Peter J. Lumb

A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism

PURPOSE The role of thyroxine replacement in subclinical hypothyroidism remains unclear. We performed a 6-month randomized, double-blind, placebo-controlled trial to evaluate the effects of thyroxine treatment for mild subclinical hypothyroidism, defined as a serum thyroid-stimulating hormone level between 5 to 10 microU/mL with a normal serum free thyroxine level (0.8-16 ng/dL). SUBJECTS AND METHODS We randomly assigned 40 women with mild subclinical hypothyroidism who had presented to their family practitioners to either thyroxine treatment (n = 23; 50 to 100 microg daily) or placebo (n = 17). Health-related quality of life (Hospital Anxiety and Depression scale, 30-item General Health Questionnaire), fasting lipid profiles, body weight, and resting energy expenditure were measured at baseline and 6 months. RESULTS The most common presenting symptoms were fatigue (n = 33 [83%]) and weight gain (n = 32 [80%]). At presentation, 20 women (50%) had elevated anxiety scores and 22 (56%) had elevated scores on the General Health Questionnaire. Thirty-five women completed the study. There were no significant differences in the changes from baseline to 6 months between women in the thyroxine group and the placebo group for any of the metabolic, lipid, or anthropometric variables measured, expressed as the mean change in the thyroxine group minus the mean change in the placebo group: body mass index, -0.3 kg/m(2) (95% confidence interval [CI]: -0.9 to 0.4 kg/m(2)); resting energy expenditure, -0.2 kcal/kg/24 h (95% CI: -1.3 to 1.0 kcal/kg/24 h); and low-density lipoprotein cholesterol, -4 mg/dL (95% CI: -23 to 15 mg/dL). There was a significant worsening in anxiety scores in the thyroxine group (scores increased in 8 of 20 women and were unchanged in 2 of 20) compared with the placebo group (scores increased in 1 of 14 women and were unchanged in 6 of 14; P = 0.03). CONCLUSIONS; We observed no clinically relevant benefits from 6 months of thyroxine treatment in women with mild subclinical hypothyroidism.

Erectile dysfunction and statin treatment in high cardiovascular risk patients.

Erectile dysfunction (ED) has been associated with risk factors for atherosclerosis. Medications used for atherosclerosis have also been implicated in ED. The aim of this study is to investigate the relationship of erectile function to cardiovascular risk factors and specific drug therapies before and after 6 months of statin therapy.

The uptake of lipoprotein-borne phylloquinone (vitamin K1) by osteoblasts and osteoblast-like cells: role of heparan sulfate proteoglycans and apolipoprotein E.

Vitamin K is essential for the γ‐carboxylation of Gla‐containing bone proteins such as osteocalcin and a suboptimal vitamin K status has been linked to osteoporosis but nothing is known of how the lipoprotein‐borne vitamin accesses the bone matrix. We have studied the mechanism of transport of lipoproteins labeled with [3H]‐phylloquinone (vitamin K1 [K1]) into osteoblasts using both tumor‐derived cell lines and normal osteoblast‐rich cell populations. We also investigated the effect of heparin in this model since long‐term heparin treatment causes osteopenia and the anticoagulant is known to impair normal lipoprotein metabolism. Heparinase treatment, which removes heparan sulfate proteoglycans (HSPG), reduced uptake of [3H]‐K1 from triglyceride‐rich lipoproteins (TRL) and low‐density lipoproteins (LDL). The effect of heparin in this model was complex depending on cell type, concentration, and time but, overall, the results were consistent with an inhibition of vitamin K uptake by osteoblasts. Anti‐apolipoprotein E (apoE) antiserum reduced uptake of TRL‐[3H]‐K1 by 55 ± 4% and LDL‐[3H]‐K1 uptake by 35 ± 2%. Exogenous apoE4 increased uptake of TRL‐[3H]‐K1 by 90 ± 1% compared with 53 ± 11% for apoE3 and 52 ± 5% for apoE2. Our findings show that HSPG on the cell surface and apoE in the lipoprotein particles contribute to lipoprotein‐K1 uptake by osteoblasts as is known for lipoprotein uptake by hepatocytes. This mechanism is significant in view of the epidemiological association of both undercarboxylation of osteocalcin and the presence of an apoϵ4 allele with increased fracture risk and reduced bone mineral density (BMD). The inhibition by heparin of lipoprotein‐mediated carriage of vitamin K and possibly other lipids to bone may provide a basis for the future understanding of heparin‐induced osteoporosis.

Waist-hip ratio and low HDL predict the risk of coronary artery disease in Pakistanis

SUMMARY Objective: To establish risk factor causal associations for coronary artery disease (CAD) in the native Pakistani population. Methods: We conducted a hospital-based, case-control study of 200 cases with angiographically documented CAD and 200 age-and sex-matched controls without angiographic evidence of CAD. Patients on lipid lowering therapy were excluded. Lifestyle, anthropometric and biochemical risk factors were assessed in both groups. Results: The presence of CAD was associated with current, past or passive smoking, a history of diabetes and high blood pressure, a positive family history of CAD, body fat percentage, waist-hip ratio (WHR), low apolipoprotein A1 or low HDL, lipoprotein (a), glucose, insulin, insulin resistance, C-reactive protein (CRP), total cholesterol to HDL ratio (TC/HDL) and creatinine on univariate conditional logistic regression analysis. In multiple regression analysis, significant independent associations were found with low HDL (OR 0.11; 95% CI 0.04–0.34; p < 0.001) positive family history (OR 1.79; 95% CI 1.09-2.93; p = 0.02), CRP (OR 1.45; 95% CI 1.19–1.75; p < 0.001) and WHR (OR 1.04; 95% CI 1.01-1.08; p = 0.01). Angiograms were also quantified for the extent and severity of CAD by the Gensini scoring system. Quantitative angiographic data showed associations with age (p = 0.01), the duration of diabetes (p = 0.04), WHR (p = 0.06), low HDL (p < 0.001), lipoprotein (a) (p = 0.001), creatinine (p < 0.001) and CRP (p = 0.007). Results indicate that total and LDL cholesterol were not significant risk factors in this study; levels were below currently accepted thresholds for treatment. Conclusions: The cardiovascular risk profile in this population is consistent with metabolic syndrome where low HDL and WHR can be used to predict the risk of CAD. Results suggest the need to redefine the currently practised approach to CAD management in this population to fit local needs.

Differential effect of pioglitazone (PGZ) and rosiglitazone (RGZ) on postprandial glucose and lipid metabolism in patients with type 2 diabetes mellitus: a prospective, randomized crossover study.

Postprandial metabolism is impaired in patients with type 2 diabetes (T2Dm). Two thiazolidinediones pioglitazone (PGZ) and rosiglitazone (RGZ) have similar effects on glycaemic control but differ in their effects on fasting lipids. This study investigated the effects of RGZ and PGZ on postprandial metabolism in a prospective, randomized crossover trial.

Efficacy of ezetimibe in patients with statin-resistant and statin-intolerant familial hyperlipidaemias

ABSTRACT Objective : To investigate the efficacy of the cholesterol absorption inhibitor ezetimibe in patients with refractory familial hyperlipidaemia or intolerant to statin therapy. Methods : This prospective study assessed the safety and efficacy of ezetimibe in 200 patients with refractory familial hyperlipidaemias not achieving a low-density-lipoprotein (LDL) cholesterol < 3 mmol/L (116 mg/dL) including 22% intolerant to all statin therapy, many consuming sterol-containing products. Results : Ezetimibe monotherapy resulted in 7% and 11% reductions in LDL-cholesterol and apolipoprotein B respectively. Ezetimibe-statin combination therapy reduced LDL-cholesterol by an additional 11 ± 27% and apolipoprotein B by 11 (+79 to –18)%. There was a similar response between various sub-groups but a wide variation within groups with the greatest effect seen in patients under-responding to statins. The number of patients achieving the LDL‐C target of 3 mmol/L rose from 5.5% to 18%. Non-significant effects included a 5 (+78 to –470)% reduction in triglycerides, 8 ± 36% increment in HDL‐cholesterol, 21 (+35 to –82)% reduction in C-reactive protein and a 1 (+20 to –50)% increase in alanine transaminase. No effects were seen on creatinine, creatine kinase, or insulin resistance. Fourteen patients (7%) discontinued ezetimibe: seven due to gastrointestinal side-effects, one patient developed an ezetimibe-induced hypercholesterolaemia (× 1.5), one developed ezetimibe-induced hypertriglyceridaemia (× 7) and five discontinued for other reasons. Conclusion : Ezetimibe is a useful addition to statins in patients with familial hyperlipidaemias but shows a highly variable response profile.

A randomised placebo controlled trial of the effects of tibolone on blood pressure and lipids in hypertensive women.

The effects of hormone replacement therapy in hypertensive women are controversial. This randomised placebo controlled trial assessed the effect of tibolone 2.5 mg on blood pressure and fasting plasma lipids in 29 hypertensive postmenopausal women over 6 months using a 2:1 randomisation to tibolone. The primary clinical end-point was mean office blood pressure. At 6 months systolic blood pressure declined by 5.30 ± 2.87% vs4.94 ± 3.37% whilst diastolic blood pressure declined 5.38 ± 2.65% vs 0.85 ± 3.69% on tibolone and placebo respectively. These differences were not statistically significant. Triglycerides decreased by 33.3 ± 6.1% vs 7.6 ± 7.9% (P < 0.01) and high-density lipoprotein (hdl)-cholesterol by 21.7 ± 3.8% vs2.4 ± 2.6% (P < 0.01) with tibolone as opposed to placebo. no significant differences were observed in total cholesterol, low-density lipoprotein (ldl)-cholesterol and lipoprotein (a). fibrinogen levels were reduced by 13.6 ± 6.8% on tibolone compared to a 19.3 ± 15.4% rise (P < 0.05) on placebo. this study suggests that tibolone has no deleterious effect on blood pressure in women with hypertension but has contrasting effects on biochemical risk factors. large-scale studies are required to determine the overall effect of tibolone on cardiovascular morbidity and mortality.

Metabolic syndrome and risk of coronary heart disease in a Pakistani cohort

Objective: To assess the relation of the metabolic insulin resistance syndrome (M-IRS) with coronary heart disease (CHD) in Pakistani patients. Subjects: 200 patients with angiographic disease (CHD(+)) matched with 200 patients with chest pain without occlusive disease (CHD(−)). Design: Prospective case–control study. Setting: Tertiary referral cardiology unit in Pakistan. Results: M-IRS was present in 37% of CHD(+) versus 27% of CHD(−) patients by criteria for white patients or 47% versus 42%, respectively, by Asian criteria (p < 0.001). After adjustment for other risk factors, M-IRS was not a significant predictor for CHD or angiographic disease. Age (p  =  0.03), smoking (p < 0.001), diabetes-years (p = 0.003), sialic acid (p  =  0.01), and creatinine (p  =  0.008) accounted for the excess risk of CHD. Similarly, age (p  =  0.005), creatinine (p < 0.001), cigarette pack-years (p  =  0.02), diabetes-years (p  =  0.003), and sialic acid (p  =  0.08) were predictors of greater angiographic disease. M-IRS differed between Pakistani and white patients, as waist circumference correlated weakly (r  =  −0.03–0.08, p  =  0.45–0.52) with triglycerides, high density lipoprotein cholesterol, systolic blood pressure, or glucose. Sialic acid was the only inflammatory marker associated with M-IRS. Conclusions: Despite strong associations between individual risk factors associated with M-IRS and a univariate association between M-IRS and CHD in native Pakistanis, the principal discriminant risk factors in this group are age, smoking, inflammation, diabetes-years, and impaired renal function. The poor sensitivity of M-IRS for CHD reflects the high underlying prevalence of M-IRS, thus reducing sensitivity, confounding by other urban lifestyle traits, or a lack of association of waist circumference with M-IRS risk factors. The definition of M-IRS may have to be revised to increase its power as a discriminant risk factor for CHD in Pakistani populations.

Renin-Angiotensin System Polymorphisms and Coronary Events in Familial Hypercholesterolemia

The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolemia (FH). Polymorphism frequencies for angiotensin-I–converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T, and angiotensin-II type I receptor (AG2R) A1166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolemia, of whom 26.7% and 41.6%, respectively, had established CHD. None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolemia in this study. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (odds ratio [OR]=3.03; 95% CI, 3.07 to 3.72;P =0.05), smoking (OR=2.91; 95% CI, 2.16 to 4.24;P =0.05), diastolic blood pressure (OR=3.70; 95% CI, 3.43 to 3.97;P =0.02), plasma glucose (OR=3.31; 95% CI, 3.10 to 3.52;P =0.04), and the AG2R A1166C polymorphism as risk factors. The OR for the AG2R A1166C polymorphism was 2.26 (95% CI, 1.26 to 3.72;P =0.06) and increased to 3.10 (95% CI, 1.20 to 7.52;P =0.04) after adjustment for other risk factors. The AG2R A1166C polymorphism may interact with severe hypercholesterolemia and other risk factors to increase risk of CHD in FH patients.

High-density lipoprotein cholesterol and triglyceride response with simvastatin versus atorvastatin in familial hypercholesterolemia.

The clinical and biochemical determinants of high-density lipoprotein (HDL) and triglyceride response to simvastatin and atorvastatin were assessed in 150 patients with severe hyperlipidemia treated in a randomized open-trial format design. Triglyceride reduction was only dependent on HDL:apolipoprotein A1, change in apolipoprotein B, and dose response, whereas an increase in HDL was dependent on initial LDL, change in LDL or dose response, and therapy with simvastatin.