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R3i EVENTS
VAS and R3i Multidisciplinary Joint Scientific Session
“Residual Risk”
30th nov 2014, 8:30 - 10:00
VAS 2014
LATEST
Landmark study
Statins and microvascular risk
Focus on...
PCSK9 inhibition in the corner: new data on safety and efficacy
PCSK9 slidekit
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The National Lipid Association (NLA)
The National Lipid Association (NLA) is a nonprofit, multidisciplinary medical society focused on enhancing the practice of lipid management in clinical medicine.
MSDA 2014 HIGHLIGHTS REPORT
9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis (MSDA) Congress
Kyoto, Japan, 12-14 September, 2014

Escalating rates of obesity, metabolic syndrome and type 2 diabetes are driving a major epidemic of cardiovascular disease (CVD). This is not just an issue affecting Western populations but a worldwide health problem.

MSDA 2014 - Prof Shinya Yamanaka

Nobel Prize of Medicine 2012, Professor Shinya Yamanaka (Kyoto, Japan) provided an overview of the development and future for iPSC technology. The discovery that it was possible to re-programme readily accessible somatic cells so that they became pluripotent, with the capacity to develop into many different cell types, is rightly a major breakthrough. Although still in its infancy, this new technology offers the hope of new cures for a range of degenerative diseases, as well as future potential for management of diabetes. As Professor Yamanaka commented: iPSC research is not just for understanding disease mechanisms, the ultimate goal is the application of this novel technology to patients. In other words, iPSC technology takes the concept of personalised medicine to new levels.

MSDA 2014 report
MSDA 2014 - Experts interviews - Part 1 / 3
Prof. Nabil Seidah
Montréal, Canada
Prof. Hidenori Arai
Kyoto, Japan
RECENT PUBLICATIONS
• USA National Lipid Association publishes recommendations for management of dyslipidaemia
In contrast to the recent ACC/AHA guideline for management of cholesterol,1,2 the NLA recommendations emphasise the importance of cholesterol goals in clinical practice, not only for clinicians to use in monitoring the efficacy of treatment, but also for patients to understand and work toward. These recommendations favour the use of non-HDL cholesterol, which includes all potentially atherogenic lipoproteins, i.e. low-density lipoprotein, intermediate density lipoproteins, very low-density lipoproteins (VLDL) and VLDL remnants, chylomicron remnants, and lipoprotein (a), as the preferable marker for risk for cardiovascular disease and to monitor therapy. The NLA also provides recommendations for the management of elevated triglycerides, closely associated with metabolic syndrome, obesity and diabetes, and an important contributor to residual cardiovascular risk. The use of fibrates, niacin or omega-3 fatty acids can be considered if triglyceride goals are not reached with statins alone.
br> 1. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934. 2. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S1-45.
National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 – executive summary.
Jacobson TA, Ito MK, Maki KC et al.
• ODYSSEY COMBO II: PCSK9 inhibitor alirocumab in high cardiovascular risk patients on statin therapy
In ODYSSEY COMBO II, the addition of the PCSK9 monoclonal antibody therapy, alirocumab, to maximally tolerated statin therapy resulted in superior control of low-density lipoprotein cholesterol (LDL-C) compared with oral ezetimibe in high cardiovascular risk patients with inadequately controlled LDL-C levels. This double-blind, multicentre study enrolled 720 patients (LDL-C =1.81 mmol/L [=70 mg/dL] in patients with established cardiovascular disease (CVD), or =2.59 mmol/L (=100 mg/dL) if no history of CVD but with other risk factors). Patients were randomised 2:1 to either alirocumab 75 mg subcutaneously every 2 weeks (increasing to 150 mg every 2 weeks at Week 12 if LDL-C was =1.81 mmol/L at Week 8) or ezetimibe 10 mg daily. The primary endpoint (% change in LDL-C from baseline to Week 24, intent-to-treat analysis), showed that treatment with alirocumab was significantly superior to ezetimibe (51% versus 21%, p<0.0001). This "treat to target" approach with alirocumab resulted in >75% of alirocumab-treated patients achieving guideline-recommended LDL-C goals (<1.81 mmol/L or<70 mg/dL) at 24 weeks. Consistent LDL-C reductions were maintained over 52 weeks (mean percent LDL-C reduction 50% versus 18% with ezetimibe, absolute LDL-C reduction 2.2 versus 1.4 mmol/L). Treatment with alirocumab was well tolerated with no adverse signal, compared with ezetimibe. In conclusion, the addition of the PCSK9 monoclonal antibody alirocumab significantly improved attainment of LDL-C goal in high CV risk patients.
Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study.
Cannon CP, Cariou B, Blom D et al.
ESC Congress, Hotline II. 31 August, 2014 [Abstract 2123].
• Antisense inhibitor of apolipoprotein C-III improves the atherogenic lipoprotein profile
ISIS-APOCIIIRx selectively inhibits hepatic synthesis of apolipoprotein (apo)C-III, which has a key role in regulating plasma triglyceride (TG) levels. The current study investigated the effect of treatment with ISIS-APOCIIIRx, either as a single agent or in combination with fibrates, on fasting lipids and lipoproteins in patients with hypertriglyceridaemia (HTG) and 1) with type 2 diabetes on = 1g/day stable metformin and not on TG-lowering medication; 2) not on TG-lowering medication or (3) on stable fibrate therapy. Treatment with ISIS-APOCIIIRx resulted in consistent and significant dose-dependent decreases in apoC-III and TG, as well as increases in high-density lipoprotein cholesterol (HDL-C), with no significant change in non-HDL-C, when given alone or in combination with a fibrate (see Table). These data support further evaluation of ISIS-APOCIIIRx, either alone or in combination with a fibrate, in the management of HTG.

Mean (SD) Percent change from baseline to 13 weeks, after treatment with ISIS-APOCIIIRx

ParameterHTG with diabetes ISIS-APOCIIIRx + metformin (n=7) ISIS-APOCIIIRx (n=11) ISIS-APOCIIIRx + fibrate (n=10)
ApoCIII -88 (6.0)* -80 (9.3)*** -71 (13.0)**
Triglycerides -72 (8.3)* -71 (14.1)*** -64 (8.9)**
HDL-C +40 (19.8)* +46 (24.0)***+52 (23.7)***

*p=0.05, **p=0.01, ***p=0.001
Antisense inhibitor of apoC-III produces significant decreases in apoC-III and triglycerides and increases in HDL-C as a single agent or in combination with fibrates in hypertriglyceridemic patients.
Alexander VJ, Gaudet D, Brisson D et al.
Eur Heart J 2014;35(Abstract Supplement):218-219. Abstract P1275.
• K-877, a SPPARM, favourably influences postprandial metabolism of remnant lipoproteins
This experimental animal model showed that the potent and selective peroxisome proliferator-activated receptor alpha (PPARa) agonist, K-877, attenuates fasting and postprandial hypertriglyceridaemia by enhancing lipoprotein lipase (LPL) activity and reducing weight gain. The study used male C57BL/6J mice, which were fed either a western diet (WD), WD containing K-877 (0.0005%) or WD containing fenofibrate (0.05%) for 4 weeks (n=10/group). Compared with the WD group, fasting triglycerides were significantly lower with K-877 (81.0±21.5 versus 32.0±8.7 mg/dL) or fenofibrate (81.0±21.5 versus 29.7±8.8 mg/); p<0.01 for each treatment group versus WD. Additionally, LPL activity was significantly increased in mice treated with K-877 or fenofibrate suggesting that both prevent the accumulation of remnant lipoproteins by increasing LPL activity. Treatment with K-877 or fenofibrate was also associated with less weight gain although dietary intake was similar. These findings from this experimental model indicate that treatment with K-877 improves postprandial hypertriglyceridaemia, and provide a rationale for investigation in humans.
A novel potent and selective PPARalpha agonist, K-877, ameriolates the atherogenic profile of fasting and postprandial hypertriglyceridemia in mice.
Masuda D, Kobayashi T, Nakaoka H et al.
Eur Heart J 2014;35( Abstract Supplement):904. Abstract: P5145.
• Atherogenic dyslipidaemia associated with increased coronary artery progression in diabetes
This study highlights the importance of managing atherogenic dyslipidaemia, elevated triglycerides (TG) and low plasma concentration of high-density lipoprotein cholesterol (HDL-C), to reduce atherosclerosis progression in patients with diabetes. A total of 109 patients (mean age 68±9 years, 31% female, 89% on statins) were included. Atheroma burden was assessed using intravascular ultrasound (IVUS), performed at baseline and a median of 1.3 years (474 days) later. The primary endpoints were normalised total atheroma volume (TAV) and percent atheroma volume (PAV), calculated in the target segment in each patient. Patients with inadequate control of both HDL-C (<40 mg/dL or 1.03 mmol/L) and TG (>150 mg/dL or 1.7 mmol/L) showed greatest coronary artery progression, as defined by both the change in TAV (7.7±21.9 mm3 versus -3.8±19.3 mm3 in patients with controlled levels p=0.006) and by the change in PAV (1.2±4.9% versus 0.5±3.4%, p=0.034). These findings emphasise the importance of atherogenic dyslipidaemia as a contributor to residual risk of coronary atherosclerosis in statin-treated patients with diabetes.
Progression of coronary atherosclerosis: importance of adequate lipid control in diabetic patients.
Hernando Marrupe L, Suarez Cuervo A, Hernandez Antolin R et al.
Eur Heart J 2014;35(Abstract Supplement): 393-394. Abstract P2281.
• FOCUS: a polypill strategy improves treatment adherence in post-MI patients
The Residual Risk Reduction Initiative has already drawn attention to unmet clinical needs in the management of secondary prevention patients. For example, in the Prospective Urban Rural Epidemiology (PURE) study, only 15% of patients were taking statins 5 years after a myocardial infarction (MI), and use was substantially lower in low to middle income countries.1 These data highlight the need for education and re-thinking of strategies to improve management in these high-risk patients. Subsequently, the use of a once-daily fixed-dose combination - or polypill - including key medications to reduce cardiovascular risk has shown promise in studies of patients with established cardiovascular disease.2 However, to date there has been no direct evaluation of the impact of this polypill strategy on treatment adherence. Consequently, the FOCUS (Fixed Dose Combination Drug for Secondary Cardiovascular Prevention) project aimed to better understand adherence to medication in the post-MI setting.

The study involved two phases:
Phase 1, a comprehensive analysis of factors that determine the appropriate use of preventive interventions including 2,118 patients in 5 countries (Argentina, Brazil, Italy, Paraguay, and Spain);
and Phase 2, a randomised, controlled clinical trial (695 patients from those previously included in Phase I) testing the effect of a fixed combination of aspirin 100 mg, simvastatin 40 mg and ramipril 2.5, 5 or 10 mg, versus treatment with the individual agents, on adherence and control of cardiovascular risk factors.

In Phase I, overall adherence was 45.5% (=20 on the self-reported Morisky-Green questionnaire); younger age, depression, being on a complex medication regimen, poorer health, insurance coverage, and a lower level of social support were all associated with reduced risk of treatment adherence across all five countries. In Phase 2, patients in the polypill group had significantly improved adherence compared with the group receiving the medications separately; after 9 months, adherence (assessed by a score of =20 on the self-reported Morisky-Green questionnaire and high pill count [80-110%]) was 51% vs 41% (p=0.019; intention-to-treat population). There was no difference in mean low-density lipoprotein cholesterol levels at follow-up (89.9 vs 91.7 mg/dL). The authors concluded that the use of a polypill significantly improves treatment adherence compared with concomitant use of three individual therapies. Longer-term trials are required to evaluate whether this improved adherence translates to improved clinical benefit.

1. Yusuf S, Islam S, Chow CK et al. Prospective Urban Rural Epidemiology Study I. Use of secondary prevention drugs for cardiovascular disease in the community in high income, middle-income, and low-income countries (the pure study): A prospective epidemiological survey. Lancet 2011;378:1231-43.
2. Thom S, Poulter N, Field J et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: The umpire randomized clinical trial. JAMA 2013;310:918-29.
A polypill strategy to improve adherence: results from FOCUS (Fixed-dose Combination Drug for Secondary Cardiovascular Prevention) Project.
Castellano JM, Sanz G, Peñalvo JL et al.
• Fasting and postprandial triglycerides: similarly effective as predictors for cardiovascular events
This study evaluated the association between fasting and postprandial serum triglycerides (TG) as risk modifiers in patients with coronary artery disease (CAD) treated with a statin. In total, the cohort included 514 patients (median age 68 years, 83% male) with angiographically confirmed, clinically stable CAD, 95% of whom were on a statin (median LDL-cholesterol 105 mg/dL). Both fasting and postprandial TG predicted cardiovascular events:
• Fasting TG (>150 mg/dL versus <106 mg/Dl): Hazard ratio 1.79, 95%-CI 1.31-2.45, p=0.0001
• Nonfasting TG AUC >1120 mg/dL vs. <750 mg/dL: Hazard ratio 1.78, 95%-CI 1.29-2.45, p=0.0003.
Risk prediction by TG was independent of traditional risk factors, medication, glucose metabolism, LDL- and HDL-cholesterol. The authors concluded that postprandial TG does not improve risk prediction over fasting TG in statin-treated patients with CAD.
Fasting serum triglycerides >150 mg/dl independently predict cardiovascular events in patients with coronary artery disease on guideline-recommended medication.
Werner C, Filmer A, Groenewold S et al.
• BMI plus visceral adipose tissue improves prediction of cardiovascular risk
Adding a measure of visceral adipose tissue (VAT) to body mass index (BMI) provides a better predictor of cardiovascular risk, according to this study. A total of 369 consecutive patients without a history of cardiovascular disease were enrolled. VAT was assessed using 64-slice computed tomography angiography (CTA), with the percent VAT calculated as VAT/(VAT + subcutaneous adipose tissue) × 100, and its median value was 39.4%. Patients were divided into four groups based on BMI (<25 and 25=) and %VAT (<39.4 and 39.4=). Cardiovascular risk factors were hypertension, hyperglycaemia, and dyslipidaemia. Over the median follow-up of 2020 days, there were 32 cardiovascular events. Cox proportional hazards analysis showed that the risk of a cardiovascular event was higher in patients with both elevated BMI and VAT, after adjustment for confounding factors (see Table). On the basis of these findings, assessing both VAT and BMI may provide added value in cardiovascular risk assessment.
Hazard ratio (% CI) for major adverse cardiovascular events, after adjustment for cardiovascular risk factors

CategoryHR (95% CI)p-value
BMI =25 kg/m2 and higher %VATVs. BMI<25 kg/m2 with lower %VAT4.38, 1.58–12.18 0.005
Vs. BMI<25 kg/m2 with higher %VAT2.74, 1.18–6.35 0.02
Vs. BMI=25 kg/m2 with lower %VAT4.68, 0.98-22.51 0.05

Impact of body mass index and visceral adipose tissue on cardiovascular risk factors and outcomes.
Kunimura A, Uetani T, Harada K et al.
Eur Heart J 2014;35(Abstract Supplement):558. [Abstract P3185].
• Incretin-based therapies favourably impact metabolic and cardiovascular risk
There is ongoing debate relating to the effects of incretin-based therapies on cardiovascular risk parameters, including lipids. This meta-analysis of 28 trials (10,171 patients with diabetes) showed that incretin-based therapies significantly reduced triglycerides (-0.29 mmol/L, 95% CI -0.48 to -0.11; p=0.002) and raised high density lipoprotein cholesterol (0.03 mmol/L, 95% Cl 0.0003-0.06; p=0.05, respectively), compared with other diabetes treatments. On the basis of these findings, not only do incretin-based therapies lower blood glucose in patients with type 2 diabetes, but there are also significant positive effects on the lipid profile.
The effect of incretin-based therapies on metabolic and cardiovascular parameters in diabetic patients: A meta-analysis of 28 randomized control trials with 10171 patients.
Klepacka A, Nikfar S, Rizzo M et al.
Eur Heart J 2014;35(Abstract Supplement): 740. [Abstract: P4239]