan Sengupta
- Department of Endocrinology, NRS Medical College, Kolkata, West Bengal, India
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21
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Sparre Hermann L, Nilsson BO, Wettre S. Vitamin B12 status of patients treated with metformin: a cross-sectional cohort study. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/14746514040040060701] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aim To assess the vitamin B12 status of patients with type 2diabetes who had been receiving metformin treatment for at least one year. Methods Patients with type 2 diabetes attending a diabetes clinic were included in a cross-sectional cohort study. Patients exposed to metformin for more than one year (n=53) were compared with a non-exposed control group (n=31). Serum cobalamin and other variables reflecting vitamin B12 status were measured. Results Patients on metformin had lower cobalamin (289±137 vs. 395±162 pmol/L; p<0.01) and holotranscobalamin (76±49 vs. 97±41 pmol/L; p<0.05), and higher HCy (11.3+3.3 vs. 10.3±2.3 µmol/L; p<0.05); these changes were correlated. Eight metformin patients, but no controls, had holotranscobalamin below the normal range (p<0.05). Methylmalonic acid and folate were similar in both groups. Conclusion Patients exposed to long-term metformin therapy had 26.7% lower cobalamin, 21.6% lower holotranscobalamin and 9.7% higher HCy serum concentrations than control subjects. Such changes indicate a potential risk for development of vitamin B12 deficiency. Our results highlight the necessity of checking B12 status during metformin therapy.
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Affiliation(s)
| | - BO Nilsson
- Department of Clinical Chemistry, Uddevalla Hospital, Uddevalla, Sweden
| | - Staffan Wettre
- Diabetes Unit, Medical Department, Uddevalla Hospital, Uddevalla, Sweden
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22
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Zdilla MJ. Metformin With Either Histamine H2-Receptor Antagonists or Proton Pump Inhibitors: A Polypharmacy Recipe for Neuropathy via Vitamin B12 Depletion. Clin Diabetes 2015; 33:90-5. [PMID: 25897192 PMCID: PMC4398011 DOI: 10.2337/diaclin.33.2.90] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Matthew J Zdilla
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV
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23
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Niafar M, Hai F, Porhomayon J, Nader ND. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med 2015; 10:93-102. [PMID: 25502588 DOI: 10.1007/s11739-014-1157-5] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 11/12/2014] [Indexed: 12/11/2022]
Abstract
Metformin is the only biguanide oral hypoglycemic drug, that is used to treat patients with type-2 diabetes mellitus. There are some reports of metformin being associated with decreased serum levels of vitamin B12 (VB12). The objective of this study is to systematically analyze the impact of metformin on the frequency of VB12 deficiency and serum levels of VB12. A search of various databases provided 18 retrospective cohort studies and 11 randomized controlled trials. Pooled estimates of odds ratio with 95% confidence interval using random effect model were conducted. Studies were examined for heterogeneity, publication bias and sensitivity analysis. Separate analysis of randomized control trials (RCTs) including both low-risk and high-risk bias was also conducted. 29 studies were selected with a total of 8,089 patients. 19 studies were rated intermediate or high quality. Primary outcome suggested increased incidence of VB12 deficiency in metformin group (OR = 2.45, 95% CI 1.74-3.44, P < 0.0001.) Heterogeneity was relatively high (I(2) = 53%), with minor publication bias. Secondary outcome suggested lower serum VB12 concentrations in metformin group (Mean difference = -65.8, 95% CI -78.1 to -53.6 pmol/L, P < 0.00001) with high heterogeneity (I(2) = 98%,) and low publication bias. RCTs analysis of low-and high-risk group revealed similar trends. We conclude that metformin treatment is significantly associated with an increase in incidence of VB12 deficiency and reduced serum VB12 levels.
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Affiliation(s)
- Mitra Niafar
- Tabriz University of Medical Sciences, Bone Research Center, Tabriz, Iran
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24
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Higher prevalence of metformin-induced vitamin B12 deficiency in sulfonylurea combination compared with insulin combination in patients with type 2 diabetes: a cross-sectional study. PLoS One 2014; 9:e109878. [PMID: 25299054 PMCID: PMC4192538 DOI: 10.1371/journal.pone.0109878] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 09/03/2014] [Indexed: 02/07/2023] Open
Abstract
Long-term and high-dose treatment with metformin is known to be associated with vitamin B12 deficiency in patients with type 2 diabetes. We investigated whether the prevalence of B12 deficiency was different in patients treated with different combination of hypoglycemic agents with metformin during the same time period. A total of 394 patients with type 2 diabetes treated with metformin and sulfonylurea (S+M group, n = 299) or metformin and insulin (I+M group, n = 95) were consecutively recruited. The vitamin B12 and folate levels were quantified using the chemiluminescent enzyme immunoassay. Vitamin B12 deficiency was defined as vitamin B12≤300 pg/mL without folate deficiency (folate>4 ng/mL). The mean age of and duration of diabetes in the subjects were 59.4±10.5 years and 12.2±6.7 years, respectively. The mean vitamin B12 level of the total population was 638.0±279.6 pg/mL. The mean serum B12 levels were significantly lower in the S+M group compared with the I+M group (600.0±266.5 vs. 757.7±287.6 pg/mL, P<0.001). The prevalence of vitamin B12 deficiency in the metformin-treated patients was significantly higher in the S+M group compared with the I+M group (17.4% vs. 4.2%, P = 0.001). After adjustment for various factors, such as age, sex, diabetic duration, duration or daily dose of metformin, diabetic complications, and presence of anemia, sulfonylurea use was a significant independent risk factor for B12 deficiency (OR = 4.74, 95% CI 1.41–15.99, P = 0.012). In conclusion, our study demonstrated that patients with type 2 diabetes who were treated with metformin combined with sulfonylurea require clinical attention for vitamin B12 deficiency and regular monitoring of their vitamin B12 levels.
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25
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Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLoS One 2014; 9:e100379. [PMID: 24959880 PMCID: PMC4069007 DOI: 10.1371/journal.pone.0100379] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 05/26/2014] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Randomized controlled trials and observational studies have yielded inconsistent results on the effects of metformin on vitamin B12 reduction. We therefore performed a systematic review to analyze the effects of metformin on vitamin B12 concentration. METHODS PubMed, Medline, Embase, and the Cochrane central registry of controlled trials were searched to identify randomized controlled trials and observational studies exploring the association between metformin and vitamin B12 concentration in patients with type 2 diabetes mellitus or polycystic ovary syndrome. The main outcome measure was changes in serum vitamin B12 concentration after 6-208 weeks of treatment with metformin, as compared with placebo or other anti-hyperglycemic therapy. RESULTS Six randomized controlled trials met the inclusion criteria. Serum vitamin B12 concentrations were significantly lower in patients treated with metformin than in those who received placebo or rosiglitazone (mean difference [MD], -53.93 pmol/L; 95% confidence interval [CI], -81.44 to -26.42 pmol/L, P = 0.0001). Subgroup analysis identified four trials in which patients received a lower dose of metformin (<2000 mg/d) and two in which they received a higher dose (≥2000 mg/d), with MDs in vitamin B12 concentration after metformin treatment of -37.99 pmol/L (95% CI, -57.44 to -18.54 pmol/L, P = 0.0001) and -78.62 pmol/L (95% CI, -106.37 to -50.86 pmol/L, P<0.00001), respectively. CONCLUSIONS The reduction of vitamin B12 may be induced by metformin in a dose dependent manner.
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Affiliation(s)
- Qilin Liu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| | - Heng Quan
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| | - Jianwei Li
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
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Devalia V, Hamilton MS, Molloy AM. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol 2014; 166:496-513. [PMID: 24942828 DOI: 10.1111/bjh.12959] [Citation(s) in RCA: 265] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard' test to define deficiency. Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies. Serum holotranscobalamin has the potential as a first-line test, but an indeterminate 'grey area' may still exist. Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid. The availability of these second-line tests is currently limited. Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established. In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment. Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue. Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate status.
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Tung ML, Tan LK. Long term use of metformin leading to vitamin B 12 deficiency. Diabetes Res Clin Pract 2014; 104:e75-6. [PMID: 24674102 DOI: 10.1016/j.diabres.2013.12.054] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 08/22/2013] [Accepted: 12/28/2013] [Indexed: 12/12/2022]
Abstract
Metformin is a commonly used oral hypoglycaemic agent worldwide. Gastrointestinal side effects and lactic acidosis related to metformin usage are commonly recognized. However, the associated vitamin B12 deficiency is less well known. We present a case of long term metformin use resulting in vitamin B12 deficiency.
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Affiliation(s)
- Moon Ley Tung
- National University Hospital, Haematology-Oncology, 1E Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228, Singapore.
| | - Lip Kun Tan
- National University Hospital, Haematology-Oncology, 1E Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228, Singapore
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Yamada C, Fujimoto S, Ikeda K, Nomura Y, Matsubara A, Kanno M, Shide K, Tanaka K, Imai E, Fukuwatari T, Shibata K, Inagaki N. Relationship of homocysteine and homocysteine-related vitamins to bone mineral density in Japanese patients with type 2 diabetes. J Diabetes Investig 2014; 2:233-9. [PMID: 24843489 PMCID: PMC4014924 DOI: 10.1111/j.2040-1124.2010.00088.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Aims/Introduction: To estimate nutritional risk factors for osteoporosis in patients with type 2 diabetes, bone mineral density, homocysteine level, and intakes and levels of Hcy‐related vitamins including folate, vitamin B6 and vitamin B12 were analyzed in a cross‐sectional study. Materials and Methods: Lumbar spine and femoral neck bone mineral density, serum concentrations of vitamin B6, vitamin B12, and folate and plasma homocysteine levels were measured in 125 Japanese patients with type 2 diabetes. Nutrient intake values were evaluated using a food frequency questionnaire. Results: Homocysteine was inversely correlated with bone mineral density, and with both dietary intake and serum concentration of folate. Intake of green vegetables was correlated with intake and level of folate and homocysteine levels. When the population was analyzed across the quartiles, bone mineral density, serum folate concentration, folate intake and intake of green vegetables were lowest in the highest homocysteine group. Conclusions: In patients with type 2 diabetes, the nutritional status of folate might affect the homocysteine level, a putative risk factor for osteoporosis. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00088.x, 2011)
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Affiliation(s)
- Chizumi Yamada
- Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University
| | - Shimpei Fujimoto
- Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University
| | - Kaori Ikeda
- Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University
| | - Yuki Nomura
- Department of Metabolism and Clinical Nutrition, Kyoto University Hospital, Kyoto
| | - Ami Matsubara
- Department of Metabolism and Clinical Nutrition, Kyoto University Hospital, Kyoto
| | - Miwako Kanno
- Department of Metabolism and Clinical Nutrition, Kyoto University Hospital, Kyoto
| | - Kenichiro Shide
- Department of Metabolism and Clinical Nutrition, Kyoto University Hospital, Kyoto
| | - Kiyoshi Tanaka
- School of Human Culture, The University of Shiga Prefecture, Hikone
| | - Eri Imai
- Department of Food and Nutrition, Kyoto Women's University, Kyoto, Japan
| | - Tsutomu Fukuwatari
- Department of Food and Nutrition, Kyoto Women's University, Kyoto, Japan
| | - Katsumi Shibata
- Department of Food and Nutrition, Kyoto Women's University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University
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29
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Xu L, Huang Z, He X, Wan X, Fang D, Li Y. Adverse effect of metformin therapy on serum vitamin B12 and folate: short-term treatment causes disadvantages? Med Hypotheses 2013; 81:149-51. [PMID: 23751310 DOI: 10.1016/j.mehy.2013.05.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 05/19/2013] [Indexed: 11/28/2022]
Abstract
Diabetes is a global public health challenge that imposes heavy burdens on communities and individuals. Metformin, the first-line medication for diabetes, has the superiority of reducing risk of macrovascular diseases, all-cause mortality and even possibly cancers. Recent observational studies, however, have demonstrated that long-term metformin therapy increases the probability of vitamin B12 and folate deficiency, and might contribute to the progression of diabetic peripheral neuropathy. Despite metformin is widely used and extensively studied, randomized controlled trials performed to explore the effects of metformin on vitamin B12 and folate are limited. Besides, whether short-term treatment causes vitamin deficiency is a pending issue. We postulate that even a few-month treatment with metformin results in the decrease of vitamin B12 and folate. However, supplementation of vitamin B12 rather than the combination of vitamin B12 and folate might be profitable based on the mechanism of metformin on vitamins in patients with type 2 diabetes. This viewpoint differs from those of majority that a combined supplementation of vitamin B12 and folate is inclined to be advised.
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Affiliation(s)
- Lijuan Xu
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, 58th of Zhongshan Er Road, Guangzhou 510080, China
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A reversible cause of skin hyperpigmentation and postural hypotension. Case Rep Hematol 2013; 2013:680459. [PMID: 23840983 PMCID: PMC3691896 DOI: 10.1155/2013/680459] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 05/22/2013] [Indexed: 11/17/2022] Open
Abstract
Vitamin B12 deficiency results in neuropsychiatric, hematologic, gynecologic, cardiovascular, and cutaneous manifestations. It is seen most commonly in the elderly, malabsorption diseases (>60% of all cases), vegans, and vegetarians. Manifestations of pernicious anemia may be similar to Addison disease and may lead to a misdiagnosis. Herein, we report two cases of vitamin B12 deficiency in which clinical features shared many similarities with Addison disease. Both patients presented with progressive darkening of hands and postural hypotension that reversed with replenishment of vitamin B12. Vitamin B12 deficiency should be considered in patients presenting with skin lesions especially with other coexisting autoimmune diseases.
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Corominas-Faja B, Quirantes-Piné R, Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Martin-Castillo B, Micol V, Joven J, Segura-Carretero A, Menendez JA. Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY) 2012; 4:480-98. [PMID: 22837425 PMCID: PMC3433934 DOI: 10.18632/aging.100472] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Metabolomic fingerprint of breast cancer cells treated with the antidiabetic drug metformin revealed a significant accumulation of 5-formimino-tetrahydrofolate, one of the tetrahydrofolate forms carrying activated one-carbon units that are essential for the de novo synthesis of purines and pyrimidines. De novo synthesis of glutathione, a folate-dependent pathway interconnected with one-carbon metabolism was concomitantly depleted in response to metformin. End-product reversal studies demonstrated that thymidine alone leads to a significant but incomplete protection from metformin's cytostatic effects. The addition of the substrate hypoxanthine for the purine salvage pathway produces major rightward shifts in metformin's growth inhibition curves. Metformin treatment failed to activate the DNA repair protein ATM kinase and the metabolic tumor suppressor AMPK when thymidine and hypoxanthine were present in the extracellular milieu. Our current findings suggest for the first time that metformin can function as an antifolate chemotherapeutic agent that induces the ATM/AMPK tumor suppressor axis secondarily following the alteration of the carbon flow through the folate-related one-carbon metabolic pathways.
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Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract 2012; 97:359-67. [PMID: 22770998 DOI: 10.1016/j.diabres.2012.06.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 05/17/2012] [Accepted: 06/12/2012] [Indexed: 12/21/2022]
Abstract
Metformin treatment is a known pharmacological cause of vitamin B12 (Cbl) deficiency with controversial responsible mechanisms. A possible diagnosis of this deficiency is based mainly on the combination of patient's medical history (usually long-term metformin use), clinical examination (possible neuropsychiatric symptoms and signs), laboratory studies which confirm a Cbl deficiency (haematological abnormalities, low serum Cbl levels, elevated serum total homocysteine and methylmalonic acid levels), and exclusion other causes of Cbl deficiency (as pernicious anaemia, food-cobalamin malabsorption syndrome, other drugs, etc.). In our review, recommendations for diagnosis and management of metformin-induced Cbl deficiency (MICD) in diabetic patients based on medical bibliography are presented and discussed.
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Affiliation(s)
- Elias E Mazokopakis
- Department of Internal Medicine, Naval Hospital of Crete, 73 200 Chania, Crete, Greece.
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Kos E, Liszek MJ, Emanuele MA, Durazo-Arvizu R, Camacho P. Effect of metformin therapy on vitamin D and vitamin B₁₂ levels in patients with type 2 diabetes mellitus. Endocr Pract 2012; 18:179-84. [PMID: 21940283 DOI: 10.4158/ep11009.or] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To determine the effect of metformin on 25-hydroxyvitamin D [25(OH)D] and vitamin B₁₂ levels in patients with type 2 diabetes mellitus. METHODS We performed a retrospective review of medical records of patients treated between 2003 and 2009 at Loyola University Medical Center, Maywood, Illinois, in both ambulatory primary care and endocrinology clinics. The study cohort consisted of 706 patients with type 2 diabetes mellitus who were 20 to 93 years old (mean age, 63 ± 13) and had a mean body mass index of 33.1 kg/m². Of these patients, 42% were treated with metformin, and 34% had been diagnosed with osteoporosis or osteopenia. RESULTS Patients taking metformin had statistically significant lower vitamin B₁₂ levels than those not receiving metformin (P<.0001; 95% confidence interval [CI] = -220 to -84 pg/mL). No statistically significant difference was found between users and nonusers of metformin in regard to 25(OH)D levels when adjusted for variables (P = .297; 95% CI for mean difference = -0.7 to 2.2 ng/mL). Metformin use did not adversely affect successful treatment of vitamin D deficiency in this patient population as a whole, nor did it affect the subgroup with osteoporosis (P = .956). The patients with osteoporosis had statistically significant lower baseline 25(OH)D levels in comparison with those without osteoporosis, when adjustments were made for all variables (P = .003; 95% CI = 0.7 to 3.5 ng/mL). CONCLUSION This study confirms the higher prevalence of vitamin B₁₂ deficiency in metformin-treated patients with type 2 diabetes than in those not treated with metformin. This study also suggests that vitamin D deficiency is not a clinical concern among metformin-treated patients with type 2 diabetes and that metformin does not negatively affect treatment of vitamin D deficiency in these patients.
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Affiliation(s)
- Elizabeth Kos
- Department of General Internal Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA.
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Abstract
BACKGROUND This review examines the associations between low vitamin B12 levels, neurodegenerative disease, and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12 therapy is efficacious for cognitive impairment and dementia. METHODS A systematic literature search identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia. Seventeen studies reported on the efficacy of vitamin B12 therapy for these conditions. RESULTS Vitamin B12 levels in the subclinical low-normal range (<250 ρmol/L) are associated with Alzheimer's disease, vascular dementia, and Parkinson's disease. Vegetarianism and metformin use contribute to depressed vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deficiency (<150 ρmol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily) were effective in correcting biochemical deficiency, but improved cognition only in patients with pre-existing vitamin B12 deficiency (serum vitamin B12 levels <150 ρmol/L or serum homocysteine levels >19.9 μmol/L). CONCLUSION Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-existing deficiency. There is a need for large, well-resourced clinical trials to close the gaps in our current understanding of the nature of the associations of vitamin B12 insufficiency and neurodegenerative disease.
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Affiliation(s)
- Eileen Moore
- Department of Psychiatry, The University of Melbourne, Department of Surgery, The Geelong Hospital, Barwon Health, Geelong, Victoria, Australia.
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Qureshi SA, Ainsworth A, Winocour PH. Metformin therapy and assessment for vitamin B12 deficiency: is it necessary? PRACTICAL DIABETES 2011. [DOI: 10.1002/pdi.1619] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Jawa AA, Akram J, Sultan M, Humayoun MA, Raza R. Nutrition-related vitamin B12 deficiency in patients in Pakistan with type 2 diabetes mellitus not taking metformin. Endocr Pract 2010; 16:205-8. [PMID: 20061275 DOI: 10.4158/ep09261.or] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To estimate the frequency of undiagnosed vitamin B12 deficiency among patients with type 2 diabetes mellitus who had not taken metformin during at least the prior 5 years and to ascertain whether vitamin B12 deficiency among the patients with type 2 diabetes was due to nutritional deficiency or malabsorption. METHODS Serum vitamin B12 levels were measured in 44 subjects with diabetes and a mean age of 51 years (range, 40 to 70), 21 (48%) of whom had low levels (<200 pg/mL). Of those 21 patients, 10 agreed to enroll in an intervention phase consisting of oral supplementation with mecobalamin, 1,500 microg daily for 3 months. Those patients in whom vitamin B12 levels failed to normalize after oral supplementation alone would be presumed to have vitamin B12 deficiency attributable to malabsorption. RESULTS Almost half of the subjects with type 2 diabetes not taking metformin had biochemically proven vitamin B12 deficiency. All 10 subjects who enrolled in the intervention phase had normalization of their vitamin B12 levels after 3 months of oral supplementation with mecobalamin. CONCLUSION We conclude that vitamin B12 deficiency is common among patients with type 2 diabetes and was related to nutrition in our study group. In addition to intensive glycemic control, vitamin B12 supplementation should be considered for treatment of diabetic neuropathy. In almost 50% of patients with low vitamin B12 levels, the deficiency was corrected with oral supplementation only. This, indeed, is an important finding, inasmuch as oral vitamin B12 supplementation is easy, convenient, and readily accepted by patients. This finding highlights the need for aggressive and early diagnosis and treatment to avoid complications of vitamin B12 deficiency.
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Affiliation(s)
- Ali A Jawa
- Jinnah-Allama Iqbal Institute of Diabetes and Endocrinology, Allama Iqbal Medical College/Jinnah Hospital, Lahore, Pakistan.
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Dobrin JS, Lebeche D. Diabetic cardiomyopathy: signaling defects and therapeutic approaches. Expert Rev Cardiovasc Ther 2010; 8:373-91. [PMID: 20222816 DOI: 10.1586/erc.10.17] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus is the world's fastest growing disease with high morbidity and mortality rates, predominantly as a result of heart failure. A significant number of diabetic patients exhibit diabetic cardiomyopathy; that is, left ventricular dysfunction independent of coronary artery disease or hypertension. The pathogenesis of diabetic cardiomyopathy is complex, and is characterized by dysregulated lipid metabolism, insulin resistance, mitochondrial dysfunction and disturbances in adipokine secretion and signaling. These abnormalities lead to impaired calcium homeostasis, ultimately resulting in lusitropic and inotropic defects. This article discusses the impact of these hallmark factors in diabetic cardiomyopathy, and concludes with a survey of available and emerging therapeutic modalities.
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Affiliation(s)
- Joseph S Dobrin
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
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Leung S, Mattman A, Snyder F, Kassam R, Meneilly G, Nexo E. Metformin induces reductions in plasma cobalamin and haptocorrin bound cobalamin levels in elderly diabetic patients. Clin Biochem 2010; 43:759-60. [DOI: 10.1016/j.clinbiochem.2010.02.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2009] [Revised: 02/24/2010] [Accepted: 02/26/2010] [Indexed: 12/16/2022]
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de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJM, Stehouwer CDA. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010; 340:c2181. [PMID: 20488910 PMCID: PMC2874129 DOI: 10.1136/bmj.c2181] [Citation(s) in RCA: 337] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/25/2010] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin. DESIGN Multicentre randomised placebo controlled trial. SETTING Outpatient clinics of three non-academic hospitals in the Netherlands. PARTICIPANTS 390 patients with type 2 diabetes receiving treatment with insulin. INTERVENTION 850 mg metformin or placebo three times a day for 4.3 years. MAIN OUTCOME MEASURES Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at 4, 17, 30, 43, and 52 months. RESULTS Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of -19% (95% confidence interval -24% to -14%; P<0.001) and in folate concentration of -5% (95% CI -10% to -0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI -1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 micromol/l (95% CI 18.8 to 30.0 micromol/l), compared with a mean homocysteine level of 18.1 micromol/l (95% CI 16.7 to 19.6 micromol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 micromol/l (95% CI 14.3 to 15.5 micromol/l; P<0.001 compared with vitamin B-12 deficiency; P=0.005 compared with low vitamin B-12) for patients with a normal vitamin B-12 concentration (>220 pmol/l). CONCLUSIONS Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered. Trial registration Clinicaltrials.gov NCT00375388.
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Affiliation(s)
- Jolien de Jager
- Department of Ophthalmology, Academic Medical Center, Amsterdam, Netherlands
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Abstract
Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidaemia. Together these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids when many antidiabetic agents cause weight gain and thereby exacerbate other cardiovascular risk factors associated with T2DM. Further, evidence suggests that some established antihypertensive agents may worsen glucose intolerance. Many patients who are obese, hypertensive, and/or hyperlipidaemic fail to achieve blood pressure, lipid and glycaemic goals, and this failure may in part be explained by physician reluctance to utilize complex combination regimens for fear of off-target effects. Thus, a clear need exists for clinicians to understand the risks and benefits of different pharmacologic, and indeed non-pharmacologic, options in order to maximize treatment outcomes. While intensive lifestyle modification remains an elusive gold standard, newer diabetes targets, including the incretin axis, may offer greater cardiovascular risk reduction than other antidiabetes therapies, although definitive clinical trial data are needed. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide and the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin effectively lower HbA1c; exenatide and liraglutide reduce weight and blood pressure and improve lipid profiles. Sitagliptin and vildagliptin are weight neutral but also appear to improve lipid profiles. Integration of incretin therapies into the therapeutic armamentarium is a promising approach to improving outcomes in T2DM, and perhaps even in reducing complications of T2DM, such as co-morbid hypertension and dyslipidaemia. Additional long-term studies, including CVD end-point studies, will be necessary to determine the appropriate places for incretin-based therapies in treatment algorithms.
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Affiliation(s)
- Kevin Niswender
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Tennessee Valley Healthcare System and Vanderbilt University School of Medicine, Nashville, TN, USA.
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Fisman EZ, Tenenbaum A. A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. Cardiovasc Diabetol 2009; 8:38. [PMID: 19619327 PMCID: PMC2723076 DOI: 10.1186/1475-2840-8-38] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Accepted: 07/20/2009] [Indexed: 02/07/2023] Open
Abstract
Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
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Affiliation(s)
- Enrique Z Fisman
- Sackler Faculty of Medicine, Tel-Aviv University, 69978 Ramat-Aviv, Tel-Aviv, Israel.
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Cardiovascular consequences of drugs used for the treatment of diabetes: potential promise of incretin—based therapies. ACTA ACUST UNITED AC 2009; 3:245-59. [DOI: 10.1016/j.jash.2009.04.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2008] [Revised: 03/23/2009] [Accepted: 04/06/2009] [Indexed: 11/20/2022]
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Ülgen MS, Soylu A, Düzenli MA. Antidiabetic Treatment In Diabetic Patients With Coronary Artery Disease. ELECTRONIC JOURNAL OF GENERAL MEDICINE 2007. [DOI: 10.29333/ejgm/82528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Abstract
OBJECTIVE Restorative proctocolectomy (RP) involves terminal ileal resection and formation of a small bowel reservoir that predisposes to bacterial overgrowth. It was anticipated that these patients would be at risk of vitamin B12 deficiency. METHOD Vitamin B12 levels were measured sequentially in 171 patients who underwent RP. Prospective results were obtained from all 20 patients undergoing pouch formation after the commencement of the study. Further results were obtained retrospectively from case notes and computerized laboratory records of the 151 patients who underwent RP prior to the commencement of the study and these were correlated with the results of follow-up samples taken prospectively from the same patients after the commencement of the study. The median age of the patients was 40 years (range: 13-67) and the median duration of follow up was 5.4 years (range: 1-12). Patients with an abnormally low serum B12 level underwent both a Schilling and a hydrogen breath test. Eight of these patients were then treated with oral vitamin B12. RESULTS Abnormally low serum B12 levels were found in 25% of patients. Forty per cent of our patient group had three or more sequential B12 measurements and of these, 66% showed steadily declining B12 levels. Ninety-four per cent of patients with low B12 had a normal Schilling test and were negative for bacterial overgrowth. CONCLUSION Subnormal vitamin B12 levels develop in almost one-quarter of patients after pouch surgery. The exact mechanism for B12 deficiency in these patients is uncertain. In the majority of patients undergoing RP, vitamin B12 levels fall on sequential measurement. Serum B12 levels should be measured during follow up and pouch patients with subnormal B12 levels, should see them successfully restored to a normal value after treatment with oral B12 replacement therapy.
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Affiliation(s)
- D B Coull
- Department of Coloproctology, Lister Surgical Unit, Glasgow Royal Infirmary, Glasgow, UK.
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Abstract
PURPOSE OF REVIEW The aim of this article is to describe the role of insulin resistance in the etiology of polycystic ovary syndrome and to review the results of treatment with the insulin sensitizing drug metformin. RECENT FINDINGS Polycystic ovary syndrome is a heterogeneous combination of clinical, hormonal, and reproductive abnormalities associated with insulin resistance and increased cardiovascular risk factors. Reduction of hyperinsulinism and improvement of insulin sensitivity with metformin has been reported to ameliorate these abnormalities in many, but not all studies, with few adverse effects. SUMMARY Metformin may be the drug of first choice for most, if not all women with polycystic ovarian syndrome, either alone or in combination with other treatments. Further investigation is necessary to determine the optimal dose and duration of treatment necessary to maximize response.
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Affiliation(s)
- Tessa G Lebinger
- Department of Pediatrics, New York Medical College, Valhalla, New York, USA.
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Abstract
Metformin is an invaluable hypoglycaemic agent. We report two cases who had symptomatic vitamin B12 deficiency related to metformin use; the mechanisms are discussed. The clinician must be aware of the possibility of metformin-associated B12 deficiency in users who suffer cognitive impairment, peripheral neuropathy, subacute combined degeneration of the cord or anaemia.
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Affiliation(s)
- Kin Wah Liu
- Medical and Geriatric Unit, Shatin Hospital, New Territories, Hong Kong, China.
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Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJM, Stehouwer CDA. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med 2003; 254:455-63. [PMID: 14535967 DOI: 10.1046/j.1365-2796.2003.01213.x] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Metformin is a key treatment option in type 2 diabetes. However, metformin may decrease vitamin B12 levels and increase levels of homocysteine, a cardiovascular risk factor. We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with insulin. DESIGN Placebo-controlled, randomized trial. MEASUREMENTS at baseline and 16 weeks later. SETTING This trial was conducted in the outpatient clinics of three general hospitals in The Netherlands. SUBJECTS A total of 745 patients with type 2 diabetes, treated with insulin and not known with a contraindication for the use of metformin, were approached; 390 gave informed consent and entered the study. Thirty-seven subjects dropped out (12 placebo and 25 metformin users). INTERVENTION Addition of metformin or placebo to insulin therapy. PRIMARY OUTCOME PARAMETERS: Serum homocysteine, folate, vitamin B12, indices of glycaemic control and body weight. RESULTS Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% (0.2 to 8; P=0.039) and with decreases in folate [-7% (-1.4 to -13); P=0.024] and vitamin B12 [-14% (-4.2 to -24); P<0.0001]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12. CONCLUSION In patients with type 2 diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in homocysteine. The clinical significance of these findings remains to be investigated.
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Affiliation(s)
- M G Wulffelé
- Department of Internal Medicine, Bethesda General Hospital, Hoogeveen, The Netherlands
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Lewerin C, Nilsson-Ehle H, Matousek M, Lindstedt G, Steen B. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6: a randomised trial. Eur J Clin Nutr 2003; 57:1426-36. [PMID: 14576756 DOI: 10.1038/sj.ejcn.1601707] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVES To investigate, in an elderly population: (1) the effects of oral B-vitamin therapy on P-tHcys, S-MMA and Hb/MCV, (2) the appropriate decision limit for 'high' metabolite concentrations and (3) the estimated prevalence of vitamin B(12)/folate deficiency on the basis of different decision limits. DESIGN Double-blind placebo-controlled intervention study. SETTING Outpatient clinic. SUBJECTS A total of 209 community-dwelling subjects, median age 76 y (range 70-93) y. INTERVENTION Four months of oral daily supplementation with 0.5 mg cyanocobalamin, 0.8 mg folic acid and 3 mg vitamin B(6). RESULTS High P- tHcys was found in 64% of men and 45% of women, high S-MMA in 11% of both. Vitamin B(12) deficiency was observed in 7.2% and folate deficiency in 11% of all subjects. Health-related upper reference limits for the metabolites at the start were higher than the laboratory's upper reference limits. The latter were, however, similar to those of the vitamin replete group. There was a significant decrease in P-tHcys (P<0.001) and S-MMA (P=0.009) after 4 months of vitamin treatment. In a multivariate analysis, the P-Hcys change correlated positively with baseline P-tHcys and inversely with baseline P-folate and transferrin saturation (Fe/TIBC ratio). The S-MMA change correlated with baseline S-MMA and inversely with baseline vitamin B(12) and age. CONCLUSIONS Suboptimal vitamin status is an important cause of elevated P-tHcys and S-MMA in apparently healthy elderly subjects. Oral B-vitamin therapy is an effective and convenient way to normalise P-tHcys and S-MMA.
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Affiliation(s)
- C Lewerin
- Department of Haematology and Coagulation, Göteborg University, Göteborg, Sweden
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Andrès E, Perrin AE, Demangeat C, Kurtz JE, Vinzio S, Grunenberger F, Goichot B, Schlienger JL. The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med 2003; 14:221-226. [PMID: 12919836 DOI: 10.1016/s0953-6205(03)00074-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND: To date, only case reports or small studies have documented the syndrome of food-cobalamin malabsorption in specific populations of patients or situations. In this paper, we present the data from 80 unselected patients with cobalamin deficiency related to food-cobalamin malabsorption. METHODS: We studied 80 patients with well-established food-cobalamin malabsorption who were extracted from an observational cohort study (1995-2000) of 127 consecutive patients with cobalamin deficiency and who were followed in a department of internal medicine. RESULTS: The median age of patients was 66 years and the female to male ratio was 1.2. The mean hemoglobin level was 113+/-27 g/l (range 32-159 g/l) and the mean erythrocyte cell volume was 95.4+/-12.3 fl (range 55-140 fl). Mean serum vitamin B12 and homocysteine levels were 153+/-74 pg/ml (range 35-200 pg/ml) and 20.6+/-15.7 μmol/l (range 8-97 μmol/l), respectively. The main clinical findings noted were peripheral neuropathy (46.2%), stroke (12.5%), confusion or dementia (10%), asthenia (18.7%), leg edema (11.2%), and digestive disorders (7.5%). The commonest associated conditions were atrophic gastritis (39%) with evidence of Helicobacter pylori infection (12.2%) and alcohol abuse (13.7%). Three patients had Sjögren's syndrome and one had systemic sclerosis. Ten percent of all patients were on long-term metformin (10%) and 7.5% on acid-suppressive drugs. Correction of the serum vitamin B12 levels and hematological abnormalities was achieved equally well in all patients treated with either intramuscular or oral crystalline cyanocobalamin. CONCLUSION: This study suggests that food-cobalamin malabsorption may be the leading cause of vitamin B12 deficiency in adults. As other studies have also reported, the condition is often associated with neuro-psychiatric findings and with several other conditions. Oral and parenteral cobalamin appear to be equally effective in correcting serum B12 levels and hematological abnormalities and, in many cases, they also relieve symptoms.
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Affiliation(s)
- Emmanuel Andrès
- Department of Internal Medicine and Nutrition, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, Kohanovski M, Rotzak R, Schneider H, Behar S, Motro M. Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up. Clin Cardiol 2001; 24:151-8. [PMID: 11460818 PMCID: PMC6655246 DOI: 10.1002/clc.4960240210] [Citation(s) in RCA: 84] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2000] [Accepted: 05/12/2000] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND A sulfonylurea--usually glyburide--plus metformin constitute the most widely used oral antihyperglycemic combination in clinical practice. Both medications present undesirable cardiovascular effects. The issue whether the adverse effects of each of these pharmacologic agents may be additive and detrimental to the prognosis for coronary patients has not yet been specifically addressed. HYPOTHESIS This study was designed to examine the survival in type 2 diabetics with proven coronary artery disease (CAD) receiving a combined glyburide/metformin antihyperglycemic treatment over a long-term follow-up period. METHODS The study sample comprised 2,275 diabetic patients, aged 45-74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition, 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253). RESULTS The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%), 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time-related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow-up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long-term follow-up, with a time-related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all-cause mortality of 1.53 (95% confidence interval [CI] 1.20-1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02-1.45) and HR 1.26 (95% CI 0.81-1.96), respectively. CONCLUSIONS We conclude that after a 7.7-year follow-up, monotherapy with either glyburide or metformin in diabetic patients with CAD yielded a similar outcome and was associated with a modest increase in mortality. However, time-related mortality was markedly increased when a combined glyburide/metformin treatment was used.
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Affiliation(s)
- E Z Fisman
- Cardiac Rehabilitation Institute, the Chaim Sheba Medical Center, Tel-Hashomer, Israel
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