M Krempf

French National Centre for Scientific Research, Lutetia Parisorum, Île-de-France, France

Are you M Krempf?

Claim your profile

Publications (227)620.77 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Individuals with heterozygous familial hypercholesterolemia (heFH) have higher levels of low-density lipoprotein cholesterol (LDL-C) and are predisposed to premature cardiovascular disease. Alirocumab is a fully-human, monoclonal antibody targeted to proprotein convertase subtilisin/kexin type 9 currently in Phase 3 development for the treatment of hypercholesterolemia. Described here are three ODYSSEY Phase 3 trials, FH I (NCT01623115), FH II (NCT01709500) and HIGH FH (patients with heFH and LDL-C levels ≥160 mg/dL) (NCT01617655), in which alirocumab is further evaluated in the heFH population.
    Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating agent Niaspan® on both insulin action and triglyceride decrease in 20 nondiabetic, dyslipidemic men with metabolic syndrome receiving Niaspan® (2 g/day) or placebo for 8 weeks in a randomized, cross-over study. The effects on plasma lipid profile were characterized at the beginning and the end of each treatment period; insulin sensitivity was assessed using the 2-step euglycemic hyperinsulinemic clamp and VLDL-triglyceride turnover by measuring plasma glycerol enrichment, both at the end of each treatment period. The mechanism of action of nicotinic acid was studied in HuH7 and mouse primary hepatocytes. Lipid profile was improved after Niaspan® treatment with a significant-28% decrease in triglyceride levels, a+17% increase in HDL-C concentration and unchanged levels of fasting nonesterified fatty acid. VLDL-tri-glyceride production rate was markedly reduced after Niaspan® (-68%). However, the treatment induced hepatic insulin resistance, as assessed by reduced inhibition of endogenous glucose production by insulin (0.7±0.4 vs. 1.0±0.5 mg/kg · min, p<0.05) and decrease in fasting hepatic insulin sensitivity index (4.8±1.8 vs. 3.2±1.6, p<0.05) in the Niaspan® condition. Nicotinic acid also reduced insulin action in HuH7 and primary hepatocytes, independently of the activation of hepatic PKCε. This effect was associated with an increase in diacylglycerol and a decrease in tri-glyceride contents that occurred in the absence of modification of DGAT2 expression and activity. Eight weeks of Niaspan® treatment in dyslipidemic patients with metabolic syndrome induce hepatic insulin resistance. The mechanism could involve an accumulation of diacylglycerol and an alteration of insulin signaling in hepatocytes.
    Hormone and Metabolic Research 05/2014; · 2.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptoralpha agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.
    Cardiovascular Diabetology 01/2014; 13(1):26. · 4.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Heterozygous Familial Hypercholesterolemia (heFH) is an autosomal disease that affects about 1/500 people. It is characterized by markedly elevated plasma LDL-cholesterol (C) levels and an increased risk of cardiovascular disease (CVD). The aim of this study was to measure changes in LDL-C levels in heFH patients over two decades, and to evaluate if patients achieved LDL-C targets. Methods Data from 1669 heFH patients in five academic French centers were recorded between 1988 and 2011. Results The mean LDL-C concentrations under medical care improved between 1988 and 2011 (245 mg/dL before 1995, 164 mg/dL after 2009; p < 0.0001). However, mean LDL-C level and the number of patients treated with statins (79.3%) have not improved since 2005. In patients registered and treated after 2005 (n = 616), only 10.4% reached target LDL-C levels of <100 mg/dL. Indeed, 29.4% (n = 181) were treated with a maximal therapy (statins with a potency of >45% LDL-C reduction plus at least another lipid-lowering agent). Despite maximal treatment, only 18.8% of these heFH patients (n = 34/181) reached target LDL-C levels of <100 mg/dL. In addition, 75.3% of patients with CVD did not reach the LDL-C of <100 mg/dL. Conclusion This study demonstrates that after significant improvement over the past two decades, the mean LDL-C levels in heFH French patients has remained stable since 2005. We also show that most heFH patients are not achieving their recommended LDL-C goals: this highlights the need for improved treatment and for new therapeutics in this population.
    Atherosclerosis 01/2014; 234(1):136–141. · 3.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A comparative study of the electrochemical conversion and the biotransformation performed by the cytochrome P450 (CYP450) obtained by rat liver microsomes has been achieved to elucidate the oxidation mechanism of both acebutolol and alprenolol. For this purpose, a wide range of reactions such as N-dealkylation, O-dealkoxylation, aromatic hydroxylation, benzyl hydroxylation, alkyl hydroxylation, and aromatic hydroxylation have been examined in this study, and their mechanisms have been compared. Most of the results of the electrochemical oxidation have been found to be in accordance with those obtained by incubating acebutolol and alprenolol in the presence of CYP450, i.e., N-dealkylation, benzyl hydroxylation, and O-dealkoxylation reactions catalyzed by liver microsomes were found to be predicted by the electrochemical oxidation. The difficulty for the electrochemical process to mimic both aromatic and alkyl hydroxylation reactions has also been discussed, and the hypothesis for the absence of aromatic hydroxylated and alkyl hydroxylated products, respectively, for alprenolol and acebutolol, under the anodic oxidation has been supported by theoretical calculation. The present study highlights the potential and limitation of coupling of electrochemistry-liquid chromatography-high-resolution mass spectrometry for the study of phase I and phase II reactions of acebutolol and alprenolol.
    Analytical and Bioanalytical Chemistry 05/2013; · 3.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In situ NMR spectroelectrochemistry is presented in this study as a useful hybrid technique for the chemical structure elucidation of unstable intermediate species. An experimental setting was designed to follow the reaction in real time during the experimental electrochemical process. The analysis of (1)H NMR spectra recorded in situ permitted us (1) to elucidate the reaction pathway of the electrochemical oxidation of phenacetin and (2) to reveal the quinone imine as a reactive intermediate species without using any trapping reaction. Phenacetin has been considered as hepatotoxic at high therapeutic amounts, which is why it was chosen as a model to prove the applicability of the analytical method. The use of 1D and 2D NMR experiments led to the elucidation of the major species produced from the oxidation process. We demonstrated that in situ NMR spectroelectrochemistry constitutes a fast way for monitoring unstable quinone imines and elucidating their chemical structures.
    Analytical and Bioanalytical Chemistry 05/2013; · 3.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Familial hypercholesterolemia (FH) is a frequent monogenetic disease (1/500 for heterozygous and 1/1,000,000 for homozygous). The FH patients are exposed to a dramatic increase of vascular risk of about 50% for men and 30% for women compared to the general population. The diagnosis can be suspected in case of high plasma concentration of LDL-C over 2.20mg/dL, first relatives with FH in the family, xantomas and early cardiovascular events. The "Simon Broone criteria" or the Deutch scale are useful tools to ascertain the diagnosis but DNA testing is the gold standard. The mutations are mainly located on the LDL receptor gene and less frequently on Apo B100 or PCSK9 genes. The "cascade" testing of the family from the index patient is a critical step to detect new cases and start early treatment. Long-term treatment with statins has dramatically decreased the vascular risk to the level of the general population. In primary prevention, LDL-C should be less than 130mg/dL and in secondary prevention less than 100mg/dL (as a best<70mg/dL). It is often difficult to reach these goals and combined treatments with ezetimibe or other drugs can be used. When the goals are not reached with the maximum tolerated drug treatment, a decrease of 50% of LDL-C can be acceptable but the patients should be referred to lipid clinics. A yearly vascular survey of the FH patients is recommended, especially in adults or when the treatment goal is not reached. Homozygous FH patients must be referred to a specialized center.
    La Presse Médicale 04/2013; · 0.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The EVOLUTIV survey was carried out through Internet among 135 general practitioners (GPs) and 135 specialists (endocrinologists/diabetologists: 82.8%) used to treat type 2 diabetic (T2D) patients. Using the methodology of clinical vignettes they were proposed five T2D patient's profiles – each with two different clinical case redactions – combining clinical practice situations (oral bitherapy, recently diagnosed or long standing diabetes, insufficient glucose control or uncontrolled diabetes, absence of or existing microvascular or cardiovascular complications). Each physician had to determine the antidiabetic treatment for each of these 10 clinical cases in which two key parameters, HbA1c and BMI, varied in turn. For each clinical case they had to answer four questions on glucose control (HbA1c) objective, weight loss objective, recommended therapeutic strategy and main decision criteria supporting their therapeutic choice. A total of 2570 clinical cases were collected and analyzed. Main results were: –Glycemic and weight loss objectives were globally ambitious; however chosen therapeutic strategies, particularly by GPs, were not always adapted to these objectives;–A different attitude of GPs and specialists with regard to therapeutic intensification. GPs preferentially chose maintenance of oral strategies and underutilized injectable strategies (GLP-1 analogs and insulin), these latter more largely and more precociously preconized by specialists, particularly in case of HbA1c ≥8% and/or BMI ≥29 kg/m2. Use of the DPP-4 inhibitors class as add-on to metformin was predominant for GPs as for specialists with as a consequence a delayed introduction of GLP-1 analogs, particularly for GPs (except for BMI 35 kg/m2);–HbA1c was the major decision criteria; however at early diabetes stages treatments/drugs preconized by GPs were generally not adapted to a strict glycemic control objective. At more complex stages (long standing diabetes uncontrolled and/or with complications), referral to specialist increased considerably, mainly for the highest HbA1c levels (≥9%) and was more marked with increasing BMI (≥29 kg/m2).
    Médecine des Maladies Métaboliques 02/2013; 7(1):58–78.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The coupling between an electrochemical cell (EC) and a mass spectrometer (MS) is a useful screening tool (EC-MS) to study the oxidative transformation pathways of various electroactive species. For that purpose, we showed that the EC-MS method, carried out in the presence and absence of isotope (18)O labeled water leads not only to a fast identification of oxidation products but also leads to a fast elucidation of the mechanism pathway reaction. We examined herein the case of the electrochemical hydrolysis of activated aromatic ether. Acebutolol (β-blockers) was selected herein as model of activated aromatic ether, and its electrochemical oxidation was examined in both the presence and absence of isotope (18)O labeled water. To elucidate electrochemical hydrolysis pathway reaction: O-dealkylation or O-dealkoxylation, our approach was used to prove its applicability. The electrochemical oxidation mechanism was then elucidated showing an O-dealkoxylation reaction. In addition, density functional theory (DFT) calculations fully support the experimental conclusions.
    Analytica chimica acta 01/2013; 762C:39-46. · 4.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters. METHODS: We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1). FINDINGS: HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman's correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=-0.59, p= 0.0065) insulin sensitivity. CONCLUSIONS: Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.
    Nutrition & Metabolism 01/2013; 10(1):4. · 3.16 Impact Factor
  • M. Krempf
    [Show abstract] [Hide abstract]
    ABSTRACT: The Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI 53) trial was designed to test the effect of saxagliptin, a DPP-4 inhibitor, on the prevention of the occurrence of cardiovascular events in patients with type 2 diabetes (T2D). It is a 5-year, randomized, double-blind trial, conducted against placebo in 27 countries on 16,496 T2D patients. They received either a placebo or the saxagliptin 5 mg, or 2,5 mg in patients with renal failure (creatinine clearance <50 ml/minute). The treatment was given in addition to the usual treatment but gliptins or GLP-1 analogues were excluded. Patients were in secondary (80%) or primary cardiovascular prevention but with an additional risk factor (20%). The primary endpoint was a combined endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial was built to test a hypothesis from a non-inferiority to suggest the cardiovascular safety of the saxagliptin but also an assumption of superiority in cardiovascular prevention with a goal to reduce the relative risk of major cardiovascular events (primary endpoint) by 17%. The number of patients enrolled allowed testing these hypotheses with a good statistical power when 1040 events were observed. Patients were included in 27 countries with a large majority in North America and Western Europe. At inclusion the average age was 65.0 years with predominantly male (67%) patients. The average duration of diabetes was 11.9 years and mean HbA1c at baseline was 8.0+1.4%. Almost 12% of patients had retinopathy, 18% nephropathy and 2.5% amputation. Only 5% had no diabetes treatment and ~41% received insulin ± oral antidiabetics. The vast majority of patients (80%) received treatment with statins, antihypertensive and antiplatelet agents. Patients with cardiovascular history had more microvascular complications and were more often treated with insulin. The overall incidence of the primary endpoint was 2%/year. Investigators were asked to minimize the drop out of the patients less than 2,8%/year. The results of this study are expected in September 2013.
    Médecine des Maladies Métaboliques 01/2013; 7(4):354–359.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to investigate macrophage reverse cholesterol transport (RCT) in hamster, a CETP-expressing species, fed omega 3 fatty acids (ω3PUFA) supplemented high fat diet (HFD). Three groups of hamsters (n = 6/group) were studied for 20 weeks: 1) control diet: Control, 2) HFD group: HF and 3) HFD group supplemented with ω3PUFA (EPA and DHA): HFω3. In vivo macrophage-to-feces RCT was assessed after an intraperitoneal injection of (3)H-cholesterol-labelled hamster primary macrophages. Compared to Control, HF presented significant (p<0.05) increase in body weight, plasma TG (p<0.01) and cholesterol (p<0.001) with an increase in VLDL TG and in VLDL and LDL cholesterol (p<0.001). Compared to HF, HFω3 presented significant decrease in body weight. HFω3 showed less plasma TG (p<0.001) and cholesterol (p<0.001) related to a decrease in VLDL TG and HDL cholesterol respectively and higher LCAT activity (p<0.05) compared to HF. HFω3 showed a higher fecal bile acid excretion (p<0.05) compared to Control and HF groups and higher fecal cholesterol excretion (p<0.05) compared to HF. This increase was related to higher gene expression of ABCG5, ABCA1 and SR-B1 in HFω3 compared to Control and HF groups (<0.05) and in ABCG1 and CYP7A1 compared to HF group (p<0.05). A higher plasma efflux capacity was also measured in HFω3 using (3)H- cholesterol labeled Fu5AH cells. In conclusion, EPA and DHA supplementation improved macrophage to feces reverse cholesterol transport in hamster fed HFD. This change was related to the higher cholesterol and fecal bile acids excretion and to the activation of major genes involved in RCT.
    PLoS ONE 01/2013; 8(4):e61109. · 3.73 Impact Factor
  • M. Krempf
    [Show abstract] [Hide abstract]
    ABSTRACT: Lipoproteins exchange of cholesterol esters and triglycerides through CETP (cholesteryl ester transfer protein), a transfer protein. It allows the exchange of cholesterol esters between HDL and LDL or VLDL triglycerides give back to HDL. In humans, this activity would allow more than 70 % of cholesterol esters present in the HDL to be transferred to LDL. The return of cholesterol to the liver via the LDL is very effective if they are properly metabolized. Otherwise, it is a particularly atherogenic metabolic pathway since the load LDL cholesterol esters which will accumulate in the circulation and be picked up by macrophages to promote lipid deposits. A number of preclinical and clinical data suggest that CETP would facilitate atherosclerosis in humans. By blocking its action, cholesterol esters remain on HDL to be eliminated by the liver. Genetic studies with loss of function mutations support this hypothesis, but the data are contradictory. In addition, it is unclear whether changes in the composition of lipoproteins obtained and especially HDL allow them to keep all their functions. Four molecules have been developed to block the activity of CETP with a consequent significant increase in HDL cholesterol of 30 to 130% depending on the degree of inhibition but also a reduction in LDL cholesterol up to 25%. Development of torcetrapib a potent inhibitor was discontinued due to adverse vascular effects primarily related to a specific action of this molecule on the renin-angiotensin system. Dalcetrapib which inhibited about 30% of the activity of the molecule has been interrupted for inefficiency. Two other potent inhibitors (anacetrapib and evacetrapib) are being developed and the first results of the cardiovascular intervention trials are expected in 2016.
    Médecine des Maladies Métaboliques 01/2013; 7(6):575–579.
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: Assess the cardiovascular safety of Thiazolidinediones (TZD) in routine clinical practice. BACKGROUND: TZD are insulin-sensitizing antidiabetic drugs commonly used in type 2 diabetes, but their cardiovascular safety has been questioned. We examined the association between TZD use and major cardiovascular outcomes. METHODS: We examined 2-year mortality, non-fatal myocardial infarction (MI), and congestive heart failure (CHF) rates among outpatients with high cardiovascular risk and diabetes according to TZD use in the REACH Registry. Multivariable adjustment and propensity scores were used in the analyses. RESULTS: A total of 4997 out of 28,332 patients took TZDs at baseline. During follow-up, 1532 patients died. The mortality rates (95% confidence interval [CI]) were 6.5% (5.5-7.6) with TZD and 7.2% (6.33-8.06) without; adjusted hazard ratio (HR) was 1.06 (0.89-1.26, P=0.54). The lack of association with mortality was consistent across subgroups regardless of history of atherothrombosis or CHF. Rates of non-fatal MI (HR 1.10, 95% CI 0.83-1.45, P=0.50) and non-fatal CHF (HR 0.90, CI 0.75-1.09, P=0.27) were similar in users and non-users. TZD use was associated with an increased risk of CHF in patients aged >80years (HR 1.59, CI 1.06-2.40, P=0.03). CONCLUSIONS: Use of TZD was not associated with increased incidence of major cardiovascular events in patients with diabetes from this large registry. Older patients experienced an increased risk of CHF over the study interval. Limitations of this study include its observational design, and thus unmeasured confounders cannot be excluded.
    International journal of cardiology 05/2012; · 7.08 Impact Factor
  • Electrochimica Acta 05/2012; 69:351-357. · 3.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anderson disease is a rare inherited lipid malabsorption syndrome associated with hypocholesterolemia and linked to SAR1B mutations. The aim of this article was to analyze the mechanisms responsible for the low plasma apolipoprotein Apo-B100 and Apo-AI in 2 patients with Anderson disease. A primed constant infusion of (13)C-leucine was administered for 14 hours to determine the kinetics of lipoproteins. In the 2 patients, total cholesterol (77 and 85 mg/dL versus 155±32 mg/dL), triglycerides (36 and 59 versus 82±24 mg/dL), Apo-B100 (48 and 43 versus 71±5 mg/dL), and Apo-AI (47 and 62 versus 130±7 mg/dL) were lower compared with 6 healthy individuals. Very-low-density lipoprotein-B100 production rate of the patients was lower (4.08 and 5.52 mg/kg/day versus 12.96±2.88 mg/kg/day) as was the fractional catabolic rate (5.04 and 4.32 day(-1) versus 12.24±3.84 day(-1)). No difference was observed in intermediate-density lipoprotein-B100 and LDL-B100 kinetic data. The production rate of high-density lipoprotein Apo-AI was lower in the patients (7.92 and 8.64 versus 11.96±1.92 mg/kg/day) and the fractional catabolic rate was higher (0.38 and 0.29 versus 0.22±0.01 day(-1)). The low plasma Apo-B100 and Apo-AI concentrations in the patients with Anderson disease were mainly related to low rates of production.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2012; 32(6):1520-5. · 6.34 Impact Factor
  • Bertrand Cariou, Michel Krempf
    [Show abstract] [Hide abstract]
    ABSTRACT: Low-density lipoprotein cholesterol (LDL-c) concentration is an independent cardiovascular risk factor, which mostly contributes to the development and progression of atherosclerosis. Results of randomized clinical trial with statins demonstrate that the optimal LDL-c target is < 70 mg/dL. The physiological range of LDL-c in hunter-gatherers and wild mammals, who do not develop atherosclerosis, is 0.5 to 0.7 g/L. No major safety concern was found in human with genetically-related low levels of LDL-c. A moderate increase in haemorrhagic stroke and diabetes was found in some trials with statins. Guidelines recommend to modulate the LDL-c target according to the level of the total cardiovascular risk.
    La Revue du praticien 10/2011; 61(8):1104-9.
  • B Cariou, M Krempf
    La Revue du praticien 10/2011; 61(8):1106-7.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glucose intolerance and dyslipidaemia are independent risk factors for endothelium dysfunction and CVD. The aim of the present study was to analyse the preventive effect of n-3 PUFA (EPA and DHA) on lipid and carbohydrate disturbances and endothelial dysfunction. Three groups of adult hamsters were studied for 20 weeks: (1) control diet (Control); (2) high-fat diet (HF); (3) high-fat diet enriched with n-3 PUFA (HFn-3) groups. The increase in body weight and fat mass in the HF compared to the Control group (P < 0·05) was not found in the HFn-3 group. Muscle TAG content was similar in the Control and HF groups, but significantly lower in the HFn-3 group (P = 0·008). Glucose tolerance was impaired in the HF compared to the Control group, but this impairment was prevented by n-3 PUFA in the HFn-3 group (P < 0·001). Plasma TAG and cholesterol were higher in the HF group compared to the Control group (P < 0·001), but lower in the HFn-3 group compared to the HF group (P < 0·001). HDL-cholesterol was lower in the HFn-3 group compared to the Control and HF groups (P < 0·0005). Hepatic secretion of TAG was lower in the HFn-3 group compared to the HF group (P < 0·005), but did not differ from the Control group. Hepatic gene expression of sterol regulatory element-binding protein-1c, diacylglycerol O-acyltransferase 2 and stearyl CoA desaturase 1 was lower in the HFn-3 group, whereas carnitine palmitoyl transferase 1 and scavenger receptor class B type 1 expression was higher (P < 0·05). In adipocytes and adipose macrophages, PPARγ and TNFα expression was higher in the HF and HFn-3 groups compared to the Control group. Endothelium relaxation was higher in the HFn-3 (P < 0·001) than in the HF and Control groups, and was correlated with glucose intolerance (P = 0·03) and cholesterol (P = 0·0003). In conclusion, n-3 PUFA prevent some metabolic disturbances induced by high-fat diet and improve endothelial function in hamsters.
    The British journal of nutrition 09/2011; · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a post-transcriptional inhibitor of LDL-receptor. In non-diabetic men, plasma PCSK9 levels were found to be inversely correlated with low-density lipoprotein (LDL) apolipoprotein B100 (apoB) fractional catabolic rate (FCR). Here, we aimed to determine the effect of type 2 diabetes on the association between plasma PCSK9 and FCR of LDL. A kinetic study of LDL-apoB100, using stable isotopes, was performed in 38 individuals (20 men, 18 women) including 23 non-diabetic normolipidemic subjects and 15 patients with type 2 diabetes. In the non-diabetic group, plasma PCSK9 was positively correlated with LDL-C (r=0.64, p=0.001), apoB (r=0.67, p<0.001), and inversely correlated with LDL-apoB FCR (r=-0.61, p=0.002). In contrast, in type 2 diabetic patients, plasma PCSK9 was not associated with LDL-C, apoB and LDL-apoB FCR. However, the lack of association between PCSK9 and LDL-apoB FCR seemed to be limited to the patients with "uncontrolled" diabetes (HbA1c>7%) since a borderline significant negative correlation between PCSK9 and LDL FCR (r=-0.70, p=0.08) was retrieved in patients with HbA1c≤7%. In multivariate analysis, LDL-apoB FCR was independently associated with PCSK9 (p=0.001) and fasting glycaemia (log) (p=0.030) in the non-diabetic population and with PCSK9 (p=0.040) and HbA1c (p=0.029) in diabetic patients. Our data indicate that both PCSK9 and glycaemia are independent factors influencing LDL catabolism. Plasma PCSK9 influences significantly the catabolism of LDL-apoB100 in individuals without diabetes, but not in patients with uncontrolled type 2 diabetes. Thus, the influence of diabetes on LDL-apoB FCR catabolism may overwhelm the influence of PCSK9.
    Atherosclerosis 07/2011; 219(1):342-8. · 3.71 Impact Factor

Publication Stats

2k Citations
620.77 Total Impact Points

Institutions

  • 2012–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2001–2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1998–2013
    • University of Nantes
      Naoned, Pays de la Loire, France
    • Hôpital Universitaire Necker
      Lutetia Parisorum, Île-de-France, France
  • 1997–2013
    • Le Centre de Recherche en Nutrition Humaine Rhône-Alpes
      Rhône-Alpes, France
  • 1990–2013
    • Centre Hospitalier Universitaire de Nantes
      • • Service d'endocrinologie - maladies métaboliques et nutrition
      • • Service de néphrologie et immunologie clinique
      Naoned, Pays de la Loire, France
  • 2011
    • Centre Hospitalier Universitaire de Dijon
      Dijon, Bourgogne, France
  • 2010
    • Institut de France
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      Lutetia Parisorum, Île-de-France, France
  • 2003–2010
    • Nestlé S.A.
      Vevey, Vaud, Switzerland
  • 2003–2008
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2002
    • Hotel Dieu Hospital
      Kingston, Ontario, Canada
  • 2000
    • French National Institute for Agricultural Research
      Lutetia Parisorum, Île-de-France, France
  • 1997–2000
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 1999
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
    • École Nationale Vétérinaire, Agroalimentaire et de l'Alimentation Nantes-Atlantique
      Naoned, Pays de la Loire, France
  • 1990–1993
    • Massachusetts Institute of Technology
      • School of Science
      Cambridge, MA, United States