Ambulatory pulse pressure, decreased nocturnal blood pressure reduction and progression of nephropathy in type 2 diabetic patients.

AIMS/HYPOTHESIS: We followed type 2 diabetic patients over a long period to evaluate the predictive value of ambulatory pulse pressure (PP) and decreased nocturnal BP reduction (non-dipping) for nephropathy progression. METHODS: Type 2 diabetic patients (n = 112) were followed for an average of 9.5 (range 0.5-14.5) years. At baseline, all patients underwent 24 h ambulatory BP measurement. Urinary albumin excretion rate was evaluated by three urinary albumin:creatinine ratio measurements at baseline and follow-up. RESULTS: At baseline, patients who subsequently progressed to a more advanced nephropathy stage (n = 35) had reduced diastolic night/day BP variation and higher 24 h systolic BP and PP values; they also had more advanced nephropathy and were more likely to smoke than those with no progression of nephropathy (n = 77). In a Cox regression analysis, independent predictors of nephropathy progression were 24 h PP (p < 0.01), diastolic night:day BP ratio (p = 0.02) and smoking (p = 0.02). The adjusted hazards ratio (95% CI) for each mmHg increment in 24 h PP was 1.04 (1.01-1.07), whereas the adjusted hazards ratio (95% CI) for each 1% increase in diastolic night:day BP ratio was 1.06 (1.01-1.11). Only one of 33 patients (3.0%) with both a diastolic night:day BP ratio and a 24 h PP below the median progressed, whereas 17 of 32 patients (53.1%) with both a diastolic night:day BP ratio and a 24 h PP equal to or above the median progressed to a more advanced nephropathy stage (p < 0.001). CONCLUSIONS/INTERPRETATION: Ambulatory PP, impaired nocturnal BP decline and smoking are strong, independent predictors of nephropathy progression in type 2 diabetic patients.

Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.

BACKGROUND: Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs. METHODS: The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925. FINDINGS: After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68-0.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75-0.98, p=0.03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline. INTERPRETATION: Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients with left ventricular hypertrophy and diabetes.

In type 2 diabetes the degree of albuminuria is strongly related to progression of diabetic renal disease, as well as to the risk for cardiovascular complications. If normoalbuminuria is maintained, the risk of diabetic nephropathy is very low. In individuals with microalbuminuria, the rate of decline in glomerular filtration rate is closely related to the degree of albuminuria, and regression to normoalbuminuria slows down the rate of decline in renal function. Data from the LIFE-diabetes subgroup showed that levels of albuminuria well below what is usually defined as microalbuminuria, strongly predicted risk for cardiovascular complications. This indicates that when albuminuria is used as a risk predictor for cardiovascular events, so called normal values should be redefined. Traditional values for normo-micro-macroalbuminuria are primarily defined as predictors for the risk of development of diabetic nephropathy. In the LIFE-diabetes subgroup we found that reduction in albuminuria was more pronounced in losartan-based as compared with atenolol-based treatment. The benefit in favor of losartan was partly related to its major influence on albuminuria. Individuals with the highest baseline values of albuminuria had the greatest benefit in terms of reduction in cardiovascular morbidity and mortality on losartan as compared with atenolol. The level of albuminuria during treatment was closely related to the risk for cardiovascular events. We conclude that tiny amounts of albuminuria, well below traditional levels for microalbuminuria, predict cardiovascular morbidity and mortality. Reduction in albuminuria during treatment translates to reduction in cardiovascular events. Monitoring of albuminuria should be an integrated part of management of hypertension in diabetic as well as nondiabetic patients.

How to protect the kidney in diabetic patients: with special reference to IDDM.

During the development to overt nephropathy, diabetic patients go through several characteristic stages of renal disease, moving from normo- to micro- to macroalbuminuria. Microalbuminuria is defined as a urinary albumin excretion between 20 and 200 microg/min; values <20 microg/min are designated as normoalbuminuria, and values >200 microg/min are designated as macroalbuminuria. Only with macroalbuminuria does the glomerular filtration rate (GFR) fall consistently. The decisive intermediary endpoints are postponement or prevention of micro/macroalbuminuria and reduction or prevention of the fall in GFR (stronger endpoint), with postponement of end-stage renal disease as a final endpoint. Good metabolic control can prevent or postpone the development of microalbuminuria, the earliest sign of diabetic renal disease. The ideal realistic therapeutic window may be an HbA1c value between 7 and 8.5% (mean reference value 5.5%). Thus, efforts should aimed at implementing the best possible control before the onset of microalbuminuria, with the other important aim of minimizing hypoglycemic side effects. In patients with microalbuminuria, blood pressure gradually increases, and early antihypertensive treatment becomes crucial. Good glycemic control (with the same glycemic goal as above) may be difficult to achieve in some of these patients, but it is still important. With overt nephropathy, defined as clinical proteinuria, a relentless decline in GFR is inflicted, unless patients are carefully treated with antihypertensive agents, often in combination therapy. Good metabolic control is still strongly warranted because patients with high HbA1c progress much more rapidly. The natural history of the rate of fall in GFR may be reduced from 12 to 3 ml x min(-1) x year(-1), but genetic factors may be involved; the ACE-genotype DD seems to progress more rapidly during treatment. Protein restriction is also of some interest. Early screening is recommended in all guidelines, with emphasis on testing for albuminuria, including microalbuminuria, along with careful control of glycemia and blood pressure.

Renal function changes in diabetes.

The present studies show that a number of functional abnormalities are present in the kidney in early diabetes, especially during poor regulation. Normalization of these functions and changes in renal and glomerular size are found during complete diabetes control. The results further support the idea that great efforts should be made to maintain the best possible control situation in diabetic patients. Our studies also indicate that antihypertensive therapy may be beneficial for young, proteinuric diabetics and may postpone the stage of renal insufficiency.

Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to microalbuminuria?

This perspective deals with prediction of overt diabetic nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). The role of elevated urinary albumin excretion rate (microalbuminuria) in predicting diabetic nephropathy has been emphasized by new follow-up studies. Development of severe kidney impairment was seen in a large percentage of patients with microalbuminuria, but with more intensive care for diabetic patients, this percentage may be falling. Herein, I analyzed alternatives to microalbuminuria in predicting kidney disease in diabetes. 1) Parental predisposition to hypertension is not seen in all studies and therefore may not be a decisive factor, and it cannot be used in prediction of nephropathy. 2) Prediabetic blood pressure may predict nephropathy in certain non-insulin-dependent diabetic patients, but elevated blood pressure seems to develop after early microalbuminuria and is likely to be an aggravating factor in established microalbuminuria in IDDM patients. 3) At the clinical diagnosis of IDDM, diabetic nephropathy cannot be predicted. 4) Glycemic control is poor in normoalbuminuric patients with later development of microalbuminuria, and multiple glycosylated hemoglobin measurements are therefore important. 5) In diabetes, glomerular hyperfiltration is associated with late nephropathy, but it alone cannot be the decisive factor, because hyperfiltration in nondiabetic individuals does not produce kidney disease, according to new long-term follow-up studies. 6) Studies of glomerular structure and ultrastructure have not yet documented predictive values for overt nephropathy, but further studies are in progress. 7) Isolated blood pressure elevation without microabuminuria (probably representing essential hypertension in diabetes) has not been predictive. 8) It is clear that elevation of serum creatinine is a very late and insensitive parameter, occurring only with pronounced proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)

The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy.

Alterations in renal function and structure are found even at the onset of diabetes mellitus. Studies performed over the last decade now allow definition of a series of stages in the development of renal changes in diabetes. Such a classification may be useful both in clinical work and in research activities. Stage 1 is characterized by early hyperfunction and hypertrophy. These changes are found at diagnosis, before insulin treatment. Increased urinary albumin excretion, aggravated during physical exercise, is also a characteristic finding. Changes are at least partly reversible by insulin treatment. Stage 2 develops silently over many years and is characterized by morphologic lesions without signs of clinical disease. However, kidney function tests and morphometry on biopsy specimens reveal changes. The function is characterized by increased GFR. During good diabetes control, albumin excretion is normal; however, physical exercise unmasks changes in albuminuria not demonstrable in the resting situation. During poor diabetes control albumin excretion goes up both at rest and during exercise. A number of patients continue in stage 2 throughout their lives. Stage 3, incipient diabetic nephropathy, is the forerunner of overt diabetic nephropathy. Its main manifestation is abnormally elevated urinary albumin excretion, as measured by radioimmunoassay. A level higher than the values found in normal subjects but lower than in clinical disease is the main characteristic of this stage, which appeared to be between 15 and 300 micrograms/min in the baseline situation. A slow, gradual increase over the years is a prominent feature in this very decisive phase of renal disease in diabetes when blood pressure is rising. The increased rate in albumin excretion is higher in patients with increased blood pressure. GFR is still supranormal and antihypertensive treatment in this phase is under investigation, using the physical exercise test. Stage 4 is overt diabetic nephropathy, the classic entity characterized by persistent proteinuria (greater than 0.5 g/24 h). When the associated high blood pressure is left untreated, renal function (GFR) declines, the mean fall rate being around 1 ml/min/mo. Long-term antihypertensive treatment reduces the fall rate by about 60% and thus postpones uremia considerably. Stage 5 is end-stage renal failure with uremia due to diabetic nephropathy. As many as 25% of the population presently entering the end-stage renal failure programs in the United States are diabetic. Diabetic nephropathy and diabetic vasculopathy constitute a major medical problem in society today.

Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by 6 mo of aldose reductase inhibition.

Hyperglycemia causes enhanced glucose metabolism by the polyol pathway in tissues not requiring insulin for glucose uptake. It has been suggested that the high level of aldose reductase activity may cause functional and structural abnormalities in diabetes and may be involved in the development of late complications. To elucidate the effect of an aldose reductase inhibitor (ponalrestat) on kidney function in uncomplicated insulin-dependent diabetes mellitus (IDDM), 20 normoalbuminuric IDDM patients were randomized to follow either 6 mo of treatment with ponalrestat (n = 11, mean +/- SD age 30 +/- 8 yr, diabetes duration 10 +/- 6 yr) or 6 mo of placebo (age 33 +/- 7 yr, diabetes duration 12 +/- 6 yr). The glomerular filtration rate (clearance of [125I]iothalamate) was significantly reduced from 140 +/- 18 to 129 +/- 10 ml.min-1.1.73 m-2, 2P = 0.02) in the ponalrestat-treated patients, whereas no change was seen after placebo (142 +/- 12 vs. 141 +/- 12 ml.min-1.1.73 m-2). The renal plasma flow (clearance of 131I-labeled hippuran), urinary albumin excretion rate (radioimmunoassay), fractional albumin clearance, and renal vascular resistance were unchanged in both groups. HbA1c showed a modest increase during ponalrestat (7.9 +/- 1.8 vs. 8.7 +/- 1.5%, 2P = 0.01) but was unchanged during placebo. No side effects of ponalrestat were observed. Thus, inhibition of aldose reductase may reduce the characteristic hyperfiltration in uncomplicated IDDM.

Cardiac hyperfunction in insulin-dependent diabetic patients developing microvascular complications.

Cardiac function was studied by echocardiography in 80 insulin-dependent diabetic patients with no signs of ischemic heart disease and in 40 healthy control subjects. Echocardiographic findings were related to the urinary albumin excretion rate (UAE). In the diabetes group, fractional shortening of the left ventricle (FS) was 37.3% versus 34.3% (P less than .01) in the control group, whereas indices of preload and afterload were at the same levels as in control subjects. In diabetic patients with preclinical nephropathy (UAE 20-200 micrograms/min), FS was 41.1% compared to 37.0% (P less than .002) in patients with no signs of nephropathy (UAE less than 20 micrograms/min) and 34.8% (P less than .001) in patients with clinical nephropathy (UAE less than 200 micrograms/min). Furthermore, in patients with preclinical nephropathy, afterload was significantly decreased, whereas preload was at the same level as in the other two groups of UAE. In conclusion, a condition of cardiac hyperfunction has been found in diabetic patients with no signs of ischemic heart disease and seems pronounced in diabetic patients developing microvascular disease (patients with preclinical nephropathy), probably secondarily to a condition of hyperperfusion in these patients.

Ambulatory blood pressure in the transition from normo- to microalbuminuria. A longitudinal study in IDDM patients.

To describe the development in blood pressure (BP) in relation to urinary albumin excretion (UAE) more exactly, 44 initially normoalbuminuric type I diabetic patients and 21 healthy individuals were included in a 3.1-year follow-up study by using ambulatory BP (AMBP) monitoring. Six patients developed microalbuminuria according to accepted criteria (progressors; UAE at follow-up was > 20 micrograms/min). Initial UAE was higher in this group (9.0 x/divided by 1.4 micrograms/min) compared with both the nonprogressors (5.2 x/divided by 1.6 micrograms/min) and the control subjects (3.9 x/divided by 1.6 micrograms/min), P < 0.01. The values were almost identical for initial 24-h AMBP between the progressors and the two other groups. The transition to microalbuminuria (31.7 x/divided by 1.8 micrograms/min) was associated with an increase in 24-h systolic AMBP of 11.5 +/- 8.3 mmHg, which was significantly higher than the increase in the nonprogressors (3.1 +/- 7.7 mmHg) and the control subjects (2.2 +/- 6.1 mmHg, P = 0.02). Significant correlations were detected between development in UAE and development in systolic and diastolic 24-h AMBP (r = 0.39, r = 0.41, P < 0.01). In addition, an increase in UAE, even including increases within the normoalbuminuric range, was always associated with an increase in 24-h AMBP (P < 0.01). Ordinary clinical measurements did not reveal any of these differences or correlations. In conclusion, a close association between increases in UAE and 24-h AMBP emerges in this study. Initial BP was not increased in the progressors.(ABSTRACT TRUNCATED AT 250 WORDS)

Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.

The isokinetic muscle strength in 56 IDDM patients with > 20 years of diabetes duration and in their individually sex-, age-, weight-, and height-matched control subjects was assessed. Peak torque of foot dorsal and plantar flexion and knee and wrist extension and flexion was measured. The neuropathic condition was assessed by a neurological disability score, a neuropathy symptom score, nerve conduction studies, and quantitative sensory examination. All results were summed to obtain a neuropathy rank-sum score for each patient. According to their renal albumin excretion, the patients were classified to have normo-, micro-, or macroalbuminuria. In addition, according to their retinal status, patients were classified as having no, simple, or proliferative retinopathy. The IDDM patients had a 21% reduction of muscle strength of both ankle dorsal (P < 1 x 10(-4)) and plantar flexors (P < 0.01), compared with control subjects. A 16% reduction of knee extensors (P < 0.005) and a 17% reduction of knee flexors (P < 0.01) was found. In contrast, muscle strength in wrist flexors and extensors was not significantly reduced (10 and 11%, respectively [NS]). In patients with the most severe weakness, muscle strength of the calf muscles was only 50% of the expected performance. Correlations were found between the neuropathy rank-sum score and the muscle strength of ankle dorsal (r = -0.66, P < 1 x 10(-7)) and plantar flexors (r = -0.51, P < 0.0005), knee extensors (r = -0.51, P < 0.0005) and flexors (r = -0.44, P < 0.005), and wrist flexors (r = -0.41, P < 0.005). No correlation was found for wrist extensors (r = 0). Neither were there any relationships between muscle strength at the ankle and knee and the degree of albuminuria or retinopathy. In conclusion, motor performance is substantially impaired in long-term IDDM patients, and the weakness is related to the presence of neuropathy but not to albuminuria or retinopathy per se.

Autonomic and somatosensory nerve function after 2 years of continuous subcutaneous insulin infusion in type I diabetes.

Autonomic and somatosensory nerve function was studied in 24 insulin-dependent diabetic subjects (aged 29 +/- 7 yrs, diabetes duration 8 +/- 4 yr) randomly allocated to either continuous subcutaneous insulin infusion (CSII; n = 12) or unchanged conventional insulin therapy (CIT; n = 12). Measures of glycemic control and somatosensory and autonomic nerve function were comparable in the two groups at the start. Glycemic control was significantly improved in the CSII group throughout study, whereas it remained unchanged in the CIT group. In the CIT group, vibratory perception threshold (VPT) of the great toe and the medial malleolus deteriorated, as did heart rate variation (HRV) at rest, at deep breathing (.05 less than P less than .06), and at standing. In contrast, CSII patients retained their VPT and HRV. Comparison of nerve function alterations during the 2-yr trial showed better preservation in CSII than in CIT patients of VPT in the great toe (0.8 +/- 1.7 vs. -1.4 +/- 1.9 V, P less than .01) and the medial malleolus (1.5 +/- 2.9 vs. -1.4 +/- 1.8 V, P less than .05) and of HRV at rest (10 +/- 24 vs. -13 +/- 22 ms, P less than .05) and at standing (-0.01 +/- 0.13 vs. -0.15 +/- 0.16 ms, P less than .05). We conclude that intensified glycemic control can favorably influence parasympathetic and somatosensory nerve function in insulin-dependent diabetes mellitus.

Association of 24-h cardiac parasympathetic activity and degree of nephropathy in IDDM patients.

In insulin-dependent diabetic patients, nephropathy is a predictor of mortality and coronary heart disease. Impaired cardiac vagal function is an important factor in the pathophysiology of sudden cardiac death in coronary heart disease. Autonomic neuropathy in diabetes in particular involves vagal function. Bedside tests and 24-h measurements of cardiac parasympathetic activity were compared in 37 insulin-dependent diabetic patients, and the relationship between 24-h vagal activity and degree of nephropathy was investigated. Nephropathy was classified according to urinary albumin excretion as normoalbuminuria, incipient, and overt nephropathy. Mean age (approximately 30 yr) was not different among groups. The 24-h measurements of parasympathetic activity appeared more sensitive than bedside tests, as 33% of patients without cardiac autonomic neuropathy in bedside tests had 24-h vagal activity values below the 95% confidence limits of 14 healthy control subjects. Patients with incipient or overt nephropathy had significantly lower mean values for vagal activity during both wake and sleep time than healthy control subjects. Increasing degree of nephropathy was associated significantly with increasing attenuation of 24-h vagal activity (P less than 0.001). The covariation of degree of neuropathy and nephropathy may suggest common pathogenetic mechanisms. The reduced 24-h vagal activity, even in the early stages of nephropathy, could be an important risk factor for cardiac death in insulin-dependent diabetic patients.

Autonomic neuropathy in nondiabetic offspring of type 2 diabetic subjects is associated with urinary albumin excretion rate and 24-h ambulatory blood pressure: the Fredericia Study.

The aim of this study was to examine the impact of parental type 2 diabetes on the autonomic nervous system and to determine whether autonomic neuropathy is present and associated with changes in 24-h ambulatory blood pressure (AMBP) and urinary albumin excretion rate (UAER) in nondiabetic subjects with parental type 2 diabetes. We examined 223 nondiabetic offspring of type 2 diabetic subjects and a control group of 258 offspring of nondiabetic subjects. The autonomic nervous system was assessed by three cardiovascular reflex tests, 24-h AMBP was measured with an oscillometric recorder (90207; Spacelabs, Redmond, WA), and UAER was determined through three overnight urine samples. The subjects with parental type 2 diabetes had significantly lower heart rate variation in all three bedside tests (P < 0.01) than subjects without parental diabetes. The prevalence of autonomic neuropathy in the nondiabetic offspring with parental type 2 diabetes (6.7%) was significantly (P < 0.01) higher compared with the control group (1.6%). Autonomic neuropathy was associated with a higher fasting insulin level (P < 0.05), higher UAER (P < 0.001), higher 24-h mean AMBP (P < 0.01), and reduced diurnal blood pressure variation (P < 0.001) after adjustment for age, sex, and BMI. In conclusion, parental type 2 diabetes was found to be associated with alterations in the autonomic nervous system in nondiabetic subjects. The presence of autonomic neuropathy in subjects with parental type 2 diabetes was associated with higher UAER, fasting insulin level, and 24-h AMBP and a reduced diurnal blood pressure variation. This study indicates that parental type 2 diabetes has an impact on the cardiac autonomic function in nondiabetic subjects.

Increased QTc dispersion is related to blunted circadian blood pressure variation in normoalbuminuric type 1 diabetic patients.

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 microg/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 HbA1c. 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.

Poor prognosis in proteinuric type 2 diabetic patients with retinopathy: insights from the RENAAL study.

BACKGROUND: Retinopathy is the clinical hallmark of generalized microangiopathy in diabetes. AIM: To examine the relation of this abnormality to end-stage renal disease (ESRD) and death in type 2 diabetes. DESIGN: Retrospective analysis. METHODS: Of 1513 type 2 diabetic patients with nephropathy participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, 1456 (96.5%) were assessed at baseline by ophthalmoscopy or fundus photography. RENAAL was a multinational double masked, randomized, placebo-controlled intervention study, whose primary end-point was the composite of a doubling of the baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. RESULTS: Of those assessed at baseline, 65% had diabetic retinopathy. Patients with retinopathy had higher systolic blood pressure, albuminuria and lower glomerular filtration rate (GFR), haemoglobin and serum albumin values than those without. In univariate analyses, the presence of retinopathy was associated with a 44% increase in the primary composite end-point (hazard ratio 1.44, 95%CI 1.22-1.70, p < 0.001). Patients with retinopathy had a 52% increase in doubling of serum creatinine (p < 0.001), a 47% increased risk of ESRD (p = 0.002) and a 33% increase in risk of death (p = 0.026) compared to those without. In multivariate analyses, the presence of retinopathy was associated with a 23% increase (p = 0.015) in the primary composite end-point and a 22% increase in ESRD or death (p = 0.038). DISCUSSION: The presence of diabetic retinopathy at baseline is associated with more proteinuria, lower GFR, and a higher risk for ESRD and death in type 2 diabetic patients.

New concepts in blood pressure-lowering management in diabetic patients: the case for early ACE inhibitor combination therapy with diuretics.

Type II diabetes and the dysmetabolic syndrome are becoming more and more prevalent, not only in the Western world, but also in many developing countries. The key issue is early prevention and treatment, not only antihyperglycaemic and antihyperlipidaemic treatment, but also, and maybe in particular, antihypertensive treatment. The first issue is first of all screening patients for elevated blood pressure and for microalbuminuria, especially if blood pressure elevation or diabetes is present. Especially, diabetic patients are at risk. The key feature in the therapeutic approach is blocking the renin-angiotensin system, which has proven effective in many original studies. Also the combination with diuretics is a key issue, since these patients have sodium retention. It has been discussed whether ACEi, ARBs or diuretics should be initial treatment, but usually a combination treatment is recommended to reduce blood pressure early and efficiently. The PREMIER study emphasized combination therapy, since the study had very efficient outcomes with combination therapy compared to an ACEi alone as far as blood pressure lowering is concerned, but also with reduction in microalbuminuria and, indeed, end point-reduction. Cardiovascular events showed a decreased incidence with the combination therapy with Preterax (perindopril/indapamide) compared with the enalapril group.

Therapeutic interventions in nephropathy of IDDM.

The pathophysiology of diabetic renal disease has been greatly clarified in recent years. A better understanding of its developmental stages has led to a series of therapeutic intervention trials. I describe the natural history of untreated insulin-dependent diabetes mellitus (IDDM) and the effects of various intervention modalities. Selected trials, some of them still in progress, are summarized, including studies of therapy with insulin, antihypertensives, and low-protein diets.

Systolic blood pressure relates to the rate of decline of glomerular filtration rate in type II diabetes.

OBJECTIVE: To relate deterioration in kidney function to some potential cardiovascular risk factors in type II diabetic patients. RESEARCH DESIGN AND METHODS: Twenty-four normoalbuminuric and 13 microalbuminuric patients completed a 3.4-yr prospective observational study. Glomerular filtration rate, urinary albumin excretion rate, blood pressure, glycemic control, and lipids were measured on entry and at the end of the study. Of the patients, 19 normoalbuminuric and 8 microalbuminuric (73%) patients had no history of antihypertensive treatment. RESULTS: The glomerular filtration rate was significantly reduced during the follow-up period (-1.34 +/- 0.54 ml.min-1.1.73 m-2 [mean +/- SE], P < 0.02). The rate of decline varied considerably in normoalbuminuric and microalbuminuric patients (from -13.5 to 4.3 and from -7.0 to 4.2 ml.min-1.1.73 m-2 per year, respectively) but was on average not accelerated in normoalbuminuric or microalbuminuric patients (-1.3 +/- 0.7 and -1.5 +/- 0.8 ml.min-1.1.73 m-2 per year, respectively). Significant correlations were observed between the glomerular filtration rate fall rate and initial systolic blood pressure (r = -0.47, P < 0.01; patients without antihypertensive treatment: r = -0.42, P = 0.03) but not diastolic blood pressure. In a stepwise multiple linear regression analysis, baseline systolic blood pressure significantly determined the fall rate of the glomerular filtration rate (regression coefficient = -0.050, SE = 0.018, P = 0.011; patients without antihypertensive treatment: regression coefficient = -0.047, SE = 0.021, P = 0.030). CONCLUSIONS: In these type II diabetic patients neither normoalbuminuria nor microalbuminuria are at an average associated with an accelerated decline in kidney function. Still, systolic blood pressure is a determining factor for the rate of decline in the glomerular filtration rate. A longer follow-up time with consecutive glomerular filtration rate measurements are needed to determine the long-term implications of normoalbuminuria and microalbuminuria on kidney function in type II diabetic patients.

Similar insulin sensitivity in NIDDM patients with normo- and microalbuminuria.

OBJECTIVE: To investigate whether insulin resistance and microalbuminuria are associated in non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed using a hyperinsulinemic euglycemic clamp in 11 normoalbuminuric and 9 microalbuminuric NIDDM patients matched for sex, age, body composition, glycemic control, diabetes duration, and therapy. RESULTS: Isotopically determined glucose disposal was similar in normo- and microalbuminuric patients in the basal state (mean +/- SD; 3.30 +/- 1.01 vs. 3.46 +/- 0.82 mg.kg lean body mass [LBM]-1.min-1; NS) and during hyperinsulinemia (7.16 +/- 2.65 vs. 6.63 +/- 2.88 mg.kg LBM-1.min-1;NS). No difference was observed in nonoxidative glucose disposal or lipid oxidation. Endogenous glucose production was equally suppressed by insulin (-0.08 +/- 0.99 vs. 0.30 +/- 1.12 mg.kg-1 LBM.min-1; NS). Glucose oxidation tended to be lower in the normoalbuminuric patients in the basal state (1.16 +/- 0.37 vs. 1.41 +/- 0.36 mg.kg LBM-1.min-1) and during hyperinsulinemia (2.35 +/- 0.72 vs. 2.90 +/- 0.77 mg.kg LBM-1.min-1; both P < 0.15). Urinary albumin excretion rate correlated with the insulin-stimulated glucose oxidation rate (r = 0.59, P = 0.0064), and a similar trend was seen in the basal state (r = 0.42, P = 0.063). Protein oxidation was higher in normoalbuminuric patients (1.6 +/- 0.5 vs. 1.0 +/- 0.4 mg.kg LBM-1.min-1; P = 0.017) and correlated inversely with albuminuria (r = -0.70, P = 0.0007). Serum growth hormone increased during insulin infusion; however, the increase was significantly greater in microalbuminuric patients. Plasma lipoproteins, maximal aerobic capacity, and 24-h ambulatory blood pressure were similar in the two groups. CONCLUSIONS: Basal and insulin-stimulated glucose uptakes are comparable in carefully matched normo- and microalbuminuric NIDDM patients, and glucose oxidation may be positively related to albuminuria. The inverse relation between protein oxidation and albuminuria may be due to higher growth hormone levels during daily life perturbations in glucose in microalbuminuric patients.