Robert J. Straka

Patient Self‐Reporting of Compliance Does Not Correspond with Electronic Monitoring: An Evaluation Using Isosorbide Dinitrate as a Model Drug

Study Objective. To assess the accuracy of patient‐kept diaries relative to electronic monitoring of compliance with isosorbide dinitrate prescribed 3 times/day for ischemic heart disease.

Fenofibrate Effect on Triglyceride and Postprandial Response of Apolipoprotein A5 Variants The GOLDN Study

Objective—Apolipoprotein A5 (APOA5) is a key determinant of plasma triglyceride (TG) concentrations. Genetic variation at the APOA5 locus could be responsible for some of the observed differences in response to fenofibrate therapy. Methods and Results—We examined the association between tag SNPs (−1131T>C and 56C>G) at APOA5 and TG and HDL-C response to fenofibrate and a postprandial lipid challenge in 791 men and women participating in the GOLDN study. After 3-week drug treatment, APOA5 56G carriers displayed significant decrease in TG (P=0.006), and increase in HDL-C (P=0.002) levels relative to their basal values in the fasting state when compared with noncarriers (a TG reduction of −35.8±2.8% versus −27.9±0.9% and a HDL-C increase of 11.8±1.3% versus 6.9±0.5%, respectively). In the postprandial lipemia after a fat load, the 56G carriers showed a significant decrease in the area under curve for TG and increase for HDL-C than the noncarriers. These diverse beneficial responses of 56G carriers to fenofibrate were further characterized by a higher increase in large LDL-C concentrations and LDL size. On the other hand, subjects with different APOA5-1131T>C genotypes showed no significant response to fenofibrate intervention. Conclusion—This study suggests that the APOA5 56G carriers benefited more from the fenofibrate treatment than noncarriers in lowering plasma TG and increasing HDL-C levels.

ADIPOQ Polymorphisms, Monounsaturated Fatty Acids, and Obesity Risk : The GOLDN Study

Serum adiponectin levels have been positively associated with insulin sensitivity and are decreased in type 2 diabetes (T2D) and obesity. Genetic and environmental factors influence serum adiponectin and may contribute to risk of metabolic syndrome and T2D. Therefore, we investigated the effect of ADIPOQ single‐nucleotide polymorphisms (SNPs), −11377C>G and −11391G>A, on metabolic‐related traits, and their modulation by dietary fat in white Americans. Data were collected from 1,083 subjects participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Mean serum adiponectin concentration was higher for carriers of the −11391A allele (P = 0.001) but lower for the −11377G allele carriers (P = 0.017). Moreover, we found a significant association with obesity traits for the −11391G>A SNP. Carriers of the −11391A allele had significantly lower weight (P = 0.029), BMI (P = 0.019), waist (P = 0.003), and hip circumferences (P = 0.004) compared to noncarriers. Interestingly, the associations of the −11391G>A with BMI and obesity risk were modified by monounsaturated fatty acids (MUFAs) intake (P‐interaction = 0.021 and 0.034 for BMI and obesity risk, respectively). In subjects with MUFA intake above the median (≥13% of energy intake), −11391A carriers had lower BMI (27.1 kg/m2 for GA+AA vs. 29.1 kg/m2 for GG, P = 0.002) and decreased obesity risk (odds ratio for −11391A = 0.52, 95% confidence interval (CI); 0.28–0.96; P = 0.031). However, we did not detect genotype‐related differences for BMI or obesity in subjects with MUFA intake <13%. Our findings support a significant association between the −11391G>A SNPs and obesity‐related traits and the potential to moderate such effects using dietary modification.

ADIPOQ polymorphisms, monounsaturated fatty acids, and obesity risk

Serum adiponectin levels have been positively associated with insulin sensitivity and are decreased in type 2 diabetes (T2D) and obesity. Genetic and environmental factors influence serum adiponectin and may contribute to risk of metabolic syndrome and T2D. Therefore, we investigated the effect of ADIPOQ single‐nucleotide polymorphisms (SNPs), −11377C>G and −11391G>A, on metabolic‐related traits, and their modulation by dietary fat in white Americans. Data were collected from 1,083 subjects participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Mean serum adiponectin concentration was higher for carriers of the −11391A allele (P = 0.001) but lower for the −11377G allele carriers (P = 0.017). Moreover, we found a significant association with obesity traits for the −11391G>A SNP. Carriers of the −11391A allele had significantly lower weight (P = 0.029), BMI (P = 0.019), waist (P = 0.003), and hip circumferences (P = 0.004) compared to noncarriers. Interestingly, the associations of the −11391G>A with BMI and obesity risk were modified by monounsaturated fatty acids (MUFAs) intake (P‐interaction = 0.021 and 0.034 for BMI and obesity risk, respectively). In subjects with MUFA intake above the median (≥13% of energy intake), −11391A carriers had lower BMI (27.1 kg/m2 for GA+AA vs. 29.1 kg/m2 for GG, P = 0.002) and decreased obesity risk (odds ratio for −11391A = 0.52, 95% confidence interval (CI); 0.28–0.96; P = 0.031). However, we did not detect genotype‐related differences for BMI or obesity in subjects with MUFA intake <13%. Our findings support a significant association between the −11391G>A SNPs and obesity‐related traits and the potential to moderate such effects using dietary modification.

Assessment of Hypercholesterolemia Control in a Managed Care Organization

To determine the extent of achievement of goal low‐density lipoprotein cholesterol (LDL) as defined by National Cholesterol Education Program—Adult Treatment Panel II (NCEP‐ATP II) and American Diabetes Association (ADA) 2000 guidelines, we conducted a retrospective study by integrating data from medical, laboratory, and pharmacy claims databases. Subjects were selected from a 232,000‐member staff‐model managed care organization consisting of 19 clinics in the Minneapolis—St. Paul, Minnesota, metropolitan area. A total of 124,971 members aged 18 years and older, who had been continuously enrolled from July 1, 1996–June 6, 1998, were included. Outcome measures were the extent of achievement of goal LDL as defined by NCEP‐ATP II and the use of antihyperlipidemic drugs for patients with and without diabetes at various levels of risk for coronary heart disease (CHD). Of 124,971 subjects, 6538 had a history of CHD, 1523 of whom met their LDL goal. Of the population with CHD who did not achieve goal, 1141 (43%) missed by over 30 mg/dl; 621 (54%) of these patients were not receiving drug therapy. A total of 17,267 had no history of CHD but had two or more risk factors; 3298 of these achieved their LDL goal. Of those who did not achieve goal, 1136 (35%) missed by over 30 mg/dl; 897 (79%) of these were not receiving drug therapy. A total of 6586 had a history of diabetes; 1004 and 2340 reached an LDL of 100 mg/dl or lower and less than 130 mg/dl, respectively. Of those with diabetes who had an LDL greater than 100 mg/dl, 1276 (49%) missed their goal by over 30 mg/dl; 898 (70%) of these were not receiving drug therapy. Inadequate use of pharmacologic agents plays a significant role in failure to achieve goal LDL for patients with CHD, without CHD, and with diabetes. Analysis of the data based on the new ADA guidelines for LDL demonstrates the need for continued vigilance. Finally, the successful merging of medical, laboratory, and pharmacy claims databases provides a benchmark for other institutions.

A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network.

Objective Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation. Methods Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-&agr;)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect. Results Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10−9 and rs12722605, P=5×10−8). Associations of the MCP1-TNF-&agr; pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10−7, 5×10−7, 6×10−7, and 7×10−7, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-&agr; pattern (P=3×10−7). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10−7). Conclusion We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.

Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity

Study Objective. To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N‐acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus.

Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: A pilot study

BACKGROUND Primary biliary cirrhosis and primary sclerosing cholangitis are two cholestatic diseases characterised by hepatic accumulation of bile acids. AIMS This study compares serum bile acid levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis and from age and sex-matched non cholestatic donors. METHODS Seventeen bile acids were quantified using liquid chromatography coupled to tandem mass spectrometry. Serum samples from cholestatic patients were compared with those of non-cholestatic donors. RESULTS The concentration of total bile acids, taurine and glycine conjugates of primary bile acids was elevated in both patients with primary biliary cirrhosis and primary sclerosing cholangitis when compared to non-cholestatic donors. Samples from primary sclerosing cholangitis patients displayed reduced levels of secondary acids, when compared to non cholestatic and primary biliary cirrhosis sera. The ratio of total glycine versus total taurine conjugates was reduced in patients with primary biliary cirrhosis, but not in primary sclerosing cholangitis. CONCLUSION The present study suggests that circulating bile acids are altered differentially in primary biliary cirrhosis and primary sclerosing cholangitis patients.

Profiling Circulating and Urinary Bile Acids in Patients with Biliary Obstruction before and after Biliary Stenting

Bile acids are considered as extremely toxic at the high concentrations reached during bile duct obstruction, but each acid displays variable cytotoxic properties. This study investigates how biliary obstruction and restoration of bile flow interferes with urinary and circulating levels of 17 common bile acids. Bile acids (conjugated and unconjugated) were quantified by liquid chromatography coupled with tandem mass spectrometry in serum and urine samples from 17 patients (8 men and 9 women) with biliary obstruction, before and after biliary stenting. Results were compared with serum concentrations measured in 40 age- and sex-paired control donors (20 men and 20 women). The total circulating bile acid concentration increases from 2.7 µM in control donors to 156.9 µM in untreated patients with biliary stenosis. Serum taurocholic and glycocholic acids exhibit 304- and 241-fold accumulations in patients with biliary obstruction compared to controls. The enrichment in chenodeoxycholic acid species reached a maximum of only 39-fold, while all secondary and 6α-hydroxylated species –except taurolithocholic acids – were either unchanged or significantly reduced. Stenting was efficient in restoring an almost normal circulating profile and in reducing urinary bile acids. Conclusion These results demonstrate that biliary obstruction affects differentially the circulating and/or urinary levels of the various bile acids. The observation that the most drastically affected acids correspond to the less toxic species supports the activation of self-protecting mechanisms aimed at limiting the inherent toxicity of bile acids in face of biliary obstruction.

Profile of serum bile acids in noncholestatic volunteers: Gender-related differences in response to fenofibrate

Fenofibrate belongs to the group of hypolipidemic fibrates that act as activators of the peroxisome proliferator–activated receptor‐α (PPARα), which is a regulator of bile acid synthesis, metabolism, and transport. The present study aimed at evaluating the effects of fenofibrate on the circulating bile acid profile in humans. A study population of 200 healthy individuals comprising both genders completed a 3‐week intervention with fenofibrate, and 17 bile acid species were measured in serum samples drawn before and after fenofibrate treatment. Fenofibrate caused significant reductions in levels of chenodeoxycholic (CDCA) (−26.4%), ursodeoxycholic (UDCA) (−30.5%), lithocholic (LCA) (−18.4%), deoxycholic (DCA) (−22.3%), and hyodeoxycholic (HDCA) (−19.2%) acids. A gender‐related difference was observed in the responses of various bile acids, and the total bile acid concentration was significantly reduced only in men (−18.6%), whereas it remained almost unchanged in women (+0.36%). This difference suggests that fenofibrate would be more efficient at reducing bile acid toxicity in men than in women in cholestatic liver diseases.