Michel Krempf

A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management

BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P<0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.).

PCSK9: a promising therapeutic target for dyslipidemias?

PCSK9 is the third gene to be implicated in autosomal dominant hypercholesterolemia. The recent discovery of mutations in PCSK9 protein associated with low plasma low-density lipoprotein in humans, the characterization of PCSK9-deficient mice hypersensitive to statins and the severely pathological phenotype of D374Y PCSK9-mutated patients shed a new light on this gene: is it a promising therapeutic target for dyslipidemias?

Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults

BackgroundAccumulating data suggest a novel role for bile acids (BAs) in modulating metabolic homeostasis. BA treatment has been shown to improve glucose tolerance and to increase energy expenditure in mice. Here, we investigated the relationship between fasting plasma BAs concentrations and metabolic parameters in humans.FindingsFasting plasma glucose, insulin and lipid profile were measured in 14 healthy volunteers, 20 patients with type 2 diabetes (T2D), and 22 non-diabetic abdominally obese subjects. Insulin sensitivity was also assessed by the determination of the glucose infusion rate (GIR) during a hyperinsulinemic-euglycemic clamp in a subgroup of patients (9 healthy and 16 T2D subjects). Energy expenditure was measured by indirect calorimetry. Plasma cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) concentrations were analyzed by gas chromatograph-mass spectrometry. In univariable analysis, a positive association was found between HOMA-IR and plasma CDCA (β = 0.09, p = 0.001), CA (β = 0.03, p = 0.09) and DCA concentrations (β = 0.07, p < 0.0001). Spearman analysis retrieved an inverse relationship between plasma CDCA (r = -0.44, p = 0.03), CA (r = -0.65, p = 0.001) and the GIR. HOMA-IR remained positively associated with CDCA (β = 0.11, p = 0.01), CA (β = 0.04, p = 0.01) and DCA (β = 0.06, p = 0.007) in multivariable analysis, after adjustment for age, gender, BMI, HbA1C and plasma lipid parameters. In contrast, HbA1c, energy expenditure and plasma lipid concentrations were not correlated with plasma BAs levels in multivariable analysis.ConclusionsBoth plasma CDCA, CA and DCA concentrations were negatively associated with insulin sensitivity in a wide range of subjects.

PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo An Effect Blunted by Alirocumab

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Influence of the type of indigestible carbohydrate on plasma and urine short-chain fatty acid profiles in healthy human volunteers

Background/Objectives:Health effects of whole grain foods are becoming more evident. In this study, we analysed the short-chain fatty acid profiles in urine and serum derived from the colonic fermentation process of 13C-barley meals, prepared from barley grown under 13CO2 atmosphere.Subjects/Methods:In a crossover study, five volunteers ingested intact barley kernels (high content of non-starch polysaccharides (NSP) and resistant starch (RS)) and barley porridge (high content of NSP only). Using a newly developed stable isotope technology, we monitored 14 and 24 h postprandially 13C-acetate, 13C-propionate and 13C-butyrate in plasma and urine, respectively. The oro-cecal transit time (OCTT) of the meals was measured with the hydrogen breath test.Results:The OCTT was 6 h and did not differ between the two test meals. An increase of 13C-acetate was observed already early after ingestion of the meals (<6 h) and was attributed to early fermentation of the test meal. A rise in plasma 13C-propionate in the fermentation phase could only be detected after the porridge and not after the kernel meal. An increase in 13C-butyrate was only found in the fermentation phase and was higher after the barley kernels. Urine 13C-short-chain fatty acids data were consistent with these observations.Conclusions:The difference in the profiles of 13C-acetate, 13C-propionate and 13C-butyrate indicates that NSP combined with RS results in an altered fermentation profile than dietary fibre alone.

Cardiovascular risk in relation to body mass index and use of evidence-based preventive medications in patients with or at risk of atherothrombosis

AIM Explore the relation between body mass index (BMI) and cardiovascular disease, and the influence of optimal medical therapy (OMT) on this relationship. METHODS AND RESULTS Patients from the REACH cohort, an international, prospective cohort of patients with or at high risk of atherosclerosis with documentation of potential confounders, including treatments and risk factors, were followed up to 4 years (n = 54 285). Patients were categorized according to baseline BMI (ranging from underweight to Grade III obesity). Optimal medical therapy was defined as the use of the four cardioprotective medication classes (statins, ACE inhibitors/angiotensin II receptor blockers, β-blockers, and antiplatelet agents). The main outcomes were all-cause mortality, cardiovascular (CV) mortality, and CV events. In primary and secondary prevention, a reverse J-shaped curve best described the relationship between BMI categories and the incidence of the various outcomes. In secondary prevention, the highest adjusted risks were observed for underweight patients (1.97, P < 0.01, and 1.29, P = 0.03, for CV mortality and CV events) and the lowest HRs were observed, respectively, in Grade II and Grade III obese patients (0.73, P < 0.01 and 0.80, P < 0.01). The proportion of patients on OMT increased with BMI from 10.1 to 36% (P < 0.001). The apparent CV protection conferred by obesity persisted in patients receiving OMT. CONCLUSION An obesity paradox was observed in both primary and secondary CV prevention patients. The intensity of use of evidence-based preventive medications does not account for the paradoxical CV protection associated with obesity. At extremes of BMI, further interventions beyond OMT may be needed to reduce CV risk.

In situ NMR spectroelectrochemistry for the structure elucidation of unstable intermediate metabolites

AbstractIn 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 1H 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. FigureIn situ NMR spectroelectrochemistry for drug metabolism studies

Acebutolol and alprenolol metabolism predictions: comparative study of electrochemical and cytochrome P450-catalyzed reactions using liquid chromatography coupled to high-resolution mass spectrometry

AbstractA 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. FigureThe electrochemical conversion versus the biotransformation catalyzed by CYP450

Voltammetry coupled to mass spectrometry in the presence of isotope 18O labeled water for the prediction of oxidative transformation pathways of activated aromatic ethers: Acebutolol

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.

Thiazolidinedione use is not associated with worse cardiovascular outcomes: a study in 28,332 high risk patients with diabetes in routine clinical practice: brief title: thiazolidinedione use and mortality.

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 >80 years (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.