Giancarlo Viberti

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.

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.).

Microalbuminuria Predicts Mortality in Noninsulin‐dependent Diabetes

Forty‐four non‐insulin‐dependent diabetics (NIDD), all with urine negative to Albustix, were studied in 1966/67. By the end of 1980, 17 had died, all but two from cardiovascular causes. All causes of mortality and time to death were significantly related in univariate analyses to age and to the overnight urinary albumin excretion rate (AER), but not to systolic and diastolic blood pressure levels or to duration of diabetes when the latter was corrected for age. Age and duration were highly correlated with each other. In multivariate analyses age and AER were independent predictors of both mortality and time to death, with AER having the greater degree of significance.

Prevention of Diabetic Renal Disease with Special Reference to Microalbuminuria

In the past year six sets of recommendations on the prevention of diabetic nephropathy, with special reference to microalbuminuria, have been published [1–6]. The background to this activity was the large and increasing number of diabetic patients in whom end-stage renal failure (ESRD) develops and who therefore require dialysis or renal transplantation. Throughout the world about half a million patients are registered as being on renal replacement therapy, and diabetic nephropathy is the cause in nearly one-fifth of them [7]. These data are extrapolated from countries which have registries but in many areas, especially in the densely populated countries of the Far East, accurate information on numbers of patients with ESRD is not yet available. Moreover, the half-million figure probably underestimates the number of diabetic patients with ESRD because selection criteria for renal replacement therapies vary from country to country. Both insulin dependent (IDDM) and non-insulin-diependent (NIDDM) diabetic patients contribute to the increase in ESRD. Prevention of diabetic renal disease, or at least the postponement or slowing down of the disease process, has emerged as a key issue. Our strategy is to develop programmes for all patients with diabetes, focused on early detection of renal disease followed by intervention.

Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT).

OBJECTIVE—The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS—Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS—In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS—Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

Prospective Study of Microalbuminuria as Predictor of Mortality in NIDDM

Retrospective studies of patients with non-insulin-dependent diabetes mellitus (NIDDM) have suggested that microalbuminuria predicts early all-cause (mainly cardiovascular) mortality independently of arterial blood pressure. These findings have not been confirmed in prospective studies, and it is not known whether the predictive power of microalbuminuria is independent of other major cardiovascular risk factors. During 1985–1987, we examined a representative group of 141 nonproteinuric patients with NIDDM for the prevalence of coronary heart disease and several of its established and putative risk factors, including raised urinary albumin excretion (UAE) rate. Thirty-six patients had microalbuminuria (UAE 20–200 μg/min), and 105 had normal UAE (< 20 μg/min). At follow-up, an average of 3.4 yr later, 14 patients had died. There was a highly significant excess mortality (chiefly from cardiovascular disease) among those with microalbuminuria (28%) compared to those without microalbuminuria (4%, P < 0.001). In univariate survival analysis, significant predictors of all-cause mortality included microalbuminuria (P < 0.001), hypercholesterolemia (P < 0.01), hypertriglyceridemia (P < 0.05), and preexisting coronary heart disease (P < 0.05). The predictive power of microalbuminuria persisted after adjustment for the effects of other major risk factors (P < 0.05). We conclude that microalbuminuria is a significant risk marker for mortality in NIDDM, independent of the other risk factors examined. Its presence can be regarded as an index of increased cardiovascular vulnerability and a signal for vigorous efforts at correction of known risk factors.

Increased Sodium-Lithium Countertransport Activity in Red Cells of Patients with Insulin-Dependent Diabetes and Nephropathy

Susceptibility to diabetic nephropathy may be related to a predisposition to arterial hypertension. We have studied the activity of sodium-lithium countertransport in red cells, a marker of risk for essential hypertension, in white European adults with insulin-dependent diabetes and diabetic nephropathy, a matched group of patients with diabetes without renal disease, and nondiabetic patients with renal disease. Measures of metabolic control and concentrations of plasma free insulin and growth hormone were similar in the two diabetic groups. The degree of impairment in renal function was similar in the diabetic and nondiabetic patients with renal disease. Body-mass index and plasma potassium concentrations were similar in all three groups. Diastolic blood pressure was elevated to a similar degree in the two groups with renal disease, as compared with that in the diabetic patients without renal disease. The rates of sodium-lithium countertransport in red cells were significantly higher in the diabetic patients with renal disease (mean +/- SD, 0.55 +/- 0.19 mmol of lithium per liter of red cells per hour) than in the diabetic patients without renal disease (0.33 +/- 0.16; P less than 0.005) and in the nondiabetic patients with renal disease (0.31 +/- 0.14; P less than 0.001). Predisposition to hypertension, as indicated by elevated sodium-lithium countertransport activity in red cells, may serve as a marker for the risk of renal disease in patients with insulin-dependent diabetes.

Rosiglitazone Associated Fractures in Type 2 Diabetes: An Analysis From ADOPT

OBJECTIVE—The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS—Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS—In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS—Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

Effect of Control of Blood Glucose on Urinary Excretion of Albumin and β2 Microglobulin in Insulin-Dependent Diabetes

To study the effects of improved control of blood glucose on markers of renal glomerular and tubular function, we initially determined, by radioimmunoassay technics, urinary excretion rates of albumin and beta2 microglobulin in 17 nondiabetic subjects and in 43 insulin-dependent, clinically nonproteinuric diabetic patients. Duration of diabetes ranged from six months to 39 years, and the patients were studied while receiving conventional therapy. Mean urinary albumin excretion was significantly elevated in the diabetics, but beta2-microglobulin excretion rates were not different from those of the controls, suggesting that the increased albumin excretion was due to increased transglomerular loss of albumin. Seven patients with long-term diabetes (duration of six to 33 years), selected because of elevated albumin excretion, were studied before and during a continuous, subcutaneous insulin infusion for a period of one to three days. Urinary albumin excretion was significantly reduced during the insulin infusion, but mean beta2-microglobulin excretion did not change. Strict control of blood glucose, even in the short term, may reverse a functional renal abnormality in long-duration, insulin-dependent diabetes.

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.