Gary K. Grunwald

Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels

IMPORTANCE Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown. A recent randomized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety. OBJECTIVES To assess the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease. DESIGN, SETTING, AND PATIENTS A retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011. MAIN OUTCOMES AND MEASURES Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke. RESULTS Of the 8709 men with a total testosterone level lower than 300 ng/dL, 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. Of the 1710 outcome events, 748 men died, 443 had MIs, and 519 had strokes. Of 7486 patients not receiving testosterone therapy, 681 died, 420 had MIs, and 486 had strokes. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. At 3 years after coronary angiography, the Kaplan-Meier estimated cumulative percentages with events were 19.9%in the no testosterone therapy group vs 25.7%in the testosterone therapy group,with an absolute risk difference of 5.8%(95%CI, -1.4%to 13.1%) [corrected].The Kaplan-Meier estimated cumulative percentages with events among the no testosterone therapy group vs testosterone therapy group at 1 year after coronary angiography were 10.1% vs 11.3%; at 2 years, 15.4% vs 18.5%; and at 3 years, 19.9% vs 25.7 [corrected].There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease (test for interaction, P = .41). CONCLUSIONS AND RELEVANCE Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes. These findings may inform the discussion about the potential risks of testosterone therapy.

The role of low-fat diets in body weight control: a meta-analysis of ad libitum dietary intervention studies.

OBJECTIVES: Low-fat high-carbohydrate diets are recommended to prevent weight gain in normal weight subjects and reduce body weight in overweight and obese. However, their efficacy is controversial. We evaluated the efficacy of ad libitum low-fat diets in reducing body weight in non-diabetic individuals from the results of intervention trials.DESIGN: Studies were identified from a computerized search of the Medline database from January 1966 to July 1999 and other sources. Inclusion criteria were: controlled trials lasting more than 2 months comparing ad libitum low-fat diets as the sole intervention with a control group consuming habitual diet or a medium-fat diet ad libitum.MAIN OUTCOME MEASURES: Differences in changes in dietary fat intake, energy intake and body weight. Weighted mean differences for continuous data and 95% confidence intervals (CIs) were calculated.RESULTS: Two authors independently selected the studies meeting the inclusion criteria and extracted data from 16 trials (duration of 2–12 months) with 19 intervention groups, enrolling 1910 individuals. Fourteen were randomized. Weight loss was not the primary aim in 11 studies. Before the interventions the mean proportions of dietary energy from fat in the studies were 37.7% (95% CI, 36.9–38.5) in the low-fat groups, and 37.4% (36.4–38.4) in the control groups. The low-fat intervention produced a mean fat reduction of 10.2% (8.1–12.3). Low-fat intervention groups showed a greater weight loss than control groups (3.2 kg, 95% confidence interval 1.9–4.5 kg; P<0.0001), and a greater reduction in energy intake (1138 kJ/day, 95% confidence interval 564–1712 kJ/day, P=0.002). Having a body weight 10 kg higher than the average pre-treatment body weight was associated with a 2.6±0.8 kg (P=0.011) greater difference in weight loss.CONCLUSION: A reduction in dietary fat without intentional restriction of energy intake causes weight loss, which is more substantial in heavier subjects.

Simvastatin Lowers C-Reactive Protein Within 14 Days An Effect Independent of Low-Density Lipoprotein Cholesterol Reduction

Background—The early response of C-reactive protein to initiation of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) is not known. The purpose of this study was to determine the rate at which highly sensitive C-reactive protein (hsCRP) levels change after initiation of simvastatin and whether this occurs independently of the change in LDL cholesterol. Methods and Results—The study was a crossover, double-blind design including 40 subjects with elevated LDL cholesterol. Subjects were randomly assigned to 1 of 2 groups: simvastatin 40 mg for 14 days, then placebo for 14 days, or placebo first, then simvastatin. Simvastatin decreased LDL cholesterol by 56±4 mg/dL (P <0.0001) at day 7 and by an additional 8±3 mg/dL (P =0.02) at day 14. Baseline log(hsCRP) levels were similar in the 2 groups. By day 14, log(hsCRP) was significantly lower in patients on simvastatin when compared with placebo (P =0.011). Although there was no significant difference in fibrinogen levels, simvastatin produced a modest increase in log[lipoprotein(a)] (P =0.03) at days 7 and 14. There were no relationships between the decrease in LDL cholesterol and the decrease in hsCRP. Conclusions—Simvastatin lowers hsCRP by 14 days, independent of its effect on LDL cholesterol. This rapid impact of a statin on hsCRP has potential implications in the management of acute coronary syndromes.

The role of dietary fat in body fatness: evidence from a preliminary meta-analysis of ad libitum low-fat dietary intervention studies

The role of high-fat diets in weight gain and obesity has been questioned because of inconsistent reports in the literature concerning the efficacy of ad libitum low-fat diets to reduce body weight. We conducted a meta-analysis of weight loss occurring on ad libitum low-fat diets in intervention trials, and analysed the relationship between initial body weight and weight loss. We selected controlled trials lasting more than 2 months comparing ad libitum low-fat diets with a control group consuming their habitual diet or a medium-fat diet ad libitum published from 1966 to 1998. Data were included from 16 trials with a duration of 2-12 months, involving 1728 individuals. No trials on obese subjects fulfilled the inclusion criteria. The weighted difference in weight loss between intervention and control groups was 2.55 kg (95% CI, 1.5-3.5; P < 0.0001). Weight loss was positively and independently related to pre-treatment body weight (r = 0.52, P < 0.05) and to reduction in the percentage of energy as fat (0.37 kg/%, P < 0.005) in unweighted analysis. Extrapolated to a BMI of about 30 kg/m2 and assuming a 10% reduction in dietary fat, the predicted weight loss would be 4.4 kg (95% CI, 2.0 to -6.8 kg). Because weight loss was not the primary aim in 12 of the 16 studies, it is unlikely that voluntary energy restriction contributed to the weight loss. Although there is no evidence that a high intake of simple sugars contributes to passive overconsumption, carbohydrate foods with a low glycaemic index may be more satiating and exert more beneficial effects on insulin resistance and cardiovascular risk factors. Moreover, an increase in protein content up to 25% of total energy may also contribute to reducing total energy intake. In conclusion, a low-fat diet, high in protein and fibre-rich carbohydrates, mainly from different vegetables, fruits and whole grains, is highly satiating for fewer calories than fatty foods. This diet composition provides good sources of vitamins, minerals, trace elements and fibre, and may have the most beneficial effect on blood lipids and blood-pressure levels. A reduction in dietary fat without restriction of total energy intake prevents weight gain in subjects of normal weight and produces a weight loss in overweight subjects, which is highly relevant for public health.

Analysis of repeated measures data with clumping at zero.

Longitudinal or repeated measures data with clumping at zero occur in many applications in biometrics, including health policy research, epidemiology, nutrition, and meteorology. These data exhibit correlation because they are measured on the same subject over time or because subjects may be considered repeated measures within a larger unit such as a family. They present special challenges because of the extreme non-normality of the distributions involved. A model for repeated measures data with clumping at zero, using a mixed-effects mixed-distribution model with correlated random effects, is presented. The model contains components to model the probability of a nonzero value and the mean of nonzero values, allowing for repeated measurements using random effects and allowing for correlation between the two components. Methods for describing the effect of predictor variables on the probability of nonzero values, on the mean of nonzero values, and on the overall mean amount are given. This interpretation also applies to the mixed-distribution model for cross-sectional data. The proposed methods are illustrated with analyses of effects of several covariates on medical expenditures in 1996 for subjects clustered within households using data from the Medical Expenditure Panel Survey.

Off-pump coronary artery bypass is associated with improved risk-adjusted outcomes

BACKGROUND The impact of off-pump median sternotomy coronary artery bypass grafting procedures on risk-adjusted mortality and morbidity was evaluated versus on-pump procedures. METHODS Using the Department of Veterans Affairs Continuous Improvement in Cardiac Surgery Program records from October 1997 through March 1999, nine centers were designated as having experience (with at least 8% coronary artery bypass grafting procedures performed off-pump). Using all other 34 Veterans Affairs cardiac surgery programs, baseline logistic regression models were built to predict risk of 30-day operative mortality and morbidity. These models were then used to predict outcomes for patients at the nine study centers. A final model evaluated the impact of the off-pump approach within these nine centers adjusting for preoperative risk. RESULTS Patients treated off-pump (n = 680) versus on-pump (n = 1,733) had lower complication rates (8.8% versus 14.0%) and lower mortality (2.7% versus 4.0%). Risk-adjusted morbidity and mortality were also improved for these patients (0.52 and 0.56 multivariable odds ratios for off-pump versus on-pump, respectively, p < 0.05). CONCLUSIONS An off-pump approach for coronary artery bypass grafting procedures is associated with lower risk-adjusted morbidity and mortality.

Idiopathic Pulmonary Fibrosis: Physiologic Tests, Quantitative CT Indexes, and CT Visual Scores as Predictors of Mortality

PURPOSE To retrospectively evaluate quantitative computed tomographic (CT) indexes, pulmonary function test results, and visual CT scoring as predictors of mortality and to describe serial changes in quantitative CT indexes over 12 months in patients with idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS Institutional review board approval and informed consent were obtained at all participating institutions. One hundred sixty-seven patients (110 men, 57 women; mean age, 63 years +/- 9 [standard deviation]) with IPF were enrolled in a clinical trial. Patients underwent thin-section CT in the supine position at full inspiration at enrollment (baseline) and at 12-month follow-up. After segmentation of the lungs, mean lung attenuation (MLA), skewness, and kurtosis were measured. Extent of ground glass opacity and lung fibrosis were assessed visually. Forced vital capacity (FVC) and total lung capacity (TLC) were measured. Median duration of follow-up for mortality was 1.5 years. Univariate and multivariate survival analyses were used to determine the predictive value of baseline variables for survival. RESULTS At univariate analysis, baseline variables predictive of death included TLC, fibrosis, skewness, and kurtosis. At multivariate analysis, FVC (P = .006) and fibrosis (P = .002) were predictors of short-term mortality. In 95 patients who had both baseline and follow-up CT scans, fibrosis (P = .030), MLA (P = .003), skewness (P < .001), and kurtosis (P < .001) all showed change indicating disease progression. CONCLUSION Visually determined disease extent on CT images is a strong independent predictor of mortality in IPF. Serial evaluation of quantitative CT measures can show disease progression in these patients.

Relation between calcium intake and fat oxidation in adult humans

OBJECTIVE: To determine if total calcium (Ca2+) intake and intake of Ca2+ from dairy sources are related to whole-body fat oxidation.DESIGN: Cross-sectional study.SUBJECTS: A total of 35 (21 m, 14 f) non-obese, healthy adults (mean±s.d., age: 31±6 y; weight: 71.2±12.3 kg; BMI: 23.7±2.9 kg m−2; body fat: 21.4±5.4%).MEASUREMENTS: Daily (24 h) energy expenditure (EE) and macronutrient oxidation using whole-room indirect calorimetry; habitual Ca2+ intake estimated from analysis of 4-day food records; acute Ca2+ intake estimated from measured food intake during a 24-h stay in a room calorimeter.RESULTS: Acute Ca2+ intake (mg· kcal−1) was positively correlated with fat oxidation over 24 h (r=0.38, P=0.03), during sleep (r=0.36, P=0.04), and during light physical activity (r=0.32, P=0.07). Acute Ca2+ intake was inversely correlated with 24-h respiratory quotient (RQ) (r=−0.36, P=0.04) and RQ during sleep (r=−0.31, P=0.07). After adjustment for fat mass, fat-free mass, energy balance, acute fat intake, and habitual fat intake, acute Ca2+ intake explained ∼10% of the variance in 24-h fat oxidation. Habitual Ca2+ intake was not significantly correlated to fat oxidation or RQ. Total Ca2+ intake and Ca2+ intake from dairy sources were similarly correlated with fat oxidation. In backwards stepwise models, total Ca2+ intake was a stronger predictor of 24 h fat oxidation than dairy Ca2+ intake.CONCLUSION: Higher acute Ca2+ intake is associated with higher rates of whole-body fat oxidation. These effects were apparent over 24 h, during sleep and, to a lesser extent, during light physical activity. Calcium intake from dairy sources was not a more important predictor of fat oxidation than total Ca2+ intake.

The effect of a probiotic milk product on plasma cholesterol: a meta-analysis of short-term intervention studies

Introduction: Certain fermented dairy milk products may have beneficial effects on plasma cholesterol levels. However, a number of studies have produced conflicting results as to whether dietary supplementation by a probiotic dairy product containing the bacteria culture Causido® reduces plasma cholesterol.Objective: To conduct a meta-analysis of intervention studies to evaluate the effect of the Causido® culture on plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol.The probiotic milk product: The yoghurt product Gaio® is fermented with Causido®, composed of one strain of Enterococcus faecium (human species) with the proposed cholesterol-lowering effect, and two strains of Streptococcus thermophilus.Study inclusion and data extraction: Six studies were identified from a literature search and from the yoghurt producer. All studies met the inclusion criteria. Summary data for plasma concentrations of total cholesterol and LDL-cholesterol were extracted from the original publications or by personal request to the authors. Data from 4–8 weeks of treatment duration was used.Statistical analysis: We performed a traditional meta-analysis where mean differences between intervention and control of the pre–post changes in total cholesterol and LDL-cholesterol were calculated, as well as 95% confidence intervals (CIs).Results: In the six studies included in the meta-analysis, the Gaio® interventions produced changes in total cholesterol above those of the control groups ranging from −0.02 to −1.02 mmol/l and in LDL-cholesterol ranging from −0.02 to −1.15 mmol/l. After inclusion of an open-label study, the meta-analysis of the double-blind studies showed that Gaio® as compared to the control group changed total cholesterol by −0.22 mmol/l (95% CI: −0.35 to −0.08, P<0.01) and LDL-cholesterol by −0.20 mmol/l (95% CI: −0.33 to −0.06, P<0.005). The outcome was essentially the same if all studies were included.Conclusions: The present meta-analysis of controlled short-term intervention studies shows that the fermented yoghurt product produced a 4% decrease in total cholesterol and a 5% decrease in LDL-cholesterol when the open-label study is excluded. To demonstrate sustained effects on blood lipids, long-term studies are required.Sponsorship: MD Foods A/S, Denmark. European Journal of Clinical Nutrition (2000) 54, 856–860

Nonobstructive coronary artery disease and risk of myocardial infarction.

IMPORTANCE Little is known about cardiac adverse events among patients with nonobstructive coronary artery disease (CAD). OBJECTIVE To compare myocardial infarction (MI) and mortality rates between patients with nonobstructive CAD, obstructive CAD, and no apparent CAD in a national cohort. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of all US veterans undergoing elective coronary angiography for CAD between October 2007 and September 2012 in the Veterans Affairs health care system. Patients with prior CAD events were excluded. EXPOSURES Angiographic CAD extent, defined by degree (no apparent CAD: no stenosis >20%; nonobstructive CAD: ≥1 stenosis ≥20% but no stenosis ≥70%; obstructive CAD: any stenosis ≥70% or left main [LM] stenosis ≥50%) and distribution (1, 2, or 3 vessel). MAIN OUTCOMES AND MEASURES The primary outcome was 1-year hospitalization for nonfatal MI after the index angiography. Secondary outcomes included 1-year all-cause mortality and combined 1-year MI and mortality. RESULTS Among 37,674 patients, 8384 patients (22.3%) had nonobstructive CAD and 20,899 patients (55.4%) had obstructive CAD. Within 1 year, 845 patients died and 385 were rehospitalized for MI. Among patients with no apparent CAD, the 1-year MI rate was 0.11% (n = 8, 95% CI, 0.10%-0.20%) and increased progressively by 1-vessel nonobstructive CAD, 0.24% (n = 10, 95% CI, 0.10%-0.40%); 2-vessel nonobstructive CAD, 0.56% (n = 13, 95% CI, 0.30%-1.00%); 3-vessel nonobstructive CAD, 0.59% (n = 6, 95% CI, 0.30%-1.30%); 1-vessel obstructive CAD, 1.18% (n = 101, 95% CI, 1.00%-1.40%); 2-vessel obstructive CAD, 2.18% (n = 110, 95% CI, 1.80%-2.60%); and 3-vessel or LM obstructive CAD, 2.47% (n = 137, 95% CI, 2.10%-2.90%). After adjustment, 1-year MI rates increased with increasing CAD extent. Relative to patients with no apparent CAD, patients with 1-vessel nonobstructive CAD had a hazard ratio (HR) for 1-year MI of 2.0 (95% CI, 0.8-5.1); 2-vessel nonobstructive HR, 4.6 (95% CI, 2.0-10.5); 3-vessel nonobstructive HR, 4.5 (95% CI, 1.6-12.5); 1-vessel obstructive HR, 9.0 (95% CI, 4.2-19.0); 2-vessel obstructive HR, 16.5 (95% CI, 8.1-33.7); and 3-vessel or LM obstructive HR, 19.5 (95% CI, 9.9-38.2). One-year mortality rates were associated with increasing CAD extent, ranging from 1.38% among patients without apparent CAD to 4.30% with 3-vessel or LM obstructive CAD. After risk adjustment, there was no significant association between 1- or 2-vessel nonobstructive CAD and mortality, but there were significant associations with mortality for 3-vessel nonobstructive CAD (HR, 1.6; 95% CI, 1.1-2.5), 1-vessel obstructive CAD (HR, 1.9; 95% CI, 1.4-2.6), 2-vessel obstructive CAD (HR, 2.8; 95% CI, 2.1-3.7), and 3-vessel or LM obstructive CAD (HR, 3.4; 95% CI, 2.6-4.4). Similar associations were noted with the combined outcome. CONCLUSIONS AND RELEVANCE In this cohort of patients undergoing elective coronary angiography, nonobstructive CAD, compared with no apparent CAD, was associated with a significantly greater 1-year risk of MI and all-cause mortality. These findings suggest clinical importance of nonobstructive CAD and warrant further investigation of interventions to improve outcomes among these patients.