In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.
Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).
OBJECTIVETo determine the relative contributions of basal hyperglycemia (BHG) versus postprandial hyperglycemia (PPHG) before and after treatment intensification in patients with glycated hemoglobin A1c (A1C) >7.0% while on prior oral therapy.RESEARCH DESIGN AND METHODSSelf-measured, plasma-referenced glucose profiles and A1C values were evaluated from participants in six studies comparing systematically titrated insulin glargine with an alternative regimen (adding basal, premixed, or prandial insulin, or increasing oral agents). Hyperglycemic exposure (>100 mg/dL [5.6 mmol/L]) as a result of BHG versus PPHG was calculated.RESULTSOn prior oral therapy, 1,699 participants (mean age 59 years, diabetes duration 9 years) had mean fasting plasma glucose (FPG) of 194 mg/dL (10.8 mmol/L), and mean A1C was 8.7%. BHG contributed an average of 76–80% to hyperglycemia over the observed range of baseline A1C levels. Adding basal insulin for 24 or 28 weeks lowered mean FPG to 117 mg/dL (6.5 mmol/L), A1C to 7.0%, and BHG contribution to 32–41%. Alternative regimens reduced FPG to 146 mg/dL (8.1 mmol/L), A1C to 7.1%, and the contribution of BHG to 64–71%. BHG contributions for patients with A1C averaging 7.6–7.7% were 76% at baseline and 34 and 68% after adding basal insulin or other therapies, respectively.CONCLUSIONSWhen A1C is >7.0% despite oral therapy, BHG routinely dominates exposure. Intensified therapy reduces A1C and changes this relationship, but BHG amenable to further intervention still accounts for one-third of total hyperglycemia after basal insulin treatment and two-thirds after alternative methods.
Objective-Pharmacological inhibition of the cholesteryl ester transfer protein (CETP) in humans increases high-density lipoprotein (HDL) cholesterol (HDL-C) levels; however, its effects on apolipoprotein A-I (apoA-I) containing HDL subspecies, apoA-I turnover, and markers of reverse cholesterol transport are unknown. The present study was designed to address these issues. Methods and Results-Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor torcetrapib (120 mg QD) for 4 weeks. In 6 subjects from the nonatorvastatin cohort, the everyday regimen was followed by a 4-week period of torcetrapib (120 mg BID). At the end of each phase, subjects underwent a primed-constant infusion of (5,5,5-2 H 3 )-L-leucine to determine the kinetics of HDL apoA-I. The lipid data in this study have been reported previously. Relative to placebo, 120 mg daily torcetrapib increased the amount of apoA-I in ␣1-migrating HDL in the atorvastatin (136%; PϽ0.001) and nonatorvastatin (153%; PϽ0.01) cohorts, whereas an increase of 382% (PϽ0.01) was observed in the 120 mg twice daily group. HDL apoA-I pool size increased by 8Ϯ15% in the atorvastatin cohort (Pϭ0.16) and by 16Ϯ7% (PϽ0.0001) and 34Ϯ8% (PϽ0.0001) in the nonatorvastatin 120 mg QD and BID cohorts, respectively. These changes were attributable to reductions in HDL apoA-I fractional catabolic rate (FCR), with torcetrapib reducing HDL apoA-I FCR by 7% (Pϭ0.10) in the atorvastatin cohort, by 8% (PϽ0.001) in the nonatorvastatin 120 mg QD cohort, and by 21% (PϽ0.01) in the nonatorvastatin 120 mg BID cohort. Torcetrapib did not affect HDL apoA-I production rate. In addition, torcetrapib did not significantly change serum markers of cholesterol or bile acid synthesis or fecal sterol excretion. Conclusions-These data indicate that partial inhibition of CETP via torcetrapib in patients with low HDL-C: (1) normalizes apoA-I levels within ␣1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) pidemiologic studies have consistently demonstrated that plasma concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are inversely correlated with the incidence of coronary heart disease (CHD). 1-3 Clinical trial results indicate that even modest increases in HDL cholesterol (HDL-C) concentrations can significantly reduce CHD risk. 4 -5 However, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, have only modest effects on HDL-C levels, raising them on average by 5% to 10%. 6 Although fibrates and niacin can raise HDL-C levels, the increases in HDL-C are rarely Ͼ25%, and niacin is often not well tolerated.Among the alternative HDL-raising strategies actively being explored is cholesteryl ester transfer protein (CETP) inhibition. 7 CETP is a plasma glycoprotein that facilitates the transfer of cholesteryl esters (CEs) from HDL to apoBcontaining lipoproteins. 8,9 Humans with CETP deficiency attributab...
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