Future Directions to Establish Lipoprotein(a) as a Treatment for Atherosclerotic Cardiovascular Disease

In both epidemiologic and genetic studies, increased levels of Lp(a) have been associated with increased risk for cardiovascular diseases as well as aortic stenosis. However, until recently, it has been difficult to lower levels of Lp(a). Diet and lifestyle have little effect on plasma levels of Lp(a) which are mainly genetically determined. Emerging therapeutic agents which have recently become available, or which are undergoing clinical trials, can significantly lower Lp(a) levels. Studies with these agents will hopefully be able to provide more direct information whether reductions in Lp(a) will reduce CVD events independently of reduction in LDL-cholesterol levels.     

trans‐resveratrol alone and hydroxystilbenes of rhubarb (Rheum rhaponticum L.) root reduce liver damage induced by chronic ethanol administration: a comparative study in mice

The hepatoprotective effects and pharmacokinetics of trans‐resveratrol and hydroxystilbenes of the garden rhubarb (Rheum rhaponticum L., R. rhaponticum) root ethanol extract were studied. Ethanol was administered to male BALB/c mice for 35 days in an inhalation chamber. During this time vehicle, trans‐resveratrol (20 mg/kg per day) or R. rhaponticum extract was intraperitoneally (i.p.) administered and mice were sacrificed for the collection of liver and blood. In an additional experiment, the level of parent compounds and metabolites was estimated in the blood after acute i.p. administration of trans‐resveratrol or R. rhaponticum extract. The levels of hydroxystilbenes, their metabolites and fatty acid oxy‐metabolites (oxylipins) were studied by LC‐tandem DAD‐MS/MS. Ethanol induced hepatotoxicity, as evidenced by histological changes and accumulation of oxylipins in the blood. Both trans‐resveratrol and R. rhaponticum extract reduced the extent of these changes. The pharmacokinetics of trans‐resveratrol was characterized by a rapid removal from the blood and metabolism to sulfates and glucuronides. After the administration of R. rhaponticum extract, in addition to trans‐resveratrol glucoside and its metabolites, several other hydroxystilbenes were found. Inhibition of oxidation of polyunsaturated fatty acids is proposed as a basis of the hepatoprotective effect of both trans‐resveratrol and R. rhaponticum extract. Copyright © 2008 John Wiley & Sons, Ltd.     

Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia

Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P<0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P<0.01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r=0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.     

Postprandial lipaemia, metabolic syndrome and LDL particle size in urbanised South African blacks with and without coronary artery disease

BACKGROUND: Postprandial lipaemia, characterised by a rise in triglycerides (TG) after eating, is associated with coronary artery disease (CAD) and metabolic syndrome (MetS). Small, dense, low-density lipoprotein (LDL) particles are implicated in atherogenesis. Little is known about postprandial lipaemia or small, dense LDL particles in urbanised black South Africans. AIMS: Assess postprandial lipaemia in black CAD patients with and without MetS and measure their fasting and postprandial lipid profiles and LDL particles. METHODS: Anthropometric data, biochemical variables and LDL particles were measured in 40 patients and 20 control subjects. Twenty three patients met International Diabetes Federation criteria for MetS and were subdivided according to fasting TG concentration either < or > or = 1.7 mmol/l. Postprandial lipaemia was assessed by an oral fat tolerance test (OFTT) and area under the curve (AUC). RESULTS: CAD patients with and without MetS had similar fasting lipid profiles, postprandial responses during OFTT and AUCs. MetS patients with fasting TG > or = 1.7 mmol/l had greater postprandial responses (P < 0.001) and higher AUC (P < 0.0001) than patients with TG < 1.7 mmol/l. AUC was higher in all patients than controls (P < 0.03). The most significant correlation was between fasting TG and AUC (r = 0.8703; P < 0.0001). Small, dense LDL particles were present in 29 patients (72.5%) and 3 controls (15%) (p = 0.0001). CONCLUSION: Postprandial lipaemia was common in black CAD patients, including patients with MetS. Fasting TG concentration was the strongest determinant. Small, dense LDL particles were highly associated with CAD.     

Glycaemic,blood pressure and cholesterol control in 25 629 diabetics

Objective

To examine and compare the extent to which people with type 2 diabetes (T2DM) are achieving haemoglobin A_1c (HbA_1c), blood pressure (BP) and LDL cholesterol (LDL-C) treatment targets.

Methods

A review of databases (MEDLINE Ovid, Pubmed and Sabinet) was performed and limited to the following terms: type 2 diabetes mellitus AND guideline AND goal achievement for the years 2009 to 2014 (five years).

Results

A total of 14 studies (25 629 patients) were selected across 19 different countries. An HbA_1c level of 7.0% (or less) was achieved by 44.5% of subjects (range 19.2–70.5%), while 35.2% (range 7.4–66.3%) achieved BP of 130/80 mmHg (or less), and 51.4% (range 20.0–82.9%) had an LDL-C level of either 2.5 or 2.6 mmol/l (100 mg/dl or less).

Conclusion

Despite guideline recommendations that lowering of HbA_1c, BP and lipids to target levels in T2DM will lead to a reduction in morbidity and mortality rates, we found that control of these risk factors remains suboptimal, even across different settings.     

Different lipid profiles according to ethnicity in the Heart of Soweto study cohort of de novo presentations of heart disease

Background

Historically, sub-Saharan Africa has reported low levels of atherosclerotic cardiovascular disease (CVD). However as these populations undergo epidemiological transition, this may change.

Methods

This was an observational cohort study performed at Chris Hani Baragwanath Hospital in Soweto, South Africa. As part of the Heart of Soweto study, a clinical registry captured detailed clinical data on all de novo cases of structural and functional heart disease presenting to the Cardiology unit during the period 2006 to 2008. We examined fasting lipid profiles in 2 182 patients (of 5 328 total cases) according to self-reported ethnicity. The study cohort comprised 1 823 patients of African descent (61% female, aged 56 ± 16 years), 142 white Europeans (36% female, aged 57 ± 13 years), 133 Indians (51% female, aged 59 ± 12 years) and 87 of mixed ancestry (40% female, aged 56 ± 12 years).

Results

Consistent with different patterns in heart disease aetiology, there were clear differences in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides across ethnicities (p < 0.001): patients of African descent had the lowest TC and LDL-C levels and Indians the highest. However, there were no significant differences in high-density lipoprotein cholesterol (HDL-C) levels between ethnicities (p = 0.20). Adjusting for age, gender and body mass index, patients of African descent were significantly less likely to record a TC of > 4.5 mmol/l (OR 0.33, 95% CI: 0.25–0.41) compared to all ethnic groups (all p < 0.001).

Conclusions

These data confirm important blood lipid differentials according to ethnicity in patients diagnosed with heart disease in Soweto, South Africa. Such disparities in CVD risk factors may justify the use of specialised prevention and management protocols.     

Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher

Purpose

Even with statins and other lipid-lowering therapy (LLT), many patients with heterozygous familial hypercholesterolemia (heFH) continue to have elevated low-density lipoprotein cholesterol (LDL-C) levels. ODYSSEY HIGH FH (NCT01617655) assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 monoclonal antibody, versus placebo in patients with heFH and LDL-C ≥ 160 mg/dl despite maximally tolerated statin ± other LLT.

Methods

Patients were randomized to subcutaneous alirocumab 150 mg or placebo every 2 weeks (Q2W) for 78 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24.

Results

Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab (n = 71) and 201.0 mg/dl in the placebo groups (n = 35). Significant mean (standard error [SE]) reductions in LDL-C from baseline to week 24 were observed with alirocumab (?45.7 [3.5] %) versus placebo (?6.6 [4.9] %), a difference of ?39.1 (6.0) % (P < 0.0001). Absolute mean (SE) LDL-C levels were reduced from baseline by 90.8 (6.7) mg/dl with alirocumab at week 24, with reductions maintained to week 78. Treatment-emergent adverse events were generally comparable between groups. Injection-site reactions were more frequent in the alirocumab group (8.3 %) versus placebo (5.7 %); most were mild in severity and did not result in study medication discontinuation.

Conclusions

In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT, alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals. Alirocumab was generally well tolerated.