There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 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.

BackgroundThe ratio between urinary albumin concentration (UAC) and urinary creatinine concentration (UCC) is widely used to estimate renal involvement. We examined how UAC and UCC associate with each other, with other risk factors, and with diabetic complications in a population-based sample of Type 2 diabetic patients.MethodsA freshly voided morning urine specimen was provided by 1284 consecutive, newly diagnosed diabetic patients aged 40 years or over in general practice. Albumin was measured by a polyethyleneglycol radioimmunoassay and creatinine by a modified Jaffe method.ResultsIn a multivariate model including UAC, UCC, age, sex, HbA1c, and urinary glucose concentration, UAC increased with both age (P=.042) and HbA1c (P=.014), while UCC decreased (P<.001 and P<.001, respectively). In two regression models, the prevalence of diabetic retinopathy (P<.001) and relatively high resting heart rate (P<.001) increased with increasing UAC but decreased with increasing UCC (P=.002 and P=.005, respectively).ConclusionThe use of albumin/creatinine ratio (ACR) may introduce bias of unpredictable size and direction in comparisons of ACR with variables that are associated with UCC in their own right. In daily clinical practice, renal involvement in the individual patient can be estimated reliably with UAC or ACR measured in a freshly voided morning urine specimen, especially when considered together. However, the associations of the combined measure ACR should be interpreted with great caution in clinical and epidemiological research.

Objective: To investigate whether myocardial fibrosis assessed non-invasively is related to left ventricular (LV) longitudinal systolic function in patients with essential hypertension.Design: The study consisted of 30 control subjects and 40 patients with hypertension with normal LV ejection fraction. Tissue Doppler echocardiography was performed to assess LV longitudinal systolic strain from the apical views. Mean strain was calculated from the basal and mid segments. Plasma concentrations of the amino-terminal propeptide of type III procollagen ( PIIINP) were measured.Results: In the hypertension group, mean strain was significantly reduced (mean (SD) 13 (6)% v 21 (6)%, p < 0.01) and plasma PIIINP were increased compared with controls (3.0 (0.7) mu g/l v 2.1 (0.3) mu g/l, p < 0.001). A significant correlation was found between mean strain and PIIINP (r = -0.56, p < 0.001). In patients with abnormal diastolic filling (n = 21) mean strain was reduced compared with patients with normal LV filling (n = 19) (10 (6)% v 15 (6)%, p < 0.01) and the serological marker PIIINP was increased (3.5 (0.6) mu g/l v 2.5 (0.5) mu g/l, p, 0.001).Conclusions: There is a significant association between the extent of myocardial fibrosis and reduced LV longitudinal contractility.

OBJECTIVE:To examine levels of NT-proBNP and its relation to hypertension, as well as diastolic function in normoalbuminuric patients with Type 2 diabetes.RESEARCH DESIGN AND METHODS:The study comprised 60 Type 2 diabetic patients without albuminuria. Thirty patients were normotensive and 30 had hypertension. Exclusion criteria were cardiac symptoms and an ejection fraction < 55%. Thirty age- and sex-matched normal subjects served as controls. Diastolic dysfunction was assessed with echocardiography, by means of mitral inflow and colour M-Mode flow propagation recordings.RESULTS:Overall NT-proBNP was significantly elevated in the Type 2 diabetes group, compared with the controls [54.5 pg/ml (5-162) vs. 32.7 pg/ml (5-74.3) P = 0.02]. NT-proBNP was significantly higher among hypertensive patients compared with both normotensive patients and controls but no difference was found between the normotensive patients and the controls [58.0 pg/ml (8.5-162), P < 0.05 vs. 50.8 pg/ml (5-131) P = 0.4]. Patients with concentric and eccentric hypertrophy had significantly higher NT-proBNP levels compared with the control group [81.0 pg/ml (5-147), P < 0.001 and 66.8 pg/ml (42-128), P < 0.001], whereas patients with left ventricular remodelling (enlarged relative wall diameter but normal left ventricular mass) were comparable with the control group [42.3 pg/ml (8.3-142) P = 0.55]. Patients with left atrial enlargement also had incremental NT-proBNP values. NT-proBNP was only moderately correlated to age (r = 0.33, P < 0.05) and left ventricular diastolic diameter (r = 0.41, P < 0.05), but unrelated to diastolic function.CONCLUSIONS:NT-proBNP is significantly increased in hypertensive, normoalbuminuric patients with Type 2 diabetes. These findings were related to left ventricular hypertrophy and increased left atrial and ventricular diameters.

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria < 2000 mg/g or >= 2000 mg/g, within the higher proteinuria stratum (>= 2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.

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.

Aims The primary aim of ADVANCE is to determine the effects on macrovascular and microvascular disease of blood pressure lowering (with an ACE inhibitor-diuretic combination), irrespective of initial blood pressure level; and of intensive glucose lowering, in high-risk individuals with Type 2 diabetes.Methods The study is a 2 x 2 factorial randomized controlled trial. Following 6 weeks on active perindopril-indapamide combination, eligible participants were randomized to perindopril/indapamide (initially 2.0/0.625 mg daily, increasing to 4.0/1.25 mg daily after 3 months) or matching placebo; and to an intensive gliclazide MR-based glucose control regimen aiming for a haemoglobin A(1c) (HbA(1c)) value of 6.5% or lower, or local standard therapy. The study is being conducted in 215 centres in 20 countries within Australasia, Asia, Europe and North America.Results Recruitment commenced in June 2001 and was completed in March 2003, with the inclusion of 11 140 randomized participants. Fifty-seven per cent of participants are male and the mean age at baseline was 66 years. On average, the diagnosis of diabetes was made 8 years before study entry. At baseline 32 and 10% of patients had a history of macrovascular and microvascular disease, respectively. The mean blood pressure at baseline was 145/81 mmHg; the mean HbA(1c) concentration was 7.5%. While blood pressure and HbA(1c) values were broadly similar, certain characteristics of randomized participants varied between countries.Conclusions With successful worldwide recruitment completed, ADVANCE should provide reliable and broadly generalizable results on the effects of routine blood pressure lowering and intensive glucose control in high-risk individuals with Type 2 diabetes.

OBJECTIVE:To assess and compare the long-term effects of the combination of candesartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes.RESEARCH DESIGN AND METHODS:This was a prospective, randomized, parallel-group, double-blind, double-dummy study with a 12-month follow-up. Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily. The study comprised 75 type 1 and type 2 diabetic patients aged 35-74 years. The main outcome measures were seated and 24-h ambulatory systolic blood pressure.RESULTS:Reduction in systolic blood pressure (24-h systolic blood pressure) reduction was obtained in both treatment arms (mean reduction at final follow-up: dual blockade 6 mmHg vs. lisinopril 2 mmHg), but no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P = 0.10). Both treatments were generally well tolerated, and similar low rates of side effects were found in the two groups.CONCLUSIONS:There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes.

Diabetic MedicineVolume 21, Issue 1 p. 4-17 Diabetic renal disease: from recent studies to improved clinical practice C. E. Mogensen, C. E. Mogensen Medical Department M, Aarhus Kommunehospital, Aarhus, Denmark, andSearch for more papers by this authorM. E. Cooper, Corresponding Author M. E. Cooper Vascular Division, Baker Medical Research Institute, Melbourne, Victoria, Australia Medical Department M, Aarhus Kommunehospital, Aarhus, Denmark, andCorrespondence to: Professor Mark E. Cooper, University of Melbourne, Department of Medicine, Austin & Repatriation Medical Centre, Repatriation Campus, Banksia Street, West Heidelberg, Victoria 3081, Australia. E-mail: [email protected]Search for more papers by this author C. E. Mogensen, C. E. Mogensen Medical Department M, Aarhus Kommunehospital, Aarhus, Denmark, andSearch for more papers by this authorM. E. Cooper, Corresponding Author M. E. Cooper Vascular Division, Baker Medical Research Institute, Melbourne, Victoria, Australia Medical Department M, Aarhus Kommunehospital, Aarhus, Denmark, andCorrespondence to: Professor Mark E. Cooper, University of Melbourne, Department of Medicine, Austin & Repatriation Medical Centre, Repatriation Campus, Banksia Street, West Heidelberg, Victoria 3081, Australia. E-mail: [email protected]Search for more papers by this author First published: 06 January 2004 https://doi.org/10.1111/j.1464-5491.2004.01121.xCitations: 32Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Cooper ME. Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 1998; 352: 213–219. 2 Lee HB, Ha HJ, Kim SI, Ziyadeh FN. Diabetic kidney disease research: where do we stand at the turn of the century? Kidney Int 2000; 58: S1–S2. 3 Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 2001; 44: 1957–1972. 4 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853. 5 The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction and stroke in high-risk patients. N Engl J Med 2000; 342: 145–153. 6 Opie LH. Renoprotection by angiotensin-receptor blockers and ACE inhibitors in hypertension. Lancet 2001; 358: 1829–1831. 7 Hansen HP, Tauber-Lassen E, Jensen BR, Parving H-H. Effect of protein restriction on prognosis in type 1 diabetic patients with diabetic nephropathy. Kidney Int 2002; 62: 220–228. 8 Weir MR, Dworkin LD. Antihypertensive drugs, dietary salt, and renal protection—how low should you go and with which therapy. Am J Kidney Dis 1998; 32: 1–22[Review]. 9 Jandeleit-Dahm K, Cao ZM, Cox AJ, Kelly DJ, Gilbert RE, Cooper ME. Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. Kidney Int 1999; 56: S31–S36. 10 Brenner BM. Remission of renal disease: recounting the challenge, acquiring the goal. J Clin Invest 2002; 110: 1753–1758. 11 Taguma Y, Kitamoto Y, Futaki G, Ueda H, Monma H, Ishizaki M et al. Effect of captopril on heavy proteinuria in azotemic diabetics. N Engl J Med 1985; 313: 1617–1620. 12 Hommel E, Parving HH, Mathiesen E, Edsberg B, Damkjaer Nielsen M, Giese J. Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy. Br Med J (Clin Res Ed) 1986; 293: 467–470. 13 Marre M, Chatelier G, Leblanc H, Guyenne T-T, Menard J, Passa P. Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. Br Med J 1988; 297: 1092–1095. 14 Tatti P, Pahor M, Byington RP, DiMauro P, Guarisco R, Strollo G et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomised Trial (FACET) in patients with hypertension and non-insulin dependent diabetes mellitus. Diabetes Care 1998; 21: 597–603. 15 Gerstein HC, Yusuf S, Mann JFE, Hoogwerf B, Zinman B, Held C et al. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–259. 16 Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A et al. Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 611–616. 17 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–1462. 18 Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ. Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Collaborative Study Group. Am J Kidney Dis 1999; 34: 809–817. 19 The ACE Inhibitors in Diabetic nephropathy Trialist group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001; 134: 370–379. 20 Rudberg S, Osterby R, Bangstad HJ, Dahlquist G, Persson B. Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular structural changes in young microalbuminuric patients with Type I (insulin-dependent) diabetes mellitus. Diabetologia 1999; 42: 589–595. 21 Osterby R, Bangstad HJ, Nyberg G, Rudberg S. On glomerular structural alterations in type-1 diabetes—companions of early diabetic glomerulopathy. Virchows Arch—Int J Pathol 2001; 438: 129–135. 22 Osterby R, Bangstad HJ, Rudberg S. Follow-up study of glomerular dimensions and cortical interstitium in microalbuminuric type 1 diabetic patients with or without antihypertensive treatment. Nephrol Dialysis Transplantation 2000; 15: 1609–1616. 23 Mathiesen ER, Hommel E, Hansen HP, Smidt UH, Parving HH. Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. Br Med J 1999; 319: 24–25. 24 The European Study for the Prevention of Renal Disease in Type 1 Diabetes (ESPRIT). Effect of 3 years of antihypertensive therapy on renal structure in type 1 diabetic patients with albuminuria. Diabetes 2001; 50: 843–850. 25 The EUCLID study group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997; 349: 1787–1792. 26 Chaturvedi N, Sjolie A-K, Stephenson JM, Abrahamian H, Kelpes M, Castellarin A et al. Effect of lisinopril on progression of retinopathy in people with type 1 diabetes. Lancet 1998; 351: 28–31. 27 Moravski CJ, Kelly DJ, Cooper ME, Gilbert RE, Bertram JF, Shahinfar S et al. Retinal neovascularization is prevented by blockade of the renin–angiotensin system. Hypertension 2000; 36: 1099–1104. 28 Kvetny J, Gregersen G, Pedersen RS. Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus. QJM 2001; 94: 89–94. 29 Poulsen PL, Hansen KW, Mogensen CE. Ambulatory blood pressure in the transition from normo- to microalbuminuria. A longitudinal study in IDDM patients. Diabetes 1994; 43: 1248–1253. 30 Cooper ME, Johnston CI. Optimizing treatment of hypertension in patients with diabetes. JAMA 2000; 283: 3177–3179. 31 Jandeleit-Dahm K, Cooper ME. Hypertension and diabetes. Curr Opin Nephrol Hypertens 2002; 11: 221–228. 32 Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 1996; 156: 286–289. 33 Sano T, Kawamura T, Matsumae H, Sasaki H, Nakayama M, Hara T et al. Effects of long-term enalapril treatment on persistent micro-albuminuria in well-controlled hypertensive and normotensive NIDDM patients. Diabetes Care 1994; 17: 420–424. 34 Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care 1997; 20: 1576–1581. 35 Agardh CD, Garcia Puig J, Charbonnel B, Angelkort B, Barnett AH. Greater reduction of urinary albumin excretion in hypertensive type II diabetic patients with incipient nephropathy by lisinopril than by nifedipine. J Hum Hypertens 1996; 10: 185–192. 36 Chan JCN, Ko GTC, Leung DHY, Cheung RCK, Cheung MYF, So WY et al. Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. Kidney Int 2000; 57: 590–600. 37 Fogari R, Preti P, Zoppi A, Rinaldi A, Corradi L, Pasotti C et al. Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients. Am J Hypertens 2002; 15: 1042–1049. 38 Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002; 61: 1086–1097. 39 Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000; 23: B54–B64. 40 Fernandez R, Puig JG, Rodriguez-Perez JC, Garrido J, Redon J. Effect of two antihypertensive combinations on metabolic control in type-2 diabetic hypertensive patients with albuminuria: a randomised, double-blind study. J Hum Hypertens 2001; 15: 849–856. 41 Mogensen C, Viberti GC, Halimi S, Ritz E, Ruilope L, Jermendy G et al. Treatment based on a low dose combination of perindopril and indapamide reduces albuminuria more effectively than enalapril in hypertensive type 2 diabetic patients. Am J Hypertens 2002; 15: (Suppl. 1): A21–A22 (Abstract). 42 Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW et al. Randomised controlled trial of dual blockade of renin–angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and Lisinopril microalbuminuria (CALM) study. Br Med J 2000; 321: 1440–1444. 43 Houlihan CA, Allen TJ, Baxter AL, Panangiotopoulos S, Casley DJ, Cooper ME et al. A low-sodium diet potentiates the effects of losartan in type 2 diabetes. Diabetes Care 2002; 25: 663–671. 44 Gæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383–393. 45 Ravid M, Brosh D, Levi Z, Bardayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus—a randomized, controlled trial. Ann Intern Med 1998; 128: 982–988. 46 Yoshida H, Kuriyama S, Atsumi Y, Tomonari H, Mitarai T, Hamaguchi A et al. Angiotensin I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus. Kidney Int 1996; 50: 657–664. 47 Jacobsen P, Rossing K, Rossing P, Tarnow L, Mallet C, Poirier O et al. Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney Int 1998; 53: 1002–1006. 48 Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999; 341: 1127–1133[Review]. 49 Mogensen CE. Genetics and diabetic renal disease: still a big black hole. Diabetes Care 2003; 26: 1631–1632. 50 Lacourciere Y, Belanger A, Godin C, Halle JP, Ross S, Wright N et al. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kidney Int 2000; 58: 762–769. 51 Allen TJ, Cao Z, Youssef S, Hulthen UL, Cooper ME. The role of angiotensin II and bradykinin in experimental diabetic nephropathy: functional and structural studies. Diabetes 1997; 46: 1612–1618. 52 Rippin J, Bain SC, Barnett AH. Rationale and design of diabetics exposed to telmisartan and enalapril (DETAIL) study. J Diabetes Complications 2002; 16: 195–200. 53 Brenner BM, Cooper ME, De Zeeuw D, Keane WF, Mitch WE, Parving HH et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869. 54 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–860. 55 Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–878. 56 Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002; 106: 672–678. 57 Sasso FC, Carbonara O, Persico M, Iafusco D, Salvatore T, D’Ambrosio R et al. Irbesartan reduces the albumin excretion rate in microalbuminuric type 2 diabetic patients independently of hypertension: a randomized double-blind placebo-controlled crossover study. Diabetes Care 2002; 25: 1909–1913. 58 Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003. 59 Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, De Faire U et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–1010. 60 Mifsud SA, Skinner SL, Cooper ME, Kelly DJ, Wilkinson-Berka JL. Effects of low-dose and early versus late perindopril treatment on the progression of severe diabetic nephropathy in (mREN-2)27 rats. J Am Soc Nephrol 2002; 13: 684–692. 61 O'Hare JP, Bilous R, Mitchell T, O'Callaghan CJ, Viberti GC, Willoughby R et al. Low-dose ramipril reduces microalbuminuria in type 1 diabetic patients without hypertension results of a randomized controlled trial—results of a randomized controlled trial. Diabetes Care 2000; 23: 1823–1829. 62 Rossing K, Christensen PK, Jensen BR, Parving H-H. Dual blockade of the renin–angiotensin system in diabetic nephropathy: a randomized double blind crossover study. Diabetes Care 2002; 25: 95–100. 63 Jacobsen P, Andersen S, Rossing K, Hansen BV, Parving HH. Dual blockade of the renin–angiotensin system in type 1 patients with diabetic nephropathy. Nephrol Dial Transplant 2002; 17: 1019–1024. 64 Azizi M, Chatellier G, Guyene TT, Murietageoffroy D, Menard J. Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives. Circulation 1995; 92: 825–834. 65 Andersen NH, Mogensen CE. Inhibition of the renin–angiotensin system with particular reference to dual blockade treatment. JRAAS 2001; 2: 146–152. 66 Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis. Am J Cardiol 2002; 89: 18A–25A. 67 Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–717. 68 Hostetter TH, Rosenberg ME, Ibrahim HN, Juknevicius I. Aldosterone in renal disease. Curr Opin Nephrol Hypertension 2001; 10: 105–110[Review]. 69 Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am J Kidney Dis 2001; 37: 677–688. 70 Delyani JA. Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology. Kidney Int 2000; 57: 1408–1411. 71 Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med 2001; 345: 925–926. 72 Epstein M, Buckalew V Jr, Martinez F, Altamirano J, Roniker B, Kleiman J et al. Antiproteinuric efficacy of eplerenone, enalapril and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria. Am J Hypertens 2002; 15: 24A. 73 Tarnow L, Rossing P, Jensen C, Hansen BV, Parving HH. Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 2000; 23: 1725–1730. 74 Mimran A, Insua A, Ribstein J, Monnier L, Bringer J, Mirouse J. Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. J Hypertens 1988; 6: 919–923. 75 Jerums G, Allen TJ, Campbell DJ, Cooper ME, Gilbert RE, Hammond JJ et al. Long-term comparison between perindopril and nifedipine in normotensive patients with type 1 diabetes and microalbuminuria. Am J Kidney Dis 2001; 37: 890–899. 76 Crepaldi G, Carta Q, Deferrari G, Mangili R, Navalesi R, Santeusanio F et al. Effects of lisinopril and nifedipine on the progression to overt albuminuria in IDDM patients with incipient nephropathy and normal blood pressure. Diabetes Care 1998; 21: 104–110. 77 Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care 2000; 23: 888–892. 78 Chan JC, Cockram CS, Nicholls MG, Cheung CK, Swaminathan R. Comparison of enalapril and nifedipine in treating non-insulin dependent diabetes associated with hypertension: one year analysis. Br Med J 1992; 305: 981–985. 79 Bohlen L, De Courten M, Weidmann P. Comparative study of the effect of ACE-inhibitors and other antihypertensive agents on proteinuria in diabetic patients. Am J Hypertens 1994; 7: 84s–92s. 80 Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993; 118: 129–138. 81 Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium channel or beta-blockade on the progression of diabetic nephropathy in African Americans. Hypertension 1997; 29: 744–750. 82 Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996; 50: 1641–1650. 83 Christensen PK, Akram K, Konig KB, Parving HH. Autoregulation of glomerular filtration rate in patients with type 2 diabetes during isradipine therapy. Diabetes Care 2003; 26: 156–162. 84 Davis BJ, Cao Z, De Gasparo M, Kawachi H, Cooper ME, Allen TJ. Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: Potential role of nephrin. J Hypertens 2002; 21: 209–216. 85 Cooper ME, Mundel P, Boner G. Role of nephrin in renal disease including diabetic nephropathy. Semin Nephrol 2002; 22: 393–398. 86 Bakris GL, Weir MR, Shahinfar S, Zhang Z, Douglas J, Van Dijk DJ et al. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med 2003; 163: 1555–1565. 87 Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000; 36: 646–661. 88 UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes—UKPDS 39. Br Med J 1998; 317: 713–720. 89 Schnack C, Hoffmann W, Hopmeier P, Schernthaner G. Renal and metabolic effects of 1-year treatment with ramipril or atenolol in NIDDM patients with microalbuminuria. Diabetologia 1996; 39: 1611–1616. 90 Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving HH. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 1997; 46: 1182–1188. 91 Elving LD, Wetzels JF, Van Lier HJ, De Nobel E, Berden JH. Captopril and atenolol are equally effective in retarding progression of diabetic nephropathy. Results of a 2-year prospective, randomized study. Diabetologia 1994; 37: 604–609. 92 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000; 283: 1967–1975. 93 Rachmani R, Levi Z, Slavachevsky I, Half-Onn E, Ravid M. Effect of an alpha-adrenergic blocker, and ACE inhibitor and hydrochlorothiazide on blood pressure and on renal function in type 2 diabetic patients with hypertension and albuminuria. A randomized cross-over study. Nephron 1998; 80: 175–182. 94 Rossing P, Hommel E, Smidt UM, Parving HH. Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment. Diabetologia 1994; 37: 511–516. 95 Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339: 1448–1456[Review]. 96 Mogensen CE, Keane WF, Bennett PH, Jerums G, Parving HH, Passa P et al. Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet 1995; 346: 1080–1084. 97 Lane PH, Steffes MW, Mauer SM. Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion. Diabetes 1992; 41: 581–586. 98 Tsalamandris C, Allen TJ, Gilbert RE, Sinha A, Panagiotopoulos S, Cooper ME et al. Progressive decline in renal function in diabetic patients with and without albuminuria. Diabetes 1994; 43: 649–655. 99 Sackmann H, Tran-Van T, Tack I, Hanaire-Broutin H, Tauber JP, Ader JL. Contrasting renal functional reserve in very long-term Type I diabetic patients with and without nephropathy. Diabetologia 2000; 43: 227–230. 100 Mogensen CE. Glomerular filtration rate and renal plasma flow in long-term juvenile diabetics without proteinuria. Br Med J 1972; 4: 257–259. 101 Hansen KW, Poulsen PL, Mogensen CE. Ambulatory blood pressure and abnormal albuminuria in type 1 diabetic patients. Kidney Int Suppl 1994; 45: S134–140. 102 Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002; 347: 797–805. 103 Poulsen PL, Hansen KW, Mogensen CE. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2003; 348: 260–264[Letter]. 104 Svensson P, De Faire U, Sleight P, Yusuf S, Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE Substudy. Hypertension 2001; 38: E28–32. 105 Hansen KW, Poulsen PL, Ebbehoj E, Mogensen CE. What is hypertension in diabetes? Ambulatory blood pressure in 137 normotensive and normoalbuminuric Type 1 diabetic patients. Diabet Med 2001; 18: 370–373. 106 Ramsay LE, Williams B, Johnston GD, MacGregor GA, Poston L, Potter JF et al. British Hypertension Society guidelines for hypertension management 1999: summary. Br Med J 1999; 319: 630–635. 107 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413–2445. 108 Guidelines Subcommittee. 1999 World Health Organization—International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999; 17: 151–183. 109 Bakris GL, Weir MR, Dequattro V, McMahon FG. Effects of an ACE inhibitor calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998; 54: 1283–1289. 110 Cao Z, Burrell LM, Tikkanen I, Bonnet F, Cooper ME, Gilbert R. Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomised rats. Kidney Int 2001; 60: 715–721. 111 Davis BJ, Burns WC, Kubota E, Burrell LM, Johnston CI, Cooper ME et al. Renoprotective effects of dual ACE/NEP inhibition in an experimental model of diabetic nephropathy. Diabetologia 2003; 46: 961–971. 112 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342: 381–389. 113 Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Progression of diabetic nephropathy. Kidney Int 2001; 59: 702–709. 114 Tarnow L, Kjeld T, Knudsen E, Major-Pedersen A, Parving HH. Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin angiotensin system on risk of developing diabetic nephropathy in Type I diabetic patients. Diabetologia 2000; 43: 794–799. 115 American Diabetes Association. Diabetic nephropathy. Diabetes Care 2002; 25: S85–S89. 116 The Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002; 287: 2563–2569. 117 Yu HCM, Burrell LM, Black MJ, Wu LL, Dilley RJ, Cooper ME et al. Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation 1998; 98: 2621–2628. 118 Allen TJ, Waldron MJ, Casley D, Jerums G, Cooper ME. Salt restriction reduces hyperfiltration, renal enlargement and albuminuria in experimental diabetes. Diabetes 1997; 46: 119–124. 119 Dodson PM, Beevers M, Hallworth R, Webberley MJ, Fletcher RF, Taylor KG, et al. Sodium restriction and blood pressure in hypertensive type II diabetes: randomized blind controlled and crossover studies of moderate sodium restriction and sodium supplementation. Br Med J 1989; 298: 227–230. 120 Missouris CG, Macgregor GA. Rebound sodium and water retention occurs when diuretic treatment is stopped. Br Med J 1998; 316: 628. 121 Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991; 324: 78–84. 122 Walker JD, Bending JJ, Dodds RA, Mattock MB, Murrells TJ, Keen H et al. Restriction of dietary protein and progression of renal failure in diabetic nephropathy. Lancet 1989; 2: 1411–1415. 123 Hermansen K. Diet, blood pressure and hypertension. Br J Nutrition 2000; 83: S113–S119. 124 Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984; 310: 356–360. 125 Valmadrid CT, Klein R, Moss SE, Klein BEK. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med 2000; 160: 1093–1100. 126 Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989; 32: 219–226. 127 Parving HH, Nielsen FS, Bang LE, Smidt UM, Svendsen TL, Chen JW et al. Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy. Diabetologia 1996; 39: 1590–1597. 128 Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001; 134: 629–636. 129 Mather HM, Chaturvedi N, Kehely AM. Comparison of prevalence and risk factors for microalbuminuria in South Asians and Europeans with Type 2 diabetes mellitus. Diabet Med 1998; 15: 672–677. 130 Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63: 225–232. 131 Forbes JM, Soulis T, Thallas V, Panagiotopoulos S, Long DM, Vasan S et al. Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia 2001; 44: 108–114. 132 Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996; 272: 728–731. 133 Gilbert RE, Tsalamandris C, Allen TJ, Colville D, Jerums G. Early nephropathy predicts vision-threatening retinal disease in patients with type I diabetes mellitus. J Am Soc Nephrol 1998; 9: 85–89. 134 Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353: 617–622. 135 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 2002; 288: 2981–2997. 136 Passa P, Chatellier G. The Diab-HYCAR study. Diabetologia 1996; 39: 1662–1667. 137 Chalmers J, Cooper M, Ferrannini E, Glasziou P, Grobbee D, Hamet P et al. Study rationale and design of ADVANCE: Action in and vascular disease—preterax and diamicron MR evaluation. Diabetologia 2001; 44: 1118–1120. 138 Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000; 405: 421–424. 139 Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998; 338: 645–652. Citing Literature Volume21, Issue1January 2004Pages 4-17 ReferencesRelatedInformation

After years of controversy, there is no doubt that poor glycemic control is the main and fundamental basis for development of albuminuria and renal lesions in diabetes. Blood pressure elevation usually comes secondarily, at least in type 1 diabetes, but in type 2 diabetes, microalbuminuria and some blood pressure elevation may be present already with the diagnosis of diabetes, along with dyslipidemia. Genetic factors have been proposed to be important, and so far, analysis of genotypes has no place in clinical practice1.Mogensen C.E. Microalbuminuria and hypertension with focus on type 1 and type 2 diabetes.J Intern Med. 2003; 254: 45-66Crossref PubMed Scopus (195) Google Scholar, 2.Mogensen C.E. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas.in: Mogensen C.E. The Kidney and Hypertension in Diabetes Mellitus. Taylor & Francis Group, London2004: 883-938Crossref Google Scholar, 3.Mogensen C.E. Cooper M.E. Diabetic renal disease: From recent studies to improved clinical practice.Diabetic Medicine. 2004; 21: 4-17Crossref PubMed Scopus (38) Google Scholar. In many studies, microalbuminuria along with blood pressure elevation, even minor, is crucial to the later outcome of patients, and also regarding strategy for treatment. When microalbuminuria is found along with increased blood pressure, the prognosis is even poorer than with only one of these abnormalities present in the patients. Indeed, high blood pressure may be part of the family history of some patients and, therefore, again emerging as a familiar risk factor, although only relevant to few patients. Microalbuminuria in type 1 and type 2 diabetes Albuminuria is a continuum not only in its range, but also in time. Initially, all patients with type 1 diabetes will have a urinary albumin excretion rate (UAER) in the normal range unless they have ketosis. In type 2 diabetes, the disease may have been present for several years at clinical presentation, so patients may also present with microalbuminuria due to elevated blood pressure along with poor glycemic control. This is in contrast to patients with type 1 diabetes, where microalbuminuria is not found in the early years, although it may be present in cases of poor metabolic control, which may be a reversible abnormality. Several studies have been conducted on the significance of upper-normal albuminuria, which certainly represents a risk factor1.Mogensen C.E. Microalbuminuria and hypertension with focus on type 1 and type 2 diabetes.J Intern Med. 2003; 254: 45-66Crossref PubMed Scopus (195) Google Scholar. Hyperfiltration precedes microalbuminuria, an abnormality that can be ameliorated by better metabolic control3.Mogensen C.E. Cooper M.E. Diabetic renal disease: From recent studies to improved clinical practice.Diabetic Medicine. 2004; 21: 4-17Crossref PubMed Scopus (38) Google Scholar. Microalbuminuria and mortality In a follow-up study first communicated in 1983 and 1984, it was shown that microalbuminuria in type 2 diabetes is strongly predictive of an increased mortality. This observation has since been confirmed in numerous studies. It also seems to be a strong, or even the strongest, overall predictor of mortality, even in nondiabetic population-based studies. Other factors that could be associated with poor prognosis include continued long-term hyperglycemia and high blood pressure. Interestingly, poor metabolic control predicts microalbuminuria and could also be a risk factor for its progression, whereas high blood pressure can be more important in more advanced disease. New studies have shown structural abnormalities in patients with type 2 diabetes and microalbuminuria. Among the many risk factors analyzed, hyperglycemia and hypertension seem to be of particular importance, as documented in initial studies on the relevance of higher UAE rates in relation to other risk factors. It again appears that there is a requirement for two risk factors: hyperglycemia and high blood pressure factors must combine to produce a clinically important disease. Since microalbuminuria in type 2 diabetes is a better predictor of cardiovascular than of microvascular disease, other macrovascular disease factors must be taken into consideration. Microalbuminuria as a predictor for early mortality was recently confirmed in a United States follow-up study where patients with a risk of retinopathy were examined. Similar observations are now available both for the U.S. and Europe, including the UKPDS. Long-term studies in T1 DM The very long-term prognostic significance of microalbuminuria and blood pressure variables for all-cause mortality in type 1 diabetes is now being clarified. In 1977, 272 patients were identified through outpatient clinics and general practitioners related to our center. The cohort constituted a representative sample of adult type 1 diabetic patients in Aarhus County. Inclusion criteria were age 15 years or over (mean 33.9 ± 12.8) and duration of diabetes 5 years or more (mean 18.0 ± 10.5). Urinary albumin concentration (UAC), blood pressure, presence of macrovascular disease, degree of retinopathy, a composite measure for glycemic control, s-creatinine, s-cholesterol, and smoking habits (pack years) were determined. Only three patients were lost to follow-up. All-cause mortality was 37% (99/269) over 25 years for the whole group. As indicated in Table 2, baseline blood pressure and pulse pressure increased significantly with increasing albuminuria levels, as did total mortality over 25 years.Table 2Data on long-term follow-up in type 1 diabetic patientsUrinary albuminBaseline blood pressureBaseline pulse pressure25-year total mortalityRR vs. background population<20 mg/L130/824829% (58/202)2.320–200 mg/L136/865052% (23/44)5.8>200 mg/L154/985778% (18/23)13.3P value<0.001/<0.0010.02<0.001<0.001 Open table in a new tab Table 1Type 1 diabetes prediction of worsening nephropathyPublicationMogensen CE et al, N Engl J Med 1984; 311: 89–93 [6]Diabetes Control and Complications Trial. N Engl J Med 2000; 342: 381–389 [10]Initial micro14 patients64 patients% to proteinuria8.5%/year8%/yeara2% with intensive therapy. (conv. control)a 2% with intensive therapy. Open table in a new tab Cox multiple regression analysis (age-stratified) identified the following significant independent predictors of all-cause mortality: microalbuminuria [RR 2.8; 95% CI (1.5–5.2)], duration of diabetes [1.6 per 10 years (1.1–2.3)], macrovascular disease at baseline [1.9 (1.1–3.79)], smoking [1.9 (1.1–3.3)], glycemic control [2.3 (1.1–4.7)], and pulse pressure [2.8 (1.3–6.3)]. Systolic, diastolic, and mean BP was excluded from the model as was gender, s-cholesterol, s-creatinine, and retinopathy. Mortality in patients with UAC 20 to 200 mg/L was significantly increased compared with patients with UAC <20 mg/L (P < 0.001) and similar in patients with short (<16 years) and long (>16 years) duration (P=0.9, age-corrected). For comparison, age-specific, sex-specific, and calendar year–specific mortality rates were obtained from the Danish Institute of Epidemiology. As indicated in the Table, relative risk (RR) for total mortality was significantly increased in the diabetic patients versus the background population. This long-term study documents that abnormally increased urinary albumin concentration, pulse pressure, glycemic control, and smoking, all potentially modifiable risk factors, are important predictors of increased mortality in type 1 diabetes. Microalbuminuria is part of a dangerous network associated with many adverse factors. This means that we can talk about a ‘microalbuminuric syndrome’ also in type 2 diabetes.

OBJECTIVES:To examine a possible relationship between baseline albuminuria and effect of losartan versus atenolol on cardiovascular (CV) events in hypertensive patients with left ventricular hypertrophy, the effect of losartan versus atenolol on albuminuria, and whether the benefits of losartan versus atenolol could be explained by influence of losartan on albuminuria.DESIGN:Double-blind, randomized, controlled trial of 4.8 years.SETTING:Out-patient setting.PATIENTS:A total of 8206 with hypertension and left ventricular hypertrophy.INTERVENTIONS:Losartan or atenolol, supplemented with diuretics and/or calcium antagonists to reach blood pressure < 140/90 mmHgMAIN OUTCOME MEASURES:The urine albumin/creatinine ratio, and the primary composite endpoint (CEP) of CV death, myocardial infarction, and stroke.RESULTS:The blood pressure was reduced similarly on losartan (30.2/16.6 mmHg) versus atenolol (29.1/16.8 mmHg). The risk of a primary CEP increased linearly from the lowest to the highest decile of baseline albuminuria. The benefits of losartan versus atenolol for the primary CEP and for stroke tended to be more pronounced among patients above the median value for baseline albuminuria (urine albumin/creatinine ratio, 1.28 mg/mmol). The decrease in albuminuria was significantly greater with losartan versus atenolol throughout the study (a decrease from baseline to year 2 of 33% losartan versus 25% atenolol). One-fifth of the difference in favor of losartan on the primary CEP was explained by the greater reduction in albuminuria on losartan.CONCLUSIONS:Baseline albuminuria is a powerful risk factor for CV events. Baseline albuminuria did not identify the group of patients with greatest benefit on losartan versus atenolol in LIFE. Reduction in albuminuria explained one-fifth of the benefits of losartan versus atenolol.

AIMS:To characterize left ventricular function in hypertensive patients with Type 2 diabetes and normal ejection fraction, and to relate these findings to pathogenic factors and clinical risk markers.METHODS:We examined 70 hypertensive patients with Type 2 diabetes mellitus with ejection fraction > 0.55 and fractional shortening > 0.25, all without any cardiac symptoms. Thirty-five non-diabetic subjects served as control subjects. Left ventricular longitudinal function was examined by tissue Doppler derived myocardial strain rate and peak systolic velocities.RESULTS:Hypertensive patients with diabetes had a significantly higher systolic strain rate (-1.1 +/- 0.3 s(-1) vs. -1.6 +/- 0.3 s(-1), P < 0.001) and lower systolic peak velocities (3.3 +/- 1.0 vs. 5.6 +/- 1.0 cm/s, P < 0.001) compared with control subjects. Myocardial systolic strain rate correlated significantly to left ventricular mass (r = 0.40, P < 0.01) and to both HbA1c (r = 0.43, P < 0.01), and fructosamine (r = 0.40, P < 0.01), but was not related to serum levels of carboxymethyllysine, albuminuria, blood pressure (dipping/non-dipping), or oral hypoglycaemic therapy. Patients with diastolic dysfunction had significantly higher levels of urine albumin [21.0 (5-2500) mg/l, vs. 9.5 (1-360), P < 0.01], heart rate (78 +/- 13 vs. 67 +/- 10 b.p.m., P < 0.005), and seated diastolic blood pressure (85 +/- 6 vs. 81 +/- 7 mmHg, P < 0.05) and non-dipping diastolic blood pressure was more frequent.CONCLUSIONS:Long axis left ventricular systolic function was significantly decreased in hypertensive patients with Type 2 diabetes mellitus, and is associated with hyperglycaemia and left ventricular hypertrophy. Diastolic dysfunction was closely related to increased diastolic blood pressure, non-dipping and increased urinary albumin excretion.

Adiponectin is a secretory protein derived from adipose tissue with potential insulin sensitizing, anti-inflammatory, and anti-atherogenic properties [1]. Reduced plasma adiponectin concentrations are found in obesity, type 2 diabetes, and coronary artery disease; low plasma levels predict the development of type 2 diabetes in Pima Indians [1]. Conversely, plasma adiponectin increases after weight loss. However, modification of insulin sensitivity without changes in body fat mass, such as chronic physical exercise training [2] and short-term (experimental) changes in plasma free fatty acids (FFA) [3], fail to alter circulating adiponectin concentrations. On the other hand, treatment with insulin-sensitizing thiazolidinediones increases plasma adiponectin in humans [4]. It has therefore been speculated that drugs targeted at increasing adiponectin production may also improve insulin sensitivity and potentially prevent development of type 2 diabetes and atherosclerosis. Treatment of insulin-resistant, essential hypertensive patients with angiotensin II receptor blockers has been shown to be associated with improved sensitivity to insulin mediated glucose metabolism [5] [6] and increased plasma adiponectin concentrations [6]. Recently, we reported improved basal and insulin-mediated glucose metabolism after six weeks of treatment with losartan 50 mg o. d. in a study of normotensive, normoalbuminuric type 1 diabetic men [7]. Here, we have examined whether the effects of losartan on glucose metabolism were associated with changes in plasma adiponectin.

OBJECTIVES:We examined whether the finding of glycosuria and its level in themselves give information of clinical relevance, apart from being an unreliable indicator of glycemic control.METHODS:Subjects were a population-based sample of 1,284 newly diagnosed type 2 diabetic patients. Median age was 65.2 years. Urinary glucose concentration (UGC) was determined quantitatively in a freshly voided morning urine specimen.RESULTS:The over-all prevalence of peripheral vascular disease (PVD) was 16.5%. Bivariately, high values of UGC were associated with low prevalence of PVD (p<0.001, chi2-test). The predictive value of PVD--together with HbA1c, glomerular filtration rate (GFR) and 10 other possible predictors--was confirmed in a logistic regression analysis with glycosuria (Y/N) as outcome variable (p=0.0004).CONCLUSION:Surprisingly, type 2 diabetic patients with PVD tend not to have glycosuria as compared to patients without PVD. PVD may be indicative of generalized atherosclerotic lesions in the major vessels, including the renal arteries. This could lead to a lowering of GFR and thereby of the amount of glucose filtered. Assuming no, or only a minor direct effect of PVD on tubular function, this would lead to an increased renal threshold for glucose in patients with PVD.

Guidelines for medical treatment are becoming increasingly popular and many guidelines have been produced by various societies in diabetes, hypertension, and renal disease as well as general medicine. By their nature, they are outdated considering the rapid and efficient publication of many papers related to the treatment of hypertension in diabetes. Increased blood glucose causes vascular damage and abnormal vascular structure all over the body, an abnormal structure that is especially vulnerable to high blood pressure, even within the so-called normal range. There is now more and more evidence, especially in diabetics, that blood pressure should be as low as possible. In this context, it is important to stress that the so-called J-shaped relationship between blood pressure and mortality may not be so relevant. Major epidemiological studies came from the Framingham and the Multiple Risk Factor Intervention Trial (MRFIT) Diabetic Cohort. The MRFIT Cohort showed that cardiovascular mortality was increased by a factor of 2-4 in diabetic patients, and there was a clear association between systolic blood pressure and complications without any threshold value. It could be suggested that since diabetes is an important cardiovascular risk factor, a lower value (130/85 mmHg) than for non-diabetics (140/90 mmHg) should be proposed. The tight blood pressure control arm of the United Kingdom Prospective Diabetes Study was <150/85 mmHg (achieved 144/82 mmHg) and the aim in the less tight control arm was <180/105 mmHg (achieved 154/87 mmHg). In the tight control group, 29% needed three or more antihypertensive drugs. In the Hypertension Optimal Treatment study, the frequency of major cardiovascular disease events in the group with target <80 mmHg (achieved 144/81 mmHg) was 11.9/1000 patients/year, which was significantly lower than the event rate (24.4/1000 patients/year) in the group with target <90 mmHg (achieved 148/85 mmHg). A reduction in the frequency of diabetic nephropathy by angiotensin-converting enzyme (ACE) inhibitor treatment in normotensive lean microalbuminuric type 2 diabetic patients has been shown. However, it is impossible from the present data to draw any conclusions with respect to effect on the main composite endpoint of ACE inhibition in microalbuminuric type 2 diabetic patients without previous cardiovascular events or without hypertension. Recent published studies have also demonstrated beneficial effects with angiotensin receptor blockers (ARBs) in hypertensive patients with type 2 diabetes and nephropathy. Diuretics form a very important basis for antihypertensive treatment, also often in combination with agents that inhibit the renin-angiotensin system. Several studies show that treatment with the diuretic indapamide reduces the level of microalbuminuria in patients with type 2 diabetes. Diuretics were used as an adjunctive to reduce blood pressure in all studies; it is therefore understandable that many guidelines suggest that diuretics form part of the treatment of hypertension in diabetics. Many studies of an epidemiological nature and follow-up studies in diabetic patients show that blood pressure control is of vital concern in the prevention of diabetic complications, and indeed the usual criteria for good blood pressure control may not be stringent enough in diabetic patients. Many classes of antihypertensives may be used, but it appears that diuretics, such as indapamide sustained release (SR), constitute an important proposal in all treatment strategies.