thienopyridine and Diabetes-Mellitus

Adenosine 5'-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Biological Products; Biphenyl Compounds; Diabetes Complications; Diabetes Mellitus; Energy Metabolism; Humans; Hypoglycemic Agents; Mitochondria; Pyridines; Pyrones; Thiophenes

Platelets from patients affected by diabetes mellitus and metabolic syndrome show an impaired sensitivity to physiological antiaggregating agents and an enhanced activation state, mirrored by an increased expression of membrane activation markers; furthermore, they are more prone to form spontaneous microaggregates with ADP receptor involvement. These abnormalities are responsible for a pro-thrombotic condition, contributing to a high cardiovascular risk. This pattern of platelet abnormalities provides a strong rationale for aggressive antiplatelet therapy strongly recommended by guidelines both in diabetes mellitus and in metabolic syndrome, not only in the setting of acute coronary syndromes, but also for the long-term prevention of the cardiovascular events. Antiplatelet therapy in these pathological conditions, however, is still a matter of intense debate, especially because a high prevalence of "resistance" to these drugs (and to aspirin in particular) has been described in these patients. This may result in non-significant reductions in cardiovascular events. Different factors seem to be involved, including: i) genetic polymorphisms; ii) hyperglycemia and poor metabolic control; iii) reduced sensitivity to nitric oxide; iv) a pro-inflammatory and/or pro-thrombotic status, and, v) increased oxidative stress. This review will take into consideration: i) the results of the most relevant studies addressing the effects of the anti-aggregating treatment in patients affected by diabetes mellitus and/or metabolic syndrome, and, ii) the biochemical mechanisms accounting for the impaired sensitivity to aspirin and thienopyridines in the above mentioned clinical conditions.

Topics: Aspirin; Cardiovascular Diseases; Diabetes Mellitus; Drug Resistance; Humans; Metabolic Syndrome; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridines; Risk Factors

Patients with diabetes mellitus (DM) are at high risk for recurrent ischemic events after coronary stenting. We assessed the effects of continued thienopyridine among patients with DM participating in the Dual Antiplatelet Therapy (DAPT) Study as a prespecified analysis.. After coronary stent placement and 12 months treatment with open-label thienopyridine plus aspirin, 11 648 patients free of ischemic or bleeding events and who were medication compliant were randomly assigned to continued thienopyridine or placebo, in addition to aspirin, for 18 more months. After randomization, patients with DM (n=3391), in comparison with patients without DM (n=8257), had increased composite outcome of death, myocardial infarction (MI), or stroke (6.8% versus 4.3%, P<0.001), increased death (2.5% versus 1.4%, P<0.001), and MI (4.2% versus 2.6%, P<0.001). Among patients with DM, in a comparison of continued thienopyridine versus placebo, rates of stent thrombosis were 0.5% versus 1.1%, P=0.06, and rates of MI were 3.5% versus 4.8%, P=0.058; and among patients without DM the rates were 0.4% versus 1.4%, P<0.001 (stent thrombosis, P interaction=0.21) and 1.6% versus 3.6%, P<0.001 (MI, P interaction=0.02). Bleeding risk with continued thienopyridine was similar among patients with or without DM (interaction P=0.61).. In patients with DM, continued thienopyridine beyond 1 year after coronary stenting is associated with reduced risk of MI, although this benefit is attenuated in comparison with patients without DM.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00977938.

Topics: Aged; Aspirin; Diabetes Mellitus; Drug Therapy, Combination; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines

Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding.. To develop a clinical decision tool to identify patients expected to derive benefit vs harm from continuing thienopyridine beyond 1 year after PCI.. Among 11,648 randomized DAPT Study patients from 11 countries (August 2009-May 2014), a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. Validation was internal via bootstrap resampling and external among 8136 patients from 36 countries randomized in the PROTECT trial (June 2007-July 2014).. Twelve months of open-label thienopyridine plus aspirin, then randomized to 18 months of continued thienopyridine plus aspirin vs placebo plus aspirin.. Ischemia (myocardial infarction or stent thrombosis) and bleeding (moderate or severe) 12 to 30 months after PCI.. Among DAPT Study patients (derivation cohort; mean age, 61.3 years; women, 25.1%), ischemia occurred in 348 patients (3.0%) and bleeding in 215 (1.8%). Derivation cohort models predicting ischemia and bleeding had c statistics of 0.70 and 0.68, respectively. The prediction rule assigned 1 point each for myocardial infarction at presentation, prior myocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; -1 point for age 65 to younger than 75 years; and -2 points for age 75 years or older. Among the high score group (score ≥2, n = 5917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference [RD], -3.0% [95% CI, -4.1% to -2.0%], P < .001) compared with the low score group (score <2, n = 5731; 1.7% vs 2.3%; RD, -0.7% [95% CI, -1.4% to 0.09%], P = .07; interaction P < .001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4% [95% CI, -0.3% to 1.0%], P = .26) compared with the low score group (3.0% vs 1.4%; RD, 1.5% [95% CI, 0.8% to 2.3%], P < .001; interaction P = .02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding.. Among patients not sustaining major bleeding or ischemic events 1 year after PCI, a prediction rule assessing late ischemic and bleeding risks to inform dual antiplatelet therapy duration showed modest accuracy in derivation and validation cohorts. This rule requires further prospective evaluation to assess potential effects on patient care, as well as validation in other cohorts.. clinicaltrials.gov Identifier: NCT00977938.

Topics: Age Factors; Aged; Antineoplastic Agents, Phytogenic; Aspirin; Diabetes Mellitus; Drug-Eluting Stents; Female; Hemorrhage; Humans; Ischemia; Linear Models; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Risk Assessment; Risk Factors; Smoking; Thrombosis; Time Factors

Patients with diabetes mellitus (DM) experience higher rates of in-stent restenosis and greater benefit from drug-eluting stents implant at the time of percutaneous coronary intervention (PCI), necessitating prolonged dual anti-platelet therapy (DAPT). While DAPT reduces risk of ischemic events post-PCI, it also increases risk of bleeding. Whether bleeding rates differ among patients with and without DM, receiving long-term DAPT is unknown.. Among patients who underwent PCI and were maintained on DAPT for 1 year in a multicenter US registry, we assessed patient-reported bleeding over one year following PCI in patients with and without DM. Multivariable, hierarchical Poisson regression was used to evaluate the association of DM with bleeding during follow-up.. Among 2334 PCI patients from 10 US hospitals (mean age 64, 54% ACS), 32.6% had DM. In unadjusted analyses, patients with DM had fewer bleeding events over the year following PCI (DM vs no DM: BARC = 1: 78.0% vs 87.7%, P < .001; BARC ≥2: 4.3% vs 5.3%, P = .33). Following adjustment, patients with (vs without DM) had a lower risk of BARC ≥1 bleeding during follow-up (relative risk [RR] 0.89, 95% CI 0.83-0.96). This decreased bleeding risk persisted after removing bruising from the endpoint definition.. In a real-world PCI registry, patients with DM experienced lower risk of bleeding risk on DAPT. As patients with DM also derive greater ischemic benefit from drug-eluting stents, which requires prolonged DAPT, our findings suggest that the balance between benefit and risk of this therapeutic approach may be even more favorable in patients with DM than previously considered.

Topics: Aged; Aspirin; Comorbidity; Coronary Artery Disease; Diabetes Mellitus; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hemorrhage; Humans; Long Term Adverse Effects; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Registries; Risk Assessment

Diabetes mellitus (DM) accounts for >25% of all percutaneous coronary interventions. In patients with DM, drug-eluting stent implantation is associated with a reduced risk of restenosis and target lesion revascularization. However, concern has been raised about the incidence of late and very late stent thrombosis and the increased mortality rate, mostly after thienopyridine withdrawal. We evaluated the long-term prognostic effect of thienopyridine discontinuation after drug-eluting stent implantation on the subsequent occurrence of stent thrombosis and all-cause death among a cohort of high-risk "de novo" diabetic patients. From May 2002 to December 2005, 542 consecutive patients with DM underwent drug-eluting stent implantation at 2 hospitals in Milan, Italy. For study purposes, only the 217 patients who had not previously undergone percutaneous or surgical revascularization were considered in the final analysis. The follow-up time was curtailed at 3.5 years. Detailed information about dual antiplatelet therapy (DAT) were collected for all patients included. Of the 217 patients, 15 died (6.9%); in 9 cases, the cause of death was cardiac (4.1%). The incidence of cumulative stent thrombosis was 4.6% (10 patients); 3 stent thromboses were early (1.38%), 5 late (2.3%), and only 2 were very late (0.9%). Of the 10 cases of stent thrombosis, 5 were definite and 5 were probable. Most (80%) of the stent thromboses occurred within the first 6 months during DAT. The median duration of DAT was 420 days (interquartile range 350 to 859). DAT discontinuation was the only independent predictor of the follow-up events (hazard ratio 20.42, 95% confidence interval 4.99 to 83.62). In conclusion, DM remains an independent adverse factor on clinical outcome. In this setting, prolonged DAT, even beyond that recommended in the guidelines, might be beneficial.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Cause of Death; Cohort Studies; Combined Modality Therapy; Confidence Intervals; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Hospital Mortality; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Probability; Proportional Hazards Models; Prospective Studies; Pyridines; Risk Assessment; Severity of Illness Index; Survival Analysis

Topics: Clopidogrel; Coronary Artery Disease; Diabetes Mellitus; Disease Progression; Drug-Eluting Stents; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Ticlopidine; Time Factors; Treatment Outcome