Ernesto Germán Cardona-Muñoz

Effect of telmisartan on renal outcomes: a randomized trial.

Context Few trials have evaluated whether angiotensin-receptor blockers (ARBs) prevent renal disease in people without proteinuria. Contribution In this trial, patients with cardiovascular disease or diabetes, but without macroalbuminuria or heart failure, were randomly assigned to receive telmisartan or placebo. During 4 to 5 years of follow-up, telmisartan recipients had albuminuria less often but had doubling of serum creatinine and slight decreases in estimated glomerular filtration rate more often than placebo recipients. Few patients in either group required dialysis. Implication The effects of ARBs on renal variables are complicated, but no strong evidence indicates that they prevent clinically important renal disease in patients without proteinuria. The Editors The TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) study examined cardiovascular outcomes with telmisartan, an angiotensin-receptor blocker (ARB), compared with placebo in people at high vascular risk who were intolerant of angiotensin-converting enzyme (ACE) inhibitors. Telmisartan had no statistically significant effect on the primary cardiovascular outcome, but it reduced the risk for the secondary composite outcome of cardiovascular death, myocardial infarction, and stroke to a moderate extent and had no effect on cardiovascular or total mortality (1). Renal outcomes were prespecified, important secondary outcomes of the TRANSCEND study, because a growing number of patients with atherosclerotic vascular disease are starting renal replacement therapy (2). For example, in a German registry, the proportion of individuals with vascular causes of nephropathy leading to long-term dialysis increased from 12% in 1995 to 23% in 2005 (3). Drugs used to reduce vascular events may also affect the kidney, so the effects of such drugs on renal outcomes in people with vascular disease are relevant. Angiotensin-receptor blockers reduce elevated blood pressure (4) and urinary protein excretion (5), which are both considered to be surrogate variables of renal benefit. Large trials in patients with overt diabetic nephropathy have demonstrated that ARBs reduce the rate of dialysis and doubling of serum creatinine (6, 7). The impact of ARBs on renal outcomes in other patients is not reliably known. This prespecified analysis of the TRANSCEND study (1) examined the effects of telmisartan on renal function in a large sample that was intolerant of ACE inhibitors and had vascular disease but not macroalbuminuria. The composite renal outcome was dialysis or doubling of serum creatinine. We also report changes in estimated glomerular filtration rate (GFR) and albuminuria. Methods Design Overview We enrolled and randomly assigned participants age 55 years or older with documented cardiovascular disease or diabetes with end-organ damage who could not tolerate ACE inhibitors between November 2001 and May 2004 to receive telmisartan, 80 mg/d, or matching placebo along with standard treatment. Follow-up was completed by March 2008. The main trial primary outcome, reported elsewhere (1), was the composite of myocardial infarction, stroke, cardiovascular death, and hospitalization for heart failure. We report the prespecified renal outcomes in this article. The ethics committees at all participating institutions and the regulatory authorities in each country approved the study protocol, and each participant provided written informed consent. Setting and Participants In 630 centers in 40 countries, we enrolled 5926 patients age 55 years or older who were intolerant of ACE inhibitors if they had coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage (1, 8). We defined ACE inhibitor intolerance as discontinuation of an ACE inhibitor for a documented reasonmost commonly cough (88.2%), symptomatic hypotension (4.1%), angioedema (1.3%), and renal dysfunction (1%) (1, 8). We excluded patients who, according to the clinical investigators, needed an ARB; were known to be hypersensitive or intolerant to ARBs; or had heart failure, significant valvular or cardiac outflow tract obstruction, constrictive pericarditis, complex congenital heart disease, unexplained syncope, planned cardiac surgery, cardiac revascularization in the previous 3 months, systolic blood pressure of 160 mm Hg or greater, heart transplantation, subarachnoid hemorrhage, known significant renal artery stenosis (formal exclusion not required), serum creatinine levels greater than 265 mol/L (>3.0 mg/dL), or hepatic dysfunction. The Appendix Table lists all exclusion criteria. Macroalbuminuria (urinary albumincreatinine ratio [UACR] >33.9 mg/mmol) was an exclusion criterion, but it was detected at baseline in 78 participants (1.44%) when the urine was analyzed centrally. Before entering the study, 1773 participants (29.9%) were receiving or had received ARBs. Appendix Table. Exclusion Criteria The study was coordinated by the Population Health Research Institute at McMaster University, Hamilton, Ontario, Canada. The steering committee designed and oversaw the trial and implemented an operations committee, an independent data safety and monitoring board, and an end point adjudication committee. Clinical sites in 40 countries, selected by the national coordinators, used a wide variety of recruitment strategies, including chart review, referral from other physicians, and mass mailing. Randomization and Interventions After a 3- to 4-week run-in phase, participants were randomly assigned to telmisartan, 80 mg/d, or placebo. During the run-in phase, all participants received single-blind placebo for 1 week followed by telmisartan, 80 mg/d, for 2 to 3 weeks. Of 6666 participants entering the run-in phase, 11 (0.2%) withdrew because of elevated serum creatinine levels and 26 (0.4%) withdrew because of elevated serum potassium levels. Figure 1 shows the study flow diagram and reasons for exclusion; baseline characteristics of the participants are published elsewhere (1). Participants were randomly assigned by telephone through a central automated system. Randomization was stratified by hospital or clinic. All participants and trial investigators were blinded to randomized treatment. Tablets identical in color, shape, and taste were provided in blister packs. Unblinded data were made available exclusively to the independent data safety and monitoring board by a statistician who was independent of the trial. Figure 1. Study flow diagram. All participants received randomized therapy and were followed, except for 18 (0.3%) who were followed until the end of the study or until a primary event occurred. The number of patients considered for the trial who did not enter the run-in phase is unknown. A figure showing trial follow-up and cardiovascular outcomes is published elsewhere (1). Progression of proteinuria was defined as new microalbuminuria, macroalbuminuria, or both. eGFR= estimated glomerular filtration rate; UACR= urinary albumincreatinine ratio. Outcomes and Measurements In August 2007, before completion of the TRANSCEND study, we developed a statistical analysis plan for the renal outcomes. As in other large renal trials, the primary composite outcome was defined as the first occurrence of dialysis, renal transplantation, doubling of serum creatinine, or death (6, 7, 9). No cases of renal transplantation were reported in this trial. The secondary renal outcome was the composite of dialysis or doubling of serum creatinine. After completion of the analysis, deatha nonspecific outcomeoutnumbered the other components of the primary outcome by 4-fold. Therefore, we determined the secondary outcome as the composite outcome measure of this analysis. Further outcomes were components of the composite outcome, changes in estimated GFR and UACR, and progression of proteinuria (defined as development of new micro- or macroalbuminuria), as well as the original primary composite outcome and the composite of dialysis; doubling of serum creatinine; or development of new microalbuminuria, macroalbuminuria, or both. Dialysis was categorized as short-term (2 months) or long-term (>2 months). Such information was missing in 1 patient. Urinary albumin and creatinine were measured centrally (10), and serum creatinine was measured locally at study sites. The estimated GFR was calculated from serum creatinine by using the 4-variable Modification of Diet in Renal Disease Study formula (11). Serum creatinine values below 35 mol/L (<0.4 mg/dL) were considered implausible, and we excluded participants with such values from the analysis (10 patients at baseline and 15 patients at follow-up). Information about dialysis was recorded at each visit. Follow-up Procedures and Monitoring We followed participants after 6 weeks, 6 months, and every 6 months thereafter for a mean of 56 months. At each visit, we collected information about adverse events, including dialysis; adherence to trial medication; and outcomes. We began data management as soon as data had been submitted, usually within 1 week of the patient visit. The data were sent through the datafax system and examined for ranges, plausibility, and missing data. Queries were sent to the investigator until responses were obtained. We measured serum creatinine before the run-in phase, 6 weeks after randomization, after 2 years, and at the end of the study, and we measured UACR before the run-in phase, at 2 years, and at the penultimate visit in a first morning urine sample. A UACR between 3.4 and 33.9 mg/mmol was defined as microalbuminuria and a value greater than 33.9 mg/mmol (approximately 300 mg/g creatinine) as macroalbuminuria. A blinded central committee, using standardized criteria, adjudicated all deaths and primary outcomes. After trial conclusion, a questionnaire was sent to all sites that reported dialysis to obtain information about duration of dialysis. Statistical Analysis The original sample size esti

Serum leptin levels in women with systemic lupus erythematosus

Abstract The purpose of this study was to evaluate serum leptin levels in systemic lupus erythematosus (SLE). Forty-one women with SLE were compared with 23 healthy women of similar age and body mass index (BMI). Clinical characteristics and Mexican systemic lupus erythematosus disease activity index (Mex-SLEDAI) score were assessed. Serum leptin levels (ng/dl) were measured by enzyme-linked immunosorbent assay (ELISA). Comparisons of leptin levels were made with the Mann-Whitney U-test. In a multiple regression analysis, those factors that could influence the leptin levels were adjusted. Patients with SLE had higher leptin levels than the control group (SLE median 31 vs control median 15, P=0.023). After adjusting by other variables, the serum leptin levels remained higher in SLE than in controls (P=0.02). Patients with SLE had no association between leptin levels and Mex-SLEDAI score, age, duration of disease, or prednisone doses. Those with SLE had higher leptin levels than controls. Further longitudinal studies are required to evaluate the role of this hormone in the exacerbations of SLE.

The DISCOVERY PENTA study: a DIrect Statin COmparison of LDL‐C Value – an Evaluation of Rosuvastatin therapY compared with atorvastatin

ABSTRACT Background: International guidelines emphasize the need to achieve recommended low-density lipoprotein cholesterol (LDL‐C) levels in order to reduce morbidity and mortality associated with coronary heart disease (CHD). However, many patients with hypercholesterolemia fail to achieve LDL‐C goals on treatment. Objective: The primary objective was to compare the efficacy of rosuvastatin and atorvastatin for enabling patients to achieve National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL‐C goals. Secondary objectives were European LDL‐C goal achievement, changes in the lipid profile, and safety. Research design and methods: This 12‐week, multicenter, multinational, randomized, open-label trial compared the efficacy and safety of rosuvastatin 10 mg with atorvastatin 10 mg in statin-naïve and switched patients with primary hypercholesterolemia from Brazil, Colombia, Mexico, Portugal, and Venezuela. Results: A total of 1124 patients with similar baseline characteristics were randomized to the two treatment groups. After 12 weeks of treatment, a significantly greater percentage of patients receiving rosuvastatin 10 mg compared with atorvastatin 10 mg achieved NCEP ATP III LDL‐C goals (71.2% vs 61.4%, p < 0.001), 1998 European LDL‐C goals (73.5% vs 59.2%, p < 0.001) and 2003 European LDL‐C goals (58.9% vs 44.6%, p < 0.001). Rosuvastatin treatment was associated with significant reductions in LDL‐C and total cholesterol (TC) and, in statin-naïve patients, a significant increase in high-density lipoprotein cholesterol (HDL‐C) compared with atorvastatin treatment. Both treatments were well tolerated with a similar incidence of adverse events. Clinically significant elevations in creatinine, creatine kinase or hepatic transaminases were low and similar between treatment groups. Conclusions: Rosuvastatin 10 mg is significantly more effective at achieving NCEP ATP III and European LDL‐C goals, lowering LDL‐C and TC in both naïve and switched patients and increasing HDL‐C in naïve patients than atorvastatin 10 mg, with a similar safety and tolerability profile. This study also provides evidence regarding the comparative effects of rosuvastatin versus atorvastatin in Latin American and Portuguese populations.

Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function

Diabetic polyneuropathy (DPN) is defined as peripheral nerve dysfunction. There are three main alterations involved in the pathologic changes of DPN: inflammation, oxidative stress, and mitochondrial dysfunction. Inflammation induces activation of nuclear factor kappa B, activator protein 1, and mitogen-activated protein kinases. Oxidative stress induced by hyperglycemia is mediated by several identified pathways: polyol, hexosamine, protein kinase C, advanced glycosylation end-products, and glycolysis. In addition, mitochondrial dysfunction accounts for most of the production of reactive oxygen and nitrosative species. These free radicals cause lipid peroxidation, protein modification, and nucleic acid damage, to finally induce axonal degeneration and segmental demyelination. The prevalence of DPN ranges from 2.4% to 78.8% worldwide, depending on the diagnostic method and the population assessed (hospital-based or outpatients). Risk factors include age, male gender, duration of diabetes, uncontrolled glycaemia, height, overweight and obesity, and insulin treatment. Several diagnostic methods have been developed, and composite scores combined with nerve conduction studies are the most reliable to identify early DPN. Treatment should be directed to improve etiologic factors besides reducing symptoms; several approaches have been evaluated to reduce neuropathic impairments and improve nerve conduction, such as oral antidiabetics, statins, and antioxidants (alpha-lipoic acid, ubiquinone, and flavonoids).

Factors associated with hyperhomocysteinaemia in Mexican patients with rheumatoid arthritis

Background: Hyperhomocysteinaemia is a factor related to the development of atherosclerosis in rheumatoid arthritis (RA). However, Hispanics with RA develop high rates of coronary disease; there are no studies about the frequency and factors related to high levels of homocysteine in Mexican patients. Objective: To evaluate the prevalence and characteristics associated with hyperhomocysteinaemia in Mexican patients with RA. Methods: One hundred and fifty‐two patients with RA were compared with 153 controls. The assessment in RA included clinical characteristics, disease activity (RADAR), functioning (HAQ‐Di and global functional status), comorbidity, and radiological damage. Laboratory determinations included total serum homocysteine (tHcy), erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), rheumatoid factor (RF), and lipid profile. Results: Median levels of homocysteine were higher in RA compared with controls (11.3 vs. 9.3, p<0.001). Twenty per cent of the patients with RA had hyperhomocysteinaemia (>15 µmol/L) compared with 6% in controls (p<0.001). There was statistical association between hyperhomocysteinaemia in RA with male gender (p<0.001), impairment in the global functional status (p = 0.004), higher radiological damage (p = 0.001), and CRP (p = 0.04). There was no association with RADAR, HAQ‐Di, or RF, methotrexate dose or duration of use. In the adjusted multivariate model, the two variables associated with higher risk for hyperhomocysteinaemia were male gender (OR = 4.2, 95% CI 2 to 12, p = 0.006) and higher radiological damage (III–IV) (OR = 3.4, 95% CI 1.3 to 9, p = 0.01). Conclusions: Our data show a high prevalence of hyperhomocysteinaemia in Mexican patients with RA. More effort is required to evaluate and treat earlier this coronary risk factor.

Influenza Vaccination and Major Adverse Vascular Events in High-Risk Patients

Background— We sought to determine the association between influenza vaccination and major adverse vascular events because the association remains uncertain. Methods and Results— A total of 31 546 participants were enrolled from 40 countries. Eligibility included age ≥55 years and known vascular disease. The primary outcome was a composite of death resulting from cardiovascular causes, myocardial infarction, or stroke during 4 influenza seasons (2003–2007). Influenza vaccination was associated with a lower risk of the outcome during 3 influenza seasons (defined using World Health Organization FluNet reports): 2004 to 2005 (adjusted odds ratio [OR], 0.62; 95% confidence interval [CI], 0.50–0.77), 2005 to 2006 (adjusted OR, 0.69; 95% CI, 0.53–0.91), and 2006 to 2007 (adjusted OR, 0.52; 95% CI, 0.42–0.65), the same years that circulating influenza matched the vaccine antigen. In 2003 to 2004, there was an incomplete match between circulating influenza and the vaccine antigen, and there was no association between influenza vaccination and the outcome (adjusted OR, 0.96; 95% CI, 0.73–1.27). However, tests of potential biases in the analyses revealed associations between influenza vaccination and outcome during noninfluenza seasons except 2003 to 2004. The summary ORs in the influenza season (OR, 0.65; 95% CI, 0.58–0.74]) and noninfluenza season (OR, 0.66; 95% CI, 0.57–0.76) were almost identical. The reduction in risk of noncardiovascular death associated with the influenza vaccine ranged from 73% to 79%. Conclusion— Although initial analyses suggest that influenza vaccination was associated with reduced risk of major adverse vascular events during influenza seasons when the influenza vaccine matched the circulating virus, sensitivity analyses revealed that risk of bias remained. A randomized trial is needed to definitively address this question.

Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide

The aim was to determine the effects of dulaglutide, a synthetic once‐weekly, injectable human glucagon‐like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non‐fatal myocardial infarction or non‐fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all‐cause mortality. Follow‐up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trials international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle‐aged patient seen in general practice throughout the world.

The effect of ubiquinone in diabetic polyneuropathy: A randomized double-blind placebo-controlled study

INTRODUCTION Diabetic polyneuropathy aetiology is based on oxidative stress generation due to production of reactive oxygen species. Ubiquinone is reduced to ubiquinol and redistributed into lipoproteins, possibly to protect them from oxidation. AIMS To evaluate the impact of oral ubiquinone in diabetic polyneuropathy, and the role of lipid peroxidation (LPO) and nerve growth factor (NGF-β). METHODS We conducted a double-blind, placebo-controlled clinical trial, patients were randomized to ubiquinone (400 mg) or placebo daily for 12 weeks. Main outcomes were clinical scores, nerve conduction studies, LPO, NGF-β and safety. RESULTS Twenty four patients on experimental group and twenty five on control group met the inclusion criteria (mean age 56 years, 22% male and 78% female, mean evolution of type 2 diabetes mellitus 10.7 years). Significant improvement on experimental vs control group was found in neuropathy symptoms score (from 2.5 ± 0.7 to 1 ± 0.8, p<0.001), neuropathy impairment score (5.5 ± 4 to 3.1 ± 2.6, p<0.001), sural sensory nerve amplitude (13.0 ± 6.1 to 15.8 ± 5.1 μV, p=0.049), peroneal motor nerve conduction velocity (39.7 ± 5.0 to 47.8 ± 4.9 m/s, p=0.047), and ulnar motor nerve conduction velocity (48.8 ± 6.8 to 54.5 ± 6.1m/s, p=0.046). There was a significant reduction of LPO in subjects treated with ubiquinone vs placebo (16.7 ± 8.6 and 23.2 ± 15.8 nmol/mL, respectively) with p<0.05, and NGF-β did not change (control 66.5 ± 26.7 vs. experimental 66.8 ± 28.4 pg/mL, p=0.856). No drug-related adverse reactions were reported. CONCLUSIONS Twelve weeks treatment with ubiquinone improves clinical outcomes and nerve conduction parameters of diabetic polyneuropathy; furthermore, it reduces oxidative stress without significant adverse events.

Effect of rosuvastatin on diabetic polyneuropathy: a randomized, double-blind, placebo-controlled Phase IIa study.

Background Diabetic neuropathy affects 50%–66% of patients with diabetes mellitus. Oxidative stress generates nerve dysfunction by causing segmental demyelinization and axonal degeneration. Antioxidants are considered to be the only etiologic management for diabetic polyneuropathy, and statins such as rosuvastatin increase nitric oxide bioavailability and reduce lipid peroxidation. The aim of this study was to evaluate the antioxidant effect of rosuvastatin in diabetic polyneuropathy. Methods We conducted a randomized, double-blind, placebo-controlled Phase IIa clinical trial in patients with type 2 diabetes and diabetic polyneuropathy (DPN) stage ≥1b. We allocated subjects to two parallel groups (1:1) that received rosuvastatin 20 mg or placebo for 12 weeks. Primary outcomes were neuropathic symptom score, disability score, and nerve conduction studies, and secondary outcomes were glycemic control, lipid and hepatic profile, lipid peroxidation, and nerve growth factor beta (NGF-β) levels. Results Both groups were of similar age and duration since diagnosis of diabetes and DPN. We observed improvement of DPN in the rosuvastatin group from stage 2a (88.2%) to stage 1b (41.2%), improvement of neuropathic symptom score from 4.5±2 to 2.4±1.8, and significant (P=0.001) reductions of peroneal nerve conduction velocity (from 40.8±2.2 to 42.1±1.6 seconds) and lipid peroxidation (from 25.4±2 to 12.2±4.0 nmol/mL), with no significant change in glycemic control or β-NGF. Conclusion The severity, symptoms, and nerve conduction parameters of DPN improved after 12 weeks of treatment with rosuvastatin. These beneficial effects appear to be attributable to reductions in lipid peroxidation and oxidative stress.

Effects of Ezetimibe/Simvastatin and Rosuvastatin on Oxidative Stress in Diabetic Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Objective. To evaluate the effects of ezetimibe/simvastatin (EZE/SIMV) and rosuvastatin (ROSUV) on oxidative stress (OS) markers in patients with diabetic polyneuropathy (DPN). Methods. We performed a randomized, double-blind, placebo-controlled phase III clinical trial in adult patients with Type 2 Diabetes Mellitus (T2DM) and DPN, as evaluated by composite scores and nerve conduction studies (NCS). Seventy-four subjects with T2DM were allocated 1 : 1 : 1 to placebo, EZE/SIMV 10/20 mg, or ROSUV 20 mg for 16 weeks. All patients were assessed before and after treatment: primary outcomes were lipid peroxidation (LPO), and nitric oxide (NO) surrogate levels in plasma; secondary outcomes included NCS, neuropathic symptom scores, and metabolic parameters. Data were expressed as mean ± SD or SEM, frequencies, and percentages; we used nonparametric analysis. Results. LPO levels were reduced in both statin arms after 16 weeks of treatment (p < 0.05 versus baseline), without changes in the placebo group. NO levels were not significantly affected by statin treatment, although a trend towards significance concerning increased NO levels was noted in both statin arms. No significant changes were observed for the NCS or composite scores. Discussion. EZE/SIMV and ROSUV are superior to placebo in reducing LPO in subjects with T2DM suffering from polyneuropathy. This trial is registered with NCT02129231.