A pragmatic lifestyle modification programme reduces the incidence of predictors of cardio-metabolic disease and dysglycaemia in a young healthy urban South Asian population: a randomised controlled trial.

BACKGROUND: There is an increasing incidence of type 2 diabetes mellitus (T2DM) in young urban South-Asians. We tested the effect of a pragmatic trimonthly lifestyle modification (LSM) programme (P-LSM) versus a less-intensive 12-monthly control LSM (C-LSM) intervention on a primary composite endpoint of predictors of cardio-metabolic disease (new onset T2DM, hypertension, impaired glucose tolerance (IGT), impaired fasting glycaemia (IFG) and markers of cardio-renal disease) in participants aged 5-40 years with risk factors for T2DM. METHODS: This was a randomised controlled trial performed at the National Diabetes Centre, Sri-Lanka. We individually randomised 4672 participants at risk of T2DM, of whom 3539 (mean age 22.5 (range 6-40 years, 48% males) received either trimonthly (P-LSM n = 1726) or 12-monthly (C-LSM n = 1813) peer educator advice aimed at reducing weight, improving diet, reducing psychological stress and increasing physical activity. RESULTS: During a median follow-up of 3 years, the cumulative incidence of the primary endpoint was n = 479 in P-LSM (74 per 1000 person years) vs. 561 in C-LSM (96 per 1000 person years), with an incident rate ratio (IRR) of 0.89 (95% CI 0.83-0.96, P = 0.02). In post hoc analyses, new onset dysglycaemia (T2DM, IFG and IGT), was the major contributor to the composite and was significantly reduced by P-LSM (IRR 0.9, 95% CI 0.83-0.97, P = 0.01). A significant impact of P-LSM on the incidence of the composite endpoint was noted in 1725 participants (P-LSM n = 850, C-LSM n = 875) aged below 18; P-LSM n = 140 (48 per 1000 person years) versus C-LSM n = 174 (55.4 per 1000 person years), with an IRR of 0.83 (95% CI 0.73-0.94, P = 0.004). CONCLUSIONS: In a young at-risk South-Asian population, a pragmatic LSM programme significantly reduces the incidence of predictors of cardio-metabolic disease. Our results highlight the importance of early intervention in young at-risk subjects. TRIAL REGISTRATION: World Health Organization international clinical trial registry platform ( SLCTR/2008/003 ). Registration Date: March 28, 2008. Retrospectively registered.

The effect of dietary changes on distinct components of the metabolic syndrome in a young Sri Lankan population at high risk of CVD.

South Asian populations are predisposed to early onset of the metabolic syndrome. Lifestyle intervention programmes have demonstrated a reduction in the metabolic syndrome and CVD risk; however, the most effective components of the multi-faceted lifestyle interventions are unknown. We studied 2637 Sri Lankan males (n 1237) and females (n 1380), with a mean BMI of 23·9 (sd 4·2) kg/m2, aged 22·5 (sd 10·0) years, who had participated in a 5-year lifestyle-modification programme to examine the effect of dietary changes on distinct components of the metabolic syndrome. The dietary intervention comprised advice to replace polished starches with unpolished starches, high-fat meat and dairy products with low-fat products and high-sugar beverages and snacks with low-sugar varieties. For the purposes of this analysis, data from the control and intensive lifestyle groups were combined. Anthropometric and biochemical data were recorded, and a FFQ was completed annually. Multiple regression was used to determine the effect of the dietary changes on distinct components of the metabolic syndrome. The ratio unpolished:polished rice was inversely related to change in fasting glucose (ß=-0·084, P=0·007) and TAG (ß=-0·084, P=0·005) and positively associated with change in HDL-cholesterol (ß=0·066, P=0·031) at the 5-year follow-up after controlling for relevant confounders. Red meat intake was positively associated with fasting glucose concentrations (ß=0·05, P=0·017), whereas low-fat (ß=-0·046, P=0·018) but not high-fat dairy products (ß=0·003, P=0·853) was inversely related to glucose tolerance at the follow-up visit. Replacement of polished with unpolished rice may be a particularly effective dietary advice in this and similar populations.

The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes.

BACKGROUND: Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. METHODS: In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. RESULTS: The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P=0.02). CONCLUSIONS: Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.).

Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study.

BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 µg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment. RESULTS: Mean estimated glomerular filtration rate change from baseline to end of follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar versus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified. CONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks' treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone. TRIAL REGISTRATION: NCT01043029 January 5, 2010.

Proteinuria in diabetes: bystander or pathway to cardiorenal disease?

The development of albuminuria in diabetics is closely associated with an enhanced risk of renal and cardiovascular disease. However, the role of albuminuria in the pathogenesis of these clinical conditions remains controversial. Whether albuminuria is simply a biomarker or qualifies as a surrogate endpoint for cardiorenal disease has wide-ranging implications from the monitoring and treatment of patients to the design of clinical trials and drug development. We critically review available data to determine whether the association between albuminuria and cardiorenal disease is causative. Current evidence suggests the significance of albuminuria depends on its severity (degree or level) and on the specific clinical outcome under consideration. For diabetic kidney disease, there is convincing epidemiologic and experimental evidence to assign clinical albuminuria status as a surrogate endpoint, but for lower levels of albuminuria (microalbuminuria and normoalbuminuria), the evidence is inconclusive or not available. Albuminuria of any degree is unlikely to be causally related to diabetic cardiovascular disease, but its onset might be useful to identify those subjects at cardiovascular risk and to detect and treat other modifiable risk factors.

Avosentan for overt diabetic nephropathy.

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

Peroxisome proliferator-activated receptor-γ agonist rosiglitazone prevents albuminuria but not glomerulosclerosis in experimental diabetes.

BACKGROUNDS/AIMS: Renal inflammation and nephrin downregulation contribute to albuminuria in diabetes. We studied, in streptozotocin-induced diabetic rats, the effect of rosiglitazone (RSG), a peroxisome proliferator-activated receptor-γ agonist, on renal macrophage infiltration, MCP1, and nephrin expression in relation to albuminuria. METHODS: We investigated control and diabetic rats treated or untreated with RSG. Animals were sacrificed at 1, 3, and 9 months. Renal MCP1 and nephrin expression were studied by immunoblotting, renal macrophage infiltration by immunohistochemistry, and albuminuria by ELISA. Electron microscopy was used to assess glomerular ultrastructural morphology. In vitro experiments were conducted in isolated cultured rat glomeruli. RESULTS: Glycaemic control was similar in diabetic rats treated and untreated with RSG, and blood pressure was comparable in all groups. RSG prevented diabetes-induced albuminuria at 9 months, and renal macrophage infiltration and MCP1 upregulation at 3 and 9 months. Diabetes-mediated nephrin downregulation was abolished by RSG. Diabetes-induced glomerulosclerosis, glomerular basement membrane thickening, and foot process fusion were not affected by RSG. In isolated glomeruli, MCP1 directly induced nephrin downregulation and this was prevented by RSG. RSG had no effect on nephrin expression. CONCLUSION: RSG prevents albuminuria and nephrin downregulation in experimental diabetes independently of glycaemic and blood pressure control. This effect likely occurs via correction of diabetes-induced inflammatory processes.

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.

BACKGROUND: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. METHODS: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function. RESULTS: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). CONCLUSIONS: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

Mechanical forces and TGFbeta1 reduce podocyte adhesion through alpha3beta1 integrin downregulation.

BACKGROUND: Podocyturia is a marker of diabetic nephr- opathy, a possible determinant of its progression and a powerful risk factor for cardiovascular disease. A reduction in podocyte adhesion to the glomerular basement membrane (GBM) via downregulation of alpha3beta1 integrin expression, the main podocyte anchoring dimer to the GBM, may represent one of the mechanisms of podocyturia in glomerular disease. This study investigated the role of mechanical forces and transforming growth factor beta1 (TGFbeta1) in podocyte adhesion and integrin expression. METHODS: Conditionally immortalized murine podocytes were exposed to mechanical stretch and/or TGFbeta1 for 48 h. Podocyte adhesion, apoptosis and alpha3beta1 integrin expression were assessed. RESULTS: Stretch and TGFbeta1 significantly reduced podocyte adhesion and alpha3beta1 integrin expression, events paralleled by increased apoptosis. Blockade of beta1 integrin, with a specific antibody, demonstrated a reduced podocyte adhesion indicating that beta1 integrin downregulation was required for the loss of podocyte adhesion. This was linked to an increase in podocyte apoptosis. The role of apoptosis in podocyte adhesion was further investigated using caspase-3 inhibitors. Podocyte apoptosis inhibition did not affect stretch- and TGFbeta1-mediated integrin downregulation and the loss of podocyte adhesion, suggesting that alpha3beta1 integrin downregulation is sufficient to alter cell adhesion. Although stretch significantly increased podocyte TGFbeta type I, II and III receptors but not podocyte TGFbeta1 secretion, the combination of stretch and TGFbeta1 did not show any additive or synergistic effects on podocyte adhesion and alpha3beta1 integrin expression. CONCLUSIONS: These results suggest that downregulation of alpha3beta1 integrin expression, by mechanical forces or TGFbeta1, is per se sufficient to reduce podocyte adhesion. Apoptosis may represent a parallel important determinant of the podocyte loss from the GBM.

Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes.

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA(1c) [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (

Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus.

OBJECTIVE: Renin-angiotensin system blockade is now standard in the management of the patient with type 2 diabetes mellitus. We aimed to investigate whether high doses of valsartan, an angiotensin receptor blocker, are superior to conventional doses to reduce urinary albumin excretion rates (UAER) in such patients. PATIENTS AND METHODS: Three hundred and ninety-one hypertensive patients with type 2 diabetes mellitus and UAER 20-700 microg/min were randomized to 160, 320 or 640 mg valsartan. All received valsartan 160 mg for the first 4 weeks. Valsartan dose was then increased in two of three groups for 30 weeks. Overnight urine collections at baseline, 4, 16, and 30 weeks in triplicate were used to assess proteinuria. RESULTS: Comparable albuminuria reductions occurred in all groups at week 4 (P<0.001). Subsequently, a highly significant albuminuria fall occurred with valsartan 320 and 640 mg (P<0.001) versus a modest additional change with 160 mg (P=0.03). At week 30, twice as many patients returned to normal albuminuria with valsartan 640 mg versus 160 mg (24 versus 12%; P<0.01). High doses were well tolerated, with no dose-related increases in adverse events, including hypotension and hyperkalemia. CONCLUSION: High doses of valsartan reduced albuminuria more than the more commonly used 160 mg dose, apparently independent of blood pressure. Thus, at least in type 2 diabetes mellitus, higher doses of valsartan are required to optimize tissue protection than for blood pressure control.

Serum lipids and the progression of nephropathy in type 1 diabetes.

OBJECTIVE: Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8-9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS: In patients with normoalbuminuria (n = 66), progression was associated with male sex (P < 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P < 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (>3 ml x min(-1) x year(-1)) was independently associated with poor glycemic control, hypertension, and LDL size (P < 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P < 0.05), which masked the importance of triglyceride enrichment in microalbuminuria. CONCLUSIONS: Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.

Increased Arterial Stiffness is an Independent Predictor of Renal Function Decline in Patients With Type 2 Diabetes Mellitus Younger Than 60 Years.

BACKGROUND: The objective of this study was to evaluate whether aortic pulse wave velocity (Ao-PWV) predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus. METHODS AND RESULTS: This prospective single-center cohort study investigated 211 type 2 diabetes mellitus patients with eGFR ≥45 mL/min with a baseline mean age of 60.1 years (range, 30-82 years). The mean±SD baseline eGFR was 85±26.1 mL/min. We divided the cohort into 2 groups above (n=117, "older") and below (n=94, "younger") the mean age to evaluate whether Ao-PWV predicted progression of kidney disease differentially in older and younger patients. The primary end point was reaching a final eGFR below the median for the age group and an eGFR fall ≥1 mL/min per year. Median follow-up was 9 years (range, 3-11 years) and ≈50% of patients in both groups reached the primary end point. In older patients, Ao-PWV was similar in those who did and did not reach the primary end point. By contrast, younger patients who reached the primary end point had a higher Ao-PWV at baseline compared with those who did not (10.8 m/s versus 9.5 m/s, respectively; mean difference of 1.36 m/s [95% CI, 0.38-2.33], P=0.007). Ao-PWV was an independent predictor of the primary end point (incident risk ratio, 1.09; 95% CI, 1.02-1.18) after adjustment for traditional risk factors only in younger patients (P=0.02). A 1m/s increase in Ao-PWV was associated with a mean fall in eGFR of 2.1 mL/min per year (95% CI, 0.09-4.1) independent of other risk factors in younger patients (P=0.04). CONCLUSIONS: Ao-PWV predicts eGFR decline, before the onset of advanced renal dysfunction, and is a potential target for renoprotection in younger patients with type 2 diabetes mellitus.

Predictors for the development of microalbuminuria and interaction with renal function.

AIM: It is important to know which factors predict the development of microalbuminuria in patients with diabetes mellitus type II. MATERIAL: Data from the Randomized Olmesartan and Diabetes Microalbuminuria Prevention Study were used to identify predictors for the new onset of microalbuminuria. Furthermore, the interaction of baseline albuminuria and baseline estimated glomerular filtration rate (eGFR) and the effects of treatment with olmesartan were investigated. RESULTS: A total of 4447 patients were randomized to receive 40-mg olmesartan or placebo for a median of 3.2 years. Baseline urinary albumin-creatinine ratio (UACR) was the most important predictor of microalbuminuria, followed by age, weight, glycosylated hemoglobin type A1C, blood glucose, total cholesterol, SBP number of antihypertensive drugs and heart rate. The development of microalbuminuria was not affected by hemodynamic factors. The incidence of microalbuminuria increased from the lower to the higher UACR tertile at all baseline eGFR tertiles. The effects of olmesartan on prevention of new onset microalbuminuria were more obvious in those with the highest baseline UACR at all baseline eGFR tertiles. The eGFR declined more significantly in the olmesartan group (from 85.0 to 80.1 ml/min per 1.73 m), whereas the decrease in the placebo group was smaller (from 84.7 to 83.7 ml/min per 1.73 m). The highest rate of eGFR decline in the olmesartan group was in patients with the highest baseline eGFR (>95 ml/min per 1.73 m) at all baseline UACR tertiles. The transition from normoalbuminuria to microalbuminuria in the olmesartan treated patients was not accompanied by preservation of renal function. CONCLUSION: Predictors of new onset microalbuminuria are the classical cardiovascular risk factors. Microalbuminuria development was associated with baseline UACR but not baseline eGFR, whereas eGFR decrease after introduction of olmesartan was dependent on baseline eGFR but not on baseline UACR. The effects of olmesartan on microalbuminuria development and on eGFR decrease are probably mediated by different mechanisms.Clinical Trials.gov number, NCT00185159.

Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect.

BACKGROUND: Elevated urine albumin excretion (UAER) is a modifiable risk factor for renal and cardiovascular disease in type 2 diabetes. Blockade of the renin-angiotensin system lowers UAER, but whether this effect is independent of blood pressure (BP) reduction remains controversial. The MicroAlbuminuria Reduction With VALsartan (MARVAL) study was designed to evaluate the BP-independent effect of valsartan on UAER in type 2 diabetic patients with microalbuminuria. METHODS AND RESULTS: Three hundred thirty-two patients with type 2 diabetes and microalbuminuria, with or without hypertension, were randomly assigned to 80 mg/d valsartan or 5 mg/d amlodipine for 24 weeks. A target BP of 135/85 mm Hg was aimed for by dose-doubling followed by addition of bendrofluazide and doxazosin whenever needed. The primary end point was the percent change in UAER from baseline to 24 weeks. The UAER at 24 weeks was 56% (95% CI, 49.6 to 63.0) of baseline with valsartan and 92% (95% CI, 81.7 to 103.7) of baseline with amlodipine, a highly significant between-group effect (P<0.001). Valsartan lowered UAER similarly in both the hypertensive and normotensive subgroups. More patients reversed to normoalbuminuria with valsartan (29.9% versus 14.5%; P=0.001). Over the study period, BP reductions were similar between the two treatments (systolic/diastolic 11.2/6.6 mm Hg for valsartan, 11.6/6.5 mm Hg for amlodipine) and at no time point was there a between-group significant difference in BP values in either the hypertensive or the normotensive subgroup. CONCLUSIONS: For the same level of attained BP and the same degree of BP reduction, valsartan lowered UAER more effectively than amlodipine in patients with type 2 diabetes and microalbuminuria, including the subgroup with baseline normotension. This indicates a BP-independent antiproteinuric effect of valsartan.

Podocyte number in normotensive type 1 diabetic patients with albuminuria.

We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r = 0.44, P = 0.012) and negatively with podocyte number in proteinuric patients (r = -0.48, P = 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r = -0.72, P = 0.002). In conclusion, cross-sectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain.

Prevention of chronic kidney and vascular disease: toward global health equity--the Bellagio 2004 Declaration.

Chronic kidney disease (CKD) not only reflects target organ injury in systemic vascular disease in the general population and in association with diabetes, hypertension, and smoking, but it is recognized as one of the major risk factors in the pathogenesis and outcome of cardiovascular disease. Recent surveys have revealed that the prevalence of CKD, particularly the hidden mild form (mildly elevated levels of serum creatinine or urinary albumin excretion), is surprisingly high in the general population. In recent years, the global epidemic of type 2 diabetes has led to an alarming increase in the number of patients with CKD. Most patients with CKD (over 50 million individuals worldwide) succumb to cardiovascular events, while each year over 1 million develop end-stage renal failure, which requires costly treatment and in many countries of the world, unaffordable renal replacement therapy by chronic dialysis or renal transplantation. Alarmed by the immense challenge to human morbidity and the economic burden of CKD and ensuing systemic cardiovascular disease, the International Society of Nephrology convened a multidisciplinary group of expert physicians and public health leaders from around the world to develop strategies to delay and avert this bleak future by effective prevention of CKD based on awareness, early detection, and effective treatment.

Thiazolidinediones-benefits on microvascular complications of type 2 diabetes.

Type 2 diabetes is associated with serious microvascular complications, such as nephropathy, retinopathy, and neuropathy, which have a significant impact on patients' quality of life, morbidity, and mortality. Type 2 diabetes management strategies to reduce the risk of microvascular complications include treatment of hyperglycaemia, hypertension, and other vascular risk factors. The importance of glycaemic control in reducing the risk of microvascular complications of diabetes is well established. However, many antihyperglycaemic therapies fail to provide adequate glycaemic control and do not prevent complications in the long term. The thiazolidinediones (TZDs) are a class of agents that provide sustained glycaemic control, mediated primarily by reductions in insulin resistance. Evidence reviewed suggests that the TZDs may have the potential to reduce microvascular complications through benefits that go beyond glycaemic control. Insulin resistance underlies a range of metabolic abnormalities, collectively known as the metabolic syndrome (MS), which are cardiovascular (CV) risk factors. Components include visceral obesity, hyperglycaemia, hypertension, dyslipidaemia, low-grade inflammation and microalbuminuria (an early manifestation of target organ damage). Reducing insulin resistance, therefore, has the potential to reduce both microvascular and macrovascular complications.

Prevalence and concomitants of glucose intolerance in European obese children and adolescents.

OBJECTIVE: The worldwide increase in the prevalence of childhood obesity is reaching epidemic proportions and is associated with a dramatic rise in cases of type 2 diabetes. The prevalence of glucose intolerance and its determinants and the relation of cardiovascular risk factors with levels of glycemia and degree of obesity were studied in grossly obese children of European origin. RESEARCH DESIGN AND METHODS: A total of 710 grossly obese Italian children (SD score [SDS] of BMI 3.8 +/- 0.7) aged 6-18 years, including 345 male subjects, underwent an oral glucose tolerance test. Insulin resistance and insulin secretion were estimated using the homeostasis model assessment for insulin resistance and the insulinogenic index, respectively. Fibrinogen, C-reactive protein, lipids, and uric acid were measured. The 2-h postload glucose and degree of obesity, calculated as the SDS of weight/height(2), were used as dependent variables. RESULTS: The prevalence of glucose intolerance was 4.5%. Insulin resistance (P < 0.0001), impaired insulin secretion (P < 0.0001), and diastolic blood pressure (BP) (P < 0.05) were significantly and independently related to 2-h postload glucose values. The degree of obesity did not relate to insulin resistance but was independently correlated with inflammatory proteins, uric acid, and systolic BP, variables that were often abnormal in this population. CONCLUSIONS: In these grossly obese children, both insulin resistance and impaired insulin secretion contribute to the elevation of glycemia, and the degree of obesity is related to cardiovascular risk factors independently of insulin resistance.