[HbA1 and type 2 diabetes--what is optimal?].
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Diabetes Mellitus, Type 2↗
Biomedical subjects
Hans-Henrik Parving
Publications and source records attributed to Hans-Henrik Parving.
PGC-1alpha Gly482Ser polymorphism associates with hypertension among Danish whites.
PGC-1alpha is a coactivator of numerous transcription factors and is expressed in tissues with high energy demands and abundant in mitochondria. It is induced in the myocardium on fasting and physical exercise, and cardiac-specific overexpression stimulates mitochondrial biogenesis in mice. The common Gly482Ser polymorphism of PGC-1alpha has previously shown association with arterial hypertension among Austrian men. Thus, we aimed at investigating this relationship in the Danish white population. The Gly482Ser polymorphism was genotyped in a total of 2562 Danish white subjects using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and a GenoView locked nucleic acid assay (LNA), and the relationships of this variant with blood pressure levels and arterial hypertension were analyzed. Furthermore, we performed a combined analysis of the data from the present study in combination with previously published results. The Ser/Ser genotype was significantly associated with a reduced risk of hypertension and with lower systolic, diastolic, and mean arterial blood pressure levels, predominantly among women. Finally, in a combined analysis using data obtained in both sexes, the Ser/Ser genotype group had an estimated odds ratio of 0.70 (95% confidence interval, 0.56 to 0.86) for hypertension compared with Gly/X carriers (P=0.001). In conclusion, the Ser allele of PGC-1alpha Gly482Ser confers a significantly reduced risk of hypertension in whites. Further studies are needed to elucidate the differential role of this polymorphism in men and women.
Adult↗
Telmisartan vs. enalapril in type 2 diabetes.
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Angiotensin-Converting Enzyme Inhibitors↗
[Risk factors for the development of microalbuminuria in type 1 diabetes: an incidence cohort study--a secondary publication].
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Adult↗
Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease.
BACKGROUND: Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data. STUDY DESIGN: The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.
Anemia↗
Elevated placental growth factor (PlGF) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.
BACKGROUND AND AIM: Placental growth factor (PlGF) is up-regulated in early and advanced atherosclerotic lesions, acts as a primary inflammatory instigator of atherosclerotic plaque instability, and may be an independent biomarker of adverse outcome in patients with acute coronary syndromes. In diabetic nephropathy the relative cardiovascular mortality and morbidity is increased and therefore, this study investigated the prognostic value of PlGF in a large cohort of type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: In a prospective, observational follow-up study 190 type 1 diabetic patients with overt diabetic nephropathy (116 men, age (mean (SD)) 41+/-10 years, duration of diabetes 28+/-8 years, glomerular filtration rate (GFR) 76+/-33 mL/min/1.73 m2) and a matched control group of 174 patients with normoalbuminuria (104 men, age 43+/-10 years, duration of diabetes 27+/-9) were followed for 10 years (range: 0-10.3). The primary endpoint was a composite endpoint of cardiovascular death, hospitalization for myocardial infarction or stroke, coronary artery bypass grafting or percutanous coronary intervention, ischaemic amputation or peripheral bypass-surgery. Plasma PlGF was determined by an enzyme linked immunosorbent assay at baseline. RESULTS: During 10 years of follow-up 74 patients (39%) with diabetic nephropathy reached the primary endpoint versus only 18 (10%) of normoalbuminuric patients, log rank test; p<0.001. During follow-up 16 (25%) patients in the lowest, 24 (39%) in the middle and 34 (52%) patients in the upper tertile reached the primary cardiovascular endpoint, p=0.007. Hazard ratios in the second and third tertile as compared with the first tertile were 1.76 (0.92-3.38) and 2.64 (1.41-4.91) (p=0.009). Cox regression analyses including PlGF concentration as a continuous variable revealed an unadjusted hazard ratio of the primary endpoint for each 1 ng/L increase in PlGF of 1.10 (1.03-1.16), p=0.002; covariate adjusted hazard ratio 1.07 (1.00-1.14), p=0.03. CONCLUSIONS: Increased PlGF is a new independent predictor of cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.
Adult↗
Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy.
BACKGROUND: Connective tissue growth factor (CTGF) is an important profibrotic cytokine implicated in development of diabetic glomerulosclerosis. Urinary CTGF is reported to be significantly increased in patients with diabetic nephropathy. The present study aimed to investigate the short- and long term effects of angiotensin II receptor blockade by Losartan on urinary CTGF levels in hypertensive type 1 diabetic patients with diabetic nephropathy. METHODS: Seventy-one hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, the patients received Losartan 50 mg, 100 mg, and 150 mg once daily in treatment periods each lasting 2 months. Thereafter, patients were followed prospectively during treatment with Losartan 100 mg o.d. with a total mean follow-up time of 36 months. At baseline, after 2, 4, and 6 months and then biannually, urinary and plasma CTGF levels [enzyme linked immunosorbent assay (ELISA) fibroGen], albuminuria (Turbidimetry), glomerular filtration rate (GFR) [51-creatinine ethylenediaminetetraacetic acid ((51)Cr-EDTA plasma clearance)] and 24 hours blood pressure (TM2420)) were determined. RESULTS: Baseline levels of urinary and plasma CTGF were 7076 (5708 to 8770) ng/24 hours [geometric mean (95% CI)] and 12.7 (7.3) ng/mL [mean (SD)], respectively. Albuminuria, GFR, and arterial blood pressure at baseline were 1152 (937 to 1416) mg/24 hours, 88 (24) mL/min/1.73 m(2), and 153/80 (17/9) mm Hg, respectively. Losartan significantly reduced urinary CTGF by 21% (9 to 31) (95% CI) initially (P < 0.05 vs. baseline), with no further reduction after increasing dose. The sustained reduction in urinary CTGF was 22% (12 to 32) (P < 0.05 vs. baseline). Rate of decline in GFR during the study was 3.2 (-1.6 to 15.9) mL/min/year [median (range)]. Reduction in urinary CTGF was correlated with a lower rate of decline in GFR (r= 0.23, P= 0.05). Plasma CTGF remained unchanged throughout the study. CONCLUSION: Our 3-year study demonstrates that Losartan persistently reduces urinary CTGF excretion, which is associated with a slower rate of decline in GFR.
Adult↗
Impact of diabetic nephropathy and angiotensin II receptor blockade on urinary polypeptide patterns.
BACKGROUND: New insights into the pathogenesis and treatment of diabetic renal disease may emerge from recent advances in proteomics using high-throughput mass spectrometry (MS) of urine. METHODS: Using a combination of online capillary electrophoresis (CE) and MS we evaluated urinary polypeptide patterns in four groups of type 2 diabetic patients matched for age, gender, and diabetes duration, including 20 normoalbuminuric patients with and 20 without diabetic retinopathy, 20 microalbuminuric patients with diabetic retinopathy, and 18 macroalbuminuric patients with diabetic retinopathy. Furthermore, changes in urinary polypeptide patterns during treatment with the angiotensin II receptor blocker (ARB) candesartan were evaluated in the macroalbuminuric patients in a randomized double-blinded, cross-over trial where each patient received treatment with placebo, candesartan 8, 16, and 32 mg daily each for 2 months. RESULTS: Overall, 4551 different polypeptides were found in the samples. Urinary polypeptide patterns were comparable in normo- (with and without diabetic retinopathy) and microalbuminuric patients, whereas distinct differences were found in macroalbuminuric patients. Differences in urinary polypeptide patterns between normo- and macroalbuminuric patients permitted the establishment of a "diabetic renal damage" pattern consisting of 113 polypeptides. Eleven of these polypeptides had been sequenced and identified. Candesartan treatment in macroalbuminuric patients significantly changed 15 of the 113 polypeptides in the diabetic renal damage pattern toward levels in normoalbuminuric patients. Change in the diabetic renal damage pattern was not candesartan dose-dependent but individual changes correlated with changes in urinary albumin excretion at each dose level. CONCLUSION: CE-MS serves as a fast and sensitive tool for identification of biomarkers and urinary polypeptide patterns specific for macroalbuminuric type 2 diabetic patients and may be used to explore and monitor renoprotective effects of ARB.
Albuminuria↗
Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.
BACKGROUND: The purpose of this study was to evaluate the renoprotective effect as reflected by short-term changes in albuminuria of ultrahigh doses of irbesartan in type 2 diabetic patients with microalbuminuria. METHODS: This double-masked randomized crossover trial included 52 (41 males) hypertensive type 2 diabetic patients with microalbuminuria on ongoing antihypertensive medication. At inclusion, previous antihypertensive treatment was discontinued and replaced with bendroflumethiazide, 5 mg once daily, for the entire study. Following 2 months wash-out (baseline), patients were treated randomly with irbesartan 300, 600, and 900 mg once daily, each dose for 2 months. End points evaluated at the end of each study period included urinary albumin excretion rate (UAE) (mean of three 24-hour collections), 24-hour ambulatory blood pressure, and glomerular filtration rate (GFR) [chromium 51 ethylenediaminetetraacetic acid (51Cr-EDTA)]. RESULTS: Baseline values were: 24-hour UAE [geometric mean (95% CI)] 134 (103 to 170) mg/24 hours, ambulatory blood pressure [mean (SD)] 140 (10)/77 (7) mm Hg, and GFR 103 (19) mL/min/1.73 m2. All doses of irbesartan significantly reduced UAE, ambulatory blood pressure, and GFR from baseline. Reductions in UAE from baseline were 52% (46% to 57%), 49% (43% to 54%), and 59% (54% to 63%) with increasing doses of irbesartan (P < 0.01). UAE was reduced significantly more by irbesartan 900 mg compared with lower doses with an additional reduction in UAE of 15% (2% to 26%) by irbesartan 900 mg compared with 300 mg (P = 0.02). The greater reduction in albuminuria by irbesartan 900 vs. 300 mg was more pronounced in patients with UAE during irbesartan 300 mg above vs. below the median [31% (18% to 42%) vs. -9% (-25% to 6%), respectively (P < 0.05)]. With increasing doses systolic ambulatory blood pressure was reduced from baseline by 8 (4 to 12), 9 (5 to 13), and 9 (5 to13) mm Hg, and diastolic ambulatory blood pressure by 6 (4 to 7), 7 (6 to 9), and 7 (6 to 9) mm Hg (NS between doses). CONCLUSION: Ultrahigh dosing of irbesartan (900 mg once daily) is generally safe and offers additional renoprotection independent of changes in systemic blood pressure and GFR in comparison to the currently recommended dose of 300 mg.
Aged↗
Improved prognosis in type 1 diabetic patients with nephropathy: a prospective follow-up study.
BACKGROUND: In early studies, a median survival time of 5 to 7 years from onset of diabetic nephropathy was observed. Furthermore, end-stage renal disease (ESRD) was the main cause of death. We prospectively assessed the impact of reno- and cardiovascular protective treatment on prognosis in type 1 diabetic patients with diabetic nephropathy. METHODS: We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with normoalbuminuria for 10 years. Aggressive antihypertensive treatment was initiated in patients with diabetic nephropathy in mid 1980s, whereas statins and aspirin were not prescribed routinely until April 2002. The primary end point was cardiovascular mortality and morbidity. Secondary end points were all-cause mortality and ESRD. RESULTS: During follow-up, 79 patients (40%) with nephropathy reached the primary end point versus 19 (10%) of normoalbuminuric patients, log rank test P < 0.0001. Predictors of the primary end point were: nephropathy (hazard ratio 3.26; 95% confidence interval 1.89 to 5.62), previous event (3.19; 2.04 to 4.97), age (1.27; 1.04 to 1.55), and systolic blood pressure (1.13; 1.03 to 1.24). In the nephropathy group, 60 patients (30%) died; hereof, 25 deaths (42%) were ascribed to cardiovascular causes while 30 patients (50%) with nephropathy died with ESRD. The estimate of median survival time from onset of diabetic nephropathy was 21.7 years, SE 3.3 years. CONCLUSION: The survival of patients with diabetic nephropathy has improved most likely due to aggressive antihypertensive treatment and improved glycaemic control.
Adult↗
Progression of microalbuminuria in type 1 diabetes: ten-year prospective observational study.
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Adult↗
Beneficial impact of spironolactone in diabetic nephropathy.
BACKGROUND: Aldosterone has been suggested to play a role in the initiation and progression of diabetic nephropathy. Currently recommended treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers [renin-angiotensin system (RAS) blockade] does not suppress circulating aldosterone sufficiently. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on albuminuria and blood pressure in diabetic nephropathy. METHODS: Twenty Caucasian type 1 diabetic patients with persistent macroalbuminuria despite antihypertensive treatment, including RAS blockade, completed this double-masked, randomized cross-over trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for two months, respectively, on top of usual antihypertensive treatment. After each treatment period albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Spironolactone on top of usual antihypertensive treatment induced a 30% (95% CI 17 to 41) reduction in albuminuria from [geometric mean (95% CI)] 831 (624 to 1106) mg/24-hour on placebo treatment (P < 0.001), and a reduction in fractional albumin clearance of 35% (20 to 46, P < 0.001). Twenty-four-hour blood pressure showed an insignificant reduction of [mean reduction (95% CI)] 8 (-1 to 17)/3 (-0.2 to 7) mm Hg (P < 0.10). There was an insignificant reversible reduction in GFR during treatment with spironolactone. On spironolactone treatment, one patient was excluded due to hyperkalemia (plasma potassium 5.7 mmol/L) and one due to orthostatic dizziness. Otherwise treatment was well tolerated. CONCLUSION: Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy.
Adult↗
Irbesartan is projected to be cost and life saving in a Spanish setting for treatment of patients with type 2 diabetes, hypertension, and microalbuminuria.
OBJECTIVES: The purpose of this study was to project the cumulative incidence of end-stage renal disease (ESRD), life expectancy, and costs in a Spanish setting of treating patients with diabetes, hypertension, and microalbuminuria with either standard hypertension treatment alone or standard hypertension treatment plus irbesartan 300 mg daily. METHODS: A peer-reviewed, published Markov model that simulated progression from microalbuminuria to nephropathy, doubling of serum creatinine, ESRD, and all-cause mortality in patients with hypertension, type 2 diabetes, and microalbuminuria was adapted to a Spanish setting. Two strategies were compared: (1) irbesartan versus (2) standard hypertension care with comparable blood pressure control; both began in diabetic hypertensive subjects with microalbuminuria. Cumulative incidence of ESRD, costs, and life expectancy were projected for a hypothetical cohort of 1000 subjects. Future costs and life expectancy were discounted at 3% yearly. A 25-year time horizon and third party payer perspective were used. RESULTS: When compared to standard blood pressure control, irbesartan was projected to reduce the cumulative incidence of ESRD from (mean +/- standard deviation) 24 +/- 1% to 9 +/- 2%, save 11,082 +/- 2,996 euro, and add 1.40 +/- 0.27 life years per treated patient. The superiority of irbesartan over standard care was robust under a wide range of plausible assumptions. CONCLUSION: Treating patients with hypertension, microalbuminuria, and type 2 diabetes with irbesartan was projected to reduce the incidence of ESRD, extend life, and reduce costs.
Albuminuria↗
Renoprotection with and without blood pressure reduction.
BACKGROUND: AT1-receptor blockade dose dependently lowers blood pressure (BP) and albuminuria. Reduction of BP and albuminuria are independent treatment targets for renoprotection, but whether this requires similar dose titration is unknown. METHODS: We tested this in two studies designed to find the optimal antialbuminuric dose of losartan in type 1 diabetic (DM, N= 50) and nondiabetic renal patients (ND, N= 12). After baseline, treatment followed with losartan 50, 100, and 150 mg/day, each dose for eight (DM) or six weeks (ND). At the end of each period, albuminuria (24-hour samples) and mean arterial pressure (MAP) were measured. Patients were divided into "good" and "poor" BP responders (BP+, BP-) according to BP response above or below group median. RESULTS: Baseline MAP in the BP- groups was 102 (97, 104) mm Hg in DM (median, 95% CI) and 91 (80, 108) mm Hg in ND. The top of the dose response for BP (obtained at losartan 100 mg) in the BP- groups was -2 (-4, 3) mm Hg in DM and -1 (-6, 2) mm Hg in ND, versus -15 (-18, -12) mm Hg and -16 (-26, -18) mm Hg in BP+ groups (both P < 0.05). Albuminuria was reduced dose dependently both in BP- and BP+: with 100 mg, the reduction in albuminuria in DM BP- was -32% (-49, 13) versus -45% (-60, -38) in DM BP+ and -45% (-70,-7) versus -25% (-58, -6) in ND BP- and BP+ (all P > 0.05). Moreover, in patients in whom BP fell below the recommended treatment target of 130/80 mm Hg (13 in DM and 10 in ND), albuminuria was progressively reduced, with further increasing the dose of losartan in most patients. CONCLUSION: Absence of BP response to losartan does not preclude a reduction in albuminuria, and optimal reduction of albuminuria may require titration beyond the predefined BP target.
Adult↗
Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: an inception cohort study.
Inflammation and complement activation via the mannose-binding lectin (MBL) pathway have been suggested to play a role in the pathogenesis of diabetic microvascular complications. The association between the complement-activating protein MBL and the development of persistent microalbuminuria was evaluated in an inception cohort of 286 newly diagnosed type 1 diabetic patients consecutively admitted to the Steno Diabetes Center between 1 September 1979 and 31 August 1984. Serum MBL was measured with an immunofluorometric assay in 270 of the patients (159 men) after 3 years of diabetes duration. During the median (range) follow-up period of 18.0 (1.0-21.8) years, 75 patients subsequently progressed to persistent micro- or macroalbuminuria (urinary albumin excretion rate >30 mg/24 h). In patients with MBL levels above the median (1,597 microg/l), the cumulative incidence of persistent micro- or macroalbuminuria was 41% (CI 31-50) as compared with 26% (CI 17-34) in patients with MBL levels below the median (log-rank test, P = 0.003). In a Cox proportional hazard model with sex and age as fixed covariates, MBL was independently associated with later development of persistent micro- or macroalbuminuria (hazard ratio 1.21 [CI 1.02-1.42] per 1,000 microg/l increase in MBL; P = 0.03) after adjusting for possible confounders. In our study, high levels of MBL early in the course of type 1 diabetes was significantly associated with later development of persistent micro- or macroalbuminuria, suggesting that complement activation initiated by MBL may be involved in the pathogenesis of diabetic microvascular complications.
Adult↗
Oral contraceptives, angiotensin-dependent renal vasoconstriction, and risk of diabetic nephropathy.
OBJECTIVE: Diabetes, the leading cause of end-stage renal disease in the U.S., is believed to involve activation of the renin angiotensin system (RAS) as a risk factor for nephropathy. RAS activation occurs in healthy women using oral contraceptives (OCs), but the effects of OC use on the diabetic kidney are unclear. RESEARCH DESIGN AND METHODS: Renal plasma flow (RPF) response to captopril, as an index of RAS activity, was investigated in 92 women (41 nondiabetic OC nonusers, 10 nondiabetic OC users, 29 diabetic OC nonusers, and 12 diabetic OC users). Based on the hemodynamic findings, we examined the impact of OC use on the development of nephropathy as a post hoc analysis in an inception cohort of 114 female patients with newly diagnosed type 1 diabetes followed for a median of 20.7 years (range 1-24). RESULTS: Nondiabetic OC nonusers showed minimal RPF vasodilator response to captopril (9 +/- 10 ml x min(-1) x 1.73 m(-2), P = 0.6). In comparison, nondiabetic OC users showed a significant increase (69 +/- 35 ml x min(-1) x 1.73 m(-2), P = 0.02) (P = 0.04 vs. nondiabetic OC nonusers). Diabetic OC nonusers demonstrated the anticipated vasodilator response (58 +/- 12 ml x min(-1) x 1.73 m(-2), P < 0.0001). Diabetic OC users showed the largest responses (84 +/- 12 ml x min(-1) x 1.73 m(-2), P = 0.002) (P = 0.04 vs. diabetic OC nonusers). Plasma renin activity did not vary with OC use (P = 0.3). The RPF responses to captopril and angiotensin receptor blocker were highly correlated (r = 0.72, P < 0.001), suggesting clear involvement of the RAS. In the observational study, 18% (6/33 [95% CI 4.3-32.1]) of OC users developed macroalbuminuria compared with 2% (2/81 [0-5.9]) of OC nonusers (P = 0.003, univariate analysis). After adjustment for known risk factors with a Cox regression model, OC use remained a predictor for the development of macroalbuminuria (relative risk 8.90 [95%CI 1.79-44.36], P = 0.008). CONCLUSIONS: The strong association of OC use with angiotensin-dependent control of the renal circulation and the development of macroalbuminuria suggest that OC use may be a risk factor for diabetic nephropathy. Large prospective studies are required to further investigate this relationship.
Adult↗
Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study.
OBJECTIVE: The objective of this study was to evaluate the safety and short-term effect of adding spironolactone to conventional antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor or an angiotensin II receptor blocker (ARB) on albuminuria and blood pressure in type 2 diabetic patients with nephropathy. RESEARCH DESIGN AND METHODS: Twenty-one type 2 diabetic patients with nephropathy were enrolled in a randomized, double-masked, cross-over study. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 8 weeks, respectively, in addition to ongoing antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor and/or an ARB. At the end of each treatment period, albuminuria, 24-h ambulatory blood pressure (ABP), and glomerular filtration rate (GFR) were determined. RESULTS: During the addition of placebo, values were as follows: albuminuria (geometric mean [range]) 1,566 [655-7,762] mg/24 h, ABP (mean +/- SE) 138 +/- 3/71 +/- 1 mmHg, and GFR (mean +/- SE) 74 +/- 6 ml/min per 1.73 m2. During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25-41) (P < 0.001), fractional clearance of albumin by 40% (24-53) (P < 0.001), and 24-h ABP by 6 mmHg (2-10) for systolic and 4 mmHg (2-6) for diastolic (P < 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r = 0.19, P = 0.42) or diastolic 24-h ABP (r = 0.01, P = 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m2 (-0.3 to 6) (P = 0.08). One patient was excluded from the study due to hyperkalemia. Otherwise treatment was well tolerated. CONCLUSIONS: Our study suggests that spironolactone safely adds to the reno- and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and blood pressure in type 2 diabetic patients with nephropathy.
Antihypertensive Agents↗
The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: baseline characteristics.
Renin-angiotensin system blockade has been shown to be superior to other antihypertensive therapy in slowing progression of renal disease in diabetic patients, but questions remain regarding diabetic retinopathy. The primary objective of the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme is to examine primary (incidence) and secondary (progression) prevention of diabetic retinopathy when blocking angiotensin II type 1-receptors with candesartan in normoalbuminuric, normotensive Type 1 diabetic patients, and secondary prevention only in normoalbuminuric, normotensive or treated hypertensive Type 2 diabetic patients. The secondary objectives include examining the effect of candesartan treatment on urinary albumin excretion rate (UAER) in each of the three studies and to examine the incidence of proliferative retinopathy in all three populations combined. Standardised investigations for patients at enrolment include blood pressure measurement, analysis of HbA1C and serum lipids, and a detailed ophthalmological examination. Retinopathy and UAER outcomes are assessed yearly. Retinopathy is graded centrally, based on seven-field stereo photographs using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Randomisation was performed when the results of retinal gradings were available, and treatment with 16 mg candesartan cilexetil or matching placebo was initiated; the dose was increased to 32 mg after one month. Calculations of UAER are based on two timed overnight urine collections. A sample size re-assessment was carried out when approximately 70% of the patients had been randomised in the DIRECT Programme to ensure the results to be conclusive. In total, 5,231 patients were randomised in the DIRECT Programme in 30 countries. One thousand, four hundred and twenty one and 1,905 patients are evaluated in the primary and secondary prevention studies in Type 1 diabetes, respectively and 1,905 patients in the secondary prevention study in Type 2 diabetes. HbA1C showed mean values of 8.1, 8.5 and 8.2% for the Type 1 primary, Type 1 secondary and Type 2 secondary prevention studies, respectively. In the Type 1 secondary prevention study, 49% of the patients had mild nonproliferative retinopathy (level 20) in at least one eye, and 9% had moderate-moderately severe non-proliferative retinopathy (level 43-47). In Type 2 patients, 17% had level 43-47 and the remainder less severe retinopathy.
Angiotensin II Type 1 Receptor Blockers↗