Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study

Siddiqui, Moneeza K; Kennedy, Gwen; Carr, Fiona; Doney, Alex S.F.; Pearson, Ewan R.; Morris, Andrew D.; Johnson, Toby; McLaughlin, Megan M.; Williams, R.; Palmer, Colin N.A.

doi:10.1007/s00125-018-4601-7

Cited by 23 publications

(27 citation statements)

References 37 publications

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“…We did not find an association between Lp‐PLA2 levels and prevalent or incident albuminuria in cross‐sectional or longitudinal analyses. Thus, although shown to be relevant as a marker of microvascular retinopathy in Type 1 diabetes , Lp‐PLA2 might not be a suitable marker for microvascular renal complications reflected by the surrogate marker albuminuria. Although albuminuria is a strong predictor of end‐stage kidney disease and cardiovascular morbidity in diabetes, it may not be the optimal surrogate marker for microvascular renal diseases, since albuminuria may be transient and some people with overt renal disease present with normoalbuminuria .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of lipoprotein‐associated phospholipase A2 as a marker for renal microvasculopathy in adolescents with Type 1 diabetes

et al. 2019

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Aim To assess the relevance of lipoprotein‐associated phospholipase A2 activity as a diagnostic and prognostic marker for renal microvascular diseases. Methods We analysed lipoprotein‐associated phospholipase A2 activity and lysophosphatidylcholine levels (as a surrogate marker of oxidative stress) in 165 adolescents (aged 17.0 ± 2.3 years) with a history of Type 1 diabetes greater than 10 years. Clinical data were obtained from the German/Austrian nationwide Diabetes‐Patients Follow‐up (DPV) registry at blood collection and on average 2.4 ± 1.3 years later at follow‐up. Relationships between lipoprotein‐associated phospholipase A2 activity and clinical, demographic and laboratory variables, lysophosphatidylcholine levels and presence of albuminuria were evaluated by multivariable linear and logistic regression. Results Lipoprotein‐associated phospholipase A2 activity was higher in male than female adolescents (P = 0.002). Albuminuria was present in 14% (22/158) of participants at baseline, and 5% (4/86) of participants without albuminuria at baseline developed albuminuria until follow‐up. Lipoprotein‐associated phospholipase A2 activity was associated neither with present nor with incident albuminuria. Lysophosphatidylcholine did not correlate with lipoprotein‐associated phospholipase A2 activity. Cross‐sectional bivariate correlation as well as multivariable linear regression analysis revealed a negative correlation of lipoprotein‐associated phospholipase A2 activity with HbA1c and HDL‐cholesterol. Conclusions Lipoprotein‐associated phospholipase activity was not associated with surrogate markers for oxidative stress and early diabetic nephropathy. The association of decreased lipoprotein‐associated phospholipase A2 activity with poor glucose control might limit its function as a predictor of micro‐ and macrovascular diseases in Type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

Evaluation of lipoprotein‐associated phospholipase A2 as a marker for renal microvasculopathy in adolescents with Type 1 diabetes

et al. 2019

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“…Furthermore, these associations were independent of the calculated LDL‐cholesterol and other traditional risk factors but were sensitive to the temporal proximity of death and retinopathy events to the time of serum collection and Lp‐PLA2 measurement. On the basis of these observations, the authors established that Lp‐PLA2 could be used to predict the incidence and progression of DR in a time‐sensitive manner …”

Section: Biological Functions and Disease Implicationsmentioning

confidence: 99%

“…In addition, the increase in Lp-PLA2 was correlated with the severity of DR. 191 Lp-PLA2 could be used to predict the incidence and progression of DR in a time-sensitive manner. 16 In a murine model of experimental autoimmune uveoretinitis (EAU), Lp-PLA2 ablation through gene knockout or a pharmacological inhibitor failed to modify the onset or progression of EAU. 192 On the other hand, deletion of Lp-PLA2 might have prevented pericyte loss and other signs of DR microvasculopathy in a recent study of diabetic PLA2G7 knockout mice.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…In particular, the IC 50 of compound 14 against rhLp-PLA2 was 0.4 nM. 241 Our group also developed two types of darapladib analogs through bioisosteric replacement of the amide group of darapladib with an imidazole (15) or a triazole (16). Following further optimization, we identified a number of orally bioactive Lp-PLA2 inhibitors in C57BL/6 mice.…”

Section: Pyrimidone Derivativesmentioning

confidence: 99%

“…Furthermore, lysoPC was recently demonstrated to induce the pericytes loss in the central nervous system (CNS), which is indicative of an injured blood‐brain barrier (BBB) . Because of the proinflammatory effects and high distribution in blood, together with the observation that elevated plasma Lp‐PLA2 levels were associated with a number of vascular diseases in epidemiological studies, the effect of Lp‐PLA2 inhibition on vascular diseases have been assessed in animal models and clinical trials. Unfortunately, darapladib, which was discovered by GlaxoSmithKline (GSK) and is the most advanced Lp‐PLA2 inhibitor in clinical trials, missed the primary endpoints in two phase III trials in atherosclerosis patients in 2014 .…”

Section: Introductionmentioning

confidence: 99%

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Lipoprotein‐associated phospholipase A2: The story continues

Huang

Wang

Shen

2019

Medicinal Research Reviews

109

140

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Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.

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Microvascular disease and heart failure with reduced and preserved ejection fraction in type 2 diabetes

et al. 2020

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Aims Identification of patients with type 2 diabetes (T2D) at increased risk of incident heart failure (HF) beyond traditional risk factors such as prior myocardial infarction (MI) might allow selection of patients who would benefit from preventative treatment. Microvascular disease (MiVD) is thought to play a pathophysiological role in the development of HF in T2D; however, its association with new-onset HF with reduced or preserved ejection fraction has not been specifically defined. Methods and results Patients in the Genetics of Diabetes Audit and Research Tayside Scotland study were linked to echocardiography, prescriptions, and clinical outcomes. In total, 9141 patients with T2D were identified for analysis. Clinical variables and the presence of retinopathy, nephropathy, and neuropathy were assessed. Cumulative incidence was calculated for the association of both individual and the total number of MiVD states and incident HF. Median follow-up was 9.3 years. In total, there were 900 HF events. The presence of any MiVD was independently associated with both HF with reduced ejection fraction (hazard ratio 1.40; 95% confidence interval 1.11-1.76, P = 0.004) and HF with preserved ejection fraction (hazard ratio 1.38; 95% confidence interval 1.10-1.72, P = 0.005), with a stepwise association between the number of MiVD states and risk of incident HF (P for trend <0.001). Similar associations were found in sensitivity analyses limited to patients without a prior MI, and using competing risks analysis. Conclusions Individuals with T2D and with MiVD are at risk of incident HF independent of a history of prior HF or MI. Patients with MiVD could benefit from screening for HF and individualized therapy with treatments that lower HF risk.

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Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study

Cited by 23 publications

References 37 publications

Evaluation of lipoprotein‐associated phospholipase A2 as a marker for renal microvasculopathy in adolescents with Type 1 diabetes

Evaluation of lipoprotein‐associated phospholipase A2 as a marker for renal microvasculopathy in adolescents with Type 1 diabetes

Lipoprotein‐associated phospholipase A2: The story continues

Microvascular disease and heart failure with reduced and preserved ejection fraction in type 2 diabetes

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