To investigate the effect of obesity and bariatric-induced weight loss on circulating levels of proprotein convertase subtilisin/kexin 9 (PCSK9) in severely obese patients.
In this non-randomized ...interventional study, we enrolled 36 severely obese patients (BMI 43.7 ± 5.6 kg/m2), of which 20 underwent bariatric surgery, and 12 nonobese healthy controls. An oral glucose tolerance test (75-g OGTT) was performed in 31 of these obese patients at baseline (T0) and in 14 patients at 6 months after bariatric surgery (T6) to assess plasma glucose, insulin and PCSK9 levels. Plasma PCSK9 levels were also measured in 18 of these obese patients at T0 during a 2-h hyperinsulinemic-euglycemic clamp (HEC).
At T0, PCSK9 levels were higher in obese patients than in controls (274.6 ± 76.7 ng/mL vs. 201.4 ± 53.3 ng/mL) and dropped after bariatric surgery (T6; 205.5 ± 51.7 ng/mL) along with BMI (from 44.1 ± 5.9 kg/m2 to 33.1 ± 5.6 kg/m2). At T6, there was also a decrease in plasma glucose (T0 vs. T6: 6.0 ± 1.8 vs. 5.0 ± 0.5 mmol/L) and insulin (15.7 ± 8.3 vs. 5.4 ± 2.1 mU/L) levels. At T0, plasma PCSK9 levels decreased during OGTT in obese patients, reaching a nadir of 262.0 ± 61.4 ng/mL at 120 min with a hyperinsulinemic peak of 75.1 ± 40.0 mU/L, at 60 min. Similarly, at T0 insulin infusion during 2-h HEC acutely reduced plasma PCSK9 levels in obese patients. The aforementioned OGTT-induced changes in plasma PCSK9 levels were not observed neither in nonobese healthy controls nor in obese patients after bariatric-surgery weight loss.
These results suggest a pivotal role of adipose tissue and insulin resistance on PCSK9 homeostasis in severely obese patients.
•Severely obese patients have higher plasma PCSK9 levels than nonobese control subjects.•Bariatric surgery-induced weight loss markedly improved insulin resistance and normalized plasma PCSK9 levels.•PCSK9 plasma levels decline both during OGTT and HEC.•Adipose tissue and associated insulin resistance plays a role on PCSK9 clearance and/or turnover.
Background
The independent prognostic impact of diabetes mellitus (DM) and prediabetes mellitus (pre‐DM) on survival outcomes in patients with chronic heart failure has been investigated in ...observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre‐DM on survival outcomes in the GISSI‐HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure) trial.
Methods and Results
We assessed the risk of all‐cause death and the composite of all‐cause death or cardiovascular hospitalization over a median follow‐up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI‐HF trial, who were stratified by presence of DM (n=2852), pre‐DM (n=2013), and non‐DM (n=2070) at baseline. Compared with non‐DM patients, those with DM had remarkably higher incidence rates of all‐cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non‐DM patients and those with pre‐DM. Cox regression analysis showed that DM, but not pre‐DM, was associated with an increased risk of all‐cause death (adjusted hazard ratio, 1.43; 95% CI, 1.28–1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI, 1.13–1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all‐cause death: adjusted hazard ratio, 1.21; 95% CI, 1.02–1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI, 1.01–1.29, respectively).
Conclusions
Presence of DM was independently associated with poor long‐term survival outcomes in patients with chronic heart failure.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.
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