BACKGROUNDBococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODSIn two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTSAt 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of −56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs.

OBJECTIVEDiabetes prevalence and incidence increase among individuals with hypothyroidism but also among those with hyperthyroxinemia, which seems contradictory. Both high free thyroxine (fT4) and high thyroid-stimulating hormone (TSH) are present in the resistance to thyroid hormone syndrome. A mild acquired resistance to thyroid hormone might occur in the general population and be associated with diabetes. We aimed to analyze the association of resistance to thyroid hormone indices (the Thyroid Feedback Quantile-based Index [TFQI], proposed in this work, and the previously used Thyrotroph T4 Resistance Index and TSH Index) with diabetes. RESEARCH DESIGN AND METHODSWe calculated the aforementioned resistance to thyroid hormone indices based on a U.S. representative sample of 5,129 individuals ‡20 years of age participating in the 2007-2008 National Health and Nutrition Examination Survey (NHANES). Also, to approximate TFQI, a U.S.-referenced Parametric TFQI (PTFQI) can be calculated with the spreadsheet formula 5NORM.DIST(fT4_cell_in_pmol_per_L,10.075, 2.155,TRUE)1NORM.DIST(LN(TSH_cell_in_mIU_per_L),0.4654,0.7744,TRUE)21. Outcomes of interest were glycohemoglobin ‡6.5%, diabetes medication, diabetes-related deaths (diabetes as contributing cause of death), and additionally, in a fasting subsample, diabetes and metabolic syndrome. Logistic and Poisson regressions were adjusted for sex, age, and race/ethnicity. RESULTSOdd ratios for the fourth versus the first quartile of TFQI were 1.73 (95% CI 1.32, 2.27) (P trend 5 0.002) for positive glycohemoglobin and 1.66 (95% CI 1.31, 2.10) (P trend 5 0.001) for medication. Diabetes-related death rate ratio for TFQI being above versus below the median was 4.81 (95% CI 1.01, 22.94) (P trend 5 0.015). Further adjustment for BMI and restriction to normothyroid individuals yielded similar results. Per 1 SD in TFQI, odds increased 1.13 (95% CI 1.02, 1.25) for diabetes and 1.16 (95% CI 1.02, 1.31) for metabolic syndrome. The other resistance to thyroid hormone indices showed similar associations for diabetes-related deaths and metabolic syndrome. CONCLUSIONSHigher values in resistance to thyroid hormone indices are associated with obesity, metabolic syndrome, diabetes, and diabetes-related mortality. Resistance to thyroid hormone may reflect energy balance problems driving type 2 diabetes. These indices may facilitate monitoring treatments focused on energy balance.