Gene/Protein Disease Symptom Drug Enzyme Compound
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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

Diabetic foot syndrome (DFS) is the most frequent cause of hospitalization of diabetic patients and one of the most economically demanding complications of diabetes. People with diabetes have been shown to have higher mortality than people without diabetes. On this basis, the aim of our study was to evaluate the possible role of diabetic foot as a cardiovascular risk marker in patients with type 2 diabetes mellitus. We enrolled 102 consecutive patients with type 2 diabetes mellitus with diabetic foot and 123 patients with type 2 diabetes mellitus without limb lesions to compare the prevalence of main cardiovascular risk factors, subclinical cardiovascular disease, previous cardiovascular morbidity, and incidence of new vascular events on a 5-year follow-up. Diabetic patients with diabetic foot were more likely to have a higher prevalence of cardiovascular risk factors such as hypercholesterolemia, hypertriglyceridemia, hyperuricemia, and microalbuminuria or proteinuria, a higher prevalence of a previous cardiovascular morbidity (coronary artery disease, transient ischemic attack/ischemic stroke, diabetic retinopathy), and a higher prevalence of subclinical cardiovascular disease. Furthermore, diabetic patients with foot ulceration showed, on a 5-year follow-up, a higher incidence of new-onset vascular events (coronary artery disease, transient ischemic attack/ischemic stroke, diabetic retinopathy). At multivariate analysis, duration of diabetes, age, hemoglobin A1c, and DFS maintained a significant association with cardiovascular morbidity; but DFS presence showed the highest hazard ratio.
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PMID:Cardiovascular risk profile and morbidity in subjects affected by type 2 diabetes mellitus with and without diabetic foot. 1844 33

To evaluate the diabetic complications and fate of diabetic nephropathy in Saudi population, we studied 184 diabetic nephropathy (DN) patients who were referred to nephrology clinic of King Khalid University Hospital, Riyadh, Saudi Arabia from January 2003-June 2006. The patients had mean age of 61.9 +/- 13.1 years, included 128 (69.6%) males, and were followed up for a mean period of 10.2 +/- 1.5 years. The mean duration of diabetes mellitus (DM) was 19.5 +/- 5.8 years, and duration of nephropathy was 7.7 +/- 3.3 years. Family history of DN was documented in 52 (28.2%) patients. At initial visit, the mean systolic blood pressure was 164 +/- 14.5 mmHg, the mean diastolic blood pressure was 97.9 +/- 10.4 mmHg. Thirty-seven (20%) patients had normal BMI, 88 (48%) were overweight, while 55 (30%) were obese. Mean creatinine clearance was 51.7 +/- 26.3 mL/min, 24 hrs urinary proteins 1.99 +/- 2.48 gm/day, HbA1C 9.2 +/- 1.8 %, triglyceride 2.1 +/- 1.3 mmol/L, and cholesterol 5.17 +/- 1.54 mmol/L. Diabetic complications included angiography proven coronary artery disease in 106 (57.6 %) patients, stroke in 21 (11.4%), myocardial infarction (MI) in 27(14.6%), angina in 87 (47.2 %), retinopathy in 82 (44.5%), Blindness in 3 (1.6%), peripheral vascular disease in 121 (65.7%), Neuropathy in 123 (66.8%), hypertension in178 (96.7%), diabetic foot in 25 (13.5%), Amputation in 10 (5.4%), and end-stage renal disease in 70 (38%). Total of 13 (7.05%) patients died in the hospital. Thirty-seven percent of patients developed > 6 concomitant complications. 28% developed 5, 17% developed 4, and the rest developed < 3. DN was relatively refractory to therapy and progressive; 123 (66.8%) patients doubled their serum creatinine in 3.59 +/- 2.88 years, 32 (17.3%) maintained stable renal function, 136 (73.6 %) deteriorated, and 12 (6.52%) improved. we conclude that the prevalence of diabetic complications is high among Saudi patients, and many had multiple complications. Baseline creatinine clearance and proteinuria, high systolic blood pressure, advanced age, and longer duration of diabetes were the most significant risk factors for developing complications.
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PMID:Microvascular and macrovascular complications in diabetic nephropathy patients referred to nephrology clinic. 1911 22

Trandolapril is a well known angiotensin converting enzyme (ACE) inhibitor with many cardiovascular (CV) indications. The objectives of this article are to review the pharmacokinetics and pharmacodynamics properties of trandolapril and to focus on its clinical relevance in cardiovascular medicine. Various populations have been studied in large clinical trials including patients with congestive heart failure (CHF) after an acute myocardial infarction (AMI), diabetics, patients with hypertension (HTN), stable coronary artery disease (CAD) and prevention of proteinuria. Long-term treatment with trandolapril in patients with reduced left ventricular function soon after AMI significantly reduced the risk of overall mortality, mortality from CV causes, sudden death, and the development of severe CHF. Treatment with trandolapril after AMI complicated by left ventricular dysfunction appears to be of considerable importance in patients with diabetes mellitus by saving lives and substantially reducing the risk of progression to severe CHF as well. Moreover, trandolapril reduces progression to proteinuria in high-risk patients. Some of the advantages of trandolapril over other ACE inhibitors are the wide spectrum of patient populations studied, the well established dosage and its proven trough-to-peak effect ratios permitting a safe once-a-day administration.
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PMID:Update on the use of trandolapril in the management of cardiovascular disorders. 1933 28

Low serum adiponectin is associated with a high incidence of type 2 diabetes or coronary artery disease in the general population. Paradoxically, serum adiponectin is elevated in patients with chronic kidney disease (CKD), such as overt diabetic nephropathy. The current study aimed to investigate whether anemia was independently associated with the serum level of high-molecular-weight (HMW) adiponectin in patients with type 2 diabetes. We studied 207 type 2 diabetic patients (92 women and 115 men). Anemia was defined as a hemoglobin (Hb) <13.0g/dL in men and <12.0g/dL in women according to the guidelines of the World Health Organization (WHO). Overt nephropathy (CKD) was defined as clinical proteinuria and /or estimated glomerular filtration rate (eGFR) lower than 60mL/min for more than 3 months. The diabetic patients were divided into 4 groups according to the presence or absence of anemia and/or CKD. Serum HMW adiponectin levels were measured by a sandwich enzyme-linked immunosorbent assay. In all 207 patients with type 2 diabetes, serum total and HMW adiponectin levels were correlated positively with age, the duration of diabetes, high-density lipoprotein (HDL) cholesterol, urinary albumin, and serum erythropoietin, whereas negative correlations were found with body mass index, triglyceride, eGFR, Hb, hematocrit, and high sensitivity C-reactive protein. A stepwise regression analysis demonstrated that among several significant variables, Hb had the strongest independent influence on HMW adiponectin (beta =-0.487, P < 0.001). Diabetic patients of both sexes with anemia and CKD had the highest serum levels of HMW adiponectin among the 4 groups. In conclusion, anemia is associated with marked elevation of serum HMW adiponectin levels in diabetic patients who have CKD, and this elevation is independent of renal function.
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PMID:Anemia is associated with an elevated serum level of high-molecular-weight adiponectin in patients with type 2 diabetes independently of renal dysfunction. 1976 61

Diabetes and arterial hypertension continue to be the main causes of chronic renal failure in 2010, with a rising prevalence in part due to the worldwide obesity epidemic. Proteinuria is a main feature of chronic renal disease and mediated by defects in the glomerular filtration barrier and is as a good predictor of cardiovascular events. Indeed, chronic renal disease due to glomerulosclerosis is one of the important risk factors for the development of coronary artery disease and stroke. Glomerulosclerosis develops in response to inflammatory activation and increased growth factor production. Preclinical and first preliminary clinical studies provide strong evidence that endogenous endothelin-1 (ET-1), a 21-amino-acid peptide with strong growth-promoting and vasoconstricting properties, plays a central role in the pathogenesis of proteinuria and glomerulosclerosis via activation of its ET(A) subtype receptor involving podocyte injury. These studies have not only shown that endothelin participates in the disease processes of hypertension and glomerulosclerosis but also that features of chronic renal disease such as proteinuria and glomerulosclerosis are reversible processes. Remarkably, the protective effects of endothelin receptors antagonists (ERAs) are present even on top of concomitant treatments with inhibitors of the renin-angiotensin system. This review discusses current evidence for a role of endothelin for proteinuric renal disease and podocyte injury in diabetes and arterial hypertension and reviews the current status of endothelin receptor antagonists as a potential new treatment option in renal medicine.
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PMID:Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans. 2035 30

We report on a 55-year-old man who was admitted with increased serum-creatinine (3.4 mg/dl), gross proteinuria (4.6 g/24 h) and arterial hypertension. The medical history included hyperlipidemia, coronary artery disease (CAD) and a recent coronary angiography, but normal serum-creatinine and no proteinuria before coronary intervention. Serology and urinary analysis did not show any signs of a systemic disease. A renal biopsy, however, revealed multiple cholesterol crystal emboli in small vessels along with a typical infiltration of eosinophilic granulocytes. The patient was subsequently treated with an angiotensin-receptor-1 (AT1R) blocker and high-dose statins and was then evaluated for LDL-apheresis. Gross proteinuria was largely unaffected by (AT1R) blockade and renal function further declined necessitating, initiation of hemodialysis. Renal CCE with profound proteinuria is an unusual presentation of acute renal failure, potentially misleading and thereby prolonging correct diagnostics of a rare entity. Identification of high-risk patients is of utmost importance as efficient therapeutic strategies do not exist.
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PMID:Gross proteinuria and subacute renal failure after coronary angiography - a case report of cholesterol crystal embolization. 2050 25

Since the publication of "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC 7) in 2003 and "2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension" (ESH/ESC guidelines), no substantial improvement has been made in the control of hypertension. Maybe, publishing of new 2007 Guidelines for the Management of Arterial Hypertension will contribute to a more rational and purposeful management of hypertension. The question whether beta blockers will keep their place as the first-line therapy in the new guidelines has been opened. After 30 years of their use in clinical practice, beta blockers have again become the focus of great discussion and controversy. Namely, according to the National Institute for Health and Clinical Excellence (NICE), beta blockers, which were for more than 30 years the first-line therapy for the treatment of high blood pressure, and antihypertensive effects of which were well documented in large randomized placebo controlled studies, have lost the first-line therapy role. Yet the normalization of the blood pressure has been difficult in spite of using the nowadays available drugs. This makes the question of disposal of such drugs even more open and disputable. Taking this into account, the 2007 Guidelines for the Management of Arterial Hypertension have kept beta blockers as the first line therapy. Besides, the separate guidelines for treatment of arterial hypertension and hypercholesterolemia, have been replaced by the new guidelines for management of the integrated cardiovascular risk. According to the Guidelines, the cardiovascular risk score should be applied in the everyday practice. Since cardiovascular risk factors multiply and interact with each other, moderate reduction in several factors will be more beneficial than major reduction in one. Much more than the 2003 ESH/ESC guidelines do, the new 2007 Guidelines emphasize the combined drug therapy using smaller dosages for simultaneous treatment of several cardiovascular risk factors as a replacement for separate management of hypertension alone. Also, there is a new goal of < 130/80 mm Hg for people with established cardiovascular disease including coronary artery disease, diabetes, renal dysfunction, or proteinuria. However, the main benefits of antihypetensive therapy are due to lowering of blood pressure per se.
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PMID:[Arterial hypertension 2007: Guidelines for the management of arterial hypertension]. 2155 42

Cardiovascular diseases (CVD) are the leading cause of mortality in renal transplant recipients. Various traditional and unconventional cardiovascular risk factors are potentiated by the adverse effects of immunosuppressive drugs. The mammalian target of rapamycin (mTOR) inhibitors have shown cardioprotective effects in experimental studies, but their influence on CVD in renal transplantation is unclear. The study included 115 kidney transplant recipients treated with mTOR inhibitors with steroids. A group of 38 patients received additionally small doses of calcineurin inhibitor. The control group consisted of 58 kidney transplant recipients randomly chosen among the population of patients transplanted at the same time, who received a calcineurin inhibitor, mycophenolate mofetil or sodium plus steroids. No differences in age, gender, duration of pretransplantat dialysis, time after transplantation, body mass index or glycated hemoglobin existed between the groups. Blood pressure and number of antihypertensive agents, high-density lipoprotein cholesterol, and uric acid levels were similar. The prevalence of diabetic, ischemic, or hypertensive nephropathy as the reason for end-stage renal disease was similar (P=.08). The study group showed higher mean values of total cholesterol (249 vs 204.6 mg/dL; P<.0001) and low-density lipoprotein 136.5 vs 117.7 mg/dL; (P=.015), as well as median values of triglycerides (202 vs 142 mg/dL; P<.0001) and proteinuria (P=.0002). mean estimated glomerular filtration rate was lower in the study group (42.9 vs 51.9 mL/min; P=.0003). Posttransplant diabetes appeared in 38% of the study group compared to 20% of the controls (P=.08). The incidence of coronary artery disease was higher among patients treated with mTOR inhibitors (P=.04). CVD, defined as myocardial infarction, percutaneous coronary intervention, stroke, aortic aneurysm, pulmonary thromboembolism, sudden cardiac death appeared in 26 study group compared with four control patients (P=.24). The risk of any CVD was not significantly higher among patients receiving mTOR inhibitors hazard ratio 1.94; 95% confidence interval 0.83-4.52). In conclusion, no correlation was observed between the duration of mTOR therapy and CVD.
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PMID:Cardiovascular risk in kidney transplant recipients receiving mammalian target of rapamycin inhibitors. 2199 2

Hypertension occurs twice as commonly in diabetics than in comparable nondiabetics. Patients with both disorders have a markedly higher risk for premature microvascular and macrovascular complications. Aggressive control of blood pressure (BP) reduces both micro- and macrovascular complications. In diabetic hypertensives, angiotensin converting enzyme inhibitors (ACEIs) are the first line in management of hypertension, and can be replaced by angiotensin II receptor blockers (ARBs) if patients are intolerant of them. Recent studies suggest ARBs to be on par with ACEI in reducing both macro- and microvascular risks. Adding both these agents may have a beneficial effect on proteinuria, but no extra macrovascular risk reduction. Thiazides can also be used as first line drugs, but are better used along with ACEI/ARBs. Beta-blockers [especially if the patient has coronary artery disease] and calcium channel blockers are used as second line add-on drugs. Multidrug regimens are commonly needed in diabetic hypertensives. Achieving the target BP of <130/80 is the priority rather than the drug combination used in order to arrest and prevent the progression of macro- and microvascular complications in diabetic hypertensives.
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PMID:Management of diabetic hypertensives. 2214 42


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