Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Gregory G Schwartz; Michael Szarek; Vera A Bittner; Deepak L Bhatt; Rafael Diaz; Shaun G Goodman; J Wouter Jukema; Megan Loy; Garen Manvelian; Robert Pordy; Harvey D White; Philippe Gabriel Steg

doi:10.2337/dc20-2842

. 2021 Mar 15;44(5):1219–1227. doi: 10.2337/dc20-2842

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Gregory G Schwartz ^1,^✉, Michael Szarek ^1,^2,³, Vera A Bittner ⁴, Deepak L Bhatt ⁵, Rafael Diaz ⁶, Shaun G Goodman ^7,⁸, J Wouter Jukema ⁹, Megan Loy ¹⁰, Garen Manvelian ¹¹, Robert Pordy ¹¹, Harvey D White ¹², Philippe Gabriel Steg, for the ODYSSEY OUTCOMES Committees and Investigators^13,^14,¹⁵

PMCID: PMC8132323 PMID: 33722880

Abstract

OBJECTIVE

In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.

RESEARCH DESIGN AND METHODS

In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.

RESULTS

Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02−1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment–baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03−1.12; P = 0.0002) for incident type 2 diabetes.

CONCLUSIONS

In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.

Introduction

Lipoprotein(a) is an LDL particle whose concentration is primarily under genetic control and is believed to have atherogenic, proinflammatory, and prothrombotic properties (1). Epidemiologic and genetic studies show an association of elevated lipoprotein(a) concentration with the risk of coronary, peripheral artery, and cerebrovascular disease events (2–4).

For many years, no pharmacologic therapy was identified that both lowered lipoprotein(a) concentration and reduced the risk of major adverse cardiovascular events (MACE). This changed with the advent of inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9). These agents reduce the concentration of LDL cholesterol (LDL-C) substantially (by 50−60%), reduce the concentration of lipoprotein(a) modestly (by 20−25%), and reduce MACE (5,6). In large placebo-controlled trials that evaluated PCSK9 inhibitors, the risk of MACE among patients assigned to placebo was associated with lipoprotein(a) concentration (7–10) and reduction in the risk of MACE with the PCSK9 inhibitor alirocumab was associated with the magnitude of lipoprotein(a) reduction (7,10). Pharmacologic agents under development that inhibit the synthesis of apolipoprotein(a) may reduce lipoprotein(a) concentration by >70% and are being evaluated for effects on MACE (11,12).

An unexplained observation in cohort studies and clinical trials has been an association of lower lipoprotein(a) levels with greater prevalence of type 2 diabetes (13–15). Some genetic and observational cohort studies in populations without evident cardiovascular disease have also shown an association of lower levels of lipoprotein(a) with greater incidence of diabetes (13,16–18). To date, an association between lower levels of lipoprotein(a) and incident diabetes has not been demonstrated in patients with established cardiovascular disease. Importantly, to date there has been no evidence to indicate whether the incidence of diabetes is modulated by pharmacologic therapy that lowers lipoprotein(a).

In this analysis, we determined whether the incidence of diabetes was related to lipoprotein(a) concentration in patients with recent acute coronary syndrome and whether that risk was modulated by treatment with alirocumab.

Research Design and Methods

Patients and Treatments

This report is a post hoc analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) (clinicaltrials.gov, NCT01663402) (6,19), which compared the effects of alirocumab or placebo in 18,924 patients with recent acute coronary syndrome and persistent dyslipidemia despite intensive or maximum tolerated statin treatment. The protocol was approved by the institutional review board at each site, and all patients provided informed consent. Qualifying patients were hospitalized for acute myocardial infarction or unstable angina 1−12 months prior to randomization and had LDL-C ≥70 mg/dL, non-HDL cholesterol ≥100 mg/dL, or apolipoprotein B ≥80 mg/dL despite treatment with atorvastatin 40−80 mg daily, rosuvastatin 20−40 mg daily, or the highest tolerated dose of one of these statins. Lipoprotein(a) concentration was not considered in qualification. Qualifying patients were randomized in a 1:1 ratio to receive alirocumab 75 mg or matching placebo, administered subcutaneously every 2 weeks. As previously described (19), the alirocumab dose was blindly titrated between 75 and 150 mg for maximization of the number of patients who achieved an LDL-C level of 25–50 mg/dL or blindly replaced by placebo in cases of sustained LDL-C levels <15 mg/dL. Participants and physicians were blinded to the treatment allocation. For protection of the blind, all treatment kit boxes had the same look and feel and were labeled with a double-blind label. Details on randomization procedures are described in supplementary material. The primary outcome of MACE comprised death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.

Definition of Baseline and Incident Diabetes

Classification of patients according to presence of diabetes at baseline and criteria for incident diabetes after randomization have previously been published (20). In brief, diabetes was considered present at baseline if there was a medical history of type 1 or type 2 diabetes, treatment with an antihyperglycemic medication, hemoglobin A_1c at least 6.5% (48 mmol/mol), or fasting plasma glucose at least 126 mg/dL. The primary end point in this analysis was incident diabetes in those without diabetes at baseline. Incident diabetes was adjudicated by a blinded panel of expert physicians based on adverse events indicating new type 1 or type 2 diabetes, initiation of antihyperglycemic medication, two measurements of hemoglobin A_1c at least 6.5% (unless only one measurement was available or only the last value was at least 6.5%), or two measurements of fasting plasma glucose at least 126 mg/dL.

Measurement of Lipoproteins

Plasma lipids, including LDL-C and lipoprotein(a), were measured at baseline and at specified time points thereafter. LDL-C was calculated by the Friedewald formula unless levels were <15 mg/dL or the accompanying triglyceride concentration was >400 mg/dL; in those cases, LDL-C was measured by β quantification. Lipoprotein(a) mass was measured per protocol at baseline, month 4, and month 12 with an automated immunoturbidimetric assay on a Siemens BNII nephelometric analyzer (Siemens Healthcare Diagnostics, Malvern, PA) with a lower limit of detection of 2 mg/dL and an interassay coefficient of variation of 3.1–4.8% depending on the lipoprotein(a) concentration. Heterogeneity in apolipoprotein(a) size has only a moderate effect on lipoprotein(a) recovery with this assay (21). Calculated or measured LDL-C includes the concentration of cholesterol contained in lipoprotein(a). To account for this, we calculated LDL-C corrected for lipoprotein(a) cholesterol as LDL-C_corrected = LDL-C – [lipoprotein(a) × 0.3] (22,23).

Statistical Analysis

Median (quartile 1–3) baseline lipoprotein(a) was compared in patients with or without diabetes at baseline and by baseline quartile among patients without diabetes at baseline. Levels below the lower limit of detection were assigned a value of 2 mg/dL.

The probability of new-onset (incident) type 2 diabetes during follow-up as a function of baseline lipoprotein(a) as a spline effect of degree 3 (piecewise cubic curve) was estimated for each treatment group by logistic regression with a logit link function and the logarithm of follow-up time as an offset variable in the models. Additionally, the relative treatment effects on incident type 2 diabetes overall and as a function of baseline lipoprotein(a) were estimated in competing risks proportional hazards models, where death was treated as a competing terminal event. These relative relationships were also determined after adjustment for variables associated with lipoprotein(a) concentration including sex, race, geographical region, and plasma triglycerides. To determine whether assigned treatment (alirocumab or placebo) modified the relationship of baseline lipoprotein(a) with the relative risk of type 2 diabetes, P values for interaction were calculated.

Incident type 2 diabetes (cases per 100 patient-years of observation) was also determined in each treatment group according to baseline quartile of lipoprotein(a). Treatment hazard ratios (alirocumab/placebo) for incident type 2 diabetes were calculated in each baseline lipoprotein(a) quartile in competing risks models, and P_trend was calculated.

The change in lipoprotein(a) concentration from baseline to month 4 and month 12 of assigned treatment with alirocumab was calculated. Within the alirocumab group, that change was related to the subsequent risk of incident type 2 diabetes as a time-varying covariate in Cox regression models [hazard ratio per 10 mg/dL decrease in lipoprotein(a)] with death as a competing terminal event. The following models were developed: model 1, without covariates; model 2, adjusted for baseline lipoprotein(a); and model 3, additionally adjusted for demographic and clinical variables (sex, race, and geographic region; baseline statin treatment intensity, BMI, triglycerides, hemoglobin A_1c, and LDL-C_corrected; and time-varying change in LDL-C_corrected from baseline to month 4 and month 12).

In patients with diabetes at baseline, we determined whether changes from baseline to month 12 in hemoglobin A_1c and fasting serum glucose were influenced by baseline lipoprotein(a) concentration. There was no imputation for missing hemoglobin A_1c or glucose values.

Comparisons of independent groups were by Wilcoxon rank-sum tests for continuous variables and χ² tests for categorical variables. For all analyses, two-tailed P values <0.05 were considered statistically significant, with no adjustment for multiple testing. All analyses were conducted according to intention to treat, including all patients and events from randomization to the common study end date (11 November 2017). Analyses were performed in SAS, version 9.4 (IBM, Armonk, NY).

Results

Patient Characteristics and Association With Baseline Lipoprotein(a) Concentration

A total of 18,924 patients underwent randomization at 1,315 sites in 57 countries (Supplementary Table 1). Of these, 9,462 were assigned to alirocumab and 9,462 to placebo. In consideration of all trial participants, quartile boundaries for baseline lipoprotein(a) were 6.7, 21.2, and 59.6 mg/dL. The prevalence of diabetes decreased across increasing baseline lipoprotein(a) quartiles (30.7%, 29.0%, 29.0%, and 26.5%; P_trend = 0.0001).

At baseline, diabetes was present in 5,444 (28.8%) patients (n = 37 with type 1 diabetes) and not present in 13,480 patients (71.2%). Table 1 shows the characteristics of those with diabetes at baseline and by quartile of baseline lipoprotein(a) for those without diabetes at baseline. LDL-C and LDL-C_corrected did not differ in patients with or without diabetes at baseline, and neither did the use of intensive statin therapy. However, baseline lipoprotein(a) concentration was lower among those with diabetes (median 19.5 mg/dL [quartile 1–3 6.2–55.0]) in comparison with those without diabetes at baseline (21.9 mg/dL [6.9–61.1]; P < 0.0001). Among patients without diabetes at baseline, higher baseline quartile of lipoprotein(a) was associated with characteristics including female sex, black race, enrollment in North America, absence of current smoking, higher LDL-C, lower LDL-C_corrected, and lower triglycerides.

Table 1.

Baseline characteristics in patients with and patients without diabetes at baseline and according to quartile of lipoprotein(a) in patients without diabetes at baseline

Characteristic	Diabetes at baseline (n = 5,444)	No diabetes at baseline
Characteristic	Diabetes at baseline (n = 5,444)	All (n = 13,480)	Quartile 1 (<6.9 mg/dL) (n = 3,370)	Quartile 2 (6.9 to <21.9 mg/dL) (n = 3,370)	Quartile 3 (21.9 to <61.1 mg/dL) (n = 3,363)	Quartile 4 (≥61.1 mg/dL) (n = 3,377)	P ^†	P ^*
Age, years	59 (53–66)	58 (51–65)	58 (51–65)	58 (52–65)	58 (51–65)	58 (51–64)	0.36	<0.0001
Female sex	31.9	22.4	18.0	21.2	21.9	28.6	<0.0001	<0.0001
Race
White	71.6	82.5	86.4	83.1	79.0	81.6	<0.0001	<0.0001
Black	3.7	2.0	0.6	0.7	2.6	4.1
Asian	19.2	10.8	8.2	11.7	13.9	9.4
Other	5.5	4.7	4.8	4.4	4.5	4.9
Geographic region
Western Europe	14.9	25.0	24.3	23.8	25.9	25.9	<0.0001	<0.0001
Eastern Europe	26.0	29.8	37.1	31.5	26.8	24.0
North America	17.8	14.1	11.2	12.3	14.1	18.8
South America	15.0	13.1	13.3	13.4	11.5	14.3
Asia	17.2	10.1	7.8	11.0	12.9	8.5
Rest of world	9.1	7.9	6.4	8.0	8.7	8.5
Current smoking	20.1	25.7	27.7	27.1	25.0	23.0	<0.0001	<0.0001
High-intensity statin	87.9	89.2	89.1	87.9	88.6	91.3	0.0006	0.03
ACE inhibitor or ARB	81.9	76.1	77.0	76.4	75.7	75.3	0.35	<0.0001
β-Blocker	85.9	84.0	84.7	83.5	83.3	84.3	0.35	0.0009
BMI, kg/m²	29 (26–33)	28 (25–30)	28 (25–31)	28 (25–30)	27 (25–30)	27 (25–30)	<0.0001	<0.0001
Fasting blood glucose, mmol/L	7.4 (6.2–9.4)	5.4 (5.0–5.8)	5.5 (5.1–5.9)	5.4 (5.1–5.8)	5.4 (5.0–5.8)	5.4 (5.0–5.8)	<0.0001	<0.0001
Hemoglobin A_1c							0.72	<0.0001
%	7.0 (6.5–8.2)	5.7 (5.4–5.9)	5.7 (5.4–5.9)	5.7 (5.5–5.9)	5.7 (5.5–5.9)	5.7 (5.4–5.9)
mmol/mol	53 (48–66)	39 (36–41)	39 (36–41)	39 (37–41)	39 (37–41)	39 (36–41)
LDL-C, mg/dL	85 (71–103)	87 (74–104)	84 (70–101)	85 (72–102)	87 (74–104)	92 (79–109)	<0.0001	<0.0001
LDL-C_corrected, mg/dL	74 (59–93)	76 (61–94)	83 (69–100)	81 (68–98)	75 (62–92)	61 (48–78)	<0.0001	0.0006
HDL-C, mg/dL	41 (35–48)	43 (37–51)	43 (37–51)	43 (37–51)	44 (37–51)	44 (37–52)	0.21	<0.0001
Triglycerides, mg/dL	148 (106–204)	124 (90–171)	136 (96–189)	123 (90–172)	119 (88–162)	119 (88–161)	<0.0001	<0.0001
Lipoprotein(a), mg/dL	19.5 (6.2–55.0)	21.9 (6.9–61.1)	2.0 (2.0–4.9)	12.6 (9.6–16.6)	39.0 (29.5–49.6)	93.8 (74.6–121.0)	<0.0001	<0.0001
Estimated glomerular filtration rate, mL/min per 1.73 m²	77.6 (64.1–91.7)	78.2 (68.3–89.7)	78.5 (68.5–90.4)	78.2 (68.5–89.3)	78.5 (68.3–90.1)	77.9 (68.1–89.7)	0.15	0.0011

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Data are percentages or (for continuous variables) median (quartile 1–3). ARB, angiotensin receptor blocker; HDL-C, HDL cholesterol; LDL-C_corrected, LDL cholesterol corrected for cholesterol content of lipoprotein(a).

P values for comparison of characteristic between patients with diabetes at baseline and all patients without diabetes at baseline.

^†

P values for comparison across lipoprotein(a) quartiles in patients without diabetes at baseline.

Incident Type 2 Diabetes, According to Baseline Lipoprotein(a) Concentration, and Effect of Alirocumab Treatment

Median follow-up for incident diabetes was 2.7 years (quartile 1–3 2.2–3.4). Overall, 1,324 patients developed diabetes during the trial (all type 2), of whom 648 were assigned to alirocumab and 676 to placebo, corresponding to a treatment hazard ratio of 0.95 (95% CI 0.85–1.05) with death as a competing event. Supplementary Table 2 shows the criteria that were fulfilled for the diagnosis of incident type 2 diabetes in each treatment group.

Figure 1 shows incident type 2 diabetes by treatment group according to splines of continuous baseline lipoprotein(a) among those without diabetes at baseline. In the placebo group, decreasing baseline lipoprotein(a) was associated with increasing risk of incident type 2 diabetes. In proportional hazards models, each 10 mg/dL decrease in baseline lipoprotein(a) concentration was associated with a hazard ratio of 1.04 (95% CI 1.02−1.06; P < 0.0001) in unadjusted analysis and a hazard ratio of 1.03 (95% CI 1.01−1.05; P = 0.0024) in adjusted analysis. In contrast, in the alirocumab group the incidence rate for type 2 diabetes was essentially constant across the range of baseline lipoprotein(a), with a hazard ratio of 1.00 (95% CI 0.98−1.02; P = 0.96) per 10 mg/dL decrease in baseline lipoprotein(a) in unadjusted and 1.00 (95% CI 0.98−1.01; P = 0.56) in adjusted analysis. Treatment assignment significantly modified the relationship between baseline lipoprotein(a) and incident type 2 diabetes with P_interaction = 0.003 in unadjusted analysis and P_interaction = 0.006 with adjustment for baseline characteristics. As shown in Fig. 1, the crossover point of the spline curves was at a baseline lipoprotein(a) level of 50 mg/dL. Thus, in patients with baseline lipoprotein(a) <50 mg/dL the estimated incidence of type 2 diabetes was lower with alirocumab than placebo. In contrast, in patients with baseline lipoprotein(a) ≥50 mg/dL the estimated incidence of type 2 diabetes was higher with alirocumab than placebo.

Spline analysis of probability of incident type 2 diabetes by baseline lipoprotein(a) [Lp(a)] and treatment group. The probability of incident type 2 diabetes during follow-up is shown as a function of baseline lipoprotein(a) for each treatment group, estimated from a logistic regression model with a logit link function, the logarithm of follow-up time as an offset variable, and adjustment for race, current smoking, and baseline BMI and triglyceride level. Spline effect is a piecewise cubic curve with degree = 3 with knots at quartiles of baseline lipoprotein(a). Spline effect P = 0.0002 for placebo group, P = 0.82 for alirocumab group. The interaction P value of treatment and baseline lipoprotein(a) on incident type 2 diabetes (P_interaction) was 0.003 unadjusted and 0.006 adjusted for the baseline characteristics indicated above.

Similar findings were derived from analysis by baseline quartile of lipoprotein(a) (Fig. 2). In the placebo group, the incidence rate of type 2 diabetes (cases per 100 patient-years) decreased monotonically from 4.6 (95% CI 4.0–5.2) in quartile 1 to 3.6 (95% CI 3.1−4.2) in quartile 2, 3.5 (95% CI 3.0−4.1) in quartile 3, and 3.1 (95% CI 2.6–3.6) in quartile 4 (P_trend = 0.0003) (Fig. 2, left panel). In contrast, in the alirocumab group there was no apparent relationship between baseline lipoprotein(a) quartile and incident type 2 diabetes, with incidences of 3.6 (95% CI 3.1–4.2), 3.3 (95% CI 2.8−3.9), 3.7 (95% CI 3.1−4.3), and 3.4 (95% CI 2.9−3.9) in quartiles 1−4, respectively (P_trend = 0.70). The treatment hazard ratio (alirocumab:placebo) for incident type 2 diabetes increased monotonically across baseline lipoprotein(a) quartiles, from 0.79 (95% CI 0.64–0.96) in quartile 1 to 1.09 (95% CI 0.87–1.38) in quartile 4 (P_trend = 0.025) (Fig. 2, right panel).

Incidence rate for type 2 diabetes by baseline lipoprotein(a) [Lp(a)] quartile and treatment with placebo or alirocumab. Left panel: incidence rates for type 2 diabetes by treatment group and quartile of baseline lipoprotein(a) for patients without diabetes at baseline (total n = 13,480). Baseline lipoprotein(a) quartile ranges are: quartile 1, <6.9 mg/dL; quartile 2, 6.9 to <21.9 mg/dL; quartile 3, 21.9 to <61.1 mg/dL; and quartile 4, ≥61.1 mg/dL. In the placebo group, increasing quartile of baseline lipoprotein(a) was associated with decreasing incidence rate for type 2 diabetes (P_trend = 0.0003). Right panel: Forest plot depicting treatment hazard ratio (HR) (95% CI) for incident type 2 diabetes by quartile of baseline lipoprotein(a). The point estimate for the treatment hazard ratio increased monotonically from baseline lipoprotein(a) quartile 1 to quartile 4 (P_trend = 0.025).

MACE in Patients Without Diabetes at Baseline According to Baseline Lipoprotein(a) Concentration

Among all trial participants, the primary MACE outcome occurred in 1,052 patients (11.1%) treated with placebo versus 903 patients (9.5%) treated with alirocumab (P < 0.001). Among patients without diabetes at baseline assigned to placebo, the 3-year incidence of MACE in baseline lipoprotein(a) quartiles 1−4 was 7.7%, 9.9%, 9.8%, and 12.1%, respectively. Among patients without diabetes at baseline assigned to alirocumab, 3-year incidence of MACE in baseline lipoprotein(a) quartiles 1−4 was 7.5%, 8.2%, 7.6%, and 10.4%. Thus, the risk of MACE was lower with alirocumab than placebo in each baseline lipoprotein(a) quartile, particularly in quartiles 2−4.

Lipoprotein(a) Lowering by Alirocumab and Its Association With Incident Type 2 Diabetes

Among patients without diabetes at baseline, alirocumab reduced lipoprotein(a) from baseline to month 4 by a median of 23.2% (quartile 1–3 −45.8 to 0), with the absolute decrease from baseline increasing across baseline lipoprotein(a) quartiles (Supplementary Fig. 1A). The median decrease in lipoprotein(a) with alirocumab was nil in quartile 1, increasing to 20.2 mg/dL in quartile 4. In contrast, alirocumab produced similar reductions in LDL-C_corrected across baseline lipoprotein (a) quartiles. Similar results were observed for absolute decreases to month 12 (Supplementary Fig. 1B). Median percent change in lipoprotein(a) from baseline to month 4 in the placebo group was 0% (quartile 1–3 −17 to 13.3), with median changes ranging from nil in quartile 1 to 5.8 mg/dL increase in quartile 4.

As summarized in Table 2, among patients in the alirocumab group without diabetes at baseline, each 10 mg/dL decrease in lipoprotein(a) from baseline was associated with an unadjusted hazard ratio of 1.07 (95% CI 1.03−1.12; P = 0.0002) for subsequent incident type 2 diabetes (model 1). This association was similar after adjustment for baseline lipoprotein(a) (model 2) and after additional adjustment for baseline demographic and clinical characteristics (model 3).

Table 2.

Relationship of time-varying change in lipoprotein(a) with subsequent incident type 2 diabetes in the alirocumab group

Model	Model adjustments	HR (95% CI) per 10 mg/dL decrease in lipoprotein(a) from baseline	P
1	None	1.07 (1.03−1.12)	0.0002
2	Baseline lipoprotein(a)	1.10 (1.05−1.15)	<0.0001
3	Baseline lipoprotein(a), baseline LDL-C_corrected, time-varying change in LDL-C_corrected, demographic and clinical characteristics^*	1.08 (1.04−1.13)	0.0001

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HR, hazard ratio for incident type 2 diabetes; LDL-C_corrected, LDL cholesterol corrected for cholesterol content of lipoprotein(a).

Sex, race, geographic region, statin treatment intensity (none, low to moderate, or high), baseline BMI, baseline triglycerides, baseline hemoglobin A_1c.

Relationship Between Lipoprotein(a) and Glycemic Measures in Patients With Diabetes at Baseline

In patients with diabetes at baseline, Supplementary Table 3 shows absolute change in hemoglobin A_1c and fasting glucose from baseline to month 12. There were no differences according to quartile of baseline lipoprotein(a).

Conclusions

This analysis, comprising 13,480 patients in the ODYSSEY OUTCOMES trial without diabetes at baseline, provides three key insights into the relationship between lipoprotein(a) concentration and risk of type 2 diabetes. First, incident type 2 diabetes in the placebo group increased with decreasing baseline lipoprotein(a) concentration, corroborating prior observations in healthy populations (13,15,17,18), and demonstrating this for the first time in a cohort with established atherosclerotic cardiovascular disease receiving intensive or maximum tolerated statin treatment.

Second, the relationship between baseline lipoprotein(a) concentration and incident type 2 diabetes was modified by alirocumab treatment. At low baseline lipoprotein(a) concentrations, alirocumab had minimal effect on lipoprotein(a) levels and tended to reduce the estimated risk of incident type 2 diabetes compared with placebo. This was particularly evident in the lowest quartile of baseline lipoprotein(a) (<6.9 mg/dL). Conversely, at high baseline lipoprotein(a) levels, alirocumab produced notable reductions in lipoprotein(a) concentrations and tended to increase the estimated risk of incident type 2 diabetes compared with placebo. Treatment and baseline lipoprotein(a) had significant interaction on the risk of incident type 2 diabetes. The concentration of lipoprotein(a) at which alirocumab had a neutral effect on incident type 2 diabetes was ∼50 mg/dL.

Third, within the alirocumab group, each 10 mg/dL decrease in lipoprotein(a) from baseline to month 4 was associated with a significant hazard ratio for incident type 2 diabetes after adjustment for demographic and clinical variables, baseline lipoprotein(a), and the concurrent change from baseline in LDL-C_corrected. This finding suggests that treatment-induced reduction in lipoprotein(a) concentration may increase the risk of incident type 2 diabetes.

Mechanisms Linking Lipoprotein(a) With Type 2 Diabetes

Potential mechanisms linking lipoprotein(a) and type 2 diabetes remain uncertain. Specifically, it is unknown whether the association is due to an effect of insulin resistance or hyperinsulinemia to suppress levels of lipoprotein(a) or whether low levels of lipoprotein(a) are causally related to the development of insulin resistance and type 2 diabetes. In a study of 607 subjects without diabetes, those with, compared with those without, metabolic syndrome had lower lipoprotein(a) concentrations in conjunction with higher levels of insulin, C-peptide, and HOMA of insulin resistance (HOMA-IR) (24). In another study of 1,685 individuals without diabetes, lipoprotein(a) levels were also inversely associated with HOMA-IR, and lipoprotein(a) levels fell in the period immediately preceding a transition to type 2 diabetes (16). The latter finding led the authors to postulate that autoimmune phenomena might be responsible for an association of low lipoprotein(a) and incident type 2 diabetes.

In some cases, genetic data support a relationship between lipoprotein(a) levels and incident type 2 diabetes. In analyses of Chinese and Danish cohorts, increased risk of type 2 diabetes was found in individuals with genetically determined low lipoprotein(a) plasma concentration due to large lipoprotein(a) isoform size related to the number of kringle IV type 2 repeats (25–27). However, a Mendelian randomization analysis showed that genetic variants associated with fasting insulin levels bore no relation to lipoprotein(a) concentration (28), and in analyses of the European Prospective Investigation into Cancer (EPIC)-Norfolk and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) cohorts (15) there was no association found of rs10455872, a single nucleotide polymorphism of the LPA gene affecting lipoprotein(a) plasma concentration, with incident type 2 diabetes.

Effect of PCSK9 Inhibition With Alirocumab on Incident Type 2 Diabetes

Genetic data have indicated that polymorphisms affecting the HMGCR, PCSK9, or NPC1L1 genes that result in lower levels of LDL-C are associated with an increased risk of diabetes (29–31) and, conversely, that elevated LDL-C due to familial hypercholesterolemia is associated with a lower risk of diabetes (32). In the current analysis, despite substantial lowering of LDL-C levels, alirocumab had an overall neutral effect on incident type 2 diabetes. The difference in these findings may reflect a shorter duration of observation in the current study. Alternatively, the contrasting findings might be related to a protective effect of higher lipoprotein(a) concentration. In healthy observational cohorts such as those contributing to the genetic analyses, the median lipoprotein(a) concentration is typically ∼10 mg/dL (15–18); at baseline in the ODYSSEY OUTCOMES trial, the median lipoprotein(a) concentration was 21 mg/dL.

A neutral overall effect of alirocumab on incident type 2 diabetes could also be related to circulating PCSK9 levels, which have been positively correlated with levels of glucose, insulin, and HOMA-IR (33–35) and associated with the presence of metabolic syndrome (36). A rise in PCSK9 levels is observed in response to a short-term high-fructose diet in healthy subjects (37). Treatment with a PCSK9 antibody lowers the circulating concentration of free PCSK9 (38), but limited data do not indicate that treatment affects insulin sensitivity (39).

Relation of Lipoprotein(a) and Alirocumab Treatment to Glycemic Measures in Patients With Diabetes at Baseline

Among patients with established diabetes, we did not observe differential changes in hemoglobin A_1c or fasting glucose over time according to baseline lipoprotein(a) quartile. We cannot exclude the possibility that a potential influence of lipoprotein(a) concentration on glycemic measures in these patients was mitigated by changes in patient behaviors (i.e., lifestyle modification) or physician practice (i.e., intensification of antihyperglycemic drug therapy) in response to laboratory values.

Strengths and Limitations

Strengths of this analysis include a large, multinational cohort of patients at high risk for diabetes, a high incidence rate for type 2 diabetes, and a systematic, blinded process for the adjudication of incident diabetes. Among the limitations, the effect of alirocumab on incident type 2 diabetes was observed on a background of intensive statin treatment. Whether alirocumab modulated an effect of statin treatment or exerted an independent effect on the risk of incident diabetes cannot be determined. Lipoprotein(a) was measured with a mass assay. The correlation of lipoprotein(a) mass and molar concentration is imperfect. We cannot exclude the possibility that an analysis based on lipoprotein(a) molar concentration or isoform size might have yielded different results. The current findings associate lipoprotein(a) reduction due to PCSK9 inhibition with the risk of incident type 2 diabetes; however, it is unknown whether a similar association exists when lipoprotein(a) is reduced by other mechanisms. For example, niacin lowers lipoprotein(a) and increases incident diabetes (40), but to date no patient-level analysis has investigated whether these effects are associated.

Clinical Implications

LDL is the primary atherogenic lipoprotein. PCSK9 inhibitors, when added to background statin therapy, reduce LDL-C substantially and consistently across a range of concomitant lipoprotein(a) concentrations, with a corresponding reduction in the risk of MACE and without an overall increase in the risk of incident diabetes (5,6). PCSK9 inhibitors also produce a modest relative reduction in lipoprotein(a) levels, the absolute magnitude of which becomes notable in those with high baseline levels. As elevated levels of lipoprotein(a) are associated with an increased risk of MACE, patients with higher baseline lipoprotein(a) levels also achieve larger reductions in MACE with PCSK9 inhibition (7,8,10).

The current analysis indicates that among patients assigned to placebo, those with higher lipoprotein(a) levels have a lower risk of incident type 2 diabetes. Under treatment with alirocumab, patients with higher baseline lipoprotein(a) have larger absolute decreases in its concentration that in turn are associated with greater risk of incident type 2 diabetes. It remains to be determined whether the treatment hazard ratio for incident type 2 diabetes per unit decrease in lipoprotein(a) concentration determined in this analysis will apply to innovative therapies that target the synthesis of apolipoprotein(a) and reduce lipoprotein(a) concentration substantially more than PCSK9 inhibitors (12).

In the current analysis, alirocumab tended to increase incident diabetes at baseline lipoprotein(a) concentrations >50 mg/dL. However, this is also a threshold concentration of lipoprotein(a) that has been used to define significantly elevated cardiovascular risk (41). Accordingly, the current findings should not dissuade practitioners from using PCSK9 inhibitors in patients at very high cardiovascular risk who have elevated levels of LDL-C and lipoprotein(a). In such patients, the cardiovascular benefits of treatment will most likely outweigh a possible increased risk of incident diabetes, and the decision to treat should draw upon a calculus akin to the estimation of cardiovascular benefits and diabetes risk with intensive statin treatment (42). For example, the projected effects of alirocumab treatment may be considered in two hypothetical patients with recent acute coronary syndrome: one with baseline lipoprotein(a) ≤6.7 mg/dL (in quartile 1) and the other with baseline lipoprotein(a) >59.6 mg/dL (in quartile 4).

For the first patient, alirocumab treatment is projected to reduce the 3-year incidence of MACE by 0.2%. Concurrently, alirocumab would have no meaningful effect on absolute lipoprotein(a) concentration and would be projected to reduce the 3-year incidence of type 2 diabetes by 2.9%. These point estimates correspond to numbers needed to treat for 3 years of 500 to prevent one MACE and 34 to prevent one case of type 2 diabetes. In the second patient, alirocumab treatment is estimated to reduce the 3-year incidence of MACE by 1.6%. Concurrently, alirocumab would reduce lipoprotein(a) by a median of 20.2 mg/dL, associated with an increase in the 3-year incidence of type 2 diabetes of 0.9%. These point estimates correspond to a number needed to treat for 3 years of 62 to prevent one MACE and a number needed to harm of 111 to result in an additional case of type 2 diabetes. Thus, the former patient achieves a small reduction in MACE accompanied by a reduction in incident type 2 diabetes, while the latter patient achieves a larger reduction in MACE but with an increase in incident type 2 diabetes.

Conclusion

Among patients with recent acute coronary syndrome and elevated LDL-C levels despite optimized statin therapy, the prevalence and the incidence of type 2 diabetes increased with decreasing levels of baseline lipoprotein(a). Treatment with alirocumab modified the relationship between baseline lipoprotein(a) and incidence of type 2 diabetes. In patients with low baseline lipoprotein(a), alirocumab had minimal effect on lipoprotein(a) and was associated with a lower estimated incidence of type 2 diabetes compared with placebo. In contrast, in patients with high baseline lipoprotein(a), alirocumab decreased lipoprotein(a) levels in association with a higher estimated incidence of type 2 diabetes compared with placebo. An increased incidence of type 2 diabetes may be a consequence of therapeutic lipoprotein(a) reduction through PCSK9 inhibition.

Article Information

Acknowledgments. The authors thank the patients, study coordinators, and investigators who participated in this trial. Sophie Rushton-Smith (MedLink Healthcare Communications) provided editorial assistance in the preparation of the manuscript (limited to editing for style, referencing, and figure and table editing) and was funded by Sanofi, Paris, France.

Funding. D.L.B. reports serving as chair for the American Heart Association Quality Oversight Committee; serving as Trustee for the American College of Cardiology; and honoraria as follows: American College of Cardiology (ACC) (Senior Associate Editor, Clinical Trials and News, ACC.org, and Vice-Chair, ACC Accreditation Committee) and Journal of the American College of Cardiology (Guest Editor, Associate Editor) NCDR-ACTION Registry Steering Committee (Chair), and VA CART [Veterans Administration Clinical Assessment, Reporting and Tracking System for Cath Labs] Research and Publications Committee (Chair); and board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care. J.W.J. reports research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme.

Duality of Interest. The ODYSSEY OUTCOMES trial was funded by Sanofi and Regeneron Pharmaceuticals. The sponsors participated in study site selection, monitoring, and supervision of data collection. G.G.S. reports research support to the University of Colorado from AstraZeneca, Resverlogix, Roche, Sanofi, and The Medicines Company and is coinventor of pending U.S. patent 62/806,313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. M.S. reports serving as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, and Regeneron Pharmaceuticals. D.L.B. reports serving on advisory boards for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, and Regado Biosciences; reports serving on the board of directors for TobeSoft; reports serving on data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial [PORtopulmonary Hypertension Treatment wIth maCitentan - a randOmized Clinical Trial], funded by St. Jude Medical [now Abbott]), Cleveland Clinic (including for the ExCEED trial [CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement], funded by Edwards), Contego Medical (Chair, for PERFORMANCE [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System] 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE [Edoxaban Compared to Standard Care After Heart Valve Replacement] trial, funded by Daiichi Sankyo), and Population Health Research Institute; reports honoraria from Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, RE-DUAL PCI [Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention] clinical trial steering committee funded by Boehringer Ingelheim, AEGIS-II (Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome) executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE [Prostate Cancer and Cardiovascular Disease] trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education [CME] steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and U.S. national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); reports associations with Clinical Cardiology (Deputy Editor); reports research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; reports royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); reports serving as site co-investigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; and unfunded research from FlowCo, Merck, Novo Nordisk, and Takeda. V.A.B. reports grant support from Sanofi, Astra Zeneca, DalCor, Esperion, Bayer, The Medicines Company, and Amgen, all paid direct to her institution, and personal fees from Sanofi. R.D. reports research grants from Sanofi, DalCor Pharmaceuticals, Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit and personal fees, as a member of the executive steering committees, from Amgen and Cirius. S.G.G. reports research grants from Daiichi-Sankyo, Luitpold Pharmaceuticals, Merck, Novartis, Servier, Regeneron Pharmaceuticals, Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Pfizer, and Tenax Therapeutics; honoraria from Bristol-Myers Squibb, Eli Lilly, Esperion, Fenix Group International, Ferring Pharmaceuticals, Merck, Novartis, Pfizer, Servier, Regeneron Pharmaceuticals, Sanofi, Amgen, AstraZeneca, Bayer, and Boehringer Ingelheim; and serving as a consultant or on advisory boards (or both) for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Pfizer, Servier, Tenax Therapeutics, Sanofi, Amgen, and Bayer. J.W.J. reports research support from Amgen, Astellas, AstraZeneca, Daiichi- Sankyo, Lilly, Merck–Schering-Plough, Pfizer, Roche, and Sanofi. M.L. is an employee of Sanofi. G.M. and R.P. are employees of Regeneron Pharmaceuticals. H.D.W. reports receiving grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, for the ACCELERATE study (A Study of Evacetrapib in High-Risk Vascular Disease) from Eli Lilly, for the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia) from Omthera Pharmaceuticals, for the SPIRE trial (The Evaluation of Bococizumab [PF-04950615, RN 316] in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) from Pfizer, for the HEART-FID study (Randomized Placebo-Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent, for the CAMELLIA-TIMI study (A Study to Evaluate the Effect of Long-term Treatment With BELVIQ [Lorcaserin HC] on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors) from Eisai Inc, for the dal-GenE study (Effect of Dalcetrapib vs. Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK, for the AEGIS-II study from CSL Behring, for the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type2 Diabetes Post Worsening Heart Failure) from Sanofi Australia Pty Ltd, and for the CLEAR Outcomes Study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid [ETC-1002] or Placebo) from Esperion Therapeutics. H.D.W. was on the advisory boards for Acetelion, Sirtex, and Genentech (an affiliate of F. Hoffmann-La Roche, “Roche,” Lytics Post-PCI Advisory Board at European Society of Cardiology) and received lecture fees from AstraZeneca. P.G.S. reports grants and nonfinancial support (co-chair of the ODYSSEY OUTCOMES trial; as such, he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; research grants and personal fees from Bayer (Steering Committee MARINER [A Study of Rivaroxaban (JNJ-39039039) on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients], grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (co-chair of the ODYSSEY OUTCOMES trial, co-chair of the SCORED trial, consulting, speaking), Servier (Chair of the CLARIFY registry [ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease], grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT [Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial], consulting); and personal fees from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron Pharmaceuticals, Lilly, and AstraZeneca. P.G.S. also has a European application number/patent number, issued on 26 October 2016 (no. 15712241.7), for a method for reducing cardiovascular risk. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. G.G.S. conceived the research question. G.G.S. and M.S. designed the analysis plan. M.S. performed the data analysis. G.G.S. drafted the manuscript. All authors interpreted the results and critically revised the manuscript for important intellectual content and gave final approval of the version to publish. G.G.S. and M.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented in abstract form at the American Heart Association Scientific Sessions 2020, 13–17 November 2020.

Footnotes

The ODYSSEY OUTCOMES Committee members, investigators, and contributors are listed in the supplementary materials online.

Clinical trial reg. no. NCT01663402, clinicaltrials.gov

This article contains supplementary material online at https://doi.org/10.2337/figshare.13805825.

Contributor Information

Collaborators: ODYSSEY OUTCOMES Committees and Investigators, Gregory G. Schwartz, Philippe Gabriel Steg, Deepak L. Bhatt, Vera A. Bittner, Rafael Diaz, Shaun G. Goodman, Robert A. Harrington, J. Wouter Jukema, Michael Szarek, Harvey D. White, Andreas M. Zeiher, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, Robert Pordy, William J. Sasiela, Jean-François Tamby, Philip E. Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N. Gotcheva, Juan-Carlos Prieto, Huo Yong, Patricio López-Jaramillo, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Margus Viigimaa, Markku S. Nieminen, Vakhtang Chumburidze, Nikolaus Marx, Nicolas Danchin, Evangelos Liberopoulos, Pablo Carlos Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M. Correa Flores, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Jan Murin, Zlatko Fras, Anthony J. Dalby, José Tuñón, H. Asita de Silva, Emil Hagström, Ulf Landmesser, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, Pierluigi Tricoci, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez-Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean Van Diepen, Matthew D. Wilson, Andrew T. Yan, Lilia B. Schiavi, Marcelo Garrido, Andrés F. Alvarisqueta, Sonia A. Sassone, Anselmo P. Bordonava, Alberto E. Alves De Lima, Jorge M. Schmidberg, Ernesto A. Duronto, Orlando C. Caruso, Leonardo P. Novaretto, Miguel Angel Hominal, Oscar R. Montaña, Alberto Caccavo, Oscar A. Gomez Vilamajo, Alberto J. Lorenzatti, Luis R. Cartasegna, Gustavo A. Paterlini, Ignacio J. Mackinnon, Guillermo D. Caime, Marcos Amuchastegui, Oscar Salomone, Oscar R. Codutti, Horacio O. Jure, Julio O.E. Bono, Adrian D. Hrabar, Julio A. Vallejos, Rodolfo A. Ahuad Guerrero, Federico Novoa, Cristian A. Patocchi, Cesar J. Zaidman, Maria E. Giuliano, Ricardo D. Dran, Marisa L. Vico, Gabriela S. Carnero, Pablo N. Guzman, Juan C. Medrano Allende, Daniela F. Garcia Brasca, Miguel H. Bustamante Labarta, Sebastian Nani, Eduardo D.S. Blumberg, Hugo R. Colombo, Alberto Liberman, Victorino Fuentealba, Hector L. Luciardi, Gabriel D. Waisman, Mario A. Berli, Ruben O. Garcia Duran, Horacio G. Cestari, Hugo A. Luquez, Jorge A. Giordano, Silvia S. Saavedra, Gerardo Zapata, Osvaldo Costamagna, Susana Llois, Jonathon H. Waites, Nicholas Collins, Allan Soward, Chris L.S. Hii, James Shaw, Margaret A. Arstall, John Horowitz, Daniel Ninio, James F. Rogers, David Colquhoun, Romulo E. Oqueli Flores, Philip Roberts-Thomson, Owen Raffel, Sam J. Lehman, Constantine Aroney, Steven G.M. Coverdale, Paul J. Garrahy, Gregory Starmer, Mark Sader, Patrick A. Carroll, Ronald Dick, Robert Zweiker, Uta Hoppe, Kurt Huber, Rudolf Berger, Georg Delle-Karth, Bernhard Frey, Franz Weidinger, Dirk Faes, Kurt Hermans, Bruno Pirenne, Attilio Leone, Etienne Hoffer, Mathias C.M. Vrolix, Luc De Wolf, Bart Wollaert, Marc Castadot, Karl Dujardin, Christophe Beauloye, Geert Vervoort, Harry Striekwold, Carl Convens, John Roosen, Emanuele Barbato, Marc Claeys, Frank Cools, Ibrahim Terzic, Fahir Barakovic, Zlatko Midzic, Belma Pojskic, Emir Fazlibegovic, Mehmed Kulić, Azra Durak-Nalbantic, Dusko Vulic, Adis Muslibegovic, Boris Goronja, Gilmar Reis, Luciano Sousa, Jose C. Nicolau, Flavio E. Giorgeto, Ricardo P. Silva, Lilia Nigro Maia, Rafael Rech, Paulo R.F. Rossi, Maria José A.G. Cerqueira, Norberto Duda, Renato Kalil, Adrian Kormann, José Antonio M. Abrantes, Pedro Pimentel Filho, Ana Priscila Soggia, Mayler O.N. de Santos, Fernando Neuenschwander, Luiz C. Bodanese, Yorghos L. Michalaros, Freddy G. Eliaschewitz, Maria H. Vidotti, Paulo E. Leaes, Roberto V. Botelho, Sergio Kaiser, Euler Roberto Fernandes Manenti, Dalton B. Precoma, Jose C. Moura Jorge, Pedro G. Silva, Jose A. Silveira, Wladmir Saporito, Jose A. Marin-Neto, Gilson S. Feitosa, Luiz Eduardo F. Ritt, Juliana A. de Souza, Fernando Costa, Weimar K.S.B. Souza, Helder J.L. Reis, Leandro Machado, José Carlos Aidar Ayoub, Georgi V. Todorov, Fedya P. Nikolov, Elena S. Velcheva, Maria L. Tzekova, Haralambi O. Benov, Stanislav L. Petranov, Haralin S. Tumbev, Nina S. Shehova-Yankova, Dimitar T. Markov, Dimitar H. Raev, Mihail N. Mollov, Kostadin N. Kichukov, Katya A. Ilieva-Pandeva, Raya Ivanova, Maryana Gospodinov, Valentina M. Mincheva, Petar V. Lazov, Bojidar I. Dimov, Manohara Senaratne, James Stone, Jan Kornder, Stephen Pearce, Danielle Dion, Daniel Savard, Yves Pesant, Amritanshu Pandey, Simon Robinson, Gilbert Gosselin, Saul Vizel, Gordon Hoag, Ronald Bourgeois, Anne Morisset, Eric Sabbah, Bruce Sussex, Simon Kouz, Paul MacDonald, Ariel Diaz, Nicolas Michaud, David Fell, Raymond Leung, Tycho Vuurmans, Christopher Lai, Frank Nigro, Richard Davies, Gustavo Nogareda, Ram Vijayaraghavan, John Ducas, Serge Lepage, Shamir Mehta, James Cha, Robert Dupuis, Peter Fong, Sohrab Lutchmedial, Josep Rodes-Cabau, Hussein Fadlallah, David Cleveland, Thao Huynh, Iqbal Bata, Adnan Hameed, Cristian Pincetti, Sergio Potthoff, Monica Acevedo, Arnoldo Aguirre, Margarita Vejar, Mario Yañez, Guillermo Araneda, Mauricio Fernandez, Luis Perez, Paola Varleta, Fernando Florenzano, Laura Huidobro, Carlos A. Raffo, Claudia Olivares, Leonardo Nahuelpan, Humberto Montecinos, Jiyan Chen, Yugang Dong, Weijian Huang, Jianzhong Wang, Shi'An Huang, Zhuhua Yao, Xiang Li, Lan Cui, Wenhua Lin, Yuemin Sun, Jingfeng Wang, Jianping Li, Xuelian Zhang, Hong Zhu, Dandan Chen, Lan Huang, Shaohong Dong, Guohai Su, Biao Xu, Xi Su, Xiaoshu Cheng, Jinxiu Lin, Wenxia Zong, Huanming Li, Yi Feng, Dingli Xu, Xinchun Yang, Yuannan Ke, Xuefeng Lin, Zheng Zhang, Zeqi Zheng, Zhurong Luo, Yundai Chen, Chunhua Ding, Yi Zhong, Yang Zheng, Xiaodong Li, Daoquan Peng, Shuiping Zhao, Ying Li, Xuebo Liu, Meng Wei, Shaowen Liu, Yihua Yu, Baiming Qu, Weihong Jiang, Yujie Zhou, Xingsheng Zhao, Zuyi Yuan, Ying Guo, Xiping Xu, Xubo Shi, Junbo Ge, Guosheng Fu, Feng Bai, Weiyi Fang, Xiling Shou, Xiangjun Yang, Jian’An Wang, Meixiang Xiang, Yingxian Sun, Qinghua Lu, Ruiyan Zhang, Jianhua Zhu, Yizhou Xu, Zhongcai Fan, Tianchang Li, Chun Wu, Nicolas Jaramillo, Gregorio Sanchez Vallejo, Diana C. Luna Botia, Rodrigo Botero Lopez, Dora I. Molina De Salazar, Alberto J. Cadena Bonfanti, Carlos Cotes Aroca, Juan Diego Higuera, Marco Blanquicett, Sandra I. Barrera Silva, Henry J. Garcia Lozada, Julian A. Coronel Arroyo, Jose L. Accini Mendoza, Ricardo L. Fernandez Ruiz, Alvaro M. Quintero Ossa, Fernando G. Manzur Jatin, Aristides Sotomayor Herazo, Jeffrey Castellanos Parada, Rafael Suarez Arambula, Miguel A. Urina Triana, Angela M. Fernandez Trujillo, Maja Strozzi, Siniša Car, Melita Jerić, Davor Miličić, Martina Lovrić Benčić, Hrvoje Pintarić, Đeiti Prvulović, Jozica Šikić, Viktor Peršić, Dean Mileta, Kresimir Štambuk, Zdravko Babić, Vjekoslav Tomulic, Josip Lukenda, Stanka Mejic-Krstulovic, Boris Starcevic, Jindrich Spinar, David Horak, Zdenek Velicka, Josef Stasek, David Alan, Vilma Machova, Ales Linhart, Vojtech Novotny, Vladimir Kaucak, Richard Rokyta, Robert Naplava, Zdenek Coufal, Vera Adamkova, Ivo Podpera, Jiri Zizka, Zuzana Motovska, Ivana Marusincova, Premysl Svab, Petr Heinc, Jiri Kuchar, Petr Povolny, Jiri Matuska, Steen H. Poulsen, Bent Raungaard, Peter Clemmensen, Lia E. Bang, Ole May, Morten Bøttcher, Jens D. Hove, Lars Frost, Gunnar Gislason, John Larsen, Peter Betton Johansen, Flemming Hald, Peter Johansen, Jørgen Jeppesen, Tonny Nielsen, Kjeld S. Kristensen, Piotr Maria Walichiewicz, Jens D. Lomholdt, Ib C. Klausen, Peter Kaiser Nielsen, Flemming Davidsen, Lars Videbaek, Mai Soots, Veiko Vahula, Anu Hedman, Üllar Soopõld, Kaja Märtsin, Tiina Jurgenson, Arved Kristjan, Juhani K. Airaksinen, Saila Vikman, Heikki Huikuri, Pierre Coste, Emile Ferrari, Olivier Morel, Gilles Montalescot, Jacques Machecourt, Gilles Barone-Rochette, Jacques Mansourati, Yves Cottin, Florence Leclercq, Abdelkader Belhassane, Nicolas Delarche, Franck Boccara, Franck Paganelli, Jérôme Clerc, Francois Schiele, Victor Aboyans, Vincent Probst, Jacques Berland, Thierry Lefèvre, Bernard Citron, Irakli Khintibidze, Tamaz Shaburishvili, Zurab Pagava, Ramaz Ghlonti, Zaza Lominadze, George Khabeishvili, Rayyan Hemetsberger, Kemala Edward, Ursula Rauch-Kröhnert, Matthias Stratmann, Karl-Friedrich Appel, Ekkehard Schmidt, Heyder Omran, Christoph Stellbrink, Thomas Dorsel, Emmanouil Lianopoulos, Hans Friedrich Vöhringer, Roger Marx, Andreas Zirlik, Detlev Schellenberg, Thomas Heitzer, Ulrich Laufs, Christian Werner, Nikolaus Marx, Stephan Gielen, Sebastian Nuding, Bernhard Winkelmann, Steffen Behrens, Karsten Sydow, Mahir Karakas, Gregor Simonis, Thomas Muenzel, Nikos Werner, Stefan Leggewie, Dirk Böcker, Rüdiger Braun-Dullaeus, Nicole Toursarkissian, Michael Jeserich, Matthias Weißbrodt, Tim Schaeufele, Joachim Weil, Heinz Völler, Johannes Waltenberger, Mohammed Natour, Susanne Schmitt, Dirk Müller-Wieland, Stephan Steiner, Lothar Heidenreich, Elmar Offers, Uwe Gremmler, Holger Killat, Werner Rieker, Sotiris Patsilinakos, Athanasios Kartalis, Athanassios Manolis, Dimitrios Sionis, Geargios Chachalis, Ioannis Skoumas, Vasilios Athyros, Panagiotis Vardas, Frangkiskos Parthenakis, Dimitrios Alexopoulos, Georgios Hahalis, John Lekakis, Apostolos Hatzitolios, Sergio R. Fausto Ovando, Juan L. Arango Benecke, Edgar R. Rodriguez De Leon, Bryan P.Y. Yan, David C.W. Siu, Tibor Turi, Bela Merkely, Imre Ungi, Geza Lupkovics, Lajos Nagy, András Katona, István Édes, Gábor Müller, Iván Horvath, Tibor Kapin, Zsolt Szigeti, József Faluközy, Mukund Kumbla, Manjinder Sandhu, Sharath Annam, Naveen Reddy Proddutur, Reddy Regella, Rajendra K. Premchand, Ajaykumar Mahajan, Sudhir Pawar, Atul D. Abhyanakar, Prafulla Kerkar, Ravishankar A. Govinda, Abraham Oomman, Dhurjati Sinha, Sachin N. Patil, Dhiman Kahali, Jitendra Sawhney, Abhijeet B. Joshi, Sanjeev Chaudhary, Pankaj Harkut, Santanu Guha, Sanjay Porwal, Srimannarayana Jujjuru, Ramesh B. Pothineni, Minguel R. Monteiro, Aziz Khan, Shamanna S. Iyengar, Jasprakash Singh Grewal, Manoj Chopda, Mahesh C. Fulwani, Aparna Patange, Patil Sachin, Vijay K. Chopra, Naresh K. Goyal, Rituparna Shinde, Gajendra V. Manakshe, Nitin Patki, Sumeet Sethi, Vengatesh Munusamy, Sunil Karna, Sunil Thanvi, Srilakshmi Adhyapak, Chandrakant Patil, Ulhas Pandurangi, Rishabh Mathur, Jugal Gupta, Suhas Kalashetti, Ajit Bhagwat, Bagirath Raghuraman, Shiv Kumar Yerra, Prasant Bhansali, Rohidas Borse, Patil Rahul, Srihari Das, Vinay Kumar, Jabir Abdullakutty, Shireesh Saathe, Priya Palimkar, Shireesh Sathe, Shaul Atar, Michael Shechter, Morris Mosseri, Yaron Arbel, Chorin Ehud, Havakuk Ofer, Chaim Lotan, Uri Rosenschein, Amos Katz, Yaakov Henkin, Adi Francis, Marc Klutstein, Eugenia Nikolsky, Robert Zukermann, Yoav Turgeman, Majdi Halabi, Alon Marmor, Ran Kornowski, Michael Jonas, Offer Amir, Yonathan Hasin, Yoseph Rozenman, Shmuel Fuchs, Vered Zvi, Osamah Hussein, Dov Gavish, Zvi Vered, Yoseph Caraco, Mazen Elias, Naveh Tov, Efrat Wolfovitz, Michael Lishner, Nizar Elias, Giancarlo Piovaccari, Annamaria De Pellegrin, Raffaella Garbelotto, Gabriele Guardigli, Valgimigli Marco, Giovanni Licciardello, Carla Auguadro, Filippo Scalise, Claudio Cuccia, Alessandro Salvioni, Giuseppe Musumeci, Michelle Senni, Paolo Calabrò, Salvatore Novo, Pompilio Faggiano, Marco Metra, Nicoletta B. De Cesare, Sergio Berti, Claudio Cavallini, Enrico Puccioni, Marcello Galvani, Maurizio Tespili, Piermarco Piatti, Michela Palvarini, Giuseppe De Luca, Roberto Violini, Alessandro De Leo, Zoran Olivari, Pasquale Perrone Filardi, Maurizio Ferratini, Vittorio Racca, Kazuoki Dai, Yuji Shimatani, Haruo Kamiya, Kenji Ando, Yoshihiro Takeda, Yoshihiro Morino, Yoshiki Hata, Kazuo Kimura, Koichi Kishi, Ichiro Michishita, Hiroki Uehara, Toshinori Higashikata, Atsushi Hirayama, Keiji Hirooka, Yasuji Doi, Satoru Sakagami, Shuichi Taguchi, Akihiro Koike, Hiroyuki Fujinaga, Shinji Koba, Ken Kozuma, Tomohiro Kawasaki, Yujiro Ono, Masatoshi Shimizu, Yousuke Katsuda, Atsuyuki Wada, Toshiro Shinke, Takeshi Kimura, Junya Ako, Kenshi Fujii, Toshiyuki Takahashi, Tomohiro Sakamoto, Koichi Nakao, Yutaka Furukawa, Hiroshi Sugino, Ritsu Tamura, Toshiaki Mano, Masaaki Uematsu, Noriaki Utsu, Kashima Ito, Takuya Haraguchi, Katsuhiko Sato, Yasunori Ueda, Akira Nishibe, Kazuteru Fujimoto, Motomaru Masutani, Jung Han Yoon, Hack-Lyoung Kim, Hun Sik Park, In-Ho Chae, Moo Hyun Kim, Myung Ho Jeong, Seungwoon Rha, Chongjin Kim, Hyo-Soo Kim, Hae Young Kim, Taekjong Hong, Seung-Jea Tahk, Youngkwon Kim, Arija Busmane, Natalija Pontaga, Aldis Strelnieks, Iveta Mintale, Iveta Sime, Zaneta Petrulioniene, Roma Kavaliauskiene, Ruta Jurgaitiene, Gintare Sakalyte, Rimvydas Slapikas, Sigute Norkiene, Nerijus Misonis, Aleksandras Kibarskis, Raimondas Kubilius, Stojko Bojovski, Nensi Lozance, Aleksandar Kjovkaroski, Snezana Doncovska, Tiong Kiam Ong, Sazzli Kasim, Oteh Maskon, Balachandran Kandasamy, Houng B. Liew, Wan Mohd Izani Wan Mohamed, Armando García Castillo, Jorge Carrillo Calvillo, Pedro Fajardo Campos, Juan Carlos Núñez Fragoso, Edmundo Alfredo Bayram Llamas, Marco Antonio Alcocer Gamba, Jaime Carranza Madrigal, Luis Gerardo González Salas, Enrique López Rosas, Belinda González Díaz, Eduardo Salcido Vázquez, Alfredo Nacoud Ackar, Guillermo Antonio Llamas Esperón, Carlos Rodolfo Martínez Sánchez, María Guerrero De Leon, Rodrigo Suarez Otero, Guillermo Fanghänel Salmón, Jesús Antonio Pérez Ríos, José Angel Garza Ruíz, Robert W. Breedveld, Margriet Feenema-Aardema, Alida Borger-Van Der Burg, Pieter A.M. Hoogslag, Harry Suryapranata, Antonius Oomen, Paulus Van Haelst, Jacobijne J. Wiersma, Dirk Basart, Ruud M.A. Van Der Wal, Peter Zwart, Pascalle Monraats, Henricus Van Kesteren, Ioannis Karalis, Johan Jukema, Gerardus J.E. Verdel, Bart R.G. Brueren, Roland P.T. Troquay, Eric P. Viergever, Nadea Y.Y. Al-Windy, Gerard L. Bartels, Jan H. Cornel, Walter R.M. Hermans, Johannes P.R. Herrman, Robert J. Bos, Reginald G.E.J. Groutars, Coenraad C. Van Der Zwaan, Refik Kaplan, Raymond Lionarons, Eelko Ronner, Bjorn E. Groenemeijer, Patrick N.A. Bronzwaer, Anho A.H. Liem, Bernard J.W.M. Rensing, Marcel J.J.A. Bokern, Remco Nijmeijer, Ferry M.R.J. Hersbach, Frank F. Willems, Antonius T.M. Gosselink, Saman Rasoul, John Elliott, Gerard Wilkins, Raewyn Fisher, Douglas Scott, Hamish Hart, Ralph Stewart, Scott Harding, Ian Ternouth, Nicholas Fisher, Samuel Wilson, Denise Aitken, Russell Anscombe, Laura Davidson, Tadeusz Tomala, Ottar Nygård, Jon Arne Sparby, Kjell Andersen, Lars Gullestad, Jarle Jortveit, Peter S. Munk, Erlend gyllensten Singsaas, Ulf Hurtig, Jorge R. Calderon Ticona, Julio R. Durand Velasquez, Sandra A. Negron Miguel, Enrique S. Sanabria Perez, Jesus M. Carrion Chambilla, Carlos A. Chavez Ayala, Reynaldo P. Castillo Leon, Rolando J. Vargas Gonzales, Jose D. Hernandez Zuniga, Luis A. Camacho Cosavalente, Jorge E. Bravo Mannucci, Javier Heredia Landeo, Nassip C. Llerena Navarro, Yudy M. Roldan Concha, Víctor E. Rodriguez Chavez, Henry A. Anchante Hernandez, Carlos A. Zea Nunez, Walter Mogrovejo Ramos, Arthur Ferrolino, Rosa Allyn G. Sy, Louie Tirador, Rody G. Sy, Generoso Matiga, Raul Martin Coching, Alisa Bernan, Gregorio Rogelio, Dante D. Morales, Edgar Tan, Dennis Jose Sulit, Adrian Wlodarczak, Krystyna Jaworska, Grzegorz Skonieczny, Lidia Pawlowicz, Pawel Wojewoda, Benita Busz-Papiez, Janusz Bednarski, Aleksander Goch, Pawel Staneta, Elzbieta Dulak, Krzysztof Saminski, Wlodzimierz Krasowski, Wanda Sudnik, Aleksander Zurakowski, Marcin Skorski, Beata Miklaszewicz, Jacek Kubica, Jan Andrzej Lipko, Edyta Kostarska-Srokosz, Marek Piepiorka, Anna Drzewiecka, Ryszard Sciborski, Arkadiusz Stasiewski, Tomasz Blicharski, Leszek Bystryk, Michal Szpajer, Marek Korol, Tomasz Czerski, Ewa Mirek-Bryniarska, Jacek Gniot, Andrzej Lubinski, Jerzy Gorny, Edward Franek, Grzegorz Raczak, Hanna Szwed, Pedro Monteiro, Jose Mesquita Bastos, Helder H. Pereira, Dinis Martins, Filipe Seixo, Carlos Mendonça, Ana Botelho, Francisca Caetano, Bogdan Minescu, Octavian Istratoaie, Dan N. Tesloianu, Gabriel Cristian, Silviu Dumitrescu, Cristian G.C. Podoleanu, Mircea C.A. Constantinescu, Cristina M. Bengus, Constantin Militaru, Doina Rosu, Irinel R. Parepa, Adrian V. Matei, Tom M. Alexandru, Mihaela Malis, Ioan Coman, Rodica Stanescu-Cioranu, Doina Dimulescu, Yury Shvarts, Olga Orlikova, Zhanna Kobalava, Olga L. Barbarash, Valentin Markov, Nadezhda Lyamina, Alexander Gordienko, Konstantin Zrazhevsky, Alexander Y. Vishnevsky, Victor Gurevich, Raisa Stryuk, Nikita V. Lomakin, Igor Bokarev, Tatiana Khlevchuk, Sergey Shalaev, Larisa Khaisheva, Petr Chizhov, Inna Viktorova, Natalya Osokina, Vladimir Shchekotov, Evgenia Akatova, Galina Chumakova, Igor Libov, Mikhail I. Voevoda, Tatyana V. Tretyakova, Evgeny Baranov, Sergey Shustov, Sergey Yakushin, Ivan Gordeev, Niiaz Khasanov, Olga Reshetko, Tatiana Sotnikova, Olga Molchanova, Konstantin Nikolaev, Liudmila Gapon, Elena Baranova, Zaur Shogenov, Elena Kosmachova, Yuriy Karpov, Anton Povzun, Liudmila Egorova, Vadim V. Tyrenko, Igor G. Ivanov, Masterov Ilya, Sergey Kanorsky, Dragan Simic, Nikola Ivanovic, Goran Davidovic, Nebojsa Tasic, Milika R. Asanin, Stevo Stojic, Svetlana R. Apostolovic, Stevan Ilic, Biljana Putnikovic Tosic, Aleksandar Stankovic, Aleksandra Arandjelovic, Slavica Radovanovic, Branislava Todic, Jovan Balinovac, Dragan V. Dincic, Petar Seferovic, Ana Karadzic, Slobodan Dodic, Sinisa Dimkovic, Tamara Jakimov, Kian-Keong Poh, Hean Yee Ong, Justin Tang I-Shing, Karol Micko, Jan Nociar, Daniel Pella, Peter Fulop, Marian Hranai, Juraj Palka, Juraj Mazur, Ivan Majercák, Andrej Dzupina, František Fazekas, Jozef Gonsorcik, Viliam Bugan, Juraj Selecky, Gabriel Kamensky, Jaroslava Strbova, Rudolf Smik, Andrej Dukat, Peter Olexa, Ivan Žuran, Janez Poklukar, Nataša Černič Šuligoj, Matija Cevc, Henry P. Cyster, Naresh Ranjith, Clive Corbett, Junaid Bayat, Ellen Makoali Makotoko, Hendrik du Toit Theron, Ilse E. Kapp, Matthys M. de V. Basson, Hanlie Lottering, Dina Van Aswegen, Louis J. Van Zyl, Peter J. Sebastian, Thayabran Pillay, Jan A. Saaiman, Patrick J. Commerford, Soraya Cassimjee, Garda Riaz, Iftikhar O. Ebrahim, Mahomed Sarvan, Joseph H. Mynhardt, Helmuth Reuter, Rajendran Moodley, Manuel Vida, Angel R. Cequier Fillat, Vicente Bodí Peris, Francisco Fuentes Jimenez, Francisco Marín, Jose M. Cruz Fernández, Rafael Jesus Hidalgo Urbano, Blas Gil-Extremera, Pablo Toledo, Fernando Worner Diz, David Garcia-Dorado, Andres Iñiguez, José Tuñón Fernández, Jose R. Gonzalez-Juanatey, Javier Fernandez Portales, Fernando Civeira Murillo, Laia Matas Pericas, Jose Luis Zamorano, Manuel De Mora Martin, Jordi Bruguera Cortada, Joaquin J. Alonso Martin, Jose Maria Serrano Antolin, José R. De Berrazueta Fernández, José Antonio Vázquez de Prada, Jose Francisco Díaz Fernández, José Alberto García Lledó, Juan Cosín Sales, Javier Botas Rodriguez, Gabriel Gusi Tragant, Amparo Benedicto, Carlos Gonzalez-Juanatey, Mercedes Camprubí Potau, Ignacio Plaza Perez, César Morís De La Tassa, Pablo Loma-Osorio Rincon, Javier Balaguer Recena, Juan M. Escudier, Antonio Coca Payeras, Norberto Alonso Orcajo, Pedro Valdivielso, Godwin Constantine, Ruvaiz Haniffa, Nirmali Tissera, Stanley Amarasekera, Chandrike Ponnamperuma, Nimali Fernando, Kaputella Fernando, Jayanthimala Jayawardena, Santharaj Wijeyasingam, Gotabhaya Ranasinghe, Ruvan Ekanayaka, Sepalika Mendis, Vajira Senaratne, Gnanamoorthy Mayurathan, Thilak Sirisena, Ajantha Rajapaksha, Jagath I. Herath, Naomali Amarasena, Stefan Berglund, Gundars Rasmanis, Ola Vedin, Nils Witt, Georgios Mourtzinis, Peter Nicol, Ole Hansen, Stefano Romeo, Steen Agergaard Jensen, Ingemar Torstensson, Ulf Ahremark, Torbjörn Sundelin, Tiziano Moccetti, Christian Müller, Francois Mach, Ronald Binde, Oliver Gämperli, Wei-Chuan Tsai, Kwo-Chang Ueng, Wen-Ter Lai, Ming-En Liu, Juey-Jen Hwang, Wei-Hsian Yin, I-Chang Hsieh, Ming-Jer Hsieh, Wei Hsiang Lin, Jen-Yuan Kuo, Tsuei-Yuan Huang, Chih-Yuan Fang, Pinij Kaewsuwanna, Wasant Soonfuang, Woravut Jintapakorn, Apichard Sukonthasarn, Nattawut Wongpraparut, Krisada Sastravaha, Nakarin Sansanayudh, Wirash Kehasukcharoen, Dilok Piyayotai, Paiboon Chotnoparatpat, Ahmet Camsari, Hakan Kultursay, Bulent Mutlu, Murat Ersanli, Mustafa Demirtas, Cevat Kirma, Ertan Ural, Lale Koldas, Oleksandr Karpenko, Alexander Prokhorov, Ihor Vakaluyk, Halyna Myshanych, Dmytro Reshotko, Valeriy Batushkin, Leonid Rudenko, Ihor Kovalskyi, Mykola Kushnir, Vira Tseluyko, Yuriy Mostovoy, Mykola Stanislavchuk, Yulian Kyiak, Yuriy Karpenko, Yaroslav Malynovsky, Andriy Klantsa, Oles Kutniy, Ekaterina Amosova, Viktor Tashchuk, Oleh Leshchuk, Mykola Rishko, Mykola Kopytsya, Andriy Yagensky, Mykola Vatutin, Andriy Bagriy, Olga M. Barna, Olexiy Ushakov, Georgiy Dzyak, Borys Goloborodko, Anatolii Rudenko, Volodymyr Zheleznyy, Jasper Trevelyan, Azfar Zaman, Kaeng Lee, Andrew Moriarty, Rajesh K. Aggarwal, Piers Clifford, Yuk-Ki Wong, Syed M.R. Iqbal, Eduardas Subkovas, Denise Braganza, David Sarkar, Robert Storey, Huw Griffiths, Sam McClure, Rangasamy Muthusamy, Simon Smith, John Kurian, Terry Levy, Craig Barr, Honer Kadr, Robert Gerber, Audrius Simaitis, Handrean Soran, Anthony Mathur, Adrian Brodison, Mohammad Ayaz, Muhammad Cheema, Richard Oliver, Simon Thackray, Telal Mudawi, Gohar Rahman, Ayyaz Sultan, Timothy Reynolds, David Sharman, David Sprigings, Rob Butler, Peter Wilkinson, Gregory Y.H. Lip, Julian Halcox, Sean Gallagher, Nicholas Ossei-Gerning, Gil Vardi, Duccio Baldari, David Brabham, Charles Treasure II, Charles Dahl, Bruce Palmer, Alan Wiseman, Abul Khan, Sanjeev Puri, Ann Elizabeth Mohart, Carlos Ince, Enrique Flores, Scott Wright, Shi-Chi Cheng, Michael Rosenberg, William Rogers, Jr, Edward Kosinski, Les Forgosh, Jonathan Waltman, Misal Khan, Mohammad Shoukfeh, Georges Dagher, Patrick Cambier, Ira Lieber, Priya Kumar, Cara East, Perry Krichmar, Mian Hasan, Lindsey White, Thomas Knickelbine, Thomas Haldis, Eve Gillespie, Thomas Amidon, David Suh, Imran Arif, Mouhamad Abdallah, Faiq Akhter, Eric Carlson, Michael D'Urso, Fadi El-Ahdab, William Nelson, Katie Moriarty, Barry Harris, Steven Cohen, Luther Carter, Daniel Doty, Kenneth Sabatino, Tariq Haddad, Amir Malik, Sunder Rao, Angel Mulkay, Ion Jovin, Kim Klancke, Vinay Malhotra, Sai K. Devarapalli, Michael Koren, Harish Chandna, George Dodds, III, Tauqir Goraya, James Bengston, Matthew Janik, Joseph Moran, Andrew Sumner, John Kobayashi, William Davis, Shahram Yazdani, John Pasquini, Maitreya Thakkar, Amarnath Vedere, Wayne Leimbach, James Rider, Sarah Fenton, Narendra Singh, Anil V. Shah, Denise Janosik, Carl Pepine, Brett Berman, Joseph Gelormini, Christopher Daniels, Kerensky Richard, Friederike Keating, Nicholas I. Kondo, Sanjay Shetty, Howard Levite, Winfried Waider, Theodore Takata, Mazen Abu-Fadel, Vipul Shah, Rahul Aggarwal, Mark Izzo, Anil Kumar, Brack Hattler, Rose Do, Chad Link, Anna Bortnick, George Kinzfogl, III, Arnold Ghitis, John Larry, Edward Teufel, Peter Kuhlman, Brent Mclaurin, Wenwu Zhang, Stephen Thew, Jalal Abbas, Matthew White, Othman Islam, Sumeet Subherwal, Nandkishore Ranadive, Babak Vakili, Christian Gring, David Henderson, Timothy Schuchard, Naim Farhat, Geoffrey Kline, Sharan Mahal, Jack Whitaker, Shawn Speirs, Rolf Andersen, Nizar Daboul, Phillip Horwitz, Firas Zahr, George Ponce, Zubair Jafar, Joseph Mcgarvey, Jr, Vipul Panchal, Stephen Voyce, Thomas Blok, William Sheldon, Masoud M. Azizad, Carsten Schmalfuss, Mark Picone, Robert Pederson, William Herzog, Jr, Keith Friedman, Jason Lindsey, Rosemary Nowins, Eichenlaub Timothy, Parilak Leonard, Norman Lepor, Mahfouz El Shahawy, Howard Weintraub, Anand Irimpen, Alvaro Alonso, Wade May, Daniels Christopher, Thomas Galski, Alan Chu, Freny Mody, Ebrahimi Ramin, Zachary Hodes, Joseph Rossi, Gregory Rose, James Fairlamb, Charles Lambert, Jr, Ajit Raisinghani, Antonio Abbate, George Vetrovec, Marilyn King, Charles Carey, Jaime Gerber, Liwa Younis, Hyeun (Tom) Park, Mladen Vidovich, Thomas Knutson, Dennis Friedman, Fred Chaleff, Arthur Loussararian, Phillip Rozeman, Carey Kimmelstiel, Jeffrey Kuvin, Kevin Silver, Malcolm Foster, Glen Tonnessen, Andrey Espinoza, Mohamadali Amlani, Andreas Wali, Christopher Malozzi, Geert T. Jong, Clara Massey, Keattiyoat Wattanakit, Philip J. O’Donnell, Dinesh Singal, Naseem Jaffrani, Sridhar Banuru, Daniel Fisher, Mark Xenakis, Neal Perlmutter, Ravi Bhagwat, James Strader, Jr, Ronald Blonder, Ayim Akyea-Djamson, Ajay Labroo, Kwan Lee, H. John Marais, Edmund Claxton, Jr, Robert Weiss, Rohr Kathryn, Martin Berk, Peter Rossi, Parag Joshi, Amit Khera, Ajit S. Khaira, Greg Kumkumian, Steven Lupovitch, Joshua Purow, Stephen Welka, David Hoffman, Stuart Fischer, Eugene Soroka, Donald Eagerton, Samir Pancholy, Michael Ray, Norman Erenrich, Michael Farrar, Stewart Pollock, William J. French, Steve Diamantis, Douglas Guy, Lawrence Gimple, Mark Neustel, Steven Schwartz, Edward Pereira, Seals Albert, Douglas Spriggs, Janet Strain, Suneet Mittal, Anthony Vo, Majed Chane, Jason Hall, Nampalli Vijay, Kapildeo Lotun, F. Martin Lester, Ahed Nahhas, Theodore Pope, Paul Nager, Rakesh Vohra, Mukesh Sharma, Riyaz Bashir, Hinan Ahmed, Michael Berlowitz, Robert Fishberg, Robert Barrucco, Eric Yang, Michael Radin, Daniel Sporn, Dwight Stapleton, Steven Eisenberg, Joel Landzberg, Martin Mcgough, Samir Turk, Michael Schwartz, P. Sandy Sundram, Diwakar Jain, Mark Zainea, Carlos Bayron, Ronald Karlsberg, Suhail Dohad, Henry Lui, William Keen, Donald Westerhausen, Jr, Sandeep Khurana, Himanshu Agarwal, Jessica Birchem, William Penny, Jr, Mark Chang, Sherrill Murphy, John Henry, Branislav Schifferdecker, John M. Gilbert, Gopal Chalavarya, Charles Eaton, John F. Schmedtje, Jr, Stuart Christenson, Imran Dotani, Douglas Denham, Alexander Macdonell, Paul Gibson, Aref Rahman, Tammam Al Joundi, Nizar Assi, Gary Conrad, Purushotham Kotha, Michael Love, Gregory Giesler, Howard Rubenstein, Dawood Gamil, Laura Akright, Justine Krawczyk, Joanne Cobler, Terry Wells, James Welker, Robert Foster, Richard Gilmore, Jay Anderson, Douglas Jacoby, Bill Harris, Geraldine Gardner, Ramprasad Dandillaya, Kishor Vora, John Kostis, John Hunter, David Laxson, Eric Ball, Terry Wells, Kishor Vora, Eric Ball, James Welker, Renato D. Lopes, Flavia Egydio, Anelise Kawakami, Janaina Oliveira, Julianna Wozniak, Alexander Matthews, Caroline Ratky, Janine Valiris, Lisa Berdan, Anita Hepditch, Kirby Quintero, Tyrus Rorick, Melissa Westbrook, Andrea Pascual, Carla Rovito, Madeleine Bezault, Elodie Drouet, Tabassome Simon, Caroline Alsweiler, Anne Luyten, Julie Butters, Liddy Griffith, Michelle Shaw, Lena Grunberg, Shahidul Islam, Marie-France Brégeault, Nathalie Bougon, Douglas Faustino, Sylvie Fontecave, Judith Murphy, Melanie Verrier, Veronique Agnetti, Dorthe Andersen, Emmy Badreddine, Mhamed Bekkouche, Cecile Bouancheau, Imane Brigui, Maddy Brocklehurst, Joseph Cianciarulo, Dawn Devaul, Szilvia Domokos, Cecile Gache, Caroline Gobillot, Severine Guillou, Jan Healy, Megan Heath, Gayatri Jaiwal, Carine Javierre, Julien Labeirie, Myriam Monier, Ulises Morales, Asmaa Mrabti, Bicky Mthombeni, Betim Okan, Lucile Smith, Jennifer Sheller, Sebastien Sopena, Valerie Pellan, Fadela Benbernou, Nafissa Bengrait, Maud Lamoureux, Katarina Kralova, Michel Scemama, Raphael Bejuit, Anthony Coulange, Christelle Berthou, Jérôme Repincay, Christelle Lorenzato, Alexis Etienne, Valerie Gouet, Guillaume Lecorps, Virginie Loizeau, Mickael Normand, Anne Ourliac, Christelle Rondel, Antony Adamo, Pascale Beltran, Pauline Barraud, Helene Dubois-Gache, Benjamin Halle, Lamia Metwally, Maxime Mourgues, Marc Sotty, Marion Vincendet, Raluca Cotruta, Zhu Chengyue, Dominique Fournie-Lloret, Christine Morrello, Aurelie Perthuis, Patrick Picault, Isabelle Zobouyan, Helen M. Colhoun, Michael A. Dempsey, and Mark A. McClanahan

References

1. Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol 2017;69:692–711 [DOI] [PubMed] [Google Scholar]
2. Gurdasani D, Sjouke B, Tsimikas S, et al. Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol 2012;32:3058–3065 [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Langsted A, Nordestgaard BG, Kamstrup PR. Elevated lipoprotein(a) and risk of ischemic stroke. J Am Coll Cardiol 2019;74:54–66 [DOI] [PubMed] [Google Scholar]
4. Laschkolnig A, Kollerits B, Lamina C, et al. Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts. Cardiovasc Res 2014;103:28–36 [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Sabatine MS, Giugliano RP, Keech AC, et al.; FOURIER Steering Committee and Investigators . Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–1722 [DOI] [PubMed] [Google Scholar]
6. Schwartz GG, Steg PG, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators . Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–2107 [DOI] [PubMed] [Google Scholar]
7. Bittner VA, Szarek M, Aylward PE, et al.; ODYSSEY OUTCOMES Committees and Investigators . Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020;75:133–144 [DOI] [PubMed] [Google Scholar]
8. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–1492 [DOI] [PubMed] [Google Scholar]
9. Marston NA, Gurmu Y, Melloni GEM, et al. The effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of venous thromboembolism. Circulation 2020;141:1600–1607 [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Schwartz GG, Steg PG, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators* . Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial. Circulation 2020;141:1608–1617 [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Tromp TR, Stroes ESG, Hovingh GK. Gene-based therapy in lipid management: the winding road from promise to practice. Expert Opin Investig Drugs 2020;29:483–493 [DOI] [PubMed] [Google Scholar]
12. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al.; AKCEA-APO(a)-LRx Study Investigators . Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244–255 [DOI] [PubMed] [Google Scholar]
13. Gudbjartsson DF, Thorgeirsson G, Sulem P, et al. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J Am Coll Cardiol 2019;74:2982–2994 [DOI] [PubMed] [Google Scholar]
14. Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther 2016;30:87–100 [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Ye Z, Haycock PC, Gurdasani D, et al. The association between circulating lipoprotein(a) and type 2 diabetes: is it causal? Diabetes 2014;63:332–342 [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Kaya A, Onat A, Yüksel H, Can G, Yüksel M, Ademoğlu E. Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes. Postgrad Med 2017;129:611–618 [DOI] [PubMed] [Google Scholar]
17. Mora S, Kamstrup PR, Rifai N, Nordestgaard BG, Buring JE, Ridker PM. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem 2010;56:1252–1260 [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol 2017;16:38. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682–689 [DOI] [PubMed] [Google Scholar]
20. Ray KK, Colhoun HM, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators . Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol 2019;7:618–628 [DOI] [PubMed] [Google Scholar]
21. Scharnagl H, Stojakovic T, Dieplinger B, et al. Comparison of lipoprotein (a) serum concentrations measured by six commercially available immunoassays. Atherosclerosis 2019;289:206–213 [DOI] [PubMed] [Google Scholar]
22. Dahlen GH. Incidence of Lp(a) Among Populations. San Diego, CA, Academic Press, 1990 [Google Scholar]
23. Kinpara K, Okada H, Yoneyama A, Okubo M, Murase T. Lipoprotein(a)-cholesterol: a significant component of serum cholesterol. Clin Chim Acta 2011;412:1783–1787 [DOI] [PubMed] [Google Scholar]
24. Vaverková H, Karásek D, Halenka M, Cibíčková L, Kubíčková V. Inverse association of lipoprotein (a) with markers of insulin resistance in dyslipidemic subjects. Physiol Res 2017;66(Suppl. 1):S113–S120 [DOI] [PubMed] [Google Scholar]
25. Kamstrup PR, Nordestgaard BG. Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol 2013;1:220–227 [DOI] [PubMed] [Google Scholar]
26. Mu-Han-Ha-Li D-L-D-E, Zhai T-Y, Ling Y, Gao X. LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk. J Lipid Res 2018;59:884–891 [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Tolbus A, Mortensen MB, Nielsen SF, Kamstrup PR, Bojesen SE, Nordestgaard BG. Kringle IV type 2, not low lipoprotein(a), as a cause of diabetes: a novel genetic approach using SNPs associated selectively with lipoprotein(a) concentrations or with kringle IV type 2 repeats. Clin Chem 2017;63:1866–1876 [DOI] [PubMed] [Google Scholar]
28. Buchmann N, Scholz M, Lill CM, et al. Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin. Acta Diabetol 2017;54:1031–1038 [DOI] [PubMed] [Google Scholar]
29. Betteridge DJ, Carmena R. The diabetogenic action of statins - mechanisms and clinical implications. Nat Rev Endocrinol 2016;12:99–110 [DOI] [PubMed] [Google Scholar]
30. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144–2153 [DOI] [PubMed] [Google Scholar]
31. Lotta LA, Sharp SJ, Burgess S, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA 2016;316:1383–1391 [DOI] [PMC free article] [PubMed] [Google Scholar]
32. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 2015;313:1029–1036 [DOI] [PubMed] [Google Scholar]
33. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 2009;94:2537–2543 [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Baass A, Dubuc G, Tremblay M, et al. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem 2009;55:1637–1645 [DOI] [PubMed] [Google Scholar]
35. Hamamura H, Adachi H, Enomoto M, et al. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is independently associated with insulin resistance, triglycerides, lipoprotein(a) levels but not low-density lipoprotein cholesterol levels in a general population. J Atheroscler Thromb. 4 July 2020 [Epub ahead of print]. DOI: 10.5551/jat.56390 [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Ferri N, Ruscica M. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome: insights on insulin resistance, inflammation, and atherogenic dyslipidemia. Endocrine 2016;54:588–601 [DOI] [PubMed] [Google Scholar]
37. Cariou B, Langhi C, Le Bras M, et al. Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets. Nutr Metab (Lond) 2013;10:4. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Desai NR, Giugliano RP, Wasserman SM, et al. Association between circulating baseline proprotein convertase subtilisin kexin type 9 levels and efficacy of evolocumab. JAMA Cardiol 2017;2:556–560 [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Blom DJ, Koren MJ, Roth E, et al. Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome. Diabetes Obes Metab 2017;19:98–107 [DOI] [PubMed] [Google Scholar]
40. Haynes R, Valdes-Marquez E, Hopewell JC, et al.; HPS2-THRIVE Collaborative Group; HPS2-THRIVE Writing Committee members; HPS2-THRIVE Steering Committee members . Serious adverse effects of extended-release niacin/laropiprant: results from the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial. Clin Ther 2019;41:1767–1777 [DOI] [PubMed] [Google Scholar]
41. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082–e1143 [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556–2564 [DOI] [PubMed] [Google Scholar]

[B1] 1. Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol 2017;69:692–711 [DOI] [PubMed] [Google Scholar]

[B2] 2. Gurdasani D, Sjouke B, Tsimikas S, et al. Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol 2012;32:3058–3065 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B3] 3. Langsted A, Nordestgaard BG, Kamstrup PR. Elevated lipoprotein(a) and risk of ischemic stroke. J Am Coll Cardiol 2019;74:54–66 [DOI] [PubMed] [Google Scholar]

[B4] 4. Laschkolnig A, Kollerits B, Lamina C, et al. Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts. Cardiovasc Res 2014;103:28–36 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B5] 5. Sabatine MS, Giugliano RP, Keech AC, et al.; FOURIER Steering Committee and Investigators . Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–1722 [DOI] [PubMed] [Google Scholar]

[B6] 6. Schwartz GG, Steg PG, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators . Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–2107 [DOI] [PubMed] [Google Scholar]

[B7] 7. Bittner VA, Szarek M, Aylward PE, et al.; ODYSSEY OUTCOMES Committees and Investigators . Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020;75:133–144 [DOI] [PubMed] [Google Scholar]

[B8] 8. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–1492 [DOI] [PubMed] [Google Scholar]

[B9] 9. Marston NA, Gurmu Y, Melloni GEM, et al. The effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of venous thromboembolism. Circulation 2020;141:1600–1607 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B10] 10. Schwartz GG, Steg PG, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators* . Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial. Circulation 2020;141:1608–1617 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B11] 11. Tromp TR, Stroes ESG, Hovingh GK. Gene-based therapy in lipid management: the winding road from promise to practice. Expert Opin Investig Drugs 2020;29:483–493 [DOI] [PubMed] [Google Scholar]

[B12] 12. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al.; AKCEA-APO(a)-LRx Study Investigators . Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244–255 [DOI] [PubMed] [Google Scholar]

[B13] 13. Gudbjartsson DF, Thorgeirsson G, Sulem P, et al. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J Am Coll Cardiol 2019;74:2982–2994 [DOI] [PubMed] [Google Scholar]

[B14] 14. Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther 2016;30:87–100 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B15] 15. Ye Z, Haycock PC, Gurdasani D, et al. The association between circulating lipoprotein(a) and type 2 diabetes: is it causal? Diabetes 2014;63:332–342 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B16] 16. Kaya A, Onat A, Yüksel H, Can G, Yüksel M, Ademoğlu E. Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes. Postgrad Med 2017;129:611–618 [DOI] [PubMed] [Google Scholar]

[B17] 17. Mora S, Kamstrup PR, Rifai N, Nordestgaard BG, Buring JE, Ridker PM. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem 2010;56:1252–1260 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B18] 18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol 2017;16:38. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B19] 19. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682–689 [DOI] [PubMed] [Google Scholar]

[B20] 20. Ray KK, Colhoun HM, Szarek M, et al.; ODYSSEY OUTCOMES Committees and Investigators . Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol 2019;7:618–628 [DOI] [PubMed] [Google Scholar]

[B21] 21. Scharnagl H, Stojakovic T, Dieplinger B, et al. Comparison of lipoprotein (a) serum concentrations measured by six commercially available immunoassays. Atherosclerosis 2019;289:206–213 [DOI] [PubMed] [Google Scholar]

[B22] 22. Dahlen GH. Incidence of Lp(a) Among Populations. San Diego, CA, Academic Press, 1990 [Google Scholar]

[B23] 23. Kinpara K, Okada H, Yoneyama A, Okubo M, Murase T. Lipoprotein(a)-cholesterol: a significant component of serum cholesterol. Clin Chim Acta 2011;412:1783–1787 [DOI] [PubMed] [Google Scholar]

[B24] 24. Vaverková H, Karásek D, Halenka M, Cibíčková L, Kubíčková V. Inverse association of lipoprotein (a) with markers of insulin resistance in dyslipidemic subjects. Physiol Res 2017;66(Suppl. 1):S113–S120 [DOI] [PubMed] [Google Scholar]

[B25] 25. Kamstrup PR, Nordestgaard BG. Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol 2013;1:220–227 [DOI] [PubMed] [Google Scholar]

[B26] 26. Mu-Han-Ha-Li D-L-D-E, Zhai T-Y, Ling Y, Gao X. LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk. J Lipid Res 2018;59:884–891 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B27] 27. Tolbus A, Mortensen MB, Nielsen SF, Kamstrup PR, Bojesen SE, Nordestgaard BG. Kringle IV type 2, not low lipoprotein(a), as a cause of diabetes: a novel genetic approach using SNPs associated selectively with lipoprotein(a) concentrations or with kringle IV type 2 repeats. Clin Chem 2017;63:1866–1876 [DOI] [PubMed] [Google Scholar]

[B28] 28. Buchmann N, Scholz M, Lill CM, et al. Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin. Acta Diabetol 2017;54:1031–1038 [DOI] [PubMed] [Google Scholar]

[B29] 29. Betteridge DJ, Carmena R. The diabetogenic action of statins - mechanisms and clinical implications. Nat Rev Endocrinol 2016;12:99–110 [DOI] [PubMed] [Google Scholar]

[B30] 30. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144–2153 [DOI] [PubMed] [Google Scholar]

[B31] 31. Lotta LA, Sharp SJ, Burgess S, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA 2016;316:1383–1391 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B32] 32. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 2015;313:1029–1036 [DOI] [PubMed] [Google Scholar]

[B33] 33. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 2009;94:2537–2543 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B34] 34. Baass A, Dubuc G, Tremblay M, et al. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem 2009;55:1637–1645 [DOI] [PubMed] [Google Scholar]

[B35] 35. Hamamura H, Adachi H, Enomoto M, et al. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is independently associated with insulin resistance, triglycerides, lipoprotein(a) levels but not low-density lipoprotein cholesterol levels in a general population. J Atheroscler Thromb. 4 July 2020 [Epub ahead of print]. DOI: 10.5551/jat.56390 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B36] 36. Ferri N, Ruscica M. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome: insights on insulin resistance, inflammation, and atherogenic dyslipidemia. Endocrine 2016;54:588–601 [DOI] [PubMed] [Google Scholar]

[B37] 37. Cariou B, Langhi C, Le Bras M, et al. Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets. Nutr Metab (Lond) 2013;10:4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B38] 38. Desai NR, Giugliano RP, Wasserman SM, et al. Association between circulating baseline proprotein convertase subtilisin kexin type 9 levels and efficacy of evolocumab. JAMA Cardiol 2017;2:556–560 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B39] 39. Blom DJ, Koren MJ, Roth E, et al. Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome. Diabetes Obes Metab 2017;19:98–107 [DOI] [PubMed] [Google Scholar]

[B40] 40. Haynes R, Valdes-Marquez E, Hopewell JC, et al.; HPS2-THRIVE Collaborative Group; HPS2-THRIVE Writing Committee members; HPS2-THRIVE Steering Committee members . Serious adverse effects of extended-release niacin/laropiprant: results from the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial. Clin Ther 2019;41:1767–1777 [DOI] [PubMed] [Google Scholar]

[B41] 41. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082–e1143 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B42] 42. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556–2564 [DOI] [PubMed] [Google Scholar]

PERMALINK

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Gregory G Schwartz

Michael Szarek

Vera A Bittner

Deepak L Bhatt

Rafael Diaz

Shaun G Goodman

J Wouter Jukema

Megan Loy

Garen Manvelian

Robert Pordy

Harvey D White

Philippe Gabriel Steg

Abstract

OBJECTIVE

RESEARCH DESIGN AND METHODS

RESULTS

CONCLUSIONS

Introduction

Research Design and Methods

Patients and Treatments

Definition of Baseline and Incident Diabetes

Measurement of Lipoproteins

Statistical Analysis

Results

Patient Characteristics and Association With Baseline Lipoprotein(a) Concentration

Table 1.

Incident Type 2 Diabetes, According to Baseline Lipoprotein(a) Concentration, and Effect of Alirocumab Treatment

Figure 1.

Figure 2.

MACE in Patients Without Diabetes at Baseline According to Baseline Lipoprotein(a) Concentration

Lipoprotein(a) Lowering by Alirocumab and Its Association With Incident Type 2 Diabetes

Table 2.

Relationship Between Lipoprotein(a) and Glycemic Measures in Patients With Diabetes at Baseline

Conclusions

Mechanisms Linking Lipoprotein(a) With Type 2 Diabetes

Effect of PCSK9 Inhibition With Alirocumab on Incident Type 2 Diabetes

Relation of Lipoprotein(a) and Alirocumab Treatment to Glycemic Measures in Patients With Diabetes at Baseline

Strengths and Limitations

Clinical Implications

Conclusion

Article Information

Footnotes

Contributor Information

References

ACTIONS

PERMALINK

RESOURCES

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