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1
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Gallwitz B. Diabetestherapie bei herzkranken Patienten. DIABETOL STOFFWECHS 2023. [DOI: 10.1055/a-1930-2899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Ishii H. Cardiovascular events and atherosclerosis in patients with type 2 diabetes and impaired glucose tolerance -What are the medical treatments to prevent cardiovascular events in such patients? J Diabetes Investig 2022; 13:1114-1121. [PMID: 35377559 PMCID: PMC9248425 DOI: 10.1111/jdi.13799] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 11/30/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT) significantly induce advanced coronary artery disease and systemic atherosclerosis. Thus, T2DM and IGT are traditional risk factors of cardiovascular disease (CVD). On the other hand, acute coronary syndrome is frequently caused by the rupture of coronary atherosclerotic plaques, which reduces patients' quality of life and may result in death. To date, many trials have sought to identify ways to determine the coronary plaque volume and its vulnerability, and many studies have demonstrated that some specific antihyperglycemic agents may prevent coronary or carotid plaque progression, decrease plaque volume, induce plaque stability, and improve clinical outcomes in patients with T2DM and IGT. This article reviews i) the association between coronary or carotid plaques and abnormal glucose tolerance, including T2DM; and ii) the effects of oral antihyperglycemic drugs to improve clinical outcomes and stabilize atherosclerotic plaques in patients with T2DM and IGT.
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Affiliation(s)
- Hideki Ishii
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511, Japan
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Shi FH, Li H, Kong LC, Shen L, Jiang YH, Gu ZC, Ge H. Sulfonylureas Use Is Not Associated With Increased Infarct Size in Patients With Type 2 Diabetes and ST-Segment Elevation Myocardial Infarction. Front Cardiovasc Med 2021; 8:658059. [PMID: 34124195 PMCID: PMC8194070 DOI: 10.3389/fcvm.2021.658059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/08/2021] [Indexed: 11/24/2022] Open
Abstract
Aims: This retrospective study assessed the association between sulfonylureas use and infarct size in patients with type 2 diabetes (T2DM) and ST-segment elevation myocardial infarction (STEMI) by myocardial enzymology indexes and cardiac magnetic resonance (CMR) imaging. Methods: Patients presenting STEMI between July 2013 and August 2019 were included in a retrospective database at our institution. Antidiabetic agents used before STEMI were recorded. Patients with maximum recorded troponin I (max cTNI) and creatine phosphokinase isoenzyme (CK-MB) within the first 72 h of chest pain onset were selected. Infarct size was quantified by CMR imaging, and cardiovascular outcomes were also obtained at 30 days and 6 months follow-up. Multivariable regression models explored potential risk factors associated with infarct size and clinical outcomes. Results: A total of 254 T2DM and STEMI patients were included, with 101 sulfonylurea users and 153 non-users. Sulfonylureas users were not associated with higher max cTnI and max CK-MB compared to non-users. Among 65 CMR patients, no significant differences in infarct size were detected between sulfonylureas users and non-users. Whereas, the incidence of microvascular obstruction (MVO) was higher in patients receiving sulfonylureas than those taking non-sulfonylureas (88.0 vs. 62.5%, p = 0.023). No higher cardiovascular events of sulfonylureas users vs. non-users were observed, except for heart failure events (24.0 vs. 2.5% at 30 days, p = 0.011; 28.0 vs. 2.5% at 6 months, p = 0.004). Multivariable regression analyses verified that sulfonylureas users increased the risks of MVO. Conclusions: Sulfonylureas use did not associate with larger infarct size in patients with T2DM and STEMI. A potentially higher incidence of MVO in sulfonylurea users was found. Notably, since most patients presented after a relatively long period of ischemia and glibenclamide was not used by the included patients in this observational study, the results of this study should not be extrapolated to clinical settings with short periods of ischemia or to patients using glibenclamide.
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Affiliation(s)
- Fang-Hong Shi
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hao Li
- Department of Pharmacy, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ling-Cong Kong
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Long Shen
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yi-Hong Jiang
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zhi-Chun Gu
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Heng Ge
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Nizinski J, Filberek P, Sibrecht G, Krauze T, Zielinski J, Piskorski J, Wykretowicz A, Guzik P. Non-invasive in vivo human model of post-ischaemic skin preconditioning by measurement of flow-mediated 460-nm autofluorescence. Br J Clin Pharmacol 2021; 87:4283-4292. [PMID: 33792076 DOI: 10.1111/bcp.14845] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/02/2021] [Accepted: 03/13/2021] [Indexed: 11/27/2022] Open
Abstract
AIMS Transient ischaemia and reperfusion (TIAR) induce early ischaemic preconditioning (IPC) in different tissues and organs, including the skin. IPC protects tissues by modifying the mitochondrial function and decreasing the amount of the reduced form of nicotinamide adenine dinucleotide (NADH). Skin 460-nm autofluorescence is proportional to the NADH content and can be non-invasively measured during TIAR. We propose a non-invasive in vivo human model of skin IPC for studying the effects of repeated TIARs on the NADH content. METHODS Fifty-one apparently healthy volunteers (36 women) underwent three 100-second forearm ischaemia episodes induced by inflation of brachial pressure cuff to the pressure of 60 mmHg above systolic blood pressure, followed by 500-second long reperfusion episodes. Changes in skin NADH content were measured using 460-nm fluorescence before and during each of the three TIARs. RESULTS The first two TIARs caused a significant reduction in the skin NADH content before (P = .0065) and during the third ischaemia (P = .0011) and reperfusion (P = .0003) up to 3.0%. During the third TIAR, the increase in skin NADH was 20% lower than during the first ischaemia (P = .0474). CONCLUSIONS The measurement of the 460-nm fluorescence during repeated TIARs allows for a non-invasive in vivo investigation of human skin IPC. Although IPC reduces the overall NADH skin content, the most noticeable NADH reduction appears during ischaemia after earlier TIARs. Studying the skin model of IPC may provide new avenues for in vivo physiological, clinical and pharmacological research on mitochondrial metabolism.
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Affiliation(s)
- Jan Nizinski
- Department of Cardiology Intensive Care Therapy and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Filberek
- Department of Cardiology Intensive Care Therapy and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Greta Sibrecht
- Department of Cardiology Intensive Care Therapy and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Tomasz Krauze
- Department of Cardiology Intensive Care Therapy and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Jacek Zielinski
- Department of Athletics, Strength and Conditioning, Poznan University of Physical Education, Poznan, Poland
| | | | - Andrzej Wykretowicz
- Department of Cardiology Intensive Care Therapy and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Przemyslaw Guzik
- Department of Cardiology Intensive Care Therapy and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
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Webb DR, Davies MJ, Jarvis J, Seidu S, Khunti K. The right place for Sulphonylureas today. Diabetes Res Clin Pract 2019; 157:107836. [PMID: 31479704 DOI: 10.1016/j.diabres.2019.107836] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 12/28/2022]
Abstract
The place of Sulphonylurea based insulin secretagogues in the management of Type 2 diabetes appears as controversial today as it was fifty years ago. Newer therapies are associated with less hypoglycaemia and weight gain than Sulphonylureas but currently cost more and lack assurances which come with long-term exposure. Emergence of recent CVOT data for SGLT-2 inhibitors and GLP-1 receptor agonists is likely to influence therapeutic choices and guidance is now supportive of their earlier use in cases at high risk of cardiovascular disease. Meta-analyses of Sulphonylurea trials have failed to indicate a consistent effect (positive or negative) on cardiovascular disease or mortality, although are limited by the relative scarcity of studies directly reporting these outcomes. The CAROLINA trial is reassuring in demonstrating cardiovascular safety for the Sulphonylurea Glimepiride when compared directly with the DPP-4 inhibitor Linagliptin, suggesting either of these agents would be relatively safe second line options after Metformin in the majority of patients. This review provides a balanced assessment of available Sulphonylurea treatments in the context of current cardiovascular outcome trial data (CVOT) data and hopefully assists informed decision making about the place of these drugs in contemporary glucose lowering practice.
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Affiliation(s)
- David R Webb
- University of Leicester, Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
| | - Melanie J Davies
- University of Leicester, Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
| | - Janet Jarvis
- University Hospitals of Leicester NHS Trust, Leicester Diabetes Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
| | - Sam Seidu
- University of Leicester, Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
| | - Kamlesh Khunti
- University of Leicester, Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
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Filion KB, Douros A, Azoulay L, Yin H, Yu OH, Suissa S. Sulfonylureas as initial treatment for type 2 diabetes and the risk of adverse cardiovascular events: A population-based cohort study. Br J Clin Pharmacol 2019; 85:2378-2389. [PMID: 31276600 PMCID: PMC6783602 DOI: 10.1111/bcp.14056] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 06/07/2019] [Accepted: 06/17/2019] [Indexed: 12/13/2022] Open
Abstract
AIMS Sulfonylureas are recommended as second-line treatment in the management of type 2 diabetes. However, they are still commonly used also as first-line treatment instead of metformin. Given the controversial cardiovascular safety of sulfonylureas, we aimed to determine if their use as first-line treatment is associated with adverse cardiovascular events among patients with newly treated type 2 diabetes compared with metformin. METHODS We conducted a population-based cohort study of patients with newly treated type 2 diabetes using the UK's Clinical Practice Research Datalink. Initiators of metformin and sulfonylurea monotherapy were matched on high-dimensional propensity score, and Cox proportional hazards models were used to compare the rate of cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular death, and all-cause mortality) with sulfonylureas vs metformin. RESULTS Our cohort included 94 750 patients initiating treatment for type 2 diabetes, 17 612 on a sulfonylurea and 77 138 on metformin. After matching, sulfonylurea monotherapy, compared with metformin monotherapy, was not associated with an increased risk of myocardial infarction (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 0.85-1.25) but was associated with increased risks of ischaemic stroke (HR: 1.25, 95% CI: 1.002-1.56), cardiovascular death (HR: 1.25, 95% CI: 1.06-1.47), and all-cause mortality (HR: 1.60, 95% CI: 1.45-1.76). This represents an additional 2.0 ischaemic strokes, 3.5 cardiovascular deaths, and 21.4 all-cause deaths per 1,000 patients per year with sulfonylureas. CONCLUSIONS Initiating treatment of type 2 diabetes with a sulfonylurea rather than metformin is associated with higher rates of ischaemic stroke, cardiovascular death, and all-cause mortality.
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Affiliation(s)
- Kristian B. Filion
- Department of MedicineMcGill UniversityMontrealQuebecCanada
- Center for Clinical EpidemiologyLady Davis Institute, Jewish General HospitalMontrealQuebecCanada
- Department of Epidemiology, Biostatistics, and Occupational HealthMcGill UniversityMontrealQuebecCanada
| | - Antonios Douros
- Center for Clinical EpidemiologyLady Davis Institute, Jewish General HospitalMontrealQuebecCanada
- Department of Epidemiology, Biostatistics, and Occupational HealthMcGill UniversityMontrealQuebecCanada
- Institute of Clinical Pharmacology and ToxicologyCharité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu BerlinBerlinGermany
- Berlin Institute of HealthBerlinGermany
| | - Laurent Azoulay
- Center for Clinical EpidemiologyLady Davis Institute, Jewish General HospitalMontrealQuebecCanada
- Department of Epidemiology, Biostatistics, and Occupational HealthMcGill UniversityMontrealQuebecCanada
- Gerald Bronfman Department of OncologyMcGill UniversityMontrealQuebecCanada
| | - Hui Yin
- Center for Clinical EpidemiologyLady Davis Institute, Jewish General HospitalMontrealQuebecCanada
| | - Oriana H. Yu
- Center for Clinical EpidemiologyLady Davis Institute, Jewish General HospitalMontrealQuebecCanada
- Division of Endocrinology, Jewish General HospitalMcGill UniversityMontrealQuebecCanada
| | - Samy Suissa
- Department of MedicineMcGill UniversityMontrealQuebecCanada
- Center for Clinical EpidemiologyLady Davis Institute, Jewish General HospitalMontrealQuebecCanada
- Department of Epidemiology, Biostatistics, and Occupational HealthMcGill UniversityMontrealQuebecCanada
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Reiff S, Fava S. All-cause mortality in patients on sulphonylurea monotherapy compared to metformin monotherapy in a nation-wide cohort. Diabetes Res Clin Pract 2019; 147:62-66. [PMID: 30389623 DOI: 10.1016/j.diabres.2018.10.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/26/2018] [Accepted: 10/23/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Type 2 diabetes is associated with increased mortality. There is some data that sulphonylurea therapy may contribute to this. AIMS To compare all-cause 3-year mortality of patients on sulphonylurea monotherapy to that of patients on metformin monotherapy after adjusting for potential confounders. METHODS We searched the Maltese national electronic database for diabetes treatment in April 2014. This is an electronic database of all treatment that patients are prescribed through the local National Health Service. We identified patients on metformin or sulphonylurea monotherapy and linked this to the national mortality database and the laboratory information system. RESULTS There were 25,792 persons who were on treatment for diabetes in April 2014. Of these, 9977 were on metformin monotherapy and 1717 on sulphonylurea monotherapy. This cohort was followed up until April 2017. There were 2518 deaths (9.76%) during this period, giving an average of 32.5 deaths per 1000 persons with diabetes. Logistic regression showed that persons on sulphonylurea monotherapy were 2.03 (95% CI 1.68-2.44, p < .001) times more likely to die within 3 years than persons on metformin monotherapy, after adjusting for age, eGFR and HbA1c. The logistic regression model was statistically significant, p < .001. Additional adjustment for LDL-cholesterol, HDL-cholesterol and urinary albumin-creatinine ratio did not alter the results. CONCLUSION Our data shows that sulphonylurea monotherapy is associated with higher all-cause mortality when compared to metformin monotherapy after adjusting for potential confounders.
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Affiliation(s)
| | - Stephen Fava
- Diabetes & Endocrine Centre, Mater Dei Hospital, Malta; University of Malta, Malta.
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Quinones QJ, Levy JH. Ischemic Preconditioning and the Role of Antifibrinolytic Drugs: Translation From Bench to Bedside. Anesth Analg 2018; 126:384-386. [PMID: 29346202 DOI: 10.1213/ane.0000000000002690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Quintin J Quinones
- From the Divisions of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology, Duke University, Durham, North Carolina
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Fatima S, Jameel A, Ayesha FNU, Menzies DJ. The shifting paradigm in the treatment of type 2 diabetes mellitus-A cardiologist's perspective. Clin Cardiol 2017; 40:970-973. [PMID: 28841228 PMCID: PMC6490350 DOI: 10.1002/clc.22781] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 07/28/2017] [Indexed: 01/16/2023] Open
Abstract
In patients with diabetes mellitus, cardiovascular (CV) disease is the leading cause of morbidity and mortality. A multitude of contemporary antidiabetic agents presents different CV safety profiles. Metformin forms the cornerstone agent to reduce CV events. Newer agents, such as glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors, have appealing CV benefits. Insulin, dipeptidyl peptidase-4 inhibitors, and sulfonylureas have neutral CV effects. Cardiologists should familiarize themselves with these agents to promote comprehensive CV care in patients with diabetes mellitus.
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Affiliation(s)
- Saeeda Fatima
- Department of Internal MedicineBassett Medical CenterNew York
| | - Ayesha Jameel
- Department of Internal MedicineBassett Medical CenterNew York
| | - FNU Ayesha
- Department of Internal MedicineServices Institute of Medical SciencesLahorePakistan
| | - Dhananjai J. Menzies
- Interventional Cardiology and Catheterization LaboratoriesBassett Medical CenterNew York
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Abstract
New glucose-lowering drugs have raised the complexity of diabetes treatment in recent years. While metformin is still the first choice in monotherapy for most cases, various options exist for dual combination therapy. In addition, combinations of three different oral glucose-lowering drugs are increasingly used. Insulin therapy is typically initiated using once daily administration of a long-acting insulin. If basal insulin alone is no longer sufficient, treatment can be intensified by adding short-acting insulin at mealtime or by combining basal insulin with oral glucose-lowering drugs or a glucagon-like peptide (GLP)-1 analogue. The choice of the most appropriate glucose-lowering drug should take into account not only the glucose-lowering efficacy, but also the side effect profile of the respective agents; economic factors must be considered as well. Modern treatment of type 2 diabetes should aim for near-normal glucose control.
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Affiliation(s)
- J J Meier
- Abteilung für Diabetologie, Universitätsklinikum St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Gudrunstr. 56, 44791, Bochum, Deutschland.
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Freiermuth D, Mets B, Bolliger D, Reuthebuch O, Doebele T, Scholz M, Gregor M, Haschke M, Seeberger MD, Fassl J. Sevoflurane and Isoflurane—Pharmacokinetics, Hemodynamic Stability, and Cardioprotective Effects During Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth 2016; 30:1494-1501. [DOI: 10.1053/j.jvca.2016.07.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Indexed: 11/11/2022]
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Gallwitz B. [Therapy with oral antidiabetic drugs]. MMW Fortschr Med 2016; 158:48-54. [PMID: 27822846 DOI: 10.1007/s15006-016-8233-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Affiliation(s)
- Baptist Gallwitz
- Medizinische Klinik IV, Universitätsklinikum Tübingen, Otfried-Müller-Str. 10, D-72076, Tübingen, Deutschland.
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Kaneko M, Narukawa M. Meta-analysis of dipeptidyl peptidase-4 inhibitors use and cardiovascular risk in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2016; 116:171-82. [PMID: 27321333 DOI: 10.1016/j.diabres.2016.04.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 04/07/2016] [Accepted: 04/15/2016] [Indexed: 11/24/2022]
Abstract
AIMS Some meta-analyses have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors decrease the risk of major adverse cardiovascular events (MACE) compared to placebo. However, this association has not been confirmed in large placebo-controlled clinical trials with cardiovascular events as a primary endpoint. The aim of the present meta-analysis is to assess the association between DPP-4 inhibitors use and cardiovascular risk using uniform definition of MACE. METHODS Relevant studies through 31 December 2014 were searched in the electronic databases, and we identified all eligible trials comparing DPP-4 inhibitors with active drugs or placebo. Summary odds ratio (OR) with 95% confidence interval (CI) for MACE was calculated using random-effects model. RESULTS In 69 trials included in our study, 36,488 patients were treated with DPP-4 inhibitors and 31,290 with other comparators. Treatment with DPP-4 inhibitors was associated with a lower risk of MACE (OR [95% CI]=0.52 [0.36,0.76]) compared to sulfonylureas, while showed a trend toward increased risk (OR [95% CI]=1.89 [0.60,5.93]) compared to sodium-glucose cotransporter 2 (SGLT2) inhibitors. The difference was not statistically significant when compared to placebo (OR [95% CI]=1.04 [0.92,1.18]), and this tendency was similar in both subgroup analyses conducted with a general type 2 diabetes population as well as the population at high cardiovascular risk. CONCLUSIONS There is no significant difference in the risk of MACE between DPP-4 inhibitors and placebo groups. DPP-4 inhibitors show significantly lower risk of MACE when compared to sulfonylureas, while SGLT2 inhibitors might have lower risk compared to DPP-4 inhibitors.
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Affiliation(s)
- Masayuki Kaneko
- Department of Clinical Medicine (Pharmaceutical Medicine), Kitasato University Graduate School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
| | - Mamoru Narukawa
- Department of Clinical Medicine (Pharmaceutical Medicine), Kitasato University Graduate School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
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Abdelmoneim AS, Eurich DT, Senthilselvan A, Qiu W, Simpson SH. Dose-response relationship between sulfonylureas and major adverse cardiovascular events in elderly patients with type 2 diabetes. Pharmacoepidemiol Drug Saf 2016; 25:1186-1195. [DOI: 10.1002/pds.4014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 03/18/2016] [Accepted: 03/21/2016] [Indexed: 12/25/2022]
Affiliation(s)
- Ahmed S. Abdelmoneim
- Faculty of Pharmacy and Pharmaceutical Sciences; University of Alberta; Edmonton AB Canada
- Alliance for Canadian Health Outcomes Research in Diabetes; University of Alberta; Edmonton AB Canada
| | - Dean T. Eurich
- Alliance for Canadian Health Outcomes Research in Diabetes; University of Alberta; Edmonton AB Canada
- School of Public Health; University of Alberta; Edmonton AB Canada
| | | | - Weiyu Qiu
- Alliance for Canadian Health Outcomes Research in Diabetes; University of Alberta; Edmonton AB Canada
| | - Scot H. Simpson
- Faculty of Pharmacy and Pharmaceutical Sciences; University of Alberta; Edmonton AB Canada
- Alliance for Canadian Health Outcomes Research in Diabetes; University of Alberta; Edmonton AB Canada
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Deacon CF, Lebovitz HE. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes Metab 2016; 18:333-47. [PMID: 26597596 DOI: 10.1111/dom.12610] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 11/18/2015] [Accepted: 11/18/2015] [Indexed: 12/16/2022]
Abstract
Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice.
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Affiliation(s)
- C F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - H E Lebovitz
- State University of New York Health Science Center, Brooklyn, NY, USA
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Swislocki ALM, Jialal I. Diabetes Management and Cardiovascular Risk: Are SGLT-2 Inhibitors the Safest? Metab Syndr Relat Disord 2016; 14:3-6. [DOI: 10.1089/met.2015.29003.swi] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Arthur L. M. Swislocki
- Medical Service, Department of Veterans Affairs Northern California Health Care System, Sacramento, California
- Department of Internal Medicine, UC Davis School of Medicine, Sacramento, California
| | - Ishwarlal Jialal
- Medical Service, Department of Veterans Affairs Northern California Health Care System, Sacramento, California
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California
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Remote ischemic preconditioning in aortic valve surgery: Results of a randomized controlled study. J Cardiol 2016; 67:36-41. [DOI: 10.1016/j.jjcc.2015.06.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 05/13/2015] [Accepted: 06/01/2015] [Indexed: 02/06/2023]
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Floyd JS, Wiggins KL, Christiansen M, Dublin S, Longstreth WT, Smith NL, McKnight B, Heckbert SR, Weiss NS, Psaty BM. Case-control study of oral glucose-lowering drugs in combination with long-acting insulin and the risks of incident myocardial infarction and incident stroke. Pharmacoepidemiol Drug Saf 2015; 25:151-60. [PMID: 26547662 DOI: 10.1002/pds.3914] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/05/2015] [Accepted: 10/20/2015] [Indexed: 01/14/2023]
Abstract
BACKGROUND The use of oral glucose-lowering therapies with insulin is common, but the cardiovascular effects are largely unknown. Among users of long-acting insulin, we conducted a population-based case-control study to evaluate the incident myocardial infarction (MI) and incident stroke risks associated with the use of sulfonylureas and the use of metformin. METHODS Cases were Group Health Cooperative enrollees with type 2 diabetes who used long-acting insulin at the time of diagnosis with a first MI (n = 413) or first stroke (n = 247) from 1995 to 2010. Controls (n = 443) with type 2 diabetes who used long-acting insulin were matched to cases on age, sex, and calendar year. Sulfonylurea and metformin use was classified as current, past, or never using electronic pharmacy records. MI and stroke diagnoses were validated by medical record review. Analyses were adjusted for potential confounders. RESULTS Current use of sulfonylureas compared with never use was associated with a higher risk of MI (odds ratio [OR] 1.67; 95% confidence interval [CI], 1.10-2.55) but not stroke (OR 1.22; 95%CI, 0.74-2.00). Current use of metformin compared with never use was associated with a lower risk of stroke (OR 0.54; 95%CI, 0.31-0.95) but not MI (OR 0.77; 95%CI, 0.44-1.33). Past use of sulfonylureas and past use of metformin were not associated with either outcome. CONCLUSIONS Sulfonylureas in combination with long-acting insulin may increase the risk of MI compared with the use of insulin alone. Metformin may be an important cardiovascular disease prevention therapy for patients on insulin therapy. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- James S Floyd
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA
| | - Kerri L Wiggins
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
| | - Mark Christiansen
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
| | - Sascha Dublin
- Department of Epidemiology, University of Washington, Seattle, WA, USA.,Group Health Research Institute, Seattle, WA, USA
| | - William T Longstreth
- Department of Epidemiology, University of Washington, Seattle, WA, USA.,Department of Neurology, University of Washington, Seattle, WA, USA
| | - Nicholas L Smith
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.,Department of Epidemiology, University of Washington, Seattle, WA, USA.,Group Health Research Institute, Seattle, WA, USA.,Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs, Office of Research and Development, Seattle, WA, USA
| | - Barbara McKnight
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.,Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Susan R Heckbert
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.,Department of Epidemiology, University of Washington, Seattle, WA, USA.,Group Health Research Institute, Seattle, WA, USA
| | - Noel S Weiss
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.,Department of Epidemiology, University of Washington, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA.,Group Health Research Institute, Seattle, WA, USA
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Basnet S, Kozikowski A, Makaryus AN, Pekmezaris R, Zeltser R, Akerman M, Lesser M, Wolf-Klein G. Metformin and Myocardial Injury in Patients With Diabetes and ST-Segment Elevation Myocardial Infarction: A Propensity Score Matched Analysis. J Am Heart Assoc 2015; 4:e002314. [PMID: 26494519 PMCID: PMC4845135 DOI: 10.1161/jaha.115.002314] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Background Although animal studies have documented metformin's cardioprotective effects, the impact in humans remains elusive. The study objective was to explore the association between metformin and myocardial infarct size in patients with diabetes presenting with ST‐segment elevation myocardial infarction. Methods and Results Data extraction used the National Cardiovascular Data CathPCI Registry in all patients with diabetes aged >18 years presenting with ST‐segment elevation myocardial infarction at 2 academic medical centers from January 2010 to December 2013. The exposure of interest was ongoing metformin use before the event. Propensity score matching was used for the metformin and nonmetformin groups on key prognostic variables. All matched pairs had acceptable D scores of <10%, confirming an efficient matching procedure. The primary outcome was myocardial infarct size, reflected by peak serum creatine kinase–myocardial band, troponin T, and hospital discharge left ventricular ejection fraction. Of all 1726 ST‐segment elevation myocardial infarction cases reviewed, 493 patients had diabetes (28.5%), with 208 metformin users (42.1%) and 285 nonusers. Matched pairs analysis yielded 137 cases per group. The difference between metformin and nonmetformin groups was −18.1 ng/mL (95% CI −55.0 to 18.8; P=0.56) for total peak serum creatine kinase–myocardial band and −1.1 ng/mL (95% CI −2.8 to 0.5; P=0.41) for troponin T. Median discharge left ventricular ejection fraction in both groups was 45, and the difference between metformin and nonmetformin users was 0.7% (95% CI −2.2 to 3.6; P=0.99). Conclusions No statistically significant association of cardioprotection was found between metformin and myocardial infarct size in patients with diabetes and acute ST‐segment elevation myocardial infarction.
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Affiliation(s)
- Suresh Basnet
- Department of Critical Care Medicine, Valley Health System, Winchester, VA (S.B.)
| | - Andrzej Kozikowski
- Department of Medicine, North Shore-LIJ Health System, Great Neck, NY (A.K., R.P.)
| | - Amgad N Makaryus
- Department of Cardiology, North Shore-LIJ Health System, Manhasset, NY (A.N.M., R.Z.) Nassau University Medical Center, East Meadow, NY (A.N.M., R.Z.)
| | - Renee Pekmezaris
- Department of Medicine, North Shore-LIJ Health System, Great Neck, NY (A.K., R.P.)
| | - Roman Zeltser
- Department of Cardiology, North Shore-LIJ Health System, Manhasset, NY (A.N.M., R.Z.) Nassau University Medical Center, East Meadow, NY (A.N.M., R.Z.)
| | - Meredith Akerman
- Biostatistics Unit, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY (M.A., M.L.)
| | - Martin Lesser
- Biostatistics Unit, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY (M.A., M.L.)
| | - Gisele Wolf-Klein
- Department of Geriatrics, North Shore-LIJ Health System, New Hyde Park, NY (G.W.K.)
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Tanabe M, Nomiyama T, Motonaga R, Murase K, Yanase T. Reduced vascular events in type 2 diabetes by biguanide relative to sulfonylurea: study in a Japanese Hospital Database. BMC Endocr Disord 2015; 15:49. [PMID: 26382923 PMCID: PMC4574461 DOI: 10.1186/s12902-015-0045-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 09/04/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Some oral hypoglycemic agents (OHAs) have been suggested to reduce the risk of cardiovascular disease (CVD) in type-2 diabetes mellitus (T2DM). We ascertained if OHAs affect CVD risk in a cohort analysis of a multicenter medical-cost accounting database in Japan. METHODS Data of 4095 and 1273 T2DM patients in study 1 and study 2, respectively, were extracted from the database based on the following conditions: (i) began treatment with a single OHA (sulfonylurea, biguanide, thiazolidinedione, α-glucosidase inhibitor, glinide, or dipeptidyl peptidase-4 inhibitor) and continued the medication for ~1-1.4 years; (ii) hemoglobin (Hb)A1c level at baseline was available; (iii) age at baseline was 40-70 years; (iv) presence or absence of CVD history was not considered in study 1, but presence of CVD history was considered in study 2. Effects of OHAs relative to sulfonylurea on CVD risk according to ICD-10 were analysed using Kaplan-Meier curves during 104 weeks. RESULTS In study 1 targeting T2DM patients with and without a history of CVD, initial and baseline treatment with a biguanide significantly lowered the risk of CVD compared with that with a sulfonylurea, and was independent of HbA1c control. In study 2, a similar significant preventive effect of a biguanide on CVD risk relative to a sulfonylurea was observed in T2DM patients with history of CVD. CONCLUSIONS Initial treatment and baseline treatment with a biguanide can reduce CVD risk relative to a sulfonylurea independent of the blood glucose-lowering effect of the biguanide in Japanese T2DM patients.
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Affiliation(s)
- Makito Tanabe
- Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
| | - Takashi Nomiyama
- Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
| | - Ryoko Motonaga
- Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
| | - Kunitaka Murase
- Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
| | - Toshihiko Yanase
- Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
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Sulfonylurea use is associated with larger infarct size in patients with diabetes and ST-elevation myocardial infarction. Int J Cardiol 2015; 202:126-30. [PMID: 26386939 DOI: 10.1016/j.ijcard.2015.08.213] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 08/27/2015] [Indexed: 12/25/2022]
Abstract
BACKGROUND Animal models have demonstrated that sulfonylureas increase the size of myocardial infarction; however, data in humans is scarce. This study evaluated the association between sulfonylurea use and infarct size in diabetes patients with ST-elevation myocardial infarction (STEMI). METHODS Consecutive STEMI patients admitted in Edmonton, Canada between 2006 and 2011 were enrolled in a regional prospective registry program. Patients with type 2 diabetes were identified from this group and the maximum recorded troponin I (max cTnI) within the first 48 h of chest pain onset was used as the primary outcome to quantify infarct size. The relationship between preadmission sulfonylurea use and max cTnI was assessed using multivariable linear regression to adjust for patient demographics, cardiovascular risk factors, clinical data on admission, ischemia time, reperfusion therapy and preadmission drugs. RESULTS There were 560 STEMI patients with type 2 diabetes; mean (standard deviation; SD) age was 63.3 (12.8) years, 395 (70.5%) were male, 216 (38.6%) received primary percutaneous intervention, and 211 (37.7%) received thrombolysis. The max cTnI was higher in 146 sulfonylurea users compared to 414 non-sulfonylurea users (mean (SD): 49.8 (74.3) ng/mL versus 39.9 (50.4) ng/mL, respectively; adjusted between-group difference: 12.9 ng/mL; 95% CI 0.3-25.5; p=0.044). CONCLUSION This study adds further evidence to the proposed causal relationship between sulfonylureas and adverse cardiovascular events by observing a significant difference in infarct size among type 2 diabetes patients presenting with STEMI. Clinicians should consider this association when prescribing sulfonylureas to manage patients with type 2 diabetes.
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Abdelmoneim AS, Eurich DT, Light PE, Senior PA, Seubert JM, Makowsky MJ, Simpson SH. Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. Diabetes Obes Metab 2015; 17:523-532. [PMID: 25711240 DOI: 10.1111/dom.12456] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 10/10/2015] [Accepted: 02/20/2015] [Indexed: 12/12/2022]
Abstract
More than 40 years after publication of the University Group Diabetes Program trial, the cardiovascular safety of sulphonylureas is still contentious. Although several hypotheses linking sulphonylureas to adverse cardiovascular effects exist, none provide conclusive evidence. Adding to the controversy, current clinical trials and observational studies provide inconsistent, and sometimes conflicting, evidence for the cardiovascular effects of sulphonylureas. Overall, observational evidence suggests that an increased risk of adverse cardiovascular outcomes is associated with sulphonylureas; however, these data may be subject to residual confounding and bias. Although evidence from randomized controlled trials has suggested a neutral effect, the majority of these studies were not specifically designed to assess the effect of sulphonylureas on adverse cardiovascular event risk. Current ongoing large clinical trials may provide some clarity on the cardiovascular safety of sulphonylureas, but the results are not expected for several years. With the continued uncertainties concerning the cardiovascular safety of all antidiabetic drugs, a clear answer with regard to sulphonylureas is warranted. The objectives of the present article were to provide an overview of the controversy surrounding sulphonylurea-related cardiovascular effects, to discuss the limitations of the current literature, and to provide recommendations for future studies aiming to elucidate the true relationship between sulphonylureas and adverse cardiovascular effects in people with type 2 diabetes.
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Affiliation(s)
- A S Abdelmoneim
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - D T Eurich
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - P E Light
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - P A Senior
- Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - J M Seubert
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - M J Makowsky
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - S H Simpson
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
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Abstract
BACKGROUND The prevalence of diabetes mellitus type 2 in the adult population is > 7 %. Despite new therapy options and modern insulins, the therapy remains a challenge. Especially in patients with obesity or high insulin resistance it is often difficult to achieve the necessary target values. In most cases the disease is initially asymptomatic so that the aim is the early recognition and avoidance of complications. MATERIAL AND METHODS This article provides an update on the approach options of modern therapy forms in diabetes management. RESULTS The foundations of every treatment program are lifestyle interventions, including diabetes schooling. When these fail a pharmaceutical therapy must be initiated which among others is oriented to hemoglobin A1c (HbA1c). The HbA1c target value should take patient-specific circumstances into consideration and should be determined together with the patient. If no contraindications or intolerances are present, metformin is the medication of choice. Apart from metformin, the available data which can be used for guidance are limited. A combination therapy with one or two other oral or injectable medications is suitable to keep the side effects as low as possible. The advantages of other substances in individual cases could be a lower risk of hypoglycemia, reduced weight increase, oral administration and compatibility with renal insufficiency. Ultimately, insulin therapy will be necessary for many patients, either as monotherapy or in combination with other substances. Therapy decisions should be made together with the patient, taking personal preferences into consideration and should include age, body weight, comorbidities, occupational situation and compliance. CONCLUSION The Reorganization of the Pharmaceutical Market Act represents a momentarily perceived clear barrier. In the interests of an individualized therapy and personalized disease management, a target-aimed flexibility in diabetes management should be possible in the future.
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Affiliation(s)
- E Siegel
- St. Josefskrankenhaus Heidelberg, Landhausstr. 25, 69115, Heidelberg, Deutschland,
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24
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Jivraj N, Liew F, Marber M. Ischaemic postconditioning: cardiac protection after the event. Anaesthesia 2015; 70:598-612. [DOI: 10.1111/anae.12974] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2014] [Indexed: 12/11/2022]
Affiliation(s)
- N. Jivraj
- School of Medicine and BHF Centre of Excellence; Cardiovascular Division; King's College London; London UK
| | - F. Liew
- School of Medicine; University College London; London UK
| | - M. Marber
- School of Medicine and BHF Centre of Excellence; Cardiovascular Division; King's College London; London UK
- NIHR Biomedical Research Centre; Guy's and St Thomas' NHS Foundation Trust; London UK
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25
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Evaluating Cardiovascular Safety of Novel Therapeutic Agents for the Treatment of Type 2 Diabetes Mellitus. Curr Cardiol Rep 2014; 16:541. [DOI: 10.1007/s11886-014-0541-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Morgan CL, Mukherjee J, Jenkins-Jones S, Holden SE, Currie CJ. Combination therapy with metformin plus sulphonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. Diabetes Obes Metab 2014; 16:977-83. [PMID: 24762119 DOI: 10.1111/dom.12306] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 04/02/2014] [Accepted: 04/18/2014] [Indexed: 12/25/2022]
Abstract
AIMS To compare the risk of major adverse cardiovascular events (MACE) and mortality for combination therapies with metformin and either sulphonylurea (SU) or dipeptidyl peptidase-4 inhibitor (DPP-4i). METHODS Data were from the UK Clinical Practice Research Datalink (CPRD). Patients with type 2 diabetes were selected if initiated with combination therapies comprising metformin plus SU or DPP-4i 2007-2012. The co-primary endpoints were all-cause mortality and MACE (myocardial infarction or stroke). Times to endpoints were compared using Cox proportional hazards models. Additional analyses were performed on subsets matched directly on key characteristics and by propensity score. RESULTS A total of 33 983 patients were prescribed SU and 7864 DPP-4i, and 5447 patients in each cohort could be matched directly and 6901 by propensity score. In the main analysis, there were 716 MACE events and 1217 deaths. Crude event rates for MACE were 11.3 events per 1000 person-years (pkpy) for SU, versus 5.3 pkpy for DPP-4i. For all-cause mortality, rates were 16.9 versus 7.3 pkpy, respectively. Following adjustment, there was a significant increase in the adjusted hazard ratio (aHR) for all-cause mortality in those exposed to SU across all analytical models: aHR = 1.357 (95% CI 1.076-1.710) for all subjects, 1.850 (1.245-2.749) directly matched and 1.497 (1.092-2.052) propensity-matched. For MACE, aHR was 1.710 (1.280-2.285) for all subjects, 1.323 (0.832-2.105) directly matched and 1.547 (1.076-2.225) propensity-matched. CONCLUSIONS There was a reduction in all-cause mortality for patients treated with metformin combined with DPP-4i versus metformin plus SU, and a similar trend for MACE.
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Affiliation(s)
- C Ll Morgan
- Global Epidemiology, Pharmatelligence, Cardiff, UK
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Menon V, Lincoff AM. Cardiovascular Safety Evaluation in the Development of New Drugs for Diabetes Mellitus. Circulation 2014; 129:2705-13. [DOI: 10.1161/circulationaha.113.008221] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Venu Menon
- From the Robert & Suzanne Tomsich Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
| | - A. Michael Lincoff
- From the Robert & Suzanne Tomsich Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
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Rahmi Garcia RM, Rezende PC, Hueb W. Impact of hypoglycemic agents on myocardial ischemic preconditioning. World J Diabetes 2014; 5:258-266. [PMID: 24936247 PMCID: PMC4058730 DOI: 10.4239/wjd.v5.i3.258] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 03/18/2014] [Indexed: 02/05/2023] Open
Abstract
Murry et al in 1986 discovered the intrinsic mechanism of profound protection called ischemic preconditioning. The complex cellular signaling cascades underlying this phenomenon remain controversial and are only partially understood. However, evidence suggests that adenosine, released during the initial ischemic insult, activates a variety of G protein-coupled agonists, such as opioids, bradykinin, and catecholamines, resulting in the activation of protein kinases, especially protein kinase C (PKC). This leads to the translocation of PKC from the cytoplasm to the sarcolemma, where it stimulates the opening of the ATP-sensitive K+ channel, which confers resistance to ischemia. It is known that a range of different hypoglycemic agents that activate the same signaling cascades at various cellular levels can interfere with protection from ischemic preconditioning. This review examines the effects of several hypoglycemic agents on myocardial ischemic preconditioning in animal studies and clinical trials.
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Kim J, Samson SL. Cardiovascular effects of incretin therapy in diabetes care. Metab Syndr Relat Disord 2014; 12:303-10. [PMID: 24842063 DOI: 10.1089/met.2014.0035] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Diabetes patients are at high risk for development of cardiovascular disease. The cardiovascular safety of antidiabetic medications is a concern. Incretin therapies, including glucagon-like peptide 1 receptor (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, have recently been introduced to clinical practice and are widely used. Data from phase 2 and 3 trials and retrospective analyses of clinical databases have shown favorable changes in cardiovascular risk factors and outcomes. However, only a few prospective trials have been designed with cardiovascular outcomes as a primary end point. From current data, alogliptin and saxagliptin do not change cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. Vildagliptin does not alter myocardial function in T2DM patients with systolic dysfunction. However, the possibility of an increase in clinical heart failure and worsened outcomes in patients with existing heart failure is suggested by current data. Clinicians need to follow patients on DPP-4 inhibitors carefully for this possibility until more prospective randomized controlled data are available.
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Affiliation(s)
- Jongoh Kim
- Department of Medicine/Endocrinology, Baylor College of Medicine , Houston, Texas
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Rambiritch V, Maharaj B, Naidoo P. Glibenclamide in patients with poorly controlled type 2 diabetes: a 12-week, prospective, single-center, open-label, dose-escalation study. Clin Pharmacol 2014; 6:63-9. [PMID: 24741335 PMCID: PMC3983009 DOI: 10.2147/cpaa.s54809] [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] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate the effect of glibenclamide dose escalation on blood glucose and insulin in patients with poorly controlled type 2 diabetes. METHODS Twenty-two subjects with type 2 diabetes were administered increasing doses (0, 2.5, 5, 10, and 20 mg/day) of glibenclamide at 2-week intervals. Glibenclamide, glucose, and insulin determinations were performed. RESULTS The decrease in mean blood glucose from zero dose was 20%, 22%, 26%, and 28% for doses of 2.5, 5, 10, and 20 mg/day, respectively, which was significant from zero dose to 2.5 mg/day (P≤0.001). There were no significant decreases in glucose concentration beyond 2.5 mg/day. The percentage increase in mean insulin from zero dose was 51%, 58%, 44%, and 33% for 2.5, 5, 10, and 20 mg/day respectively. Mean blood insulin increased significantly from zero dose to 2.5 mg/day (P≤0.001). There were no significant increases in mean insulin concentration beyond 2.5 mg/day. CONCLUSION The results of this study suggest that increasing doses of glibenclamide do not produce a proportional increase in insulin secretion or a proportional decrease in blood glucose concentration.
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Affiliation(s)
- Virendra Rambiritch
- Biomedical Research Ethics Committee, University of Kwazulu-Natal, Durban, KwaZulu-Natal, South Africa
| | - Breminand Maharaj
- Department of Therapeutics and Medicines Management, University of Kwazulu-Natal, Durban, KwaZulu-Natal, South Africa
| | - Poobalan Naidoo
- Boehringer-Ingelheim, Medical Affairs, Johannesburg, Gauteng, South Africa
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KOTTENBERG E, THIELMANN M, KLEINBONGARD P, FREY UH, HEINE T, JAKOB H, HEUSCH G, PETERS J. Myocardial protection by remote ischaemic pre-conditioning is abolished in sulphonylurea-treated diabetics undergoing coronary revascularisation. Acta Anaesthesiol Scand 2014; 58:453-62. [PMID: 24548338 DOI: 10.1111/aas.12278] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2014] [Indexed: 02/01/2023]
Abstract
BACKGROUND Remote ischaemic pre-conditioning attenuates myocardial injury. Because sulphonylurea drugs interfere with ischaemic and anaesthetic pre-conditioning, we assessed whether remote ischaemic pre-conditioning effects are altered in sulphonylurea-treated diabetics. METHODS Using the database of our ongoing randomised, placebo-controlled study (ClinicalTrials.gov NCT01406678), we assessed the troponin I concentration area under curve (measurements: baseline, 1, 6, 12, 24, 48, and 72 h post-operatively) in sulphonylurea-treated diabetics (n = 27) and non-diabetics (n = 230) without and with remote ischaemic pre-conditioning (three 5-min periods of left upper arm ischaemia with 5-min reperfusion each) during isoflurane anaesthesia before two- to three-vessel coronary artery surgery. RESULTS Remote ischaemic pre-conditioning in non-diabetic patients evoked a 41% decrease in the troponin I concentration area under curve (514 ng/ml × 72 h ± 600 vs. 302 ± 190, P = 0.001) but no change (404 ng/ml × 72 h ± 224 vs. 471 ± 383, P = 0.62) in sulphonylurea-treated diabetics. There was no significant correlation between the troponin I concentration area under curve and arterial glucose concentrations, and the latter was not an independent confounder. CONCLUSION Cardioprotection by remote ischaemic pre-conditioning during isoflurane anaesthesia is abolished in sulphonylurea-treated diabetics.
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Affiliation(s)
- E. KOTTENBERG
- Klinik für Anästhesiologie und Intensivmedizin; Universitätsklinikum Essen; Essen Germany
| | - M. THIELMANN
- Klinik für Thorax- und Kardiovaskuläre Chirurgie; Universitätsklinikum Essen; Essen Germany
| | - P. KLEINBONGARD
- Institut für Pathophysiologie; Universitätsklinikum Essen; Essen Germany
| | - U. H. FREY
- Klinik für Anästhesiologie und Intensivmedizin; Universitätsklinikum Essen; Essen Germany
| | - T. HEINE
- Klinik für Anästhesiologie und Intensivmedizin; Universitätsklinikum Essen; Essen Germany
| | - H. JAKOB
- Klinik für Thorax- und Kardiovaskuläre Chirurgie; Universitätsklinikum Essen; Essen Germany
| | - G. HEUSCH
- Institut für Pathophysiologie; Universitätsklinikum Essen; Essen Germany
| | - J. PETERS
- Klinik für Anästhesiologie und Intensivmedizin; Universitätsklinikum Essen; Essen Germany
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Weidman-Evans E, Metz SM, Evans JD. Cardiovascular risks and benefits with oral drugs for Type 2 diabetes mellitus. Expert Rev Clin Pharmacol 2014; 7:225-33. [PMID: 24490745 DOI: 10.1586/17512433.2014.885836] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes mellitus affects approximately 321 million people worldwide. It is estimated that about half of these patients will die from cardiovascular complications. In spite of these statistics, medications for diabetes are approved based not on outcomes, but on surrogate markers such as blood glucose or glycosylated hemoglobin. In recent years, however, the safety of diabetes medications has come under scrutiny, and more studies are being undertaken to determine the effect(s) of the medications on actual outcomes. In this review the authors review available study results for all of the currently approved classes of oral medications for Type 2 diabetes, and discuss the possible mechanisms for the findings. More studies are necessary for many of these classes, however, to make definitive recommendations regarding their cardiovascular effects.
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Affiliation(s)
- Emily Weidman-Evans
- Department of Clinical and Administrative Sciences, University of Louisiana at Monroe College of Pharmacy, Louisiana 71201, LA, USA
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McAlister FA, Eurich DT, Majumdar SR, Johnson JA. The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. Eur J Heart Fail 2014; 10:703-8. [DOI: 10.1016/j.ejheart.2008.05.013] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Revised: 05/22/2008] [Accepted: 05/22/2008] [Indexed: 10/22/2022] Open
Affiliation(s)
- Finlay A. McAlister
- Division of General Internal Medicine, Department of Medicine; University of Alberta; Edmonton Alberta Canada
| | - Dean T. Eurich
- School of Public Health, University of Alberta; Edmonton Alberta Canada
| | - Sumit R. Majumdar
- Division of General Internal Medicine, Department of Medicine; University of Alberta; Edmonton Alberta Canada
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Azimova K, San Juan Z, Mukherjee D. Cardiovascular safety profile of currently available diabetic drugs. Ochsner J 2014; 14:616-32. [PMID: 25598727 PMCID: PMC4295739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023] Open
Abstract
BACKGROUND Cardiovascular disease is the leading cause of morbidity and mortality among patients with diabetes, underscoring the importance of choosing drugs that do not increase cardiovascular risk and reduce the risk of cardiovascular events. Since 2008, the US Food and Drug Administration has recommended that new drugs for type 2 diabetes undergo clinical trials to demonstrate cardiovascular safety in addition to glycemic benefit. In 2012, the European Medicines Agency issued a similar recommendation. METHODS We searched the PubMed, Cochrane CENTRAL, EMBASE, and CINAHL databases from inception through August 2013 and compiled and reviewed the existing data on the cardiovascular safety profiles of currently available diabetic drugs. RESULTS While intensive glycemic control in diabetics has been consistently shown to reduce the risk of microvascular complications, the data on macrovascular risk reduction have not been as clear, and questions have been raised about possible increases in cardiovascular morbidity and mortality. CONCLUSION Careful selection of drug therapy-paying particular attention to cardiovascular safety-is important in optimizing diabetic therapy.
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Affiliation(s)
- Komola Azimova
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul Foster School of Medicine, El Paso, TX
| | - Zinnia San Juan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul Foster School of Medicine, El Paso, TX
| | - Debabrata Mukherjee
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul Foster School of Medicine, El Paso, TX
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Nagendran J, Oudit GY, Bakal JA, Light PE, Dyck JRB, McAlister FA. Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes? Diabetes Obes Metab 2013; 15:1022-8. [PMID: 23668425 DOI: 10.1111/dom.12126] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 03/24/2013] [Accepted: 05/07/2013] [Indexed: 01/08/2023]
Abstract
AIMS Adenosine triphosphate sensitive potassium (K(ATP)) channel activity is cardioprotective during ischaemia. One of the purported mechanisms for sulphonylurea adverse effects is through inhibition of these channels. The purpose of this study is to examine whether patients using K(ATP) channel inhibitors at the time of an acute coronary syndrome are at greater risk of death or heart failure (HF) than those not exposed. METHODS Using linked administrative databases we identified all adults who had an acute coronary syndrome between April 2002 and October 2006 (n = 21 023). RESULTS Within 30 days of acute coronary syndrome, 5.3% of our cohort died and 15.6% were diagnosed with HF. Individuals with diabetes exhibited significantly higher risk of death (adjusted OR: 1.20, 95% CI: 1.03-1.40) and death or HF (aOR: 1.73, 95% CI: 1.59-1.89) than individuals without diabetes. However, there was no significantly increased risk of death (aOR: 1.00, 95% CI: 0.76-1.33) or death/HF (aOR: 1.06, 95% CI: 0.89-1.26) in patients exposed to K(ATP) channel inhibitors versus patients not exposed to K(ATP) channel inhibitors prior to their acute coronary syndrome. CONCLUSIONS Diabetes is associated with an increased risk of death or HF within 30 days of an acute coronary syndrome. However, we did not find any excess risk of death or HF associated with use of K(ATP) channel inhibitors at the time of an acute coronary syndrome, raising doubts about the hypothesis that sulphonylureas inhibit the cardioprotective effects of myocardial K(ATP) channels.
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Affiliation(s)
- J Nagendran
- Division of Cardiac Surgery, Department of Surgery, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, Faculty of Medicine and Dentistry, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
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El Messaoudi S, Rongen GA, Riksen NP. Metformin Therapy in Diabetes: The Role of Cardioprotection. Curr Atheroscler Rep 2013; 15:314. [DOI: 10.1007/s11883-013-0314-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Abstract
Myocardial infarct size is a major determinant of prognosis. Ischaemic preconditioning with brief coronary occlusion and reperfusion before a sustained period of coronary occlusion with reperfusion delays infarct development. Ischaemic postconditioning uses repetitive brief coronary occlusion during early reperfusion of myocardial infarction and reduces infarct size. Remote ischaemic preconditioning uses brief ischaemia and reperfusion of a distant organ to protect the myocardium. These conditioning protocols recruit a complex signal cascade of sarcolemmal receptor activation, intracellular enzyme activation, and ultimately mitochondrial stabilisation and inhibition of death signalling. Conditioning protocols have been successfully used in patients undergoing elective coronary revascularisation and reperfusion after acute myocardial infarction. Pharmacological recruitment of cardioprotective signalling has also been used to reduce infarct size, but so far without prognostic benefit. Outcomes of cardioprotection are affected by age, sex, comorbidities, and drugs, but also by technical issues related to determination of infarct size and revascularisation procedure.
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Affiliation(s)
- Gerd Heusch
- Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany.
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Engel SS, Golm GT, Shapiro D, Davies MJ, Kaufman KD, Goldstein BJ. Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis. Cardiovasc Diabetol 2013; 12:3. [PMID: 23286208 PMCID: PMC3585887 DOI: 10.1186/1475-2840-12-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 12/06/2012] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVE To compare the incidence of cardiovascular events and mortality in patients with type 2 diabetes mellitus treated with sitagliptin or non-sitagliptin comparators. METHODS A post hoc assessment of cardiovascular safety in 14,611 patients was performed by pooling data from 25 double-blind studies, which randomised patients at baseline to sitagliptin 100 mg/day or a non-sitagliptin comparator (i.e., non-exposed). Included studies were limited to those at least 12 weeks in duration (range: 12 to 104 weeks). Patient-level data were used in this analysis of major adverse cardiovascular events (MACE) including ischaemic events and cardiovascular deaths. Analyses were performed in three cohorts: the entire 25-study cohort, the cohort from placebo-controlled portions of studies (n=19), and the cohort from studies comparing sitagliptin to a sulphonylurea (n=3). RESULTS In the entire cohort analysis, 78 patients had at least 1 reported MACE-related event, with 40 in the sitagliptin group and 38 in the non-exposed group. The exposure-adjusted incidence rate was 0.65 per 100 patient-years in the sitagliptin group and 0.74 in the non-exposed group (incidence rate ratio = 0.83 [95% confidence interval (CI): 0.53, 1.30]). In the analysis comparing sitagliptin to placebo, the exposure-adjusted incidence rate was 0.80 per 100-patient-years with sitagliptin and 0.76 with placebo (incidence rate ratio = 1.01 [95% CI: 0.55, 1.86]). In the analysis comparing sitagliptin to sulphonylurea, the exposure-adjusted incidence rate was 0.00 per 100 patient-years with sitagliptin and 0.86 with sulphonylurea (incidence rate ratio = 0.00 [95% CI: 0.00, 0.31]). CONCLUSION A pooled analysis of 25 randomised clinical trials does not indicate that treatment with sitagliptin increases cardiovascular risk in patients with type 2 diabetes mellitus. In a subanalysis, a higher rate of cardiovascular-related events was associated with sulphonylurea relative to sitagliptin.
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Juurlink DN, Gomes T, Shah BR, Mamdani MM. Adverse cardiovascular events during treatment with glyburide (glibenclamide) or gliclazide in a high-risk population. Diabet Med 2012; 29:1524-8. [PMID: 22913620 DOI: 10.1111/j.1464-5491.2012.03772.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
AIMS Sulphonylureas promote insulin release by inhibiting pancreatic potassium channels. Older sulphonylureas such as glyburide (glibenclamide), but not newer ones such as gliclazide, antagonize similar channels in myocardium, interfering with the protective effects of ischaemic preconditioning. Whether this imparts a higher risk of adverse cardiac events is unknown. METHODS We conducted a population-based cohort study of patients aged 66 years and older who were hospitalized for acute myocardial infarction or who underwent percutaneous coronary intervention between 1 April 2007 and 31 March 2010 while receiving either glyburide or gliclazide. We used a high-dimensional propensity score matching process to ensure similarity of glyburide- and gliclazide-treated patients. The primary outcome was a composite of death or hospitalization for myocardial infarction or heart failure. RESULTS During the 2-year study period, we matched 1690 patients treated with glyburide to 984 patients treated with gliclazide at the time of hospitalization for acute myocardial infarction or percutaneous coronary intervention. We found no difference in the risk of the composite outcome among patients receiving glyburide (adjusted hazard ratio 1.01; 95% CI 0.86-1.18). We found similar results in secondary analyses of each outcome individually, and in two supplementary analyses (haemorrhage and pneumonia) in which we anticipated no difference between the two patient groups. CONCLUSIONS Among older patients hospitalized for acute myocardial infarction or percutaneous coronary intervention, treatment with glyburide is not associated with an increased risk of future adverse cardiovascular events relative to gliclazide, suggesting that the effect of glyburide on ischaemic preconditioning is of little clinical relevance.
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Affiliation(s)
- D N Juurlink
- Department of Medicine, University of Toronto, Toronto, ON, Canada.
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Hanninen M, McAlister FA, Bakal JA, van Diepen S, Ezekowitz JA. Neither diabetes nor glucose-lowering drugs are associated with mortality after noncardiac surgery in patients with coronary artery disease or heart failure. Can J Cardiol 2012; 29:423-8. [PMID: 22985785 DOI: 10.1016/j.cjca.2012.07.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 06/22/2012] [Accepted: 07/07/2012] [Indexed: 10/27/2022] Open
Abstract
BACKGROUND It is unclear whether diabetes mellitus or use of particular glucose-lowering agents is associated with increased risk of mortality after noncardiac surgery in patients with known cardiac disease. METHODS We carried out a retrospective cohort study using 4 linked administrative databases in the province of Alberta, Canada from 1999-2006. RESULTS Of the 32,834 patients with known cardiac disease in our cohort, 9305 (28%) had diabetes. All-cause 30-day mortality after noncardiac surgery was 6.4% in patients with diabetes, and 6.1% in those without diabetes (multivariate adjusted odds ratio [aOR] 0.97, 95% confidence interval [CI], 0.87-1.08). In the 24,037 patients older than 65, mortality was 7.5% in individuals with diabetes and 7.5% in those without diabetes (5.7% in those taking insulin [aOR, 0.89; 95% CI, 0.70-1.13], 8.0% in those using oral agents only [aOR, 1.08; 95% CI, 0.95-1.22]). None of the glucose-lowering drug classes were associated with perioperative mortality in elderly cardiac patients (sulfonylureas aOR, 0.94; 95% CI, 0.76-1.16; metformin aOR, 0.92; 95% CI, 0.74-1.14; thiazolidinediones aOR, 0.64; 95% CI, 0.40-1.04; insulin aOR, 0.83; 95% CI, 0.65-1.08), but use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (aOR, 0.83; 95% CI, 0.75-0.93), β-blockers (aOR, 0.82; 95% CI, 0.72-0.93), or statins (aOR, 0.65; 95% CI, 0.55-0.78) in the 100 days before surgery were associated with lower 30-day mortality. CONCLUSIONS Neither diabetes nor exposure to common classes of glucose-lowering drugs preoperatively were associated with increased perioperative mortality in cardiac patients undergoing noncardiac surgery. However, cardiac patients not using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, or statins preoperatively exhibited higher mortality rates, emphasizing the importance of optimizing evidence-based therapy before elective surgery in these patients.
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Affiliation(s)
- Mikael Hanninen
- Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada
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Breuer TGK, Meier JJ. Inpatient treatment of type 2 diabetes. DEUTSCHES ARZTEBLATT INTERNATIONAL 2012; 109:466-74. [PMID: 22833757 DOI: 10.3238/arztebl.2012.0466] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Accepted: 01/12/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Type 2 diabetes is common in hospitalized patients and is often accompanied by comorbidities; it is thus reasonable to ask whether the current standard treatments for type 2 diabetes are suitable for in-hospital use. We discuss the current glucose-lowering strategies and glycemic targets and derive practical recommendations for their application in hospitalized patients. METHODS The pertinent literature, including clinical trials, review articles, guidelines, and manufacturers' information is selectively reviewed. RESULTS In critically ill patients with diabetes, the glucose concentration target value should be 140 to 180 mg/dL. In stable patients, the target should be less than 140 mg/dL in the fasting state and less than 180 mg/dL after meals. Hypoglycemic episodes should be strictly avoided. Temporary treatment with insulin is indicated for most hospitalized patients with diabetes, although oral antidiabetic agents may be continued if the hospitalization is expected to be brief. Intravenous insulin is advisable in certain situations, e.g., long operations or metabolic decompensation. Glucose-lowering strategies must be chosen individually for each patient, with consideration of the relevant comorbidities (e.g. coronary heart disease, congestive heart failure, cirrhosis, renal failure) and special conditions (e.g. prolonged fasting, administration of contrast agents, high-dose glucocorticoid treatment). CONCLUSION The treatment of patients with type 2 diabetes in the hospital is very different from their treatment at home. The particular conditions and comorbidities that can arise in the hospital necessitate flexible, individualized strategies for lowering blood glucose concentration.
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Affiliation(s)
- Thomas G K Breuer
- Division of Diabetology and Gastrointestinal Endocrinology, St. Josef-Hospital, Ruhr-University Bochum, Germany
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Home P. Cardiovascular disease and oral agent glucose-lowering therapies in the management of type 2 diabetes. Diabetes Technol Ther 2012; 14 Suppl 1:S33-42. [PMID: 22650223 DOI: 10.1089/dia.2012.0007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Although glucose-lowering oral agents have been available for clinical use for over 60 years, the formal evidence base supporting their advantage and safety in regard of cardiovascular (CV) outcomes remains less than optimal. However, a synthesis of the evidence results in a high probability of benefit. For metformin, the United Kingdom Prospective Diabetes Study (UKPDS) substudy is convincing for a definite effect in reducing myocardial infarction (MI), but the quantitative extent of that is uncertain. For sulfonylureas, support for reduction in MI comes from the UKPDS extension study, where the central estimate for risk reduction remains the same as in the original planned end to the study, but the greater number of events was statistically significant for the sulfonylurea/insulin arm. Other studies do not support the view that metformin and sulfonylureas differ with respect to MI or indeed CV outcomes more generally. The data available for acarbose, an α-glucosidase inhibitor, are weak but not of concern, although some positive substudy data are available for people with impaired glucose tolerance. For peroxisome proliferator-activated receptor-γ agonists the CV data are more controversial, but the purpose-designed randomized controlled trials are clear that pioglitazone is advantageous to placebo (except for heart failure [HF]), whereas rosiglitazone is indistinguishable from metformin/sulfonylureas (even when including HF data). Lower-quality data do, however, lead to significant concerns for MI with rosiglitazone. Early and somewhat low-quality data for the dipeptidyl peptidase inhibitors show they are safe and hold promise for cardiovascular advantage, with major randomized controlled trials being underway. Preliminary CV data are available for one sodium/glucose cotransporter 2 inhibitor and look reassuring.
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Affiliation(s)
- Philip Home
- The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
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Hirsch IB, O'Brien KD. How to best manage glycemia and non-glycemia during the time of acute myocardial infarction. Diabetes Technol Ther 2012; 14 Suppl 1:S22-32. [PMID: 22650221 PMCID: PMC3388496 DOI: 10.1089/dia.2012.0095] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Acute myocardial infarction (AMI) is common in patients with diabetes. Reasons for this are multifactorial, but all relate to a variety of maladaptive responses to acute hyperglycemia. Persistent hyperglycemia is associated with worse left ventricular function and higher mortality during AMI, but intervention data are far from clear. Although there is a theoretical basis for the use of glucose-insulin-potassium infusion during AMI, lack of outcome efficacy (and inability to reach glycemic targets) in recent randomized trials has resulted in little enthusiasm for this strategy. Based on the increasing understanding of the dangers of hypoglycemia, while at the same time appreciating the role of hyperglycemia in AMI patients, goal glucose levels of 140-180 mg/dL using an intravenous insulin infusion while not eating seem reasonable for most patients and hospital systems. Non-glycemic therapy for patients with diabetes and AMI has benefited from more conclusive data, as this population has greater morbidity and mortality than those without diabetes. For ST-elevation myocardial infarction (STEMI), reperfusion therapy with primary percutaneous coronary intervention or fibrinolysis, antithrombotic therapy to prevent acute stent thrombosis following percutaneous coronary intervention or rethrombosis following thrombolysis, and initiation of β-blocker therapy are the current standard of care. Emergency coronary artery bypass graft surgery is reserved for the most critically ill. For those with non-STEMI, initial reperfusion therapy or fibrinolysis is not routinely indicated. Overall, there have been dramatic advances for the treatment of people with AMI and diabetes. The use of continuous glucose monitoring in this population may allow better ability to safely reach glycemic targets, which it is hoped will improve glycemic control.
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Affiliation(s)
- Irl B Hirsch
- Division of Metabolism, University of Washington School of Medicine, Seattle, Washington, USA.
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Cardiovascular effects of antidiabetic agents: focus on blood pressure effects of incretin-based therapies. ACTA ACUST UNITED AC 2012; 6:163-8. [PMID: 22433315 DOI: 10.1016/j.jash.2012.02.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 02/16/2012] [Accepted: 02/18/2012] [Indexed: 12/17/2022]
Abstract
Hyperglycemia is associated with increased risk of cardiovascular disease. Nevertheless, results of large clinical trials suggest that tight glucose control does not reduce the risk of macrovascular cardiovascular events in type 2 diabetes mellitus and may cause harm. This may reflect the adverse consequences of increased hypoglycemia or the adverse effects of many antidiabetic agents on weight gain. The consequences of intensive therapy may also depend on the mechanism of the antidiabetic agent(s) used to achieve tight control. Metformin, an antidiabetic agent that reduces weight and activates AMP-activated protein kinase, reduces risk of cardiovascular events in overweight diabetics. In contrast, the thiazolidinedione rosiglitazone increases cardiovascular risk. Sulfonylureas may increase the risk of cardiovascular events through effects on the SUR1 of the cardiac K(ATP) channel. Stable analogues of glucagon-like peptide-1 reduce body weight and blood pressure, and have favorable effects on ischemia following reperfusion in animal models. The dipeptidyl peptidase IV inhibitors prevent the breakdown of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, but also decrease the degradation of several vasoactive peptides. Dipeptidyl peptidase IV inhibitors have favorable effects in animal models of ischemia/reperfusion. They have been reported both to decrease and to increase blood pressure. Clinical trials will address the effect of the incretin-based agents on macrovascular cardiovascular events.
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Abdelmoneim AS, Hasenbank SE, Seubert JM, Brocks DR, Light PE, Simpson SH. Variations in tissue selectivity amongst insulin secretagogues: a systematic review. Diabetes Obes Metab 2012; 14:130-8. [PMID: 21923736 DOI: 10.1111/j.1463-1326.2011.01496.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIM Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses. METHODS Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug. RESULTS Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values. CONCLUSIONS Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.
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MESH Headings
- ATP-Binding Cassette Transporters/drug effects
- ATP-Binding Cassette Transporters/metabolism
- Animals
- Carbamates/adverse effects
- Cardiovascular Diseases/chemically induced
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/physiopathology
- Cricetinae
- Cyclohexanes/adverse effects
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Gliclazide/adverse effects
- Glipizide/adverse effects
- Glyburide/adverse effects
- Humans
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/pharmacology
- Ischemic Preconditioning, Myocardial
- Isoindoles/adverse effects
- Mice
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Nateglinide
- Phenylalanine/adverse effects
- Phenylalanine/analogs & derivatives
- Piperidines/adverse effects
- Potassium Channels, Inwardly Rectifying/drug effects
- Potassium Channels, Inwardly Rectifying/metabolism
- Rats
- Receptors, Drug/drug effects
- Receptors, Drug/metabolism
- Risk Factors
- Sulfonylurea Compounds/adverse effects
- Sulfonylurea Receptors
- Tolbutamide/adverse effects
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Affiliation(s)
- A S Abdelmoneim
- Faculty of Pharmacy & Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada
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Wulf MA, Joksimovic L, Tress W. Das Ringen um Sinn und Anerkennung – Eine psychodynamische Sicht auf das Phänomen des Neuroenhancement (NE). Ethik Med 2011. [DOI: 10.1007/s00481-011-0137-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
INTRODUCTION Sulfonylureas (SUs) are the most commonly prescribed medications for type 2 diabetes mellitus worldwide. Differences among SUs for kinetic and adenosine triphosphate sensitive potassium (KATP) channels selectivity and consequential extrapancreatic effects, although recognized in literature, are not considered by treatment guidelines. AREAS COVERED The roles of SUs in various system-related adverse effects have not been well understood. Inconsistencies in the literature and lack of clinical trials assessing the long-term effects of monotherapy or combination therapy with SUs add to the concern. This review provides insights in issues concerning safety of SUs based on literature published between 1980 and 2011. A comprehensive search was carried out on PubMed, Embase and Cochrane databases using the search terms: sulfonylureas, sulfonylureas and KATP channels, sulfonylureas and cardiovascular (CV) effects and sulfonylureas side effects. EXPERT OPINION SUs have been linked to CV events, growth hormone (GH) disorder, malignancy, weight gain, erectile dysfunction and central nervous system (CNS) adverse effects. These adverse effects generally get masked as they are thought to be related to diabetes per se. The current article will allow the fraternity to ponder and undertake further research on the ill effects of largely prescribed antidiabetic medication.
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Affiliation(s)
- Devindra Sehra
- Sehra Medical Centre, 29 NWA, Punjabi Bagh, New Delhi 110026, India.
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Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, Hansen ML, Fosbøl EL, Køber L, Norgaard ML, Madsen M, Hansen PR, Torp-Pedersen C. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 2011; 32:1900-8. [PMID: 21471135 DOI: 10.1093/eurheartj/ehr077] [Citation(s) in RCA: 294] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIMS The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study. METHODS AND RESULTS All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint. CONCLUSION Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.
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Affiliation(s)
- Tina Ken Schramm
- Department of Cardiology B, section 2141, Rigshospitalet, The Heart Center, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
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Zeller M, Danchin N, Simon D, Vahanian A, Lorgis L, Cottin Y, Berland J, Gueret P, Wyart P, Deturck R, Tabone X, Machecourt J, Leclercq F, Drouet E, Mulak G, Bataille V, Cambou JP, Ferrieres J, Simon T. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab 2010; 95:4993-5002. [PMID: 20702526 DOI: 10.1210/jc.2010-0449] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
BACKGROUND The impact of antidiabetic medications on clinical outcomes in patients developing acute myocardial infarction (MI) is controversial. We sought to determine whether in-hospital outcomes in patients who were on sulfonylureas (SUs) when they developed their MIs differed from that of diabetic patients not receiving SUs and whether clinical outcomes were related to the pancreatic cells specificity of SUs. METHODS AND RESULTS We analyzed the outcomes of the 1310 diabetic patients included in the nationwide French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction in 2005. Medications used before the acute episode were recorded. In-hospital complications were analyzed according to prior antidiabetic treatment. Mortality was lower in patients previously treated with SUs (3.9%) vs. those on other oral medications (6.4%), insulin (9.4%), or no medication (8.4%) (P = 0.014). Among SU-treated patients, in-hospital mortality was lower in patients receiving pancreatic cells-specific SUs (gliclazide or glimepiride) (2.7%), compared with glibenclamide (7.5%) (P = 0.019). Arrhythmias and ischemic complications were also less frequent in patients receiving gliclazide/glimepiride. The lower risk in patients receiving gliclazide/glimepiride vs. glibenclamide persisted after multivariate adjustment (odds ratio 0.15; 95% confidence interval 0.04-0.56) and in propensity score-matched cohorts. CONCLUSION In this nationwide registry of patients hospitalized for acute MI, no hazard was associated with the use of SUs before the acute episode. In addition, patients previously receiving gliclazide/glimepiride had improved in-hospital outcomes, compared with those on glibenclamide.
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Affiliation(s)
- Marianne Zeller
- Laboratory of Experimental and Cardiovascular Physiopathology and Pharmacology, Institut Fédératif de Recherche Santé-Sciences et Techniques de l'Information et de la Communication, Faculty of Medicine, 7 Bd Jeanne d'Arc, Dijon, France.
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Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N, Gislason GH, Folke F, Andersen SS, Schramm TK, Abildstrøm SZ, Poulsen HE, Køber L, Torp-Pedersen C. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Int J Cardiol 2010; 152:327-31. [PMID: 20837828 DOI: 10.1016/j.ijcard.2010.07.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2009] [Revised: 05/05/2010] [Accepted: 07/16/2010] [Indexed: 11/18/2022]
Abstract
BACKGROUND Patients with atrial fibrillation (AF) often require anticoagulation and platelet inhibition, but data are limited on the bleeding risk of combination therapy. METHODS We performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF between January 1, 1997, and December 31, 2006, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding. RESULTS A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89-4.76) for warfarin-aspirin-clopidogrel. CONCLUSIONS In patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk than did warfarin monotherapy.
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Affiliation(s)
- Morten L Hansen
- Department of Cardiology, Copenhagen University Hospital Gentofte, Niels Andersens Vej 65 2900, Hellerup, Copenhagen, Denmark.
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