Hillel Halkin

Interindividual variability in sensitivity to warfarin‐Nature or nurture?

Interindividual variability in responses to warfarin is attributed to dietary vitamin K, drug interactions, age, or genetic polymorphism in the cytochrome P4502C9 enzyme (CYP2C9) (allelic variants 2C9*2 and 2C9*3) linked with impaired metabolism of the potent enantiomere S ‐warfarin.

Elevated serum uric acid — a facet of hyperinsulinaemia

SummaryIn a representative sample of the adult Jewish population in Israel (n=1016) excluding known diabetic patients and individuals on antihypertensive medications, serum uric acid showed a positive association with plasma insulin response (sum of 1- and 2-hour post glucose load levels) in both males (r=0.316, p<0.001) and females (r=0.236, p<0.001). This association remained statistically significant in both sexes (p<0.001) after accounting by multiple regression analysis for age and major correlates of serum uric acid, i.e. body mass index, glucose response (sum of 1- and 2-hour post load levels), systolic blood pressure and total plasma triglycerides. The net portion of the variance of serum uric acid attributable to insulin response was 12% in males and 8% in females, the total variance accountable by all these variables being 17% and 19% respectively. We conclude that elevated serum uric acid is a feature of hyperinsulinaemia/insulin resistance.

Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy.

PURPOSEnWe have previously found thiamine (vitamin B1) deficiency in patients with congestive heart failure (CHF) who had received long-term furosemide therapy. In the present study, we assessed the effect of thiamine repletion on thiamine status, functional capacity, and left ventricular ejection fraction (LVEF) in patients with moderate to severe CHF who had received furosemide in doses of 80 mg/d or more for at least 3 months.nnnPATIENTS AND METHODSnThirty patients were randomized to 1 week of double-blind inpatient therapy with either i.v. thiamine 200 mg/d or placebo (n = 15 each). All previous drugs were continued. Following discharge, all 30 patients received oral thiamine 200 mg/d as outpatients for 6 weeks. Thiamine status was determined by the erythrocyte thiamine-pyrophosphate effect (TPPE). LVEF was determined by echocardiography.nnnRESULTSnTPPE, diuresis, and LVEF were unchanged with i.v. placebo. After i.v. thiamine, TPPE decreased (11.7% +/- 6.5% to 5.4% +/- 3.2%; P < 0.01). LVEF increased (0.28 +/- 0.11 to 0.32 +/- 0.09; P < 0.05), as did diuresis (1,731 +/- 800 mL/d to 2,389 +/- 752 mL/d; P < 0.02), and sodium excretion (84 +/- 52 mEq/d to 116 +/- 83 mEq/d, P < 0.05). In the 27 patients completing the full 7-week intervention, LVEF rose by 22% (0.27 +/- 0.10 to 0.33 +/- 0.11, P < 0.01).nnnCONCLUSIONSnThiamine repletion can improve left ventricular function and biochemical evidence of thiamine deficiency in some patients with moderate-to-severe CHF who are receiving longterm furosemide therapy.

Effect of past and concurrent body mass index on prevalence of glucose intolerance and Type 2 (non-insulin-dependent) diabetes and on insulin response

SummaryA representative sample (n=2140) of the Israeli Jewish population aged 40–70 (excluding known diabetic patients), whose body mass index had been measured 10 years earlier, underwent an oral glucose tolerance test and redetermination of body mass index. Irrespective of weight changes, high concurrent and high past body mass index values (≥ 27) were associated with similarly increased rates of glucose intolerance as compared with body mass index values < 27 at both time-points (rate ratio 1.76, 90% confidence limits 1.56–1.99). Glucose intolerance here includes borderline and impaired tolerance as well as Type 2 diabetes. The rate of Type 2 diabetes increased only with increasing past body mass index, while concurrent body mass index had no effect [rate ratios: 2.36 (1.48–3.75) and 1.99 (1.48–2.68) respectively for the medium-(23–26.9) versus-low (<23) and high- (≥ 27) versus-medium past body-mass-index categories]. Weight reduction was associated with only slightly reduced rate of glucose intolerance and had no effect on the rate of diabetes. Mean sum insulin (summed 1 and 2 h levels, mU/l) increased significantly with increasing concurrent body mass index (123, 150 and 190 in the low, medium and high categories) with no effect of past body mass index. It also increased significantly (p < 0.001) in all concurrent body mass index categories from normal tolerance through borderline to impaired tolerance, and decreased significantly (p < 0.001) in diabetes relative to impaired tolerance, although it remained above normal. Means of sum insulin within each glucose tolerance level were similar in the two lower concurrent body mass index categories, with markedly higher (p < 0.001) levels in the high body mass index category. All these findings held after accounting for age, sex, ethnic group and use of antihypertensive medications. We conclude that body mass index ≥ 27 leads to early impairment in glucose tolerance. A prolonged period of obesity is apparently required for the development of Type 2 diabetes and its associated reduced insulin response. The reversibility of the deterioration of glucose tolerance seems to be limited.

Obesity, glucose intolerance, hyperinsulinemia, and response to antihypertensive drugs.

Responsiveness to antihypertensive medications was investigated cross-sectionally in 559 individuals comprising all treated hypertensive patients identified within a representative sample (n=3,532, aged 40-70 years) of the Jewish population in Israel. A rate of dosage score (a summed ranking of dosages of all drugs taken) of two or more increased significantly with increasing levels of body mass index (BMI) from 37.5% in levels less than 23, 54.9% in levels 23.0-29.9, and 76.4% in levels of 30 or greater (/?<0.0001). Multivariate analyses, adjusting for age, gender, arm circumference, and ethnic group, confirmed the independent effect of BMI on dosage score (p<0.001). At each level of dosage score, mean blood pressure levels were equivalent at all levels of BMI after adjusting for potential confounders. This indicates that achieved blood pressure level and not BMI itself was the main determinant of the higher dosing regimens prescribed at higher levels of BMI. In representative subgroups, glucose tolerance (n=372) and hyperinsulinemia (n=190) were determined and were found to be positively associated with a dosage score of two or more (p<0.05) independently of BMI. These effects could not be accounted for by poor compliance or by altered drug absorption or disposition since overnight urinary drug excretion and plasma drug concentrations 2 hours after ingestion, measured in 80 randomly selected patients from the study group, were not different across BMI categories at similar dosages. These findings indicate that obesity, even at mild levels, as well as glucose intolerance and hyperinsulinemia, is associated with decreased responsiveness to antihypertensive medications, perhaps as a manifestation of the insulin resistance that characterizes these conditions.

Hyperinsulinemia is characterized by jointly disturbed plasma VLDL, LDL, and HDL levels. A population-based study.

Plasma very low density llpoproteln (VLDL) cholesterol and trlglycerlde, low density llpoproteln (LDL) cholesterol and trlglycerldea, high density llpoproteln (HDL) cholesterol, glucose and Insulin response (sums of 1- and 2-hour postload oral glucose levels), body mass Index (BMI), and blood pressure were determined In a representative sample (n = 542) of the adult Israeli Jewish population. Persons with diabetes or on antlhypertenslve medications were excluded. Total VLDL and LDL fractions were estimated from their cholesterol and trlglyceride subtraction levels that were standardized relative to the mean of the reference group (participants free of glucose Intolerance, obesity, and hypertension – the GOH conditions). Hyperinsulinemia and disturbed levels of VLDL and LDL were defined as levels equal to or greater than the 75th percentile and those of HDL, equal to or less than the 25th percent Me of their respective reference group distributions. When VLDL was disturbed jointly with LDL and HDL, the mean Insulin response adjusted for age, gender, glucose response, BMI, blood pressure, and smoking was high compared to the reference group (166.0 vs.122.5, p < 0.001). With Isolated disturbed VLDL, or disturbed LDL and HDL but normal VLDL, the mean Insulin response resembled the reference group. The adjusted risk ratio for this jointly disturbed llpoproteln profile among hyperinsullnemlc Individuals was 3.4 (95% confidence limits 2.6 to 4.4, p < 0.001) with no further association with the GOH conditions. We conclude that hyperlnsullnemia is characterized by an atherogenlc llpoproteln profile.

Significance of High HbA1 Levels in Normal Glucose Tolerance

The significance of high hemoglobin A1 (HbA1) levels (≥8.0%) found in 12.1% of 648 individuals with normal glucose tolerance constituting a part of a representative population sample was examined. Measurement error in HbA1 and/or glucose-tolerance levels was precluded by HbA1 remaining in the same range over 3.5 yr in 89.7% of 29 individuals with initially high and 68.1% of 22 individuals with initially low (<6.5%) HbA1. Rate of deterioration to glucose intolerance (6.9%) in the high group during that period resembled the rate (11.8%) in a control group (n = 279). Fasting plasma glucose significantly accounted for only 2.4% of total HbA1 - population variance. No correlation of HbA1 was found with other correlates of glucose tolerance or with daily caloric intake and physical activity. A small but significant increment in HbA1 was associated with smoking (7.1 vs. 6.8%, P < .01) and with clinically overt atherosclerosis (7.3 vs. 6.9%, P < .01). We conclude that factors unrelated to glucose metabolism are the main determinants of HbA1 level in normal glucose tolerance and play an important role in diabetes as well. These factors have bearing on evaluation of diabetic control by HbA1 and possibly on risk for diabetic complications.

Hyperinsulinemia, sex, and risk of atherosclerotic cardiovascular disease.

BackgroundThe possibility that hyperinsulinemia may be involved in the etiology of atherosclerotic cardiovascular disease (CVID) was first suggested 20 years ago. During the last decade, this possibility has received support from three large prospective studies. Methods and ResultsIn the present study, the association between CVID, glucose intolerance, obesity, and hypertension (the GOH conditions) and hyperinsulinemia was examined crosssectionally in a representative sample (n = 1,263) of the adult Jewish population aged 40–70 years in Israel. Previously known diabetics were excluded. CVID comprising clinical or ECG evidence of ischemic heart disease, as well as clinical evidence of cerebrovascular or peripheral vascular disease, was identified in 97 men and 39 women. A significant (p < 0.01) hyperinsulinemia- sex interaction was found for CVD rate, with the adjusted risk ratios (followed by 95% confidence limits), relative to the rate in 298 normoinsulinemic women, being 1.15 (0.68–1.95) in 328 normoinsulinemic men, 0.85 (0.48–1.49) in 277 hyperinsulinemic women, and 2.27 (1.33–3.08) in 360 hyperinsulinemic men. Age-adjusted CVD rates in men versus women were: a) similar and low among all normoinsulinemic normotensives and hyperinsulinemics free of any of the GOH conditions (all rates .6.5%); b) similar and high among normoinsulinemic hypertensives (13.4% versus 10.4%); c) significantly higher in men among hyperinsulinemic normotensives with glucose intolerance and/or obesity (15.2% versus 3.3%; p = 0.02) and all hyperinsulinemic hypertensives (21.5% versus 12.8%; p = 0.04). These trends remained significant after adjusting for age, ethnic group, and blood lipids. ConclusionsTherefore, hyperinsulinemia was associated with excess CVII risk in men but not in women, and all excess CVD risk in men was confined to hyperinsulinemic individuals in the presence of glucose intolerance, obesity, or hypertension.

Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers

Prolonged furosemide treatment is associated with urinary loss of thiamine and thiamine deficiency in some patients with congestive heart failure and low dietary thiamine intake. In the rat, diuretic-induced thiamine urinary loss is solely dependent on increased diuresis and is unrelated to the type of diuretic used. We studied the effects of single intravenous doses of furosemide (1, 3, and 10 mg) and of normal saline infusion (750 mL) on urinary thiamine excretion in 6 volunteers. Over a 6-hour period, furosemide induced dose-dependent increases in urine flow and sodium excretion rates (mean +/- SD), from 51 +/- 17 mL/h at baseline to 89 +/- 29 mL/h, 110 +/- 38 mL/h, and 183 +/- 58 mL/h (F = 10.4, P < .002) and from 5.1 +/- 2.3 mmol/h to 9.4 +/- 6.8 mmol/h, 12.1 +/- 2.6 mmol/h, and 20.9 +/- 10.6 mmol/h (F = 6.3, P < .005) for the three doses, respectively (104 +/- 35 mL/h and 13.0 +/- 6.2 mmol/h for the saline infusion). During this period the thiamine excretion rate doubled from baseline levels (mean of four 24-hour periods before the diuretic interventions) of 6.4 +/- 5.1 nmol/h to 11.6 +/- 8.2 nmol/h (F = 5.03, P < .01, for all four interventions, no difference being found between them), then returning over the following 18 hours to 6.1 +/- 3.9 nmol/h. The thiamine excretion rate was correlated with the urine flow rate (r = 0.54, P < .001), with no further effect of the type of intervention or sodium excretion rate. These findings complement our previous results in animals and indicate that sustained diuresis of >100 mL/h induces a nonspecific but significant increase in urinary loss of thiamine in human subjects. Thiamine supplements should be considered in patients undergoing sustained diuresis, when dietary deficiency may be present.

Warfarin and vitamin K intake in the era of pharmacogenetics.

The considerable variability in the warfarin dose-response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following: 1 The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy. 2 The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and 3 The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.