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Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark
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Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Objective
Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2–PAPP-A–IGFBP4–IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D).
Design
We followed 1284 participants with T2D from the ADDITION trial for 5 years.
Methods
Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model.
Results
During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09–3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98–3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11–1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91–4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16–2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34–0.76); P = 0.001.
Conclusions
This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A–IGF1 axis.
Significance statement
PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2–PAPP-A–IGFBP4–IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2–PAPP-A–IGFBP4–IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.
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Background
Evidence on the efficacy and safety of anticoagulation in preventing stroke and thromboembolic events in people with thyrotoxic atrial fibrillation is scarce.
Objective
We evaluated the efficacy and safety of anticoagulation in people with thyrotoxic atrial fibrillation.
Methods
Our study protocol was published in the International Prospective Register of Systematic Reviews (registration no. CRD42020222782). Four databases and two systematic review registers were searched through 25 November 2020 for interventional and observational studies comparing anticoagulation therapy with active comparators, placebo, or no treatment in people with thyrotoxic atrial fibrillation. Random-effects meta-analysis and sensitivity analysis were performed. Quality of evidence was described using the GRADE framework.
Results
In the study, 23,145 records were retrieved. One randomized controlled trial and eight cohort studies were ultimately included. Effect estimates on the efficacy and safety of anticoagulation were extracted. Meta-analysis using the inverse variance and random-effects methods was conducted on four cohort studies with 3443 participants and 277 events. Anticoagulation in people with thyrotoxic atrial fibrillation reduced the risk of ischemic stroke and systemic thromboembolism by 3% (95% CI: 1–6%). Warfarin may prevent ischemic stroke in people with thyrotoxic atrial fibrillation if the CHA2DS2-VASc score exceeds 1 and when atrial fibrillation persists beyond 7 days. Direct oral anticoagulants may be associated with fewer bleeding events than warfarin.
Conclusions
Anticoagulation prevents ischemic stroke and systemic thromboembolism in people with thyrotoxic atrial fibrillation. Direct oral anticoagulants may be associated with fewer bleeding events.
