Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of angiotensin-converting enzyme (ACE) inhibitors in diabetic patients with preserved ventricular function is uncertain. Tissue ACE inhibitors have been defined by increased lipophilicity and structural characteristics that result in greater tissue-specific ACE binding when compared with plasma ACE inhibitors. A Bayesian meta-analysis of randomized trials was conducted to evaluate tissue ACE inhibitors in prevention of cardiovascular disease among patients with diabetes mellitus and preserved left ventricular function. Four trials were selected that evaluated 2 different ACE inhibitors and included 10,328 patients (43,517 patient-years). The Perindopril Substudy in Coronary Artery Disease and Diabetes (PERSUADE) and the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) compared the effects of perindopril vs a placebo, and the Heart Outcomes Prevention Evaluation (HOPE) and the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study investigated the impact of ramipril vs a placebo. Bayesian meta-analysis of sequential trials and sensitivity analysis of therapeutic response were subsequently computed. Bayesian meta-analysis determined reduced risk of cardiovascular mortality (PB=.991), myocardial infarction (PB=.999), and the need for invasive coronary revascularization (PB=.995) when compared with placebo. Total mortality was also decreased (PB=.967), while the risk of stroke (PB=.907) and hospitalization for heart failure (PB=.923) were impacted. Bayesian meta-analysis of randomized trials suggests that tissue ACE inhibitors decrease the probability that diabetic patients with preserved left ventricular function will experience myocardial infarctions and cardiovascular death and reduce overall mortality.
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PMID:Bayesian meta-analysis of tissue angiotensin-converting enzyme inhibitors for reduction of adverse cardiovascular events in patients with diabetes mellitus and preserved left ventricular function. 1832 70

Cardiovascular risk is determined by multiple risk factors. Blockade of the renin-angiotensin system is an important approach to the prevention of cardiovascular events. In the largest angiotensin receptor blocker cardiovascular outcome study to date, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) program will compare the efficacy of therapy with telmisartan and ramipril, in reducing cardiovascular events in patients at high risk (history of coronary artery disease, stroke or transient ischemic attack, peripheral artery disease, or diabetes with evidence of end-organ damage). Recruited patients (n = 31,546) will be followed up for a period of 6 years, and more than 150,000 patient-years of data will be recorded. The primary endpoint is a composite of cardiovascular death, stroke, acute myocardial infarction, and hospitalization for congestive heart failure; secondary endpoints focus on reductions in newly diagnosed heart failure, new-onset type 2 diabetes, cognitive decline, atrial fibrillation, and nephropathy. In addition, an ambulatory blood pressure monitoring substudy will be conducted to assess the effect of treatment on endpoints after adjustment for 24-hour blood pressure values. Other substudies of the treatment effects on erectile dysfunction, blood markers, arterial stiffness, oral glucose tolerance, and the progression of target organ damage are also planned. The results of the ONTARGET program are due in 2008, and the findings are expected to have important clinical implications for the management of patients at high cardiovascular risk.
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PMID:Cardiac and vascular protection: the potential of ONTARGET. 1844 80

ONTARGET ("ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial") compared the angiotensin converting enzyme inhibitor ramipril (10 mg/day), the angiotensin-receptor blocker telmisartan 80 mg/day, and the combination of the two drugs in 25,620 patients with vascular disease or high-risk diabetes. After a median follow up of 56 months, no significant differences were observed between the three groups neither in the primary composite outcome (death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure), nor in each of its components, total mortality and other secondary outcomes. Telmisartan was equivalent to ramipril (non inferiority criterion), but was better tolerated (less cough and angioedema). The combination of the two drugs in this population (without congestive heart failure and proteinuric nephropathy) did not bring increased benefit (no superiority), but was associated with more adverse events (hypotension, syncope and renal dysfunction). In this population, the choice of the molecule in monotherapy remains optional and the use of a dual blockade is not justified in order to have a better cardiovascular protection.
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PMID:[ONTARGET: similar protection of telmisartan and ramipril and lack of benefit of combined therapy in patients at high risk for vascular events]. 1857 77

Antihypertensive drugs that inhibit the renin-angiotensin system (RAS) have been proposed to have additional benefits beyond their classic effects on the cardiovascular system, including reducing the risk of new-onset diabetes. Whether RAS inhibitors vary in ability to protect against new-onset diabetes is, however, unknown. The angiotensin II type 1 receptor (AT(1)) blocker telmisartan has been discovered to also activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), an established antidiabetic drug target. In patients with hypertension and biochemical features of the metabolic syndrome, telmisartan has had beneficial effects on lipid and glucose metabolism. As a selective modulator of PPARgamma, telmisartan does not cause the side effects of fluid retention and weight gain associated with conventional thiazolidinedione ligands of PPARgamma. These observations raise the possibility that combined AT(1) receptor blockade and selective PPARgamma modulation with molecules such as telmisartan could provide greater protection from new-onset diabetes and cardiovascular disease than drugs that target either the RAS or PPARgamma alone. The cardioprotective and antidiabetic effects of telmisartan are being assessed in two large clinical trials, the ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomised AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular Disease (TRANSCEND).
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PMID:Beyond the classic angiotensin-receptor-blocker profile. 1858 Aug 62

The development of angiotensin II receptor blockers (ARB) as a new class of drugs for the management of hypertension has elicited the attention of many clinicians worldwide with the aim of improving blood pressure (BP) control as well as cardiovascular protection. Among ARB telmisartan has been shown to be characterised by an antihypertensive efficacy fully covering the 24-hour period, thereby allowing to antagonise the adverse effects of early morning BP rise on cardiovascular risk. Other specific effects of the drug are represented by its favourable metabolic profile (particularly on insulin sensitivity) and neutral effects on sympathetic cardiovascular function. These properties are coupled with cardioprotective effects, documented by the evidence that the drug: 1) is effective in favouring the regression of cardiac and vascular organ damage, 2) reduces arterial stiffness and improves vascular distensibility and 3) reverses the endothelial dysfunction typical of the hypertensive state particularly when complicated by renal failure, diabetes, obesity or metabolic syndrome. Several of these properties can account for the results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), documenting the beneficial effects on the drug on cardiovascular morbidity and mortality.
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PMID:Cardioprotective effects of telmisartan in uncomplicated and complicated hypertension. 1858 82

To assess the safety and tolerability of ramipril 10 mg in patients at high risk of cardiovascular (CV) events by observing the levels of blood pressure (BP) and by recording the incidence of cough in these patients, a study was conducted in a total of 1048 patients who participated in the registry. Eligible patients in this prospective, observational, longitudinal, multicentre registry included all normotensives--including treated hypertensives--with BP <140/90 mm Hg, a history of coronary aritery disease and a history of cerebrovascular disease, peripheral arterial disease or diabetes (with micro-albuminuria) or dyslipidaemia, in whom ramipril was indicated for CV risk reduction and had been prescribed by the treating physician. The primary outcome was the effect on BP at 8 weeks, and the secondary outcome was the incidence of cough at 8 weeks. Ramipril was initiated at 2.5 mg once daily (OD) for a week, followed by 5 mg OD for 3 weeks and was then increased to 10 mg OD. Data was analysed using ANOVA and Chi-square test. A total of 1,048 patients participated in this registry; 868 (82.82%) continued with the treatment till the end of the registry (ie, 8 weeks). At baseline, systolic BP was 130.10 +/- 5.38 mm Hg, while diastolic BP was 81.07 +/- 4.36 mm Hg. At 8 weeks, these values changed non-significantly to 123.41 +/- 6.33 mm Hg and 79.03 +/- 4.84 mm Hg, respectively. At week 1, 41 patients had cough, which increased non-significantly to 58 by week 8. Only 6 patients complained of severe cough at week 8, which did not lead to treatment discontinuation. Tolerability of the treatment was assessed to be 'excellent' or 'good' by 63.3% patients and 67% physicians. Treatment with ramipril 10 mg daily in patients with high risk of CV events and normal/ controlled BP produced neither a significant fall in BP nor significant adverse events in real-world clinical practice and was well tolerated.
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PMID:Safety and tolerability of ramipril 10 mg in patients at high risk of cardiovascular events: an observational study. 1897 6

Thiazolidinediones (TZDs) are widely used in the type 2 diabetes mellitus (DMT2) treatment but have also been tested in cardiovascular prevention. DMT2 is associated with a marked increment in cardiovascular risk, and its prevention represents a main target in cardiometabolic protection. Both Troglitazone (Troglitazone in Prevention of Diabetes study) and Rosiglitazone (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication study) significantly reduced new-onset diabetes. A similar topic will be investigated with pioglitazone (Actos Now for Prevention of Diabetes). In the Prospective Pioglitazone Clinical Trial in Macrovascular events the primary end point (all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndromes, endovascular or surgical intervention in the coronary/leg arteries and amputation above ankles) was unaffected, whereas the secondary one (all-cause mortality, nonfatal myocardial infarction and stroke) was reduced by pioglitazone (-16%, p=0.027) compared to placebo in 5,238 patients with DMT2 and macrovascular disease. In contrast, a meta-analysis (Nissen and Wolski, N Engl J Med. 2007;356:2457-2471) reported that rosiglitazone treatment is associated with a significant increase in myocardial infarction risk (p=0.03) and a borderline significant increase in the risk of death from cardiovascular causes (p=0.06). Nevertheless, the possibility that rosiglitazone might affect cardiovascular events should be evaluated by the ongoing trial Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD). Interim findings early from RECORD did not show significant differences between the rosiglitazone and the control group regarding myocardial infarction and death from cardiovascular and any cause. Additional large-scale trials are awaited to clarify the of role TZDs in cardiovascular outcomes.
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PMID:Cardiovascular risk and cardiometabolic protection: role of glitazones. 1903 66

The recently published Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) in patients with vascular disease or high-risk diabetes, as the largest published comparative trial of these agent classes, provides further evidence concerning the comparison between the angiotensin-receptor blockers (ARBs) and the angiotensin-converting enzyme inhibitors (ACEIs). In this trial, telmisartan (an ARB) was non-inferior to ramipril (an ACEI) in reducing fatal and nonfatal cardiovascular events. Moreover, ONTARGET is an example of a high-quality noninferiority trial. However, the combination of the 2 agents was associated with more adverse effects without an increase in benefit. The study differed from several other comparative studies in which the dose and choice of ACEI was left to individual physicians. Further, in ONTARGET, the ACEI was not titrated to the maximum dose and patients with heart failure were excluded.
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PMID:Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET): implications for reduced cardiovascular risk. 1930 91

Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) are the cornerstone of therapy for cardiovascular and renal disease because they protect against worsening outcomes in the respective target organs. Recent results from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) have confirmed that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) confer similar cardioprotection and renoprotection, showing little to no benefit from the combination in cardiovascular disease. It is not yet clear whether one class is superior to another for renoprotection. Whether dual RAAS blockade is more advantageous than single blockade, and in which patients, is also yet to be clearly determined. The Long-Term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) study will compare the cardiorenoprotective effects of ACE inhibitors and ARBs in patients with albuminuria, and clarify the role of dual blockade. Preliminary evidence that RAAS inhibitors reduce incident diabetes is intriguing. Whether ARBs can reduce incident diabetes and related cardiovascular outcomes is awaited with the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.
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PMID:Are renin-angiotensin-aldosterone system blockers distinguishable based on cardiovascular and renal outcomes in nephropathy? 1933 65

In patients with arterial hypertension and/or high cardiovascular risk, including patients with diabetes, chronic ischemic heart disease and kidney disease, the risk of heart failure decreases with blood pressure reduction and the use of drugs that inhibit the renin-angiotensin system (RAS) [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)]. The heart failure incidence seen in ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) is in line with this observation. In ONTARGET, telmisartan and ramipril were equally effective in heart failure prevention and with the same blood pressure reduction. The low event rate, including the low incidence of heart failure in TRANSCEND with the greater use of diuretics in the placebo arm, may help to explain the absence of significant differences between telmisartan and placebo.
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PMID:The question of heart failure in ONTARGET and TRANSCEND: implications for clinical practice. 1949 21


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