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BACKGROUND Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. OBJECTIVES In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. METHODS ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3–74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2–111.0 mg/dL). RESULTS In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [Cl]: 0.52–0.90) and 1.11 (95% Cl: 0.83–1.49), with treatment-lipoprotein(a) interaction on MACE ( P interaction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% Cl: 0.72–0.92) and 0.89 (95% Cl: 0.75–1.06), with P interaction = 0.43. CONCLUSIONS In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402 )

Experimentally induced hyperinsulinemia reduces serum adrenal androgen levels in man, but does not alter cortisol secretion. To determine whether insulin might selectively inhibit adrenal androgen production by suppressing 17,20-lyase activity, ACTH-stimulated androgen secretion was assessed in 10 normal men after an insulin infusion (hyperinsulinemic-euglycemic clamp) or a control saline infusion. For the insulin clamp study, each man received a 2-U (14.4-nmol) insulin bolus dose, followed by a 2.0-mU/kg.min (14.4-pmol/kg.min) insulin infusion for 5 h. An average insulin level of 746 +/- 35 (+/- SE) pmol/L was achieved; serum glucose was maintained at 4.96 +/- 0.03 mmol/L. At the end of the insulin infusion, an ACTH stimulation test was performed, and serum steroid levels were determined 30 and 60 min later. Subjects returned 1-3 weeks later for control studies, during which 0.45% saline was infused at rates matched exactly to the rates of the dextrose and insulin infusions during the insulin clamp studies, and an ACTH stimulation test was performed after 5 h of saline infusion. After the insulin infusion, stimulation by ACTH resulted in a significant rise in the serum molar ratio of 17 alpha-hydroxyprogesterone to androstenedione (from 0.914 +/- 0.110 at zero time to 1.388 +/- 0.278 60 min after ACTH; P less than 0.05), whereas no change occurred in the ACTH-stimulated ratio of these steroids after the saline infusion (1.067 +/- 0.109 at zero time to 1.060 +/- 0.109 60 min after ACTH; P = NS). The insulin-induced change in this steroid ratio was due to a relative increase in precursor (17 alpha-hydroxyprogesterone) and decrease in product (androstenedione) responsiveness to ACTH. Similarly, insulin treatment resulted in a greater than 100% rise in the difference from baseline in the serum molar ratio of 17 alpha-hydroxypregnenolone to dehydroepiandrosterone 30-60 min after ACTH (P less than 0.004), whereas no change in this difference was observed after the saline infusion (P = 0.71). Again, the insulin-induced change in this steroid ratio was due to a relative increase in precursor (17 alpha-hydroxypregnenolone) and decrease in product (dehydroepiandrosterone) responsiveness to ACTH. Of note, insulin treatment altered neither cortisol responsiveness to ACTH nor 17 alpha-hydroxylase activity, as indicated by similar ACTH-stimulated responses in the serum molar ratio of progesterone to 17 alpha-hydroxyprogesterone after the insulin and saline infusions (P = 0.71). Hence, the results of this study indicate that the acute elevation of serum insulin levels into the high physiological range selectively inhibits adrenal 17,20-lyase activity in man.

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The role of renal production of dopamine in mediating the natriuretic response to acute vascular volume expansion was investigated. The effect of infusion of 0.9% saline (30 ml/kg X h) over 2 h on urine excretion of sodium and catecholamines, as well as other hemodynamic and renal function parameters, was examined in seven dogs during control and carbidopa (1 mg/kg every 8 h for 24 h before saline infusion) treatment periods. Acute vascular volume expansion with saline resulted in a rise (P less than 0.01) in the renal excretion of dopamine and a depression (P less than 0.01) in renal excretion of norepinephrine which paralleled the natriuretic response to saline infusion. Epinephrine excretion was not altered by saline infusion. Carbidopa treatment was not associated with changes in left ventricular filling pressure, arterial blood pressure, glomerular filtration rate, renal blood flow, renal excretion of norepinephrine or epinephrine. However, carbidopa eliminated the increase in renal production of dopamine and markedly attenuated the natriuretic response to saline infusion. Since carbidopa blocks tissue conversion of dopa to dopamine, it appears that renal production of dopamine is an important mechanism mediating the natriuretic response to acute volume expansion.