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Narcisse DI, Katzenberger DR, Gutierrez JA. Contemporary Medical Therapies for Patients with Peripheral Artery Disease and Concomitant Type 2 Diabetes Mellitus: a Review of Current Evidence. Curr Cardiol Rep 2022; 24:567-576. [PMID: 35201560 DOI: 10.1007/s11886-022-01677-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/12/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to highlight the evidence behind landmark trials involving these two novel drug classes in conjunction with a review of long-standing therapies used to improve cardiovascular (CV) outcomes among patients with peripheral artery disease (PAD) patients and type 2 diabetes mellitus (T2DM). RECENT FINDINGS Recently, societal guideline recommendations have expanded the management of T2DM to incorporate therapies with CV risk factor modification. This is due to CV outcome trials (CVOT) uncovering advantageous cardioprotective effects of several novel therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Providers who manage high-risk patients with T2DM, such as those with concomitant PAD, are expected to incorporate these novel medical therapies into routine patient care. The body of evidence surrounding GLP-1 RA demonstrates a strong benefit in mitigating the innate heightened CV risk among patients with T2DM. Furthermore, SGLT2i not only have a favorable CV profile but also reduce the risk of HF hospitalizations and progression of renal disease. Patients with T2DM and PAD are known to be at a heightened risk for major adverse cardiac and lower extremity events, heart failure, and chronic kidney disease. As such, the use of novel therapies such as GLP-RA and SGLT2i should be strongly considered to minimize morbidity and mortality in this vulnerable population.
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Affiliation(s)
- Dennis I Narcisse
- Division of Cardiology, Duke University Health System, Durham, NC, USA.
| | | | - J Antonio Gutierrez
- Division of Cardiology, Duke University Health System, Durham, NC, USA
- Section of Cardiology, Durham Veterans Affairs Health Care System, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
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2
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Characterization of Redox-Responsive LXR-Activating Nanoparticle Formulations in Primary Mouse Macrophages. Molecules 2019; 24:molecules24203751. [PMID: 31635211 PMCID: PMC6833070 DOI: 10.3390/molecules24203751] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 10/10/2019] [Accepted: 10/16/2019] [Indexed: 12/15/2022] Open
Abstract
Activation of the transcription factor liver X receptor (LXR) has beneficial effects on macrophage lipid metabolism and inflammation, making it a potential candidate for therapeutic targeting in cardiometabolic disease. While small molecule delivery via nanomedicine has promising applications for a number of chronic diseases, questions remain as to how nanoparticle formulation might be tailored to suit different tissue microenvironments and aid in drug delivery. In the current study, we aimed to compare the in vitro drug delivering capability of three nanoparticle (NP) formulations encapsulating the LXR activator, GW-3965. We observed little difference in the base characteristics of standard PLGA-PEG NP when compared to two redox-active polymeric NP formulations, which we called redox-responsive (RR)1 and RR2. Moreover, we also observed similar uptake of these NP into primary mouse macrophages. We used the transcript and protein expression of the cholesterol efflux protein and LXR target ATP-binding cassette A1 (ABCA1) as a readout of GW-3956-induced LXR activation. Following an initial acute uptake period that was meant to mimic circulating exposure in vivo, we determined that although the induction of transcript expression was similar between NPs, treatment with the redox-sensitive RR1 NPs resulted in a higher level of ABCA1 protein. Our results suggest that NP formulations responsive to cellular cues may be an effective tool for targeted and disease-specific drug release.
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Liu J, Huang Z, Ma W, Peng S, Li Y, Miranda KM, Tian J, Zhang Y. Design and synthesis of rosiglitazone-ferulic acid-nitric oxide donor trihybrids for improving glucose tolerance. Eur J Med Chem 2019; 162:650-665. [PMID: 30481687 DOI: 10.1016/j.ejmech.2018.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 09/30/2018] [Accepted: 10/01/2018] [Indexed: 01/11/2023]
Abstract
Glucose intolerance is associated with metabolic syndrome and type 2 diabetes mellitus (T2DM) while some new therapeutic drugs, such as rosiglitazone (Rosi), for T2DM can cause severe cardiovascular side effects. Herein we report the synthesis of Rosi-ferulic acid (FA)-nitric oxide (NO) donor trihybrids to improve glucose tolerance and minimize the side effects. In comparison with Rosi, the most active compound 21 exhibited better effects on improving glucose tolerance, which was associated with its NO production, antioxidant and anti-inflammatory activities. Furthermore, 21 displayed relatively high stability in the simulated gastrointestinal environments and human liver microsomes, and released Rosi in plasma. More importantly, 21, unlike Rosi, had little stimulatory effect on the membrane translocation of aquaporin-2 (AQP2) in kidney collecting duct epithelial cells. These, together with a better safety profile, suggest that the trihybrids, like 21, may be promising candidates for intervention of glucose intolerance-related metabolic syndrome and T2DM.
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Affiliation(s)
- Jingchao Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China
| | - Zhangjian Huang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China
| | - Wenhuan Ma
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China
| | - Sixun Peng
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China
| | - Yunman Li
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China.
| | - Katrina M Miranda
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, 85721, United States.
| | - Jide Tian
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, United States
| | - Yihua Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
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Giacalone G, Tsapis N, Mousnier L, Chacun H, Fattal E. PLA-PEG Nanoparticles Improve the Anti-Inflammatory Effect of Rosiglitazone on Macrophages by Enhancing Drug Uptake Compared to Free Rosiglitazone. MATERIALS 2018; 11:ma11101845. [PMID: 30262751 PMCID: PMC6213468 DOI: 10.3390/ma11101845] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 09/21/2018] [Accepted: 09/25/2018] [Indexed: 01/17/2023]
Abstract
Among cardiovascular diseases, atherosclerosis remains the first cause of death in the United States of America and Europe, as it leads to myocardial infarction or stroke. The high prevalence of heart diseases is due to the difficulty in diagnosing atherosclerosis, since it can develop for decades before symptoms occur, and to the complexity of the treatment since targets are also important components of the host defenses. The antidiabetics thiazolidinediones, among which is rosiglitazone (RSG), have demonstrated anti-atherosclerotic effect in animal models, and are therefore promising candidates for the improvement of atherosclerosis management. Nevertheless, their administration is hindered by the insurgence of severe side effects. To overcome this limitation, rosiglitazone has been encapsulated into polymeric nanoparticles, which permit efficient delivery to its nuclear target, and selective delivery to the site of action, allowing the reduction of unwanted effects. In the present work, we describe nanoparticle formulation using polylactic acid (PLA) coupled to polyethylene glycol (PEG), their characterization, and their behavior on RAW264.7 macrophages, an important target in atherosclerosis treatment. RSG nanocarriers showed no toxicity on cells at all concentrations tested, an anti-inflammatory effect in a dose-dependent manner, up to 5 times more efficient than the free molecule, and an increased RSG uptake which is consistent with the effect shown. These biodegradable nanoparticles represent a valid tool to be further investigated for the treatment of atherosclerosis.
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Affiliation(s)
- Giovanna Giacalone
- Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
| | - Nicolas Tsapis
- Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
| | - Ludivine Mousnier
- Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
| | - Hélène Chacun
- Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
| | - Elias Fattal
- Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
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Zhuang XD, He X, Yang DY, Guo Y, He JG, Xiao HP, Liao XX. Comparative cardiovascular outcomes in the era of novel anti-diabetic agents: a comprehensive network meta-analysis of 166,371 participants from 170 randomized controlled trials. Cardiovasc Diabetol 2018; 17:79. [PMID: 29871636 PMCID: PMC5989345 DOI: 10.1186/s12933-018-0722-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 05/23/2018] [Indexed: 01/12/2023] Open
Abstract
Background Cardiovascular (CV) safety of one anti-diabetic medication over another remains partially delineated. We sought to assess the comparative effect on CV outcomes among novel anti-diabetic agents. Methods This study was registered with the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and Cochrane Library Central Register of Controlled Trials were searched between Jan 1, 1980, and June 30, 2016. Randomized controlled trials comparing anti-diabetic drugs with other comparators in adults with type 2 diabetes were included. We used network meta-analysis to obtain estimates for the outcomes of interests. In addition, post hoc correlation analysis of severe hypoglycemia and primary outcome as per ranking order was conducted. Outcomes were major adverse cardiovascular events (MACE) and all-cause mortality. Results A total of 170 trials (166,371 participants) were included. By class and by individual, sulfonylureas (SU) ranked last. Therefore, with SU as reference, categorically sodium-glucose co-transporter 2 inhibitor (SGLT2i), insulin (INS), glucagon-like peptide-1 receptor agonist, and dipeptidyl peptidase 4 inhibitor were significantly superior in term of MACE; as were SGLT2i and INS in term of all-cause mortality. Moreover, ranking orders of MACE and all-cause mortality were both positively correlated with that of severe hypoglycemia risk (by individual: R2 = 0.3178, P = 0.018; by class: R2 = 0.2574, P = 0.038). Conclusions Novel anti-diabetic agents possess favorable CV safety profile, despite small but robust differences between individuals. In addition, increase in CV risk was again shown to be partly attributable to a concomitant increase in the risk of severe hypoglycemia, for which SU performed the worst. Electronic supplementary material The online version of this article (10.1186/s12933-018-0722-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiao-Dong Zhuang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Key Laboratory on Assisted Circulation, Ministry of Health, No. 58 Zhongshan 2nd road, Guangzhou, 510080, People's Republic of China
| | - Xin He
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Key Laboratory on Assisted Circulation, Ministry of Health, No. 58 Zhongshan 2nd road, Guangzhou, 510080, People's Republic of China
| | - Da-Ya Yang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Key Laboratory on Assisted Circulation, Ministry of Health, No. 58 Zhongshan 2nd road, Guangzhou, 510080, People's Republic of China
| | - Yue Guo
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Key Laboratory on Assisted Circulation, Ministry of Health, No. 58 Zhongshan 2nd road, Guangzhou, 510080, People's Republic of China
| | - Jian-Gui He
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Key Laboratory on Assisted Circulation, Ministry of Health, No. 58 Zhongshan 2nd road, Guangzhou, 510080, People's Republic of China
| | - Hai-Peng Xiao
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Xin-Xue Liao
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. .,Key Laboratory on Assisted Circulation, Ministry of Health, No. 58 Zhongshan 2nd road, Guangzhou, 510080, People's Republic of China.
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Worsening Heart Failure During the Use of DPP-4 Inhibitors: Pathophysiological Mechanisms, Clinical Risks, and Potential Influence of Concomitant Antidiabetic Medications. JACC-HEART FAILURE 2018. [PMID: 29525332 DOI: 10.1016/j.jchf.2017.12.016] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis. These potentially deleterious actions of DPP-4 inhibitors might not become clinically apparent if these drugs were to promote sodium excretion. However, the natriuretic effect of DPP-4 inhibitors is modest, because they act on the distal (rather than proximal) renal tubules. Accordingly, both clinical trials and observational studies have reported an increase in the risk of heart failure in patients with type 2 diabetes who were receiving DPP-4 inhibitors. This risk may be muted in trials with a high prevalence of metformin use or with low and declining background use of insulin and thiazolidinediones. Still, the most vulnerable patients (i.e., those with established heart failure) were not well represented in these studies. The only trial that specifically evaluated patients with pre-existing left ventricular dysfunction observed important drug-related adverse structural and clinical effects. In conclusion, an increased risk of worsening heart failure appears to be a class effect of DPP-4 inhibitors, even in patients without a history of heart failure. Additional clinical trials are urgently needed to elucidate the benefits and risks of DPP-4 inhibitors in patients with established left ventricular dysfunction.
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Davidson MA, Mattison DR, Azoulay L, Krewski D. Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future. Crit Rev Toxicol 2017; 48:52-108. [PMID: 28816105 DOI: 10.1080/10408444.2017.1351420] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.
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Affiliation(s)
- Melissa A Davidson
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada
| | - Donald R Mattison
- b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada
| | - Laurent Azoulay
- d Center for Clinical Epidemiology , Lady Davis Research Institute, Jewish General Hospital , Montreal , Canada.,e Department of Oncology , McGill University , Montreal , Canada
| | - Daniel Krewski
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada.,f Faculty of Medicine , University of Ottawa , Ottawa , Canada
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Paneni F, Lüscher TF. Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes. Am J Cardiol 2017; 120:S17-S27. [PMID: 28606340 DOI: 10.1016/j.amjcard.2017.05.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Patients with type 2 diabetes (T2DM) have a significantly higher risk of developing cardiovascular disease (CVD)-namely myocardial infarction, heart failure, and stroke. Despite clear advances in the prevention and treatment of CVD, the impact of T2DM on CVD outcome remains high and continues to escalate. Available evidence indicates that the risk of macrovascular complications increases with the severity of hyperglycemia, thus suggesting that the relation between metabolic disturbances and vascular damage is approximately linear. Although current antidiabetic drugs are highly effective for the management of hyperglycemia, most T2DM patients remain exposed to a substantial and concrete risk of CVD. Over the last decade many glucose-lowering agents have been tested for their safety and efficacy in T2DM with CVD. Noteworthy, most of these studies failed to show a significant benefit in terms of CV morbidity and mortality, despite intensive glycemic control. The recent trials Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME); Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6); Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER); and Insulin Resistance Intervention After Stroke (IRIS) have shed some light on this important clinical issue, thus showing a convincing effect of empagliflozin, liraglutide, and pioglitazone on CVD outcomes. Here we provide a critical and updated overview of the main glucose-lowering agents and their risk/benefit ratio for the prevention of CVD in patients with T2DM.
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9
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Paneni F, Lüscher TF. Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes. Am J Med 2017; 130:S18-S29. [PMID: 28526186 DOI: 10.1016/j.amjmed.2017.04.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Patients with type 2 diabetes (T2DM) have a significantly higher risk of developing cardiovascular disease (CVD)-namely myocardial infarction, heart failure, and stroke. Despite clear advances in the prevention and treatment of CVD, the impact of T2DM on CVD outcome remains high and continues to escalate. Available evidence indicates that the risk of macrovascular complications increases with the severity of hyperglycemia, thus suggesting that the relation between metabolic disturbances and vascular damage is approximately linear. Although current antidiabetic drugs are highly effective for the management of hyperglycemia, most T2DM patients remain exposed to a substantial and concrete risk of CVD. Over the last decade many glucose-lowering agents have been tested for their safety and efficacy in T2DM with CVD. Noteworthy, most of these studies failed to show a significant benefit in terms of CV morbidity and mortality, despite intensive glycemic control. The recent trials Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME); Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6); Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER); and Insulin Resistance Intervention After Stroke (IRIS) have shed some light on this important clinical issue, thus showing a convincing effect of empagliflozin, liraglutide, and pioglitazone on CVD outcomes. Here we provide a critical and updated overview of the main glucose-lowering agents and their risk/benefit ratio for the prevention of CVD in patients with T2DM.
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Affiliation(s)
- Francesco Paneni
- University Heart Center, Cardiology, University Hospital Zurich, Switzerland; Center for Molecular Cardiology, University of Zurich, Switzerland.
| | - Thomas F Lüscher
- University Heart Center, Cardiology, University Hospital Zurich, Switzerland; Center for Molecular Cardiology, University of Zurich, Switzerland
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Abstract
INTRODUCTION Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes. AREAS COVERED Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined. EXPERT OPINION Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin.
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Affiliation(s)
- Lisa M Younk
- a Department of Medicine , University of Maryland School of Medicine , Baltimore , MD , USA
| | - Elizabeth M Lamos
- b Division of Endocrinology, Diabetes and Nutrition , University of Maryland School of Medicine , Baltimore , MD , USA
| | - Stephen N Davis
- a Department of Medicine , University of Maryland School of Medicine , Baltimore , MD , USA
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Pladevall M, Riera-Guardia N, Margulis AV, Varas-Lorenzo C, Calingaert B, Perez-Gutthann S. Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. BMC Cardiovasc Disord 2016; 16:14. [PMID: 26769243 PMCID: PMC4714432 DOI: 10.1186/s12872-016-0187-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 01/08/2016] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The results of observational studies evaluating and comparing the cardiovascular safety of glitazones, metformin and sufonylureas are inconsistent.To conduct and evaluate heterogeneity in a meta-analysis of observational studies on the risk of acute myocardial infarction (AMI) or stroke in patients with type 2 diabetes using non-insulin blood glucose-lowering drugs (NIBGLD). METHODS We systematically identified and reviewed studies evaluating NIBGLD in patients with type 2 diabetes indexed in Medline, Embase, or the Cochrane Library that met prespecified criteria. The quality of included studies was assessed with the RTI item bank. Results were combined using fixed- and random-effects models, and the Higgins I(2) statistic was used to evaluate heterogeneity. Sensitivity analyses by study quality were conducted. RESULTS The summary relative risk (sRR) (95% CI) of AMI for rosiglitazone versus pioglitazone was 1.13 (1.04-1.24) [I(2) = 55%]. In the sensitivity analysis, heterogeneity was reduced [I(2) = 16%]. The sRR (95% CI) of stroke for rosiglitazone versus pioglitazone was 1.18 (1.02-1.36) [I(2) = 42%]. There was strong evidence of heterogeneity related to study quality in the comparisons of rosiglitazone versus metformin and rosiglitazone versus sulfonylureas (I (2) ≥ 70%). The sRR (95% CI) of AMI for sulfonylurea versus metformin was 1.24 (1.14-1.34) [I(2) = 41%] and for pioglitazone versus metformin was 1.02 (0.75-1.38) [I(2) = 17%]. Sensitivity analyses decreased heterogeneity in most comparisons. CONCLUSION/INTERPRETATION Sulfonylureas increased the risk of AMI by 24% compared with metformin; an imprecise point estimate indicated no difference in risk of AMI when comparing pioglitazone with metformin. The presence of heterogeneity precluded any conclusions on the other comparisons. The quality assessment was valuable in identifying methodological problems in the individual studies and for analysing potential sources of heterogeneity.
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Affiliation(s)
- Manel Pladevall
- RTI Health Solutions, Trav. Gracia 56 Atico 1 08006, Barcelona, Spain. .,The Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan, USA.
| | | | - Andrea V Margulis
- RTI Health Solutions, Trav. Gracia 56 Atico 1 08006, Barcelona, Spain.
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12
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Boyle SM, Simon B, Kobrin SM. Antidiabetic Therapy in End-Stage Renal Disease. Semin Dial 2015; 28:337-44. [DOI: 10.1111/sdi.12368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Suzanne M. Boyle
- Division of Nephrology and Hypertension; Drexel University College of Medicine; Philadelphia Pennsylvania
| | - Barbara Simon
- Division of Endocrinology; Drexel University College of Medicine; Philadelphia Pennsylvania
| | - Sidney M. Kobrin
- Renal, Electrolyte, and Hypertension Division; Hospital of the University of Pennsylvania; Perelman School of Medicine; University of Pennsylvania; Philadelphia Pennsylvania
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13
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Abou Daya K, Abu Daya H, Nasser Eddine M, Nahhas G, Nuwayri-Salti N. Effects of rosiglitazone (PPAR γ agonist) on the myocardium in non-hypertensive diabetic rats (PPAR γ). J Diabetes 2015; 7:85-94. [PMID: 24548695 DOI: 10.1111/1753-0407.12140] [Citation(s) in RCA: 12] [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: 07/10/2013] [Revised: 12/06/2013] [Accepted: 02/13/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND There is ongoing controversy regarding the safety of rosiglitazone and its effects on the myocardium, in some cases causing severe cardiac pathology and even in some instances mortality. In this study we aimed at examining the effects of pharmacologic doses of rosiglitazone on cardiomyocytes in diabetic non-cardiac rats receiving sub-optimal doses of insulin. METHODS Animals were distributed into six groups: normal, diabetic, and diabetic receiving insulin, each subdivided into a control group and an experimental group receiving pharmacologic doses of rosiglitazone. Cardiomyocyte hypertrophy was assessed using heart to body weight index and microscopic examination using the number of cardiomyocytes per quadrant of high power field and intercalated disks in a sector of 100 × field. Fibrosis was assessed using Masson Trichrome staining. A number of sections of each group were stained with periodic acid Shiff and others with Sudan III for glycogen and fat accumulation, respectively. One way ANOVA was used for statistical analysis as appropriate. RESULTS Diffuse cardiomyopathic changes in diabetic control animals were observed consisting of cardiomyocyte hypertrophy, loss of striations and widespread vacuolation. These changes were reduced and even prevented by treatment with insulin and rosiglitazone. Masson staining showed that all rat groups had no more than +1 fibrosis that is equal to what was present in the normal controls. CONCLUSION Rosiglitazone, in combination with even sub-optimal doses of insulin therapy, has protective effects on cardiac muscle in diabetic animals especially those expressed as muscle hypertrophy, muscle cell death, and fibrosis.
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Affiliation(s)
- Khodor Abou Daya
- School of Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Zhuo L, Farrell PJ, McNair D, Krewski D. Statistical methods for active pharmacovigilance, with applications to diabetes drugs. J Biopharm Stat 2014; 24:856-73. [PMID: 24697529 DOI: 10.1080/10543406.2014.901338] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Pharmacovigilance aims to identify adverse drug reactions using postmarket surveillance data under real-world conditions of use. Unlike passive pharmacovigilance, which is based on largely voluntary (and hence incomplete) spontaneous reports of adverse drug reactions with limited information on patient characteristics, active pharmacovigilance is based on electronic health records containing detailed information about patient populations, thereby allowing consideration of modifying factors such as polypharmacy and comorbidity, as well as sociodemographic characteristics. With the present shift toward active pharmacovigilance, statistical methods capable of addressing the complexities of such data are needed. We describe four such methods here, and demonstrate their application in the analysis of a large retrospective cohort of diabetics taking anti-hyperglycemic medications that may increase the risk of adverse cardiovascular events.
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Affiliation(s)
- Lan Zhuo
- a School of Mathematics and Statistics , Carleton University , Ottawa , Ontario , Canada
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15
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Palee S, Weerateerangkul P, Chinda K, Chattipakorn SC, Chattipakorn N. Mechanisms responsible for beneficial and adverse effects of rosiglitazone in a rat model of acute cardiac ischaemia-reperfusion. Exp Physiol 2013; 98:1028-37. [DOI: 10.1113/expphysiol.2012.070433] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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16
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C Warren F, R Abrams K, Golder S, J Sutton A. Systematic review of methods used in meta-analyses where a primary outcome is an adverse or unintended event. BMC Med Res Methodol 2012; 12:64. [PMID: 22553987 PMCID: PMC3528446 DOI: 10.1186/1471-2288-12-64] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 04/16/2012] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Adverse consequences of medical interventions are a source of concern, but clinical trials may lack power to detect elevated rates of such events, while observational studies have inherent limitations. Meta-analysis allows the combination of individual studies, which can increase power and provide stronger evidence relating to adverse events. However, meta-analysis of adverse events has associated methodological challenges. The aim of this study was to systematically identify and review the methodology used in meta-analyses where a primary outcome is an adverse or unintended event, following a therapeutic intervention. METHODS Using a collection of reviews identified previously, 166 references including a meta-analysis were selected for review. At least one of the primary outcomes in each review was an adverse or unintended event. The nature of the intervention, source of funding, number of individual meta-analyses performed, number of primary studies included in the review, and use of meta-analytic methods were all recorded. Specific areas of interest relating to the methods used included the choice of outcome metric, methods of dealing with sparse events, heterogeneity, publication bias and use of individual patient data. RESULTS The 166 included reviews were published between 1994 and 2006. Interventions included drugs and surgery among other interventions. Many of the references being reviewed included multiple meta-analyses with 44.6% (74/166) including more than ten. Randomised trials only were included in 42.2% of meta-analyses (70/166), observational studies only in 33.7% (56/166) and a mix of observational studies and trials in 15.7% (26/166). Sparse data, in the form of zero events in one or both arms where the outcome was a count of events, was found in 64 reviews of two-arm studies, of which 41 (64.1%) had zero events in both arms. CONCLUSIONS Meta-analyses of adverse events data are common and useful in terms of increasing the power to detect an association with an intervention, especially when the events are infrequent. However, with regard to existing meta-analyses, a wide variety of different methods have been employed, often with no evident rationale for using a particular approach. More specifically, the approach to dealing with zero events varies, and guidelines on this issue would be desirable.
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Affiliation(s)
- Fiona C Warren
- Peninsula College of Medicine and Dentistry, St Luke’s Campus, University of Exeter, Exeter, EX1 2LU, UK
| | - Keith R Abrams
- Department of Health Sciences, Adrian Building, University of Leicester, University Road, Leicester, LE1 7RH, UK
| | - Su Golder
- Centre for Reviews and Dissemination (CRD), University of York, York, YO10 5DD, UK
| | - Alex J Sutton
- Department of Health Sciences, Adrian Building, University of Leicester, University Road, Leicester, LE1 7RH, UK
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17
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Hurren KM, Taylor TN, Jaber LA. Antidiabetic prescribing trends and predictors of thiazolidinedione discontinuation following the 2007 rosiglitazone safety alert. Diabetes Res Clin Pract 2011; 93:49-55. [PMID: 21440324 DOI: 10.1016/j.diabres.2011.02.035] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Revised: 02/15/2011] [Accepted: 02/28/2011] [Indexed: 10/18/2022]
Abstract
This study aimed to examine the change in antidiabetic medication prescribing trends and predictors of thiazolidinedione (TZD) discontinuation six months after the 2007 rosiglitazone safety alert. We performed a retrospective cohort analysis. Patients with two prescriptions for a TZD between 1 January and 21 May 2007, including one covering 21 May 2007, and continuous enrolment during 2006-2007 were identified from the MarketScan database. Multivariate logistic regression analysis was used to compare characteristics between patients who continued and discontinued each TZD. We identified 40,836 and 37,183 individuals with a current prescription for rosiglitazone and pioglitazone, respectively. Significantly more rosiglitazone (53.5%) compared to pioglitazone users (21.4%) discontinued initial therapy six months after the alert (p<0.001). Approximately 23% of patients who discontinued rosiglitazone were switched to pioglitazone, while <1% was switched from pioglitazone to rosiglitazone. Notably, 19.4% of patients who discontinued rosiglitazone and 36.1% of those who discontinued pioglitazone did not have evidence of any antidiabetic drug at follow-up. There was a significant decrease in metformin and an increase in sitagliptin prescribing in patients who discontinued TZDs. Age, sex, region, cardiovascular comorbidities and physician specialty predicted TZD discontinuation. These findings suggest that FDA advisories may be associated with substantial changes in medication use.
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Affiliation(s)
- Kathryn M Hurren
- Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States.
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18
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Palee S, Weerateerangkul P, Surinkeaw S, Chattipakorn S, Chattipakorn N. Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart. Exp Physiol 2011; 96:778-89. [PMID: 21666037 DOI: 10.1113/expphysiol.2011.057885] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, has been used to treat type 2 diabetes. Despite debates regarding its cardioprotection, the effects of rosiglitazone on cardiac electrophysiology are still unclear. This study determined the effect of rosiglitazone on ventricular fibrillation (VF) incidence, VF threshold (VFT), defibrillation threshold (DFT) and mitochondrial function during ischaemia and reperfusion. Twenty-six pigs were used. In each pig, either rosiglitazone (1 mg kg(-1)) or normal saline solution was administered intravenously for 60 min. Then, the left anterior descending coronary artery was ligated for 60 min and released to promote reperfusion for 120 min. The cardiac electrophysiological parameters were determined at the beginning of the study and during the ischaemia and reperfusion periods. The heart was removed, and the area at risk and infarct size in each heart were determined. Cardiac mitochondria were isolated for determination of mitochondrial function. Rosiglitazone did not improve the DFT and VFT during the ischaemia-reperfusion period. In the rosiglitazone group, the VF incidence was increased (58 versus 10%) and the time to the first occurrence of VF was decreased (3 ± 2 versus 19 ± 1 min) in comparison to the vehicle group (P < 0.05). However, the infarct size related to the area at risk in the rosiglitazone group was significantly decreased (P < 0.05). In the cardiac mitochondria, rosiglitazone did not alter the level of production of reactive oxygen species and could not prevent mitochondrial membrane potential changes. Rosiglitazone increased the propensity for VF, and could neither increase defibrillation efficacy nor improve cardiac mitochondrial function.
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Affiliation(s)
- Siripong Palee
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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19
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Palee S, Chattipakorn S, Phrommintikul A, Chattipakorn N. PPARγ activator, rosiglitazone: Is it beneficial or harmful to the cardiovascular system? World J Cardiol 2011; 3:144-52. [PMID: 21666815 PMCID: PMC3110903 DOI: 10.4330/wjc.v3.i5.144] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 04/04/2011] [Accepted: 04/11/2011] [Indexed: 02/06/2023] Open
Abstract
Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with type II diabetes. Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity. Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction, inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation, and the protection of myocardial injury during ischemic/reperfusion in different animal models. Previous clinical studies in type II diabetes patients demonstrated that rosiglitazone played an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system. Despite these benefits, inconsistent findings have been reported, and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system, including increased risk of acute myocardial infarction, heart failure and chronic heart failure. As a result, rosiglitazone has been recently withdrawn from EU countries. Nevertheless, the effect of rosiglitazone on ischemic heart disease has not yet been firmly established. Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.
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Affiliation(s)
- Siripong Palee
- Siripong Palee, Nipon Chattipakorn, Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
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20
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Affiliation(s)
- Philip Home
- Newcastle University and Newcastle Diabetes Centre, Institute of Cellular Medicine (Diabetes), The Medical School, Newcastle upon Tyne, UK.
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21
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Abstract
Meta-analyses of clinical trials suggest that the use of the thiazolidinedione (TZD), rosiglitazone, in patients with type 2 diabetes mellitus may increase the risk of myocardial ischaemic events by 30-40%. Although these controversial data must be interpreted with caution, in the absence of definitive prospective cardiovascular (CV) outcomes data, they represent a prominent source of evidence concerning the CV safety of rosiglitazone. The results of meta-analyses and a large randomized-controlled CV outcomes trial provide strong evidence that pioglitazone does not increase the risk of coronary events. This article clarifies the clinical significance of these meta-analytical findings alongside other sources of evidence and assesses their impact on evolving treatment guidelines and recommendations for the use of TZDs in patients with type 2 diabetes.
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Affiliation(s)
- G Schernthaner
- Department of Medicine I, Rudolfstiftung Hospital, Vienna, Austria.
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22
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Saha SA, Tuttle KR. Influence of glycemic control on the development of diabetic cardiovascular and kidney disease. Cardiol Clin 2010; 28:497-516. [PMID: 20621253 DOI: 10.1016/j.ccl.2010.04.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Diabetes mellitus leads to the development of a host of micro- and macrovascular complications, which collectively lead to substantial morbidity and mortality. Among the microvascular complications of diabetes, diabetic kidney disease is the most common. Macrovascular complications from diabetes lead to a 2- to 4-fold increase in the incidence of cardiovascular disease and up to twice the mortality from cardiovascular causes as compared with nondiabetic individuals. This article discusses the various drug classes used to treat diabetes mellitus, and reviews the current clinical evidence linking glycemic control using these drug classes on diabetic kidney and cardiovascular disease.
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Affiliation(s)
- Sandeep A Saha
- Providence Medical Research Center, Spokane, WA 99204, USA.
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23
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Erdmann E, Spanheimer R, Charbonnel B. Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20). J Diabetes 2010; 2:212-20. [PMID: 20923486 DOI: 10.1111/j.1753-0407.2010.00082.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone. METHODS The PROactive study was a randomized double-blind prospective trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease. Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications. The effect of pioglitazone on composite endpoints was evaluated, including all-cause death, myocardial infarction (MI), and stroke, as well as safety events of edema and serious heart failure, in subgroups using nitrates, RAS blockers, or insulin at baseline. RESULTS The risk of all-cause death, MI, and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates, RAS blockers, or insulin, with hazard ratios ranging from 0.81 to 0.87. Similar results were obtained for the other composite endpoints analyzed. There were no significant interactions between baseline medication subgroups and treatment. The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups. CONCLUSIONS This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates, RAS blockers, or insulin. Rather, all patients realized the same trend towards benefit with pioglitazone, and adverse events of edema and heart failure were predictable.
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Affiliation(s)
- Erland Erdmann
- Medizinische Klinik III der Universität zu Köln, Köln, Germany.
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24
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Stewart KA, Natzke BM, Williams T, Granger E, Casscells SW, Croghan TW. Temporal trends in anti-diabetes drug use in TRICARE following safety warnings in 2007 about rosiglitazone. Pharmacoepidemiol Drug Saf 2010; 18:1048-52. [PMID: 19655338 DOI: 10.1002/pds.1819] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
PURPOSE To describe utilization patterns for anti-diabetes medications among a cohort of diabetes patients in the Military Health System (MHS) before and after warnings about rosiglitazone issued in May 2007. METHODS We used segmented regression analysis to compare changes in the level and trend of rosiglitazone utilization and use of other anti-diabetes therapies in the period prior to the drug warnings (between April 2006 and May 2007) and the period after the warnings were issued (between October 2007 and May 2008). RESULTS The level and trend of rosiglitazone use changed after the highly publicized warnings. The number of prescriptions filled fell by almost 7000 after the warning (p < 0.001). The number of prescriptions filled for pioglitazone, sulfonylureas, and other diabetes drugs increased significantly after the warnings (p < 0.05 in all models). Overall, the level and trend of filled prescriptions per month for all anti-diabetic drugs did not significantly change after the warnings. CONCLUSIONS Utilization patterns changed in response to warnings about rosiglitazone. While overall utilization of anti-diabetic drugs did not change, further study is needed to determine the associated health outcomes.
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Affiliation(s)
- Kate A Stewart
- Mathematica Policy Research, Inc., Washington, DC 20024, USA.
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25
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The thiazolidinediones rosiglitazone and pioglitazone and the risk of coronary heart disease: A retrospective cohort study using a US health insurance database. Clin Ther 2009; 31:2665-77. [DOI: 10.1016/j.clinthera.2009.11.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2009] [Indexed: 12/22/2022]
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26
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Fisher M. Improving cardiovascular risk--applying evidence-based medicine to glucose-lowering therapy with thiazolidinediones in patients with type 2 diabetes. Int J Clin Pract 2009; 63:1354-68. [PMID: 19691621 DOI: 10.1111/j.1742-1241.2009.02150.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND The management of patients with type 2 diabetes aims to reduce the elevated risk of cardiovascular disease (CVD) by addressing established risk factors including hyperglycaemia, dyslipidaemia and hypertension. The thiazolidinediones are equally effective in improving glycaemic control when used in combination regimens in patients with type 2 diabetes, but have differing effects on the diabetic dyslipidaemia. AIMS To compare the effects of rosiglitazone and pioglitazone on inflammatory mediators associated with atherosclerosis and CVD, surrogate cardiovascular endpoints, and hard cardiovascular outcomes in patients with type 2 diabetes. MATERIALS AND METHODS A search of the PubMed database plus manual search of referenced papers for other relevant citations. RESULTS Both glitazones reduce inflammatory markers and other circulating markers of CV disease. Available data suggest that pioglitazone can delay progression of atherosclerosis in patients with type 2 diabetes, as shown by the PERISCOPE and CHICAGO studies, and that it can reduce the rate of clinical CV events as shown by PROactive. Clinical end-point data for rosiglitazone are inconclusive, providing no evidence of benefit and a possible increase in myocardial infarction. DISCUSSION There is a consistency of benefit with pioglitazone on markers, surrogate cardiovascular outcomes and clinical end-point trials. CONCLUSION Pioglitazone is the preferred thiazolidinedione to reduce cardiovascular risk in people with type 2 diabetes.
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Affiliation(s)
- M Fisher
- Glasgow Royal Infirmary, Glasgow, UK.
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27
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Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R. Reply. Am J Obstet Gynecol 2009. [DOI: 10.1016/j.ajog.2009.01.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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28
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Public Disclosure of Clinical Trial Results. Pharmaceut Med 2009. [DOI: 10.1007/bf03256761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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29
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Khavandi K, Khavandi A, Asghar O, Greenstein A, Withers S, Heagerty AM, Malik RA. Diabetic cardiomyopathy--a distinct disease? Best Pract Res Clin Endocrinol Metab 2009; 23:347-60. [PMID: 19520308 DOI: 10.1016/j.beem.2008.10.016] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Diabetic individuals have a significantly increased likelihood of developing cardiovascular disease. Whilst part of this association is explained by the presence of concomitant risk factors, large epidemiological studies have consistently reported diabetes as a strong risk factor for the development of heart failure after adjusting for such covariates. This has resulted in the notion that there is a distinct cardiomyopathy specific to diabetes, termed 'diabetic cardiomyopathy'. The natural history is characterized by a latent subclinical period, during which there is evidence of diastolic dysfunction and left ventricular hypertrophy, before overt clinical deterioration and systolic failure ensue. These clinical findings have been supported by a growing body of experimental data which support the notion that diabetes inflicts a direct insult to the myocardium, with cellular, structural and functional changes manifest as the diabetic myocardial phenotype. Several of these mechanisms appear to work in unison, forming complicated reciprocal pathways of disease. Reactive oxygen species and alterations in intracellular calcium homeostasis appear to play significant roles in many of these mechanisms. Determining the hierarchy of this cascade of disease will allow identification of the pathological trigger most responsible for disease. Translational research in this field is currently hindered by a lack of clinical studies and intervention trials specifically in patients with diabetic cardiomyopathy. Future clinical and experimental studies of accurate models of diabetic cardiomyopathy should help to define the true aetiology and lead to the development of specific pharmacotherapies for this condition, ultimately reducing the increased cardiovascular morbidity and mortality in diabetic patients.
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Affiliation(s)
- Kaivan Khavandi
- Division of Cardiovascular and Endocrine Sciences, Core Technology Facility, University of Manchester, Manchester, UK
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30
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Califf RM, Kramer JM. The balance of benefit and safety of rosiglitazone: important lessons for our system of drug development and postmarketing assessment. Pharmacoepidemiol Drug Saf 2008; 17:782-6. [PMID: 18655016 DOI: 10.1002/pds.1617] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Robert M Califf
- Duke Translational Medicine Institute, Durham, NC 27715, USA.
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31
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Faich GA, Stemhagen A. Cardiac safety of diabetes therapies and postmarketing requirements. Pharmacoepidemiol Drug Saf 2008; 17:787-9. [DOI: 10.1002/pds.1622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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