Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. METHODS: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. RESULTS: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004]. CONCLUSIONS: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.

HbA1c predicts the likelihood of having impaired glucose tolerance in high-risk patients with normal fasting plasma glucose.

BACKGROUND: Although the oral glucose tolerance test (OGTT) is the 'gold standard' for diagnosing prediabetes/diabetes, it is inconvenient for the patient and time consuming. The only alternative simple screening test is fasting plasma glucose (FPG). FPG concentrations of > 6.0 mmol/L represent prediabetes/diabetes. FPG concentrations of < or = 6.0 mmol/L may be considered 'normal', although some such patients will demonstrate abnormal glucose tolerance when subjected to an OGTT. We have evaluated the use of glycated haemoglobin (HbA1c) as a screening test for diabetes or impaired glucose tolerance (IGT) in patients who have risk factors for diabetes but FPG < or = 6.0 mmol/L. METHODS AND RESULTS: A total of 580 patients with at least two risk factors for diabetes underwent an OGTT and HbA1c measurement. In all, 225 patients had a FPG < or = 6.0 mmol/L and met the inclusion criteria. Of these, 23.1% (n=52) had an abnormal OGTT result (45 had IGT and 7 had diabetes). Subjects with abnormal glucose tolerance had a higher percentage of HbA1c than subjects with normal glucose tolerance (P<0.001). An HbA1c of 5.6% gave an optimal sensitivity of 72% and specificity of 77% to predict a 2 h plasma glucose > or = 7.8 mmol/L. CONCLUSION: The use of FPG concentration followed by selective measurement of HbA1c in patients who are at high risk of developing diabetes may represent a reasonable approach to identifying patients requiring an OGTT.