LPA VARIANTS, RISK OF CORONARY DISEASE, AND ESTIMATED CLINICAL BENEFIT OF LIPOPROTEIN(A) LOWERING THERAPIES: A MENDELIAN RANDOMIZATION ANALYSIS

Importance: Human genetic studies have indicated that plasma lipoprotein(a) [Lp(a)] is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) by 25-35% have not provided any evidence that lowering Lp(a) reduces CHD risk. Objective: To estimate the magnitude of the change in plasma Lp(a) needed to have the same effect on CHD risk as a 1 mmol/L (38.67 mg/dL) change in LDL-C, a change in LDL-C that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design: Meta-analysis of Mendelian randomization studies conducted using individual participant data from 5 studies; with external validation using summarized data from 48 studies. Setting: Population based prospective cohort and case-control studies. Participants: 20,793 CHD cases and 27,540 controls with individual participant data; 62,240 CHD cases and 127,299 controls with summarized data. Exposure: Genetic Lp(a) score and plasma Lp(a) mass concentration. Main outcomes and measures: Coronary heart disease. Results: The causal effect of Lp(a) on CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10 mg/dL lower genetically-predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR]: 0.942; 95% CI, 0.933–0.951; p=3×10-37), whereas a 10 mg/dL lower genetically-predicted LDL-C estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (0.855; 0.818–0.893; p=2×10-12). Thus, a 101.5 mg/dL (95% CI: 71.0–137.0) change in Lp(a) had the same effect on CHD risk as a 1 mmol/L change in LDL-C. The effect of Lp(a) on CHD risk appeared to be independent of changes in LDL-C due to genetic variants that mimic the effect of statins, PCSK9 inhibitors and ezetimibe. Conclusions and relevance: Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to a produce clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C by 1 mmol/L. Therefore, only people with very high plasma Lp(a) concentration are likely to derive a clinical benefit from therapies that lower Lp(a)

Association of LPA variants with risk of coronary disease and the implications for Lipoprotein(a)-lowering therapies: a mendelian randomization analysis

Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.Genetic LPA score and plasma Lp(a) mass concentration.Coronary heart disease.Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L)

Association of LPA variants with risk of coronary disease and the implications for Lipoprotein(a)-lowering therapies: a mendelian randomization analysis

Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.Genetic LPA score and plasma Lp(a) mass concentration.Coronary heart disease.Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L)

Pathology in Primary Progressive Aphasia Syndromes

'Primary progressive aphasia' (PPA) refers to core linguistic disorders caused by neurodegenerative disease. Three main PPA variants are recognized: nonfluent/agrammatic, semantic and logopenic. Correctly classifying patients during life according to the underlying histopathology will become increasingly important as cause-specific treatments become available. This article reviews clinical and histopathological studies of PPA, with particular reference to updated PPA classifications. Currently, one-to-one relationships do not exist within PPA subtypes. The semantic variant has the best correspondence between the clinical syndrome and the underlying pathological cause and the logopenic variant the worst correspondence. The use of future biomarkers should facilitate accurate clinicopathological correlation of patients during life