Treating obesity in patients with cardiovascular disease: the pharmacotherapeutic options

Introduction: Obesity is a growing health problem that has numerous comorbidities, including cardiovascular disease (CVD). The multi-disciplinary treatment of obesity now includes the use of pharmacotherapy. When treating patients with obesity and CVD, certain medications may be more appropriate than others.

Areas covered: Herein, the authors review the most commonly used FDA approved medications for the treatment of obesity, describing their mechanism of action, and the efficacy and safety of the medications as seen in recent studies, particularly in patients with CVD.

Expert opinion: In the population of patients with obesity and CVD, the medications orlistat, lorcaserin and liraglutide are considered the most appropriate options for their treatment, in terms of safety. Sympathomimetic medications, such as phentermine, should be avoided in this group. The recent CAMELLIA-TIMI 61 trial supports the safety of lorcaserin in patients with CVD. Until there are more studies, it is reasonable to extrapolate the findings of the LEADER trial, which found improved CV outcomes in subjects with type 2 diabetes taking liraglutide, to the population of nondiabetic patients being treated for obesity. Further cardiovascular outcomes trials (CVOT) are needed to assess the safety of other pharmacotherapeutic options for weight loss.     

Within- and between-laboratory precision in the measurement of body volume using air displacement plethysmography and its effect on body composition assessment

OBJECTIVE: To determine and compare the extent of within- and between-laboratory precision in body volume (BV) measurements using air displacement plethysmography (ADP), the BOD POD body composition system, and to interpret any such variability in terms of body composition estimates. DESIGN: Repeated test procedures of BV assessment using the BOD POD ADP were reproduced at two laboratories for the estimation of precision, both within and between laboratories. SUBJECTS: In total, 30 healthy adult volunteers, 14 men (age, 19-48 y; body mass index (BMI), 19.7-30.3 kg/m2) and 16 women (age, 19-40 y; BMI, 16.3-35.7 kg/m2), were each subjected to two test procedures at both laboratories. Two additional volunteers were independently subjected to 10 repeated test procedures at both laboratories. MEASUREMENTS: Repeated measurements of BV, uncorrected for the effects of isothermal air in the lungs and the surface area artifact, were obtained using the BOD POD ADP, with the identical protocol being faithfully applied at both laboratories. Uncorrected BV measurements were adjusted to give estimates of actual BV that were used to calculate body density (body weight (BWt)/actual BV) from which estimates of body composition were derived. The differences between repeated BV measurements or body composition estimates were used to assess within-laboratory precision (repeatability), as standard deviation (SD) and coefficient of variation; the differences between measurements reproduced at each laboratory were used to determine between-laboratory precision (reproducibility), as bias and 95% limits of agreement (from SD of the differences between laboratories). RESULTS: The extent of within-laboratory methodological precision for BV (uncorrected and actual) was variable according to subject, sample group and laboratory conditions (range of SD, 0.04-0.13 l), and was mostly due to within-individual biological variability (typically 78-99%) rather than to technical imprecision. There was a significant (P<0.05) bias between laboratories for the 10 repeats on the two independent subjects (up to 0.29 l). Although no significant bias (P=0.077) was evident for the sample group of 30 volunteers (-0.05 l), the 95% limits of agreement were considerable (-0.68 to 0.58 l). The effects of this variability in BV on body composition were relatively greater: for example, within-laboratory precision (SD) for body fat as % BWt was between 0.56 and 1.34% depending on the subject and laboratory; the bias (-0.59%) was not significant between laboratories, but there were large 95% limits of agreement (-3.67 to 2.50%). CONCLUSION: Within-laboratory precision for each BOD POD instrument was reasonably good, but was variable according to the prevailing conditions. Although the bias between the two instruments was not significant for the BV measurements, implying that they can be used interchangeably for groups of similar subjects, the relatively large 95% limits of agreement indicate that greater consideration may be needed for assessing individuals with different ADP instruments. Therefore, use of a single ADP instrument is apparently preferable when assessing individuals on a longitudinal basis.     

Recurrent cardiac myxoma: the surgical implications of two distinct groups of patients

15 consecutive cases where patients (11 female, 4 male) had undergone surgical excision of cardiac myxoma were reviewed. The 11 survivors were re-assessed by trans-oesophageal echocardiography and recurrent myxoma was detected in 2 patients. These two were the only patients who had originally presented with multiple myxomas. Analysis of these cases in conjunction with 26 previously reported cases of recurrence identifies two distinct groups of patients. In one group (12 cases, mean age 48.7 years) recurrence occurred at the site of previous excision, typically following the removal of a single septal myxoma by partial thickness excision. In the second group, which includes our two cases, (16 cases, mean age 30.6 years) recurrent myxoma was found distant to the site of previous excision, typically in younger patients who had multiple myxomas at original operation. These results suggest that 1) single myxomas should be removed by full thickness excision 2) in younger patients with multiple myxomas surgery should be as radical as possible.     

Activator of G protein signaling 3 null mice: I. Unexpected alterations in metabolic and cardiovascular function

Activator of G protein signaling (AGS)-3 plays functional roles in cell division, synaptic plasticity, addictive behavior, and neuronal development. As part of a broad effort to define the extent of functional diversity of AGS3-regulated-events in vivo, we generated AGS3 null mice. Surprisingly, AGS3 null adult mice exhibited unexpected alterations in cardiovascular and metabolic functions without any obvious changes in motor skills, basic behavioral traits, and brain morphology. AGS3 null mice exhibited a lean phenotype, reduced fat mass, and increased nocturnal energy expenditure. AGS3 null mice also exhibited altered blood pressure control mechanisms. These studies expand the functional repertoire for AGS3 and other G protein regulatory proteins providing unexpected mechanisms by which G protein systems may be targeted to influence obesity and cardiovascular function.     

Apoprotein synthesis by human duodenojejunal mucosa.

We tested whether human duodenojejunal mucosa is able to synthesize apoproteins from amino acid precursors because lipoprotein-like particles are visualized by electron microscopy in human absorptive cells and because apoproteins are synthesized by the perfused rat intestine. Duodenojejunal biopsies from 21 normal fasting volunteers were incubated with L-[U-14C]leucine; 15.6 +/- 3.3 nmoles of the [14C]leucine was incorporated into protein by 100 mg wet weight of biopsies during an incubation of 2 hr. No [14C]leucine was incorporated by boiled biopsies. Homogenates of incubated biopsies were fractionated by ultracentrifugation: 43 +/- 2% of the incorporated 14C as found in the d less than 1.006 fraction; 3.2 +/- 0.6%, 8.1 +/- 1.0% and 48 +/- 2% were found to be associated with the d = 1.006 to 1.063, d = 1.063 to 1.25, and d greater than 1.25 fractions, respectively. The specific activity in the d less than 1.006 fraction was 5.6 times greater than that in the other fractions. Of the 14C incorporated into the d less than 1.006 fraction, 10.8, 7.2, and 7.1% were specifically precipitated by rabbit antihuman apoproteins A-I, A-II, and B, respectively. Of the 14C incorporated into the d = 1.006 to 1.063 fraction, 11.3 4.1, and 8.5% were specifically precipitated by rabbit antihuman apoprotein A-I, A-II, and B, respectively. Approximately 5% of the 14C incorporated by the d = 1.063 to 1.25 fractions were precipitated by rabbit antihuman apoprotein A-I or A-II. None of the d less than 1.25 fractions precipitated a significant amount of radioactivity with rabit antihuman apoprotein C-II, or antiarginine-rich apoprotein. None of the antibodies precipitated radioactivity from the d greater than 1.25 fraction. These experiments suggest that human duodenojejunal mucosa is able to synthesize in vitro apoproteins A-I, A-II, and B from amino acid precursors. The specificity of the immunoprecipitates was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis.     

Spinal cord injury and protection

Subsequent to traumatic injury of the spinal cord, a series of pathophysiological events occurs in the injured tissue that leads to tissue destruction and paraplegia. These include hemorrhagic necrosis, ischemia, edema, inflammation, neuronophagia, loss of Ca2+ from the extracellular space, and loss of K+ from the intracellular space. In addition, there is trauma-initiated lipid peroxidation and hydrolysis in cellular membranes. Both lipid peroxidation and hydrolysis can damage cells directly; hydrolysis also results in the formation of the biologically active prostaglandins and leukotrienes (eicosanoids). The time course of membrane lipid alterations seen in studies of antioxidant interventions suggests that posttraumatic ischemia, edema, inflammation, and ionic fluxes are the result of extensive membrane peroxidative reactions and lipolysis that produce vasoactive and chemotactic eicosanoids. A diverse group of compounds has been shown to be effective in ameliorating spinal cord injury in experimental animals. These include the synthetic glucocorticoid methylprednisolone sodium succinate (MPSS); the antioxidants vitamin E, selenium, and dimethyl sulfoxide (DMSO); the opiate antagonist naloxone; and thyrotropin-releasing hormone (TRH). With the exception of TRH, all of these agents have demonstrable antioxidant and/or anti-lipid-hydrolysis properties. Thus the effectiveness of these substances may lie in their ability to quench membrane peroxidative reactions or to inhibit the release of fatty acids from membrane phospholipids, or both. Whatever the mode of action, early administration appears to be a requirement for maximum effectiveness.     

Pathways to earned-security: The role of alternative support figures

This study explored the kinds of relationship experiences associated with earned-security, i.e., the extent to which mothers who report early negative relationship histories with their parents are later able to form a secure working model of attachment (indicated by the ability to speak clearly and coherently about these histories). Mothers from a low-risk sample (N = 121) expecting their first child completed the Adult Attachment Interview (AAI), which was used to assess earned-security retrospectively using the stringent definition recommended by Main and Hesse (Hesse, 2008 Hesse, E. 2008. “The Adult Attachment Interview: Protocol, method of analysis, and empirical studies”. In The handbook of attachment: Theory, research and clinical applications, Edited by: Cassidy, J. and Shaver, P. R. 552–598. New York, NY: The Guilford Press.  [Google Scholar]; Main, Goldwyn, & Hesse, 2002 Main, M., Goldwyn, R. and Hesse, E. 2002/2008. Adult attachment scoring and classification system, Unpublished scoring manual, University of California at Berkeley.  [Google Scholar]), as well as to identify alternative support figures. Participants also completed self-report measures of depressive symptomatology, questionnaires concerning their experiences in therapy, and later, when their babies were 12 to 15 months old, the Strange Situation procedure. Sixteen mothers were classified as earned-secure (25% of those classified as secure-autonomous and 13% of the whole sample). Women who were earned-secure (vs. insecure and continuous-secure) reported significantly higher levels of emotional support, but not instrumental support, from alternative support figures. They also spent more time in therapy than did insecure and continuous-secure women and were more likely to form secure attachments with their infants than insecure women. These findings were obtained even after controlling for depressive symptoms.     

Bromhexine in severe asthma.

Fourteen patients with acute severe asthma necessitating hospital admission were all treated with a standard therapeutic regimen, and in addition received either bromhexine or placebo (initially intravenously and subsequently orally) double-blind. We were unable to show any significant improvement in the rate of recovery of the bromhexine-treated group, in terms of either arterial blood gases or change in peak expiratory flow rates.     

Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.