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Type 2 diabetes is a serious, costly, and increasingly common disease. Several conditions commonly seen in family medicine settings confer increased risk of developing diabetes. Among these conditions are impaired glucose tolerance, impaired fasting glucose, obesity, gestational diabetes, hypertension, hyperlipidemia, and menopause. We here present the results of a systematic review of the literature examining the evidence for different strategies aimed at preventing type 2 diabetes in patients with these conditions. The strongest evidence supports an intensive lifestyle intervention designed to induce modest weight loss. The greatest degree of prevention, based on lesser quality evidence, may be imparted by bariatric surgery. Metformin and troglitazone have appreciable evidence in specific populations, and orlistat and acarbose have slightly less evidence among obese patients, for preventing diabetes. Ramipril, captopril, losartan, pravastatin, and estrogens show some very preliminary promise for preventing diabetes in patients treated for hypertension, hyperlipidemia, and menopause, but each needs a more rigorous evaluation. Although more questions remain to be answered, family physicians now have tools available to help our patients lead lives free of diabetes.
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PMID:Preventing type 2 diabetes mellitus. 1570 62

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each 2-month treatment period. Ramipril alone or combined therapy significantly reduced blood pressure when compared with simvastatin alone. When compared with ramipril alone, simvastatin alone or combined therapy significantly improved the lipoprotein profile. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and reduced plasma levels of malondialdehyde relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or ramipril alone (P<0.001 by ANOVA). When compared with simvastatin or ramipril alone, combined therapy significantly reduced high-sensitivity C-reactive protein levels (P=0.004 by ANOVA). Interestingly, combined therapy or ramipril alone significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.015 by ANOVA). Ramipril combined with simvastatin had beneficial vascular and metabolic effects when compared with monotherapy in patients with type 2 diabetes.
Hypertension 2005 Jun
PMID:Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. 1588 29

Ramipril improves cardiovascular outcome in patients with peripheral arterial disease; however, the precise mechanisms of benefit remain to be elucidated. The effect of ramipril on large-artery stiffness in patients with peripheral arterial disease was examined. In addition, we determined the effect of ramiprilat on extracellular matrix from human aortic smooth muscle cell culture. Forty patients with peripheral arterial disease were randomized to receive ramipril, 10 mg once daily or placebo for 24 weeks. Arterial stiffness was assessed globally via systemic arterial compliance and augmentation index (carotid tonometry and Doppler velocimetry), and regionally via carotid-femoral pulse wave velocity. Angiotensin-converting enzyme inhibition increased arterial compliance by 0.10+/-0.02 mL/mm Hg, (P<0.001, all probability values relative to placebo) and reduced pulse wave velocity by 1.7+/-0.2 m/s (P<0.001), augmentation index by 4.1+/-0.3% (P<0.001), and systolic blood pressure by 5+/-1 mm Hg (P<0.001). Ramipril did not reduce mean arterial pressure significantly compared with placebo (P=0.59). In cell culture, ramiprilat decreased collagen deposition by >50% and increased elastin and fibrillin-1 deposition by >3- and 4-fold respectively (histochemistry and immunohistochemistry). Fibrillin-1 gene expression was increased 5-fold (real-time reverse-transcriptase polymerase chain reaction). Ramiprilat also reduced gene and protein (Western) expression of both matrix metalloproteinase (MMP)-2 and MMP-3. In conclusion, ramipril promoted an elastogenic matrix profile that may contribute to the observed clinical reduction in large-artery stiffness and carotid pressure augmentation, which occurred independently of mean arterial blood pressure reduction in patients with peripheral arterial disease.
Hypertension 2005 Jun
PMID:Ramipril reduces large-artery stiffness in peripheral arterial disease and promotes elastogenic remodeling in cell culture. 2665 6

Angiotensin receptor blockers (ARBs) were introduced after clinical trials showed angiotensin-converting enzyme inhibitors (ACEIs) to have extensive clinical benefits in a wide range of diseases. Consequently, it has been more difficult for clinical trials to demonstrate similar, enhanced or additive benefits of ARBs. However, ARBs were introduced with the hypothesis that they were likely a more effective method of interrupting the renin-angiotensin system and would result in enhanced outcomes. Clinical trials in high-risk vascular patients (after myocardial infarction), patients with heart failure and patients with nephropathy show the benefits of ACE inhibition. ARBs likely have similar benefits as ACEIs when used after myocardial infarction, in patients with heart failure and for management of diabetic nephropathy. However, ARBs generally remain a second-line treatment because it has been more difficult to demonstrate that ARBs prevent acute vascular events, such as myocardial infarction, together with the greater clinical trial evidence for ACE inhibition. The primary application of ACEIs over ARBs is reflected in the Canadian clinical guidelines for the management of patients with diabetes, hypertension, heart failure and following myocardial infarction. Until the completion of clinical trials, such as the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), that examine whether ARBs have vascular protective properties similar to ACEIs, it is unlikely that the clinical guidelines will change.
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PMID:Have angiotensin receptor blockers lived up to expectations? 1594 Mar 55

The HOPE study was a 19 country, prospective randomized trial in which the ACE-inhibitor Ramipril but not Vitamin E significantly reduced the risk of future cardiovascular events in a high-risk population of men and women, including many with diabetes. The benefits were present in all sub-groups, independent of the presence or absence of diabetes, hypertension, evidence of cardiovascular disease, microalbuminuria, blood pressure lowering, the use of aspirin, lipid-lowering or antihypertensive medication. It provided clear evidence that Ramipril should safely and cost-effectively be used in individuals not known to have low ventricular ejection fraction or heart failure but at high-risk of cardiovascular events. It was also beneficial in patients with renal insufficiency, reducing progression of proteinuria and development of new microalbuminuria. It provided micro- and macrovascular benefits in people with diabetes, reduced the development of new cases of diabetes and showed a positive and graded association between the waist-to-hip ratio and the risk of developing diabetes. Sub-studies completed and on-going into the predictive role of natriuretic peptides, infectious and inflammatory markers, provide insight into possible mechanisms of action of Ramipril.
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PMID:The HOPE (Heart Outcomes Prevention Evaluation) Study and its consequences. 1611 72

Ramipril/felodipine extended release (ER) [Triapin and Triapin Mite, Unimax] is a once-daily fixed-dose combination of the ACE inhibitor ramipril and the ER formulation of the dihydropyridine calcium channel antagonist felodipine. It is indicated in adult patients with essential hypertension whose blood pressure (BP) is inadequately controlled with ramipril or felodipine monotherapy. In this patient population, commercially available fixed-dose combinations (i.e. 2.5 mg/2.5 mg and 5 mg/5 mg) of ramipril and felodipine ER are more effective at controlling hypertension than the individual components used as monotherapy at the same dosages. Likewise, the 5 mg/5 mg combination is as effective as felodipine ER 10 mg, and more effective than ramipril 10 mg administered as monotherapy. The addition of low-dose ramipril plus felodipine ER (fixed-dose or combination of individual components) to the existing antihypertensive regimen also appears to provide adequate BP control and renal protection in hypertensive patients with non-diabetic chronic renal disease. In these patients, the low-dose combination of ramipril and felodipine ER was as effective as standard-dose felodipine ER, but more effective than standard-dose ramipril, in providing diastolic BP (DBP) control, and as effective as standard-dose ramipril, but more effective than standard-dose felodipine ER, in slowing the rate of regression of glomerular filtration. The ramipril/felodipine ER combination is as well tolerated as ramipril or felodipine ER monotherapy administered at the same dosages, and is better tolerated than felodipine ER monotherapy given at twice the dosage used in the combination. Overall, ramipril/felodipine ER appears to be an effective option for the treatment of adults with essential hypertension that is poorly controlled with monotherapy. In addition, a fixed, low-dose combination of ramipril/felodipine ER is a potential alternative to monotherapy for the initial management of essential hypertension.
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PMID:Ramipril/felodipine extended-release fixed-dose combination: a review of its use in the management of essential hypertension. 1611 82

Ramipril is an angiotensin-converting enzyme inhibitor that has been extensively studied in randomised, controlled clinical trials in patients with cardiovascular diseases. Therapy with ramipril in patients with various cardiovascular disorders has demonstrated significant and clinically important reductions in cardiovascular death, myocardial infarction, stroke, congestive heart failure, progressive renal impairment and onset of diabetes. Ramipril is usually dosed at 2.5-10 mg/day. Beneficial effects of ramipril are observed in the treatment of hypertension and congestive heart failure, prevention of cardiovascular events in high-risk patients, prevention of congestive heart failure, diabetes and other vascular events.
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PMID:Ramipril in the treatment of vascular diseases. 1614 10

Current national guidelines recommend aggressive lowering of blood pressure (< 130/80 mm Hg) in patients with chronic kidney disease (CKD). In this paper, we summarize recent clinical trial data evaluating the effect of lower blood pressure goals on renal outcomes. The epidemiologic data relating blood pressure to progression of kidney disease, the Modification of Diet in Renal Disease (MDRD) study (in patients with > 1 g proteinuria/d), and meta-analyses of angiotensin-converting enzyme (ACE) inhibitor clinical trials all support lower blood pressure goals in CKD patients, particularly those with proteinuria. The African American Study of Kidney Disease and Hypertension (AASK) supports lower blood pressure goals in terms of reduction of proteinuria, but demonstrates no additional benefit for clinical renal outcomes. Similarly, the second Ramipril Efficacy in Nephropathy study (REIN-2) shows that in patients with proteinuric nondiabetic renal disease who are receiving ACE inhibitors, a lower than usual blood pressure goal does not improve renal outcomes. However, there are limited clinical trial data evaluating the effects of low blood pressure on the increased cardiovascular risk seen in patients with CKD. Pending further clinical studies, current recommendations to target tight blood pressure control (< 130/80 mm Hg) in patients with CKD appear reasonable.
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PMID:The African American Study of Kidney Disease: do these results indicate that 140/90 mm hg is good enough? 1615 80

Epidemiological studies have established that left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular and cerebrovascular morbidity and mortality. In turn, hypertension is a well-established risk factor for LVH. Ambulatory blood pressure monitoring has shown that 24-h mean ambulatory blood pressure is a particularly powerful predictor of LVH, being superior to casual clinic blood pressure measurements. The magnitude of the rise in blood pressure in the early morning correlates with the extent of LVH. Prospective studies have shown the advantageous effects of antihypertensive therapy on LVH in terms of regression of left ventricular mass (LVM) and subsequent reduction in overt cardiovascular disease. Meta-analysis has identified differences in the ability of different classes of anti-hypertensive agents to bring about regression of LVH, with agents that target the renin angiotensin system (RAS) appearing superior to other agents, such as beta-blockers and diuretics. The distinct pharmacological features of telmisartan suggest that it may be a suitable agent for managing hypertensive patients because it provides sustained control of blood pressure and appears to be very effective in reversing cardiac remodelling. Pre-clinical evaluation has demonstrated that telmisartan suppresses angiotensin II-induced collagen production and secretion by cultured fibroblasts, and reduces left ventricular weight in different animal models. Several clinical studies have demonstrated that, as well as reducing blood pressure (including 24-h mean ambulatory values), telmisartan brings about LVM regression in patients with hypertension, and improves left ventricular and left atrial function. Comparative studies have shown telmisartan's superiority compared with both hydrochlorothiazide and carvedilol in regressing LVM, the additional activity probably being explained by the sustained blood pressure control and the non-haemodynamic effects of targeting the RAS. The ultimate proof of the clinical value of telmisartan will be provided by the outcome trials ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) currently being conducted in high-risk patients.
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PMID:Pre-clinical and clinical experience of telmisartan in cardiac remodelling. 1622 96

Endothelial dysfunction, characterized by impaired nitric oxide activity, constitutes an early step in the pathogenesis of atherosclerotic disease. Prospective studies have shown that impaired endothelium-dependent vasorelaxation and the vasodilatory response of coronary arteries to acetylcholine predict cardiovascular events. Microalbuminuria and estimated glomerular filtration rate, which are both deeply influenced by renal nitric oxide activity, are predictors of cardiovascular outcome and total mortality but develop at a later stage of renal impairment. Endothelial dysfunction reflects early stage renal involvement in the atherosclerotic processes. The Telmisartan versus Ramipril in renal ENdothelium DYsfunction (TRENDY) trial examined endothelial function of the renal vasculature as a therapeutic target in patients with hypertension and type 2 diabetes, but without albuminuria. The rationale was that blockade of the renin-angiotensin system (RAS) is cardio- and renoprotective at later stages of the disease, but the impact of blockade of the RAS at earlier stages of disease is unknown. The results of TRENDY indicate that the endothelial function, as assessed by basal nitric oxide activity, can be improved after RAS blockade. These data complement the results of the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial, which demonstrated that telmisartan and enalapril similarly decelerate the progression of overt diabetic nephropathy. The results of TRENDY are in accordance with the observed changes in peripheral circulation. Endothelium-dependent vasorelaxation could be improved with angiotensin II receptor blockers, but not with diuretics or beta-blockers, in hypertensive patients. Intervention at the beginning of the renal and cardiovascular continuum offers the opportunity to prevent the fatal development towards renal and cardiac failure.
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PMID:Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum? 1660 59


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