Enric Esmatjes

Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy

Context Previously published results of this randomized, double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy. Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine. Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks. Cautions The trial had limited power to detect important differences between groups in mortality or strokes, and most patients received several antihypertensive agents. The Editors Patients with diabetes have an increased risk for cardiovascular complications and death (1). Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes (2-5) or were done exclusively in patients with diabetes (6-8). The meta-analysis of these studies (9), the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation (HOPE) study (2), and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial (5) demonstrated that angiotensin-converting enzyme (ACE) inhibitors (2, 9) and angiotensin-receptor blockers (5) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events. These studies randomly assigned few patients with renal involvement and overt proteinuria. Overt proteinuria occurred in fewer than 20% of the 470 patients in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (6), and only 11% of the 1195 patients in the LIFE trial (5). The Captopril Prevention Project (CAPP) (3) and the Swedish Trial in Old Patients with Hypertension-2 (STOP Hypertension-2) (4) did not state the number of patients with diabetes and overt proteinuria. There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) (7), and patients with dipstick-positive albuminuria were excluded from the HOPE trial (2). Since proteinuria is an independent risk factor for cardiovascular disease (10, 11), the data obtained in the aforementioned trials cannot be extrapolated to patients with type 2 diabetes and overt nephropathy. Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy (12, 13) without a change in all-cause mortality. Apart from studies in heart failure, few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers. We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial (IDNT) (12) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents. Methods Patients The IDNT was a randomized, double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy. The protocol of this study has been published (12, 14). Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy, as evidenced by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater, serum creatinine level of 89 mol/L (1.0 mg/dL) to 266 mol/L (3.0 mg/dL) in women or of 106 mol/L (1.2 mg/dL) to 266 mol/L (3.0 mg/dL) in men, and baseline seated blood pressure greater than 135/85 mm Hg. The institutional review boards of each center approved the protocol. All patients gave written informed consent. Treatment and Randomization Patients were randomly assigned centrally by computer to receive treatment with irbesartan, 300 mg/d (Avapro, Bristol-Myers Squibb, Princeton, New Jersey); amlodipine, 10 mg/d (Norvasc, Pfizer, New York); or matched placebo. To minimize any center effect, randomization was blocked by center. All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors, angiotensin II receptor blocking agents, or calcium-channel blockers. For the analysis of cardiovascular end points, patients were followed to initiation of treatment for end-stage renal failure (dialysis or renal transplantation), reaching a serum creatinine level of 530.4 mol/L (6.0 mg/dL) or higher, death, or administrative censoring in December 2000. Outcomes We prospectively established cardiovascular outcomes, defined in the Appendix Table. Appendix Table. Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb, Princeton, New Jersey, by trained, blinded clinical research associates to identify potential cardiovascular events. Investigators used study forms to report and characterize all cardiovascular outcomes. For all potential events, records, including laboratory values, electrocardiograms, and radiographic reports were obtained for clarification. Since myocardial infarctions may go unrecognized, a central electrocardiogram reading center was established at Brigham and Womens Hospital, Boston, Massachusetts, where two cardiologists reviewed every electrocardiogram. Electrocardiography was performed at baseline, 6 months, 12 months, and annually thereafter. A total of 5698 electrocardiograms were reviewed at the center. When a new Q-wave infarction was found, the cardiologists asked whether a clinical myocardial infarction was reported. Even when myocardial infarctions were not clinically reported, these Q-wave infarctions were adjudicated as myocardial infarctions. Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events, defined in the Appendix Table. The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee (Appendix). If the committee member agreed with the judgment of the center investigator, their combined judgment was accepted. If the center investigator and the committee member differed, the case material was reviewed by the membership of the committee, whose decision was accepted. Deaths were adjudicated by a Mortality Committee (Appendix). Each death was reviewed by two members of the committee and presented to the membership, whose decision was accepted as final. Statistical Analysis For graphical presentation (Figure) and overall testing for statistically significant differences among the three treatment groups, time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test (15). We used proportional hazards modeling to determine hazard ratios. For the cardiovascular death outcome, which could occur only once, we used the standard proportional hazards model (16), with treatment assignment as the only independent covariate. For other cardiovascular outcomes, which could occur more than once, we used the AndersonGill formulation of the proportional hazards model (17), in which patients are considered at risk for the first event from randomization to the first event, at risk for the second event from the day following the first event to the second event, and so forth, permitting use of all the data. In accordance with the method of Lee and colleagues (18), we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient. We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event. Therefore, both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses. The time-dependent covariate was statistically significant in each case, confirming the above assumption. There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent eventsand inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significances. Figure. Time to first cardiovascular composite event as a function of treatment assignment. P Data management and computations were done by using SAS software for Windows, version 8 (SAS Institute, Inc., Cary, North Carolina), or S-Plus for Windows, version 6.0 (Insightful Corp., Seattle, Washington). Statistical tests were two sided. A P value of 0.05 or less, unadjusted for the multiple comparisons, was considered statistically significant. Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to submit the manuscript for publication. Results The baseline characteristics of the three groups are shown in Table 1. A flow diagram of the study is shown in the Appendix Figure. Table 1. Baseline Characteristics Appendix Figure. Flow diagram for the Irbesartan Diabetic Nephropathy Trial. Clinical Management During the study, the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group, 141/77 mm Hg in the amlodipine group, and 144/80 mm Hg in the placebo group. Blood pressure in the two active treatment groups did not differ; values in both groups were statistically significantly lower than in the placebo group (P = 0.001). The distribution of nonstudy drugs used to achieve the target blood pressure was similar i

Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical Implications and Limitations

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP <134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.

Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.

Metabolic profile of antipsychotic-naive individuals with non-affective psychosis

BACKGROUND Some studies suggest individuals with schizophrenia have an increased risk of diabetes prior to antipsychotic use. Small sample sizes and the potential for confounding by hypercortisolaemia have decreased confidence in those results. AIMS To examine diabetes-related factors in newly diagnosed, antipsychotic-naive people with non-affective psychosis. METHOD Participants with psychosis (the psychosis group; n = 50) and matched controls (the control group; n = 50) were given a 2 h oral glucose tolerance test. Fasting concentrations were also determined for adiponectin, interleukin-6 and C-reactive protein. RESULTS Compared with the control group, the psychosis group had significant increases in 2 h glucose and interleukin-6 concentrations, and in the prevalence of abnormal glucose tolerance (16% of psychosis group v. 0% of control group). Adiponectin and C-reactive protein concentrations did not differ significantly between the two groups. These findings could not be attributed to differences in cortisol concentrations, smoking, gender, neighbourhood of residence, body mass index, aerobic conditioning, ethnicity, socioeconomic status or age. CONCLUSIONS Individuals with non-affective psychosis appear to have an increased prevalence of abnormal glucose tolerance prior to antipsychotic treatment, as well as abnormalities in a related inflammatory molecule. These underlying problems may contribute to the metabolic side-effects of antipsychotic medications.

Diabetes mellitus after liver transplantation: prevalence and predictive factors.

AIMS/METHODS To investigate the prevalence and risk factors for the development of diabetes mellitus after orthotopic liver transplantation, we reviewed 27 variables (including previous history of diabetes mellitus, data related to pre-transplant liver disease, and postoperative events) in 102 patients who survived longer than 1 year after orthotopic liver transplantation. RESULTS Fourteen patients had diabetes mellitus prior to liver transplantation and all but one were alive 2 and 3 years after transplantation, with all survivors continuing to have diabetes mellitus 1, 2 and 3 years after transplantation. Among the 88 patients without pre-transplant diabetes mellitus, the prevalence of post-transplant diabetes mellitus was 27% at 1 year, 9% at 2 years and 7% at 3 years, probably related to a significant reduction in the daily prednisone dose (13 +/- 4 mg at 1 year, 7 +/- 6 mg at 2 years and 2 +/- 4 mg at 3 years, p < 0.001). Patients with post-transplant diabetes mellitus 1 year after transplantation had a higher number of rejection episodes during the first postoperative year than those without post-transplant diabetes mellitus (1.5 +/- 1.1 vs 1.1 +/- 0.7, p < 0.05) and also had higher, but not statistically significant, cumulative steroid dose and blood cyclosporine levels. Mortality of patients with post-transplant diabetes mellitus was significantly higher during the second postoperative year in comparison with patients without post-transplant diabetes mellitus: 4/24 vs 2/64 (17% vs 3%; p < 0.05). CONCLUSIONS Liver transplantation does not significantly modify pre-transplant diabetes mellitus. Diabetes mellitus frequently develops de novo after liver transplantation, although this complication is usually transient and probably related to immunosuppressive drug administration. The prognosis of patients with post-transplant diabetes mellitus is worse than that of those without this complication.

Telomere Length and Pulse Pressure in Newly Diagnosed, Antipsychotic-Naive Patients With Nonaffective Psychosis

INTRODUCTION Recent studies suggest that in addition to factors such as treatment side effects, suicide, and poor health habits, people with schizophrenia may have an increased risk of diabetes prior to antipsychotic treatment. Diabetes is associated with an increased pulse pressure (PP) and a shortened telomere. We tested the hypothesis that prior to antipsychotic treatment, schizophrenia and related disorders are associated with a shortened telomere, as well as an increased PP. METHODS Telomere content (which is highly correlated with telomere length) and PP were measured in newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders on first clinical contact and in matched control subjects. Both groups were also administered an oral glucose tolerance test. RESULTS Compared with control subjects, the patients with psychosis had decreased telomere content and an increased PP. As previously reported, they also had increased glucose concentrations at 2 hours. These differences could not be attributed to differences in age, ethnicity, smoking, gender, body mass index, neighborhood of residence, socioeconomic status, aerobic conditioning, or an increased cortisol concentration in the psychotic subjects. DISCUSSION These results suggest that prior to antipsychotic use, nonaffective psychosis is associated with reduced telomere content and increased PP, indices that have been linked to an increased risk of diabetes and hypertension.

Glucose abnormalities in the siblings of people with schizophrenia

BACKGROUND Some studies suggest that schizophrenia may be associated with an increased risk of diabetes, independently of antipsychotic medications and other confounding factors. Previous studies have also suggested that there is an increased prevalence of diabetes in the relatives of schizophrenia probands. METHOD First-degree siblings of schizophrenia probands (N=6) and control subjects (N=12) were administered a glucose tolerance test. Subjects were matched for gender, age, body mass index, neighborhood of residence, socio-economic status and smoking habits. RESULTS The siblings of schizophrenia probands had a significantly increased two-hour mean glucose concentration compared to the control subjects (respective means [SD] were 100.5 mg/dL [27.7] vs. 78.0 [12.3]; p<0.03). Baseline glucose concentrations did not differ. CONCLUSIONS Although confirmation with larger samples is needed, these results and other studies suggest that diabetes may share familial risk factors with schizophrenia.

Epidemiology of renal involvement in Type II diabetics (NIDDM) in Catalonia

The aim of this cross-sectional study was to establish the prevalence of renal involvement and to identify associations with its most important possible risk factors in a group of patients with Type II diabetes mellitus, representative of the population living in Catalonia. One thousand two hundred and three patients (47% males, mean age: 61 +/- 6 years, diabetes duration 9 +/- 6 years) were studied. Overnight urine samples were collected to determine urinary albumin excretion (UAE). If UAE was > 15 micrograms/min, a new 24-h urine collection for UAE measurement to establish the existence of microalbuminuria (20-200 micrograms/min) or macroalbuminuria (> 200 micrograms/min) was obtained. Clinic and metabolic evaluations were also performed. The prevalence (%) of microalbuminuria, macroalbuminuria and hypertension were, respectively, 23. 1, 5.4 and 42. In comparison with normoalbuminurics, patients with microalbuminuria were predominately male (P < 0.03), with a significantly higher systolic (P < 0.001) and diastolic (P < 0.001) blood pressure and body mass index (P < 0.001). The prevalence of smokers (former + current) was higher in patients with microalbuminuria (43 vs 32%, P < 0.025). Moreover, patients with nephropathy had more prevalence of retinopathy (P < 0.001), neuropathy (P < 0.001), peripheral angiopathy (P < 0.001) and coronary disease (P < 0.001). The prevalence of microalbuminuria in Type II diabetes in Catalonia is similar to that observed in other european countries. The existence of microalbuminuria is associated with several diabetic complications, as well as tobacco consumption and obesity.

Auditory function in young patients with type 1 diabetes mellitus

Comprehension of the effect of diabetes mellitus on auditory function has been hindered by the fact that previous studies have evaluated hearing function in heterogeneous groups of patients with diabetes mellitus, thus giving conflicting results. We have performed audiometric studies in 46 consecutive patients. 13 with newly diagnosed type 1 diabetes mellitus (group 1) and 33 with type 1 diabetes mellitus of more than 3 years of duration (group 2), of 14 to 40 years of age. The results were compared to an age-matched control group. Pure-tone auditory thresholds were significantly higher in all frequencies 250-8,000 Hz in both groups when compared to the control subjects. Ten patients, all of which belonged to group 2, had auditory thresholds above 30 dB in at least one frequency, showing a conversational hearing loss that ranged between 11 and 44%. However, none of them referred subjective hypoacusia. Univariate analysis revealed significant associations between auditory thresholds and age, duration of disease as well as retinopathy, but not with neuropathy, HbA1c or hypoglycaemic episodes. Only age and duration of disease independently correlated with an auditory threshold using multiple regression. We conclude that type 1 diabetes mellitus can cause mild sensorineural hearing impairment which correlates with age and duration of disease.

Recurrence of immunological markers for type 1 (insulin-dependent) diabetes mellitus in immunosuppressed patients after pancreas transplantation.

BACKGROUND Type 1 (insulin dependent) diabetes mellitus (IDDM) is an autoimmune disease in which autoantibodies against islet cells develop concomitantly with or even preceding diagnosis. Because the recurrence of diabetes can be the cause of graft failure in patients with pancreas transplantation, we studied the possible recurrence of IDDM immunomarkers after transplantation. METHODS The following determinations were performed every 1-2 years after transplantation in 50 immunosuppressed IDDM patients with simultaneous kidney and pancreas transplantation (bladder drainage of exocrine secretion): islet cell antibodies (ICA) by direct immunofluorescence, antibodies against glutamic acid decarboxylase (GADab) by radiobinding assay, and the oral glucose tolerance test. The mean follow-up was 4.1+/-6.3 (range 1 to 9 years). RESULTS GADab were detected in 11 patients after transplantation, 10 of whom had been positive beforehand. ICA reappearance after transplantation was detected in seven patients (14%). The presence of ICA was related to GADab positivity (P=0.001) and HLA DR3 patients (P=0.04), but not with pancreatitis and rejection episodes, immunosuppression induction therapy, or donor HLA haplotype. During follow-up, an abnormal oral glucose tolerance test was more frequent in ICA-positive patients (P=0.02), with no differences in metabolic control or insulin secretion. CONCLUSION We conclude that GADab persist and ICA reappear despite immunosuppressive therapy in patients with functioning pancreas transplants. The relevance and the risk that this implies for IDDM development should be determined.