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The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes.

As compared with standard glucose control in patients with type 2 diabetes, intensive glucose control in the ADVANCE trial reduced the risk of nephropathy but not the risk of macrovascular events. There was no significant difference between the two groups in overall mortality. These findings, along with those of the ACCORD trial, raise complex questions about the role of intensive glucose control in type 2 diabetes. As compared with standard glucose control in patients with type 2 diabetes, intensive glucose control reduced the risk of nephropathy but not the risk of macrovascular events. There was no significant difference between the two groups in overall mortality. The prevalence of diabetes is increasing worldwide, and most people with diabetes will die or be disabled as a consequence of vascular complications. 1 , 2 Prospective studies have shown continuous associations of blood glucose and glycated hemoglobin levels with the risks of major vascular events. 3 , 4 However, previous randomized trials evaluating the effects of glycemic control in patients with diabetes have provided inconsistent evidence of effects on vascular disease. 5 – 11 Nevertheless, current guidelines recommend a target glycated hemoglobin level of 7.0% or less for most patients with diabetes. 12 – 14 The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release . . .

Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This position statement provides recommendations regarding the detection, prevention, and treatment of early nephropathy.

Abstract Objectives: To assess and compare the effects of candesartan or lisinopril, or both, on blood pressure and urinary albumin excretion in patients with microalbuminuria, hypertension, and type 2 diabetes. Design: Prospective, randomised, parallel group, double blind study with four week placebo run in period and 12 weeks' monotherapy with candesartan or lisinopril followed by 12 weeks' monotherapy or combination treatment. Setting: Tertiary hospitals and primary care centres in four countries (37 centres). Participants: 199 patients aged 30-75 years. Interventions: Candesartan 16 mg once daily, lisinopril 20 mg once daily. Main outcome measures: Blood pressure and urinary albumin:creatinine ratio. Results: At 12 weeks mean (95% confidence interval) reductions in diastolic blood pressure were 9.5 mm Hg (7.7 mm Hg to 11.2 mm Hg, P<0.001) and 9.7 mm Hg (7.9 mm Hg to 11.5 mm Hg, P<0.001), respectively, and in urinary albumin:creatinine ratio were 30% (15% to 42%, P<0.001) and 46% (35% to 56%, P<0.001) for candesartan and lisinopril, respectively. At 24 weeks the mean reduction in diastolic blood pressure with combination treatment (16.3 mm Hg, 13.6 mm Hg to 18.9 mm Hg, P<0.001) was significantly greater than that with candesartan (10.4 mm Hg, 7.7 mm Hg to 13.1 mm Hg, P<0.001) or lisinopril (mean 10.7 mm Hg, 8.0 mm Hg to 13.5 mm Hg, P<0.001). Furthermore, the reduction in urinary albumin:creatinine ratio with combination treatment (50%, 36% to 61%, P<0.001) was greater than with candesartan (24%, 0% to 43%, P=0.05) and lisinopril (39%, 20% to 54%, P<0.001). All treatments were generally well tolerated. Conclusion: Candesartan 16 mg once daily is as effective as lisinopril 20 mg once daily in reducing blood pressure and microalbuminuria in hypertensive patients with type 2 diabetes. Combination treatment is well tolerated and more effective in reducing blood pressure.

Several studies have shown that albuminuria is associated with increased risk for fatal and nonfatal cardiovascular events, independent of conventional risk factors. The partition values for urine albumin-creatinine ratio (UACR) used to identify microalbuminuria have been based on studies that predicted risk in diabetic patients. To determine whether the relation between albuminuria and cardiovascular risk can be used to predict cardiovascular morbidity and mortality in hypertensive patients. Multicenter cohort study derived from a randomized, controlled trial. 8206 patients with stage II or III hypertension randomly assigned to double-blind therapy with losartan or atenolol. Follow-up was 39 122 patient-years. Renal glomerular permeability evaluated by UACR. In nondiabetic hypertensive patients with left ventricular hypertrophy, the risk for the composite cardiovascular end point increased continuously as albuminuria increased (P < 0.001 for trend). There was no specific threshold for increased risk. For every 10-fold increase in UACR, hazard ratios in nondiabetic patients increased as follows: composite end point, by 57% (95% CI, 40.6% to 75.0%); cardiovascular mortality, by 97.7% (CI, 66.5% to 235%); all-cause mortality, by 75.2% (CI, 54.0% to 99.4%); stroke, by 51.0% (CI, 28.8% to 76.9%); and myocardial infarction, by 45% (CI, 19.9% to 75.4%) (P < 0.001 for all comparisons). Values were similar in diabetic patients, although for myocardial infarction the trend was weaker and not significant. Increased UACR resulted in increasing risk for cardiovascular morbidity and mortality among hypertensive patients with left ventricular hypertrophy. We found no thresholds or plateaus. Risk increases at much lower UACR values than has been reported among diabetic patients.

[...]the study has not been running for a sufficient length of time to show an effect on proteinuria. [...]as the development of overt nephropathy takes decades, useful data will not be available for some time. [...]it appears that effective treatment with ACE inhibitors can prevent or postpone advanced nephropathy in patients with type 1 and 2 diabetes and postpone end stage renal disease.

Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This American Diabetes Association position statement is based on recent review articles that discuss published research and issues that remain unresolved and provides recommendations regarding the detection, prevention, and treatment of early nephropathy.

Diabetic Nephropathy American Diabetes Association Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the U.S. and Europe; this is due to the facts that 1 ) diabetes, particularly type 2, is increasing in prevalence; 2 ) diabetes patients now live longer; and 3 ) patients with diabetic ESRD are now being accepted for treatment in ESRD programs where formerly they had been excluded. In the U.S., diabetic nephropathy accounts for about 40% of new cases of ESRD, and in 1997, the cost for treatment of diabetic patients with ESRD was in excess of $15.6 billion. About 20–30% of patients with type 1 or type 2 diabetes develop evidence of nephropathy, but in type 2 diabetes, a considerably smaller fraction of these progress to ESRD. However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of those diabetic patients currently starting on dialysis. There is considerable racial/ethnic variability in this regard, with Native Americans, Hispanics (especially Mexican-Americans), and African-Americans having much higher risks of developing ESRD than non-Hispanic whites with type 2 diabetes. Recent studies have now demonstrated that the onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this complication. This position statement is based on recent review articles that discuss published research and issues that remain unresolved and provides recommendations regarding the detection, prevention, and treatment of early nephropathy. NATURAL HISTORY OF DIABETIC NEPHROPATHY The earliest clinical evidence of nephropathy is the appearance of low but abnormal levels (≥ 30 mg/day or 20 μg/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to as having incipient nephropathy. Without specific interventions, ∼80% of subjects with … [Full Text of this Article]

Increased QTc Dispersion Is Related to Blunted Circadian Blood Pressure Variation in Normoalbuminuric Type 1 Diabetic Patients Per Løgstrup Poulsen 1 , Eva Ebbehøj 1 , Hanne Arildsen 2 , Søren Tang Knudsen 1 , Klaus Würgler Hansen 1 , Henning Mølgaard 2 and Carl Erik Mogensen 1 1 Medical Department M (Diabetes and Endocrinology), Aarhus Kommunehospital, Aarhus 2 Department of Cardiology, Skejby University Hospital, Aarhus, Denmark Abstract A reduced nocturnal fall in blood pressure (BP) and increased QT dispersion both predict an increased risk of cardiovascular events in diabetic as well as nondiabetic subjects. The relationship between these two parameters remains unclear. The role of diabetic autonomic neuropathy in both QT dispersion and circadian BP variation has been proposed, but data have been conflicting. The aim of the present study was to describe associations between QT dispersion and circadian BP variation as well as autonomic function in type 1 diabetic patients. In 106 normoalbuminuric (urinary albumin excretion <20 μg/min) normotensive patients, we performed 24-h ambulatory BP (Spacelabs 90207) and short-term (three times in 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (deep breathing test, postural heart rate, and BP response). No patient had received (or had earlier received) antihypertensive or other medical treatment apart from insulin. In a resting 12-lead electrocardiogram, the QT interval was measured by the tangent method in all leads with well-defined T-waves. The measurement was made by one observer blinded to other data. The QT interval was corrected for heart rate using Bazett’s formula. The QTc dispersion was defined as the difference between the maximum and the minimum QTc interval in any of the 12 leads. When comparing patients with QTc dispersion below and above the median (43 ms), the latter had significantly higher night BP (114/67 vs. 109/62 mmHg, P < 0.003/ P < 0.001), whereas day BP was comparable (129/81 vs. 127/79 mmHg). Diurnal BP variation was blunted in the group with QTc dispersion >43 ms with significantly higher night/day ratio, both for systolic (88.8 vs. 86.2%, P < 0.01) and diastolic (83.1 vs. 79.5%, P < 0.01) BP. The association between QTc dispersion and diastolic night BP persisted after controlling for potential confounders such as sex, age, duration of diabetes, urinary albumin excretion, and HbA 1c . Power spectral analysis suggested an altered sympathovagal balance in patients with QTc dispersion above the median (ratio of low-frequency/high-frequency power: 1.0 vs. 0.85, P < 0.01). In normoalbuminuric type 1 diabetic patients, increased QTc dispersion is associated with reduced nocturnal fall in BP and an altered sympathovagal balance. This coexistence may be operative in the ability of these parameters to predict cardiovascular events. AMBP, ambulatory blood pressure BP, blood pressure ECG, electrocardiogram HF, high-frequency LF, low-frequency UAE, urinary albumin excretion Footnotes Address correspondence and reprint requests to Per Løgstrup Poulsen, Department of Medicine M (Diabetes and Endocrinology), Aarhus Kommunehospital, DK 8000 Aarhus C, Denmark. E-mail: logstrup{at}dadlnet.dk . Received for publication 23 May 2000 and accepted in revised form 8 December 2000.

According to the second paper in this week's BMJ (p 713), 10 the answer is probably no, although larger and longer term trials may be needed to assess the effects on distant endpoints, such as progressive nephropathy and end stage renal disease. According to the new criteria a repeated fasting plasma glucose concentration of above 7.0 mmol/l is diagnostic of diabetes.