Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study.

AIMS: The PREDICT Study is a prospective cohort study designed to evaluate coronary artery calcification score (CACS) as a predictor of cardiovascular events in type 2 diabetes (T2DM). METHODS AND RESULTS: A total of 589 patients with no history of cardiovascular disease and with established T2DM had CACS measured, as well as risk factors, including plasma lipoprotein, apolipoprotein, homocysteine and C-reactive protein concentrations, homeostasis model assessment insulin resistance (HOMA-IR), and urine albumin creatinine ratio. Participants were followed for a median of 4 years and first coronary heart disease (CHD) and stroke events were identified as primary endpoints. There were 66 first cardiovascular events (including 10 strokes). CACS was a highly significant, independent predictor of events (P < 0.001), with a doubling in CACS being associated with a 32% increase in risk of events (29% after adjustment). Hazard ratios relative to CACS in the range 0-10 Agatston units (AU) were: CACS 11-100 AU, 5.4 (P = 0.02); 101-400 AU 10.5 (P = 0.001); 401-1000 AU, 11.9 (P = 0.001), and >1000 AU, 19.8 (P < 0.001). Only HOMA-IR predicted primary endpoints independently of CACS (P = 0.01). The areas under the receiver operator characteristic curve for United Kingdom Prospective Diabetes Study (UKPDS) risk engine primary endpoint risk and for UKPDS risk plus CACS were 0.63 and 0.73, respectively (P = 0.03). CONCLUSION: Measurement of CACS is a powerful predictor of cardiovascular events in asymptomatic patients with T2DM and can further enhance prediction provided by established risk models.

Cardiometabolic risk factors in Thai individuals with prediabetes treated in a high-risk, prevention clinic: Unexpected relationship between high-density lipoprotein cholesterol and glycemia in men.

AIMS/INTRODUCTION: Relationships between cardiometabolic risk and glycemia have rarely been studied in people under clinical evaluation and treatment for cardiometabolic risk and with prediabetes. We investigated relationships between glycemia and cardiometabolic risk factors in clinic participants with prediabetes. MATERIALS AND METHODS: This was a cross-sectional analysis of data collected at a center in Thailand. Clinic attendees were at high risk of diabetes or cardiovascular disease, with hemoglobin A1c (HbA1c) 39-<48 mmol/mol or fasting plasma glucose (FPG) 5.6-<7.0 mmol/L. The relationships between glycemia and cardiometabolic risk factors were explored. RESULTS: Of 357 participants, two or more insulin resistance-related metabolic disturbances were present in 84%; 61% took a statin and 75% an antihypertensive agent. Independently of age, sex, adiposity, medication use, possible non-alcoholic fatty liver disease and sex-glycemia interaction, neither FPG nor HbA1c were associated with variation in any other cardiometabolic risk factors. High-density lipoprotein cholesterol decreased with HbA1c in women (female-HbA1c interaction, P = 0.03) but, unexpectedly, increased with FPG in men (male-FPG interaction, P = 0.02). CONCLUSIONS: Overall, in Thai people treated for high cardiometabolic risk and with prediabetes defined by FPG and/or HbA1c, neither FPG nor HbA1c were associated with other cardiometabolic risk factors. However, according to sex, high-density lipoprotein cholesterol showed the expected relationship with glycemia in women, but the reverse in men.

Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women.

Common variants of TCF7L2, encoding a beta-cell-expressed transcription factor, are strongly associated with increased risk of type 2 diabetes (T2D). We examined this association using both prospective and case-control designs. A total of 2,676 healthy European white middle-aged men from the prospective NPHSII (158 developed T2D over 15 years surveillance) were genotyped for two intronic SNPs [rs 7903146 (IVS3C>T) and rs12255372 (IVS4G>T)] which showed strong linkage disequilibrium (D' = 0.88, p<0.001; R(2)=0.76, p<0.001). The IVS5T allele frequency was 0.28 (95% CI 0.27-0.29) and 0.33 (0.28-0.39) in healthy and T2D, respectively (p=0.04). Compared to CC men, CT and TT men had an adjusted [for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels] hazard ratio for T2D of 1.65 (1.13-2.41) and 1.87 (0.99-3.53), respectively, p<0.01. The population attributable fraction for diabetes risk was 17%. In 1459, European white T2D men and women (60% male), T allele frequency was 0.36 (0.34-0.38), and compared to NPHSII healthy men the OR for T2D for the CT and TT subjects was 1.43 (1.24-1.65) and 2.11 (1.69-2.63), respectively p=<0.0001. A similar effect was observed in 919 T2D Indian Asians [OR=1.50 (1.14-1.99) and 1.64 (1.03-2.63) p=0.003] and 385 Afro-Caribbean subjects [OR=1.25 (0.90-1.75) and 1.32 (0.74-2.33) p=0.17] compared to non-diabetic ethnically matched subjects from South London. Weaker associations were found for the IVS4G>T in all studies. Linkage disequilibrium between the two SNPs was high in Indian Asians (D'=0.94), but much weaker in Afro-Caribbeans (D'=0.17) and haplotype frequencies differed markedly in this group. These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D.

Debate: Are surrogate end-point studies worth the effort?

Surrogate end-points of cardiovascular disease can provide useful information in cross-sectional, prospective and interventional studies. They provide information on association with risk factors, natural history and factors associated with disease progression. Because every participant can reach an end-point, sufficient power can be attained with much smaller numbers of subjects in surrogate end-point studies than in studies that use clinical endpoints, so that the costs are likely to be substantially less. Measures of carotid intima-media thickness (IMT) by B-mode ultrasonography and of coronary calcification by electron beam computed tomography (EBCT) appear to be the most promising surrogate end-points.

Association of TLL1 gene polymorphism (rs1503298, T > C) with coronary heart disease in PREDICT, UDACS and ED cohorts.

OBJECTIVE: To determine the sequence variant of TLL1 gene (rs1503298, T > C) in three British cohorts (PREDICT, UDACS and ED) of patients with type-2 Diabetes mellitus (T2DM) in order to assess its association with coronary heart disease (CHD). STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: UCL, London, UK. Participants were genotyped in 2011-2012 for TLL1 SNP. Samples and related information were previously collected in 2001-2003 for PREDICT, and in 2001-2002 for UDACS and ED groups. METHODOLOGY: Patients included in PREDICT (n=600), UDACS (n=1020) and ED (n=1240) had Diabetes. TLL1 SNP (rs1503298, T > C) was genotyped using TaqMan technology. Allele frequencies were compared using c2 test, and tested for Hardy-Weinberg equilibrium. The risk of disease was assessed from Odds ratios (OR) with 95% Confidence Intervals (95% CI). Moreover, for the PREDICT cohort, the SNP association was tested with Coronary Artery Calcification (CAC) scores. RESULTS: No significant association was found for this SNP with CHD or CAC scores in these cohorts. CONCLUSION: This SNP could not be confirmed as a risk factor for CHD in T2DM patients. However, the low power of thesmall sample size available is a limitation to the modest effect on risk. Further studies in larger samples would be useful.

Paraoxonase-1 is not associated with coronary artery calcification in type 2 diabetes: results from the PREDICT study.

OBJECTIVES: To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM). METHODS AND RESULTS: 589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study. CONCLUSION: PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found.

Changes in lipoprotein profile and urinary albumin excretion in familial LCAT deficiency with lipid lowering therapy.

Familial lecithin:cholesterol acyltransferase deficiency (FLD) is a monogenic autosomal recessive condition, affecting cholesterol esterification and leads to progressive renal impairment and end-stage renal failure, probably due to the abnormal lipoprotein (X) (Lp(X)). We report a case of FLD, whom we treated with a combination of nicotinic acid 1.5g nocte and fenofibrate M/R 160mg od and report changes in lipid profile and Lp(X), after six weeks and serum creatinine and urine albumin/creatinine ratio after 12 months. We assessed the cardiovascular risk using electron beam computed tomography. At baseline total cholesterol was 6.61mmol/L; HDL cholesterol 0.57mmol/L; Lp(X) cholesterol 3.24mmol/L; triglyceride 4.13mmol/L; apolipoprotein A1 46mg/dL; and apolipoprotein B 53mg/dL. After six weeks of treatment his total cholesterol was 4.16; HDL cholesterol 0.52; Lp(X) cholesterol 1.73mmol/L; triglyceride 1.80mmol/L; apolipoprotein A1 36mg/dL; and apolipoprotein B 50mg/dL. Baseline serum creatinine was 106micromol/L and urine albumin/creatinine ratio was 127.3mg/mmol and after 12 months was 101micromol/L and 31.5mg/mmol respectively. His coronary artery calcification score was zero. We have shown, we believe for the first time, that combination lipid modifying therapy in FLD leads to a reduction in Lp(X) concentration and an associated reduction in urine albumin excretion at 12 months.

Computed tomography imaging, coronary calcium and atherosclerosis.

Coronary calcium score measured by electron beam tomography provides an indication of current atherosclerotic burden in the coronary arteries. It correlates with conventional risk factors, but less so with Type 2 diabetes. Measurement of coronary calcium score has been shown to be a powerful predictor of coronary heart disease events in the general population, in different racial groups, and in Type 2 diabetes. It adds incremental value to conventional risk factors and risk scores. Its role in monitoring therapy remains to be proven.

The progress of coronary heart disease in Type 2 diabetes as measured by coronary calcium score from electron beam computed tomography (EBCT): the PREDICT study.

Coronary calcification score (CACS) measured by electron beam tomography is well established in the evaluation of cardiovascular risk in general populations. The PREDICT study aims to evaluate prediction of cardiovascular events by CACS in Type 2 diabetic subjects without previous clinical cardiovascular disease. In the present PREDICT sub-study, the rate of progression of CACS and factors influencing this rate were assessed. CACS was measured at baseline and after a mean interval of 4.0 (range of 2.1-5.0) years in the 202 PREDICT participants who agreed to have a second scan. Participants also had a range of conventional and novel biochemical risk factors measured at baseline. Progression of calcification was apparent in 170 (84%), while in 32 (16%) there was regression or no progression. Those showing progression had a significantly more adverse risk factor profile. Rate of change in CACS was strongly related to baseline CACS (p<0.0001). Rate of change also correlated with, waist:hip ratio (p=0.004), male gender (p=0.009), age (p=0.04), use of antihypertensive drugs (p=0.03) and statins (p=0.05) and, independently of baseline CACS, systolic blood pressure (p=0.0006), waist circumference (p=0.001) and urine albumin:creatine ratio (p=0.04). Most subjects with Type 2 diabetes showed progression of CACS. The absence of a relationship between progression and lipid risk factors and the positive relationship with statin and antihypertensive drug use may reflect earlier risk factor exposure. Independent relationships between progression and established calcification, blood pressure, central adiposity and urine albumin:creatinine ratio suggest areas for risk factor modification that could be especially relevant in Type 2 diabetes.

Non-invasive measurement of coronary heart disease using electron beam computed tomography.

PURPOSE OF REVIEW: Electron beam computed tomography is a non-invasive investigation that can quantify calcification within the walls of coronary arteries. Coronary arteries remodel to maintain luminal integrity, so that significant plaque may be present before the development of luminal stenoses. This has led to interest in techniques that assess the coronary artery wall, rather than the lumen. This review examines the power of coronary calcification detected by electron beam computed tomography to predict coronary heart disease events, and outlines recent studies in which it has been used as a surrogate marker for coronary heart disease. RECENT FINDINGS: The predictive power of coronary calcification has been shown to exceed that of traditional coronary heart disease risk factors and possibly also coronary angiography. This may justify the use of coronary calcification as a surrogate marker for coronary heart disease, and studies have thus examined cross-sectional associations between coronary calcification and potential risk factors in healthy individuals and patients with diabetes, end-stage renal failure and familial hypercholesterolaemia. Intervention studies can use the rate of change of coronary calcification detected by serial electron beam computed tomography imaging as an end-point, rather than relying on coronary heart disease events. As every participant reaches an end-point, sufficient power can be attained with smaller numbers at substantially less cost. SUMMARY: Coronary calcification detected by electron beam computed tomography may prove an invaluable tool in the selection of at-risk individuals suitable for primary prevention, and a useful surrogate marker for coronary heart disease in clinical trials.

Coronary calcification and predicted risk of coronary heart disease in asymptomatic men with hypercholesterolaemia.

OBJECTIVE: To document the relationship between coronary calcification and coronary risk assessed clinically in asymptomatic patients with hypercholesterolaemia. DESIGN: Prospective observational study. SETTING: Health screening clinic. PATIENTS: A total of 286 asymptomatic men aged 45-64 with plasma cholesterol >or= 6.5 mmol/l. INTERVENTIONS: Electron beam computed tomography to measure coronary calcium score. MAIN OUTCOME MEASURES: The Framingham equation was used to separate subjects into groups with either low 10-year risk of coronary artery disease (or= 20%). Coronary calcium score was assessed in each group. RESULTS: The mean log calcium score was significantly higher in the 97 high-risk men than in the 189 low-risk men (1.58 +/- 0.84 versus 1.00 +/- 0.85, < 0.001). Arithmetic means (158 versus 55), and the proportion with a score > 400 (11% versus 2%, p < 0.01) were also greater. However, 27% of the high-risk group had a low calcium score (or= 20% in 10 years have minimal coronary calcification. They may therefore represent a subset at lower risk of disease. However, uncertainties about the predictive power of coronary calcification for coronary events must be resolved before electron beam computed tomography can be used to select high-risk patients for primary prevention.