Design ACCORD is a parallel group, randomized trial designed to investigate whether intensive glycemic therapy with a target HbA1c of <6.0% versus standard therapy with a target of 7.0 to 7.9% reduces cardiovascular disease (CVD) morbidity, mortality, and microvascular complications in participants with type 2 diabetes. Methods Volunteers with established type 2 diabetes, HbA1c levels ≥ 7.5% and CVD or two or more CVD risk factors were recruited at 77 clinical sites across the U.S. and Canada. Instructional materials, behavioral counseling, glucose-lowering medications and self-monitoring supplies were provided by the study. Therapeutic regimens were individualized on the basis of randomized assignment and response to therapy. This investigation examines the effect of treatment to glycemic goals on occurrence of microvascular diabetes complications. Prespecified composite outcomes were: 1) dialysis or renal transplantation, or serum creatinine >291.7 micromol/L, or retinal photocoagulation or vitrectomy, and 2) these plus peripheral neuropathy. Thirteen prespecified secondary measures of kidney, eye, and peripheral nerve function were also evaluated. Randomization was performed at clinical sites using a central randomization routine available on the study website. Both investigators and participants were unmasked to treatment arm assignment. Results A total of 10,251 participants were randomized (5,128 intensive and 5,123 standard) between January, 2001 and October, 2005. This analysis includes 10,234 patients (5,107 intensive and 5,108 standard). Intensive therapy was stopped before study end due to increased mortality, and patients were transitioned to standard therapy. Outcomes are reported at transition and at study end. At transition, the first composite outcome occurred in 443/5107 and 444/5108 participants in the intensive and standard arms, respectively (p= 0.99), and the second outcome in 1591/5107 and 1659/5108 participants in intensive and standard arms (p=0.20). Results were similar at study end. Secondary measures at study end favoring intensive therapy (p<0.05) included development of macroalbuminuria, cataract extraction, visual acuity, a score of >2.0 on the Michigan Neuropathy Screening Instrument, loss of ankle jerk and light touch. Conclusions Intensive glycemic treatment did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of macroalbuminuria and some measures of eye complications and neuropathy. These benefits must be weighed against the increase in total and CVD-related mortality, increased weight gain, and higher risk for severe hypoglycemia.

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up, 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg ⁄ d (n=15,255), amlodipine 2.5-10 mg ⁄ d (n=9048), or lisinopril 10-40 mg ⁄ d (n=9054) in a randomized double-blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145 ⁄ 83 mm Hg (27% control) to 134 ⁄ 76 mm Hg (chlorthalidone, 68% control), 135 ⁄ 75 mm Hg (amlodipine, 66% control), and 136 ⁄ 76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group-a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140 ⁄ 90 mm Hg in a majority of patients. J Clin Hypertens (Greenwich). 2008;10:751-760.ª 2008 Le Jacq M ore than 70 million Americans-nearly 1 in 3 adults-have hypertension; its prevalence increases with age.

No abstract

BACKGROUND An endogenous digitalis-like compound in mammals has long been postulated, but only recently has a substance indistinguishable from ouabain been identified in human plasma. Because of the potential significance of such a substance in patients with congestive heart failure, we sought to evaluate the pathophysiology of endogenous ouabain in these individuals. METHODS AND RESULTS Using an immunoassay, we determined plasma ouabain concentrations in 51 patients with heart failure and in 19 control subjects. Plasma ouabain concentrations in control subjects ranged from 0.16 to 0.77 nM (mean, 0.44 +/- 0.20 nM). In 19 matched heart failure patients receiving digoxin, the mean ouabain was significantly elevated at 1.59 +/- 2.2 nM (range, 0.17-8.76 nM, p less than 0.05 versus control subjects). The ouabain concentration correlated inversely with both cardiac index (r = -0.62, p less than 0.005) and mean arterial pressure (r = -0.51, p less than 0.05). However, there was no correlation between ouabain and left ventricular filling (r = 0.19, NS) or right atrial pressures (r = 0.20, NS). In 16 heart failure patients not receiving digoxin, the mean ouabain was 1.52 +/- 2.58 nM. No relation between renal function and ouabain was detected. CONCLUSIONS The unanticipated lack of correlation of ouabain with atrial pressures indicates that volume is not the chief determinant of ouabain concentration in patients with congestive heart failure. However, the significant relations of plasma ouabain concentration with cardiac index and mean arterial pressure imply that endogenous ouabain may be an important homeostatic factor in humans.

Elevated circulating levels of an endogenous ouabain (EO) have been associated with essential hypertension. To investigate structure-activity relationships relevant to blood pressure, we infused either ouabain, ouabagenin, digoxin or digitoxin at 30 ,Mg/kg/day in normal Sprague Dawley rats. After five weeks, the ouabain and ouabagenin infused rats were hypertensive, whereas blood pressures declined below their vehicle controls in rats infused with digoxin or digitoxin. In a second study, mean blood pressures were 118.5 +1.7 mmHg in rats infused with ouabain (15 ,ug/kg/day) on day 35 vs. 98.3+1.8 and 100.3±1.1 mmHg in the digoxin (30 ,ag/kg/day) and vehicle infused groups (both p<0.005 vs. ouabain), respectively. Plasma and kidney levels of ouabain immunoreactivity were increased 4-8 fold in ouabain infused rats while blood pressure and plasma levels of ouabain returned to normal one week following discontinuation of the steroid infusion. In rats with ouabain-dependent hypertension, secondary infusions of digoxin or digitoxin (30 ,ag/kglday) normalized blood pressure even though circulating ouabain remained elevated. In digoxin infused rats, neither blood pressure nor kidney digoxin immunoreactivity was raised whereas plasma digoxin was increased. Collectively, the results show that the hemodynamic effects of these sodium pump inhibitors differ dramatically during prolonged administration and that tissue rather than circulating levels of these agents appear to better explain their effects on blood pressure. These studies suggest that sodium pump inhibition is not the exclusive mediator of the hemodynamic effects of these cardiac glycosides and demonstrate the presence of structure-specific mechanisms that regulate their tissue levels and effects on long-term blood pressure. (Hypertens Res 2000; 23 Suppl: S77-S85)