David S. Schade

Recombinant Human Growth Hormone, Insulin-like Growth Factor 1, and Combination Therapy in AIDS-Associated Wasting: A Randomized, Double-Blind, Placebo-Controlled Trial

Wasting associated with the acquired immunodeficiency syndrome (AIDS) is a serious complication of human immunodeficiency virus (HIV) infection that causes progressive loss of both lean body mass and, more variably, fat mass [1-4]. The pathogenesis is probably multifactorial and includes the underlying viral infection, tissue cytokines, intercurrent infections, and poor intake of calories [1, 2]. Recombinant human insulin-like growth factor 1 (rhIGF-1) alone and recombinant human growth hormone (rhGH) alone have been administered to humans during various catabolic states, including fasting, the period immediately after surgery, and trauma, and have had positive effects on lean body mass [5-7]. The beneficial effects of rhGH on body composition and metabolism are reportedly mediated by increased levels of IGF-1 [4, 5]. Furthermore, animal studies have shown that rhIGF-1 has beneficial effects on lymphopoieses [8]. Limited studies of rhGH or rhIGF-1 treatment alone in patients with AIDS have also been promising, resulting in an increase in circulating IGF-1 levels, lean body mass, and muscle function [9-11]. We hypothesized that treating AIDS-associated wasting with rhIGF-1, alone or in combination with rhGH, would reverse the catabolic effects characteristic of this wasting. We further hypothesized that if rhGH therapy increased lean body mass, then physical strength, immune function, and quality of life would improve. We therefore did a randomized, double-blind, placebo-controlled trial to assess the effects of rhGH and rhIGF-1 therapy in patients with AIDS-associated wasting. The primary end points were changes in weight and lean body mass. The secondary end points were changes in muscle function, immune status, quality of life, and protein catabolism. The Institutional Review Boards of the University of New Mexico and the University of Texas Southwestern Medical Center approved the study, and all patients gave written informed consent before entering the study. Methods Patients We recruited 60 patients (58 men and 2 women) with AIDS (as defined by the Centers for Discase Control and Prevention [12]), unexplained wasting (defined as weight loss 10% of the weight before diagnosis or body mass index 19.8 kg/m2), and a CD4 count less than 200 cells/mm3. Weight before diagnosis was defined as the weight that an adult patient maintained for at least 2 years during the time the patient believed that he or she was healthy. In New Mexico, patients were recruited by postings at the University of New Mexico Hospital Infectious Disease Clinic and Veterans Administration Hospital and by physician referral from private practices in Albuquerque and Santa Fe. In Texas, patients were recruited from the University of Texas Southwestern Medical Center at Dallas, a collaborating institution, and private practices throughout the Southwest. In addition, an advertisement was placed in the directory of the American Federation for AIDS Research. The patients were admitted to the University of New Mexico Clinical Research Center for a 2-day inpatient screening assessment. This assessment included physical examination, neurologic examination, electrocardiography, and chest radiography. Additional inclusion criteria were a hematocrit of 0.28 or greater, negative result of a pregnancy test (in women), negative 7-day blood culture for Mycobacterium avium intracellulare within 4 weeks before study entry, negativity for cryptococcal antigen in serum within 4 weeks before study entry, and a chest radiograph showing no evidence of acute cardiopulmonary disease within 28 days before study entry. Exclusion criteria were body mass index of 26.0 kg/m2 or greater, opportunistic infection that resolved less than 4 weeks before study entry, diarrhea (defined as five or more bowel movements per day or identification of an enteric pathogen), history of endocrine disease associated with hypoglycemia or hyperglycemia, any disorder associated with moderate or severe edema, history of cancer within 3 years of study entry, active Kaposi sarcoma, diagnosed cardiovascular disease (including congestive heart failure and cardiomyopathy), medically significant liver dysfunction (serum alanine aminotransferase level > 200 IU, total bilirubin level > 51.3 mmol/L) and renal dysfunction (creatinine level > 176.8 mmol/L). Baseline dietary histories were analyzed; at study entry, all patients were consuming at least 25 kcal/kg of body weight and none was receiving intravenous or tube feeding. None had received therapy with anabolic or catabolic agents, including interferon, megestrol, dronabinol, oxandrolone, and corticosteroids, within 30 days of study entry. No patient had received any experimental agent or procedure within 30 days of enrollment other than prophylactic antimicrobial therapy directed at fungal, bacterial, viral, mycobacterial, or parasitic infections. All patients had been receiving antiretroviral therapy for at least 3 months before study entry and received prophylaxis for Pneumocystis carinii throughout the treatment period. Genentech, Inc. (South San Francisco, California), randomly assigned the 60 patients into four groups of 15 patients each so that balance was maintained across the groups with respect to body mass index, CD4 count, type of antiretroviral therapy, and age. The type of antiretroviral therapy was divided into five categories: zidovudine alone, didanosine alone, simultaneous administration of zidovudine and didanosine, simultaneous administration of zidovudine and zalcitabine, and other. The schedule for the subcutaneously injected therapy was as follows: Group 1 received 1.4 mg of rhGH once daily and 1 mL of placebo twice daily; group 2 received 5 mg of rhIGF-1 twice daily and 1 mL of placebo once daily; group 3 received 5 mg of rhIGF-1 twice daily and 1.4 mg of rhGH once daily; and group 4 received 1 mL of placebo three times daily. All patients received three subcutaneous injections per day for 12 weeks. Both patients and clinicians were blinded to treatment group assignments. The rhGH dosage used in this study was approximately one half the dosage used in our previous study [9]. The decision to use this dosage was based on the 2 2 analysis of variance (ANOVA) design and concern about the potential for increased incidence and severity of side effects if full doses of rhGH and rhIGF-1 were used in the patients receiving rhGH plus rhIGF-1. Patients were withdrawn from the study if they did not administer all three injections each day for 7 continuous days throughout the treatment period. Injection compliance was assessed by counting vials and interviewing the study clinician during assessment visits. In addition, IGF-1 levels were monitored in all patients and were compared with values at baseline and those in placebo recipients. The intended duration of all treatments was 12 weeks. Body Composition Lean body mass, fat mass, and percentage of body fat were measured by using dual-energy x-ray absorptiometry (Hologic QDR-1000/W, Waltham, Massachusetts), as described elsewhere [13]. Total Body Water We measured total body water using bioelectric impedance analysis (model 106, bioelectrical impedance analysis, RJL Systems, Detroit, Michigan). Testing was done between 1300 and 1500 hours, and all patients were fed and well hydrated before testing. We calculated body water by fitting the impedance measurements of resistance and reactance into previously derived prediction equations [14]. Protein Catabolism Protein catabolism was estimated by turnover of [2H5]phenylalanine (Cambridge Isotope Laboratories, Woburn, Massachusetts), as described elsewhere [15, 16]. The plasma phenylalanine level was measured by using gas chromatography mass spectrometry after being derivatized to its t-butyldimethylsilyl ester [17]. The concentration and level of [2H5]phenylalanine in plasma were analyzed by using multiple ion detection under electron-impact ionization conditions [17]. Muscle Function Computerized isotonic dynamometry (Baltimore Therapeutic Equipment, Baltimore, Maryland) was used to evaluate maximal voluntary contraction and maximum power (20%, 40%, and 60% maximal voluntary contraction) for a knee extension and a compound movement of the upper body. Quality of Life We measured quality of life using a self-administered 36-item Medical Outcomes Study questionnaire, which was previously validated in HIV-positive patients with AIDS-associated complex [18]. We accounted for missing values by averaging scores across completed items in the same scale for a particular patient. Eleven domains and three generalized domains were analyzed: 1) Total score was the average of the scores for all 36 questions; 2) functional status was the average of the scores in the domains for physical functioning, role functioning, social functioning, and cognitive functioning; and 3) well-being was the average of the scores in the domains for pain, mental health, energy and fatigue, health distress, and quality of life. Endocrine Assays Serum insulin levels were measured by using double-antibody radioimmunoassay (Pharmacia Diagnostics AB, Piscataway, New Jersey), and growth hormone levels were measured by using Tandem-R human growth hormone immunoradiometric assay (Hybritech, Inc., San Diego, California). Total IGF-1 levels were measured by double-antibody radioimmunoassay using rabbit antihuman IGF-1 antibody generated by Peter Gluckman (Auckland, New Zealand) at Genentech, Inc. Immunologic Studies Levels of HIV p24 antigen were measured in serum after acid dissociation by solid-phase sand-wich-type immunoassay that used a signal amplification technique (acid dissociated enzyme-linked immunoassay, DuPont Co., Boston, Massachusetts) [19]. CD3, CD4, and CD8 counts and percentage of total lymphocytes were measured in Ficol-separated peripheral blood mononuclear cell by flow cytometry using appropriate monoclonal antibodies and FACscan IV (Becton-Dickinson, Mountain Vi

Subclinical Hypothyroidism in a Biethnic, Urban Community

OBJECTIVES: To evaluate the association between hypothyroidism, and the health status of older Hispanic and non‐Hispanic white (NHW) men and women. To accomplish this, we determined the prevalences of the treated and untreated conditions and examined the associations between an elevated serum thyroid stimulating hormone (TSH) and cognitive and affective (mood) functions and the prevalences of symptoms and comorbidity, specifically coronary heart disease (CHD), diabetes, hypertension, and hyperlipidemia.

Randomized, double-blind, placebo-controlled trial of orlistat for weight loss in adolescents.

OBJECTIVE To evaluate the efficacy of orlistat to enhance weight loss in obese adolescents. METHODS The study was a 6-month randomized, double-blind, placebo-controlled trial to compare the effects of orlistat (120 mg orally 3 times a day) and placebo on reduction of body mass index (BMI). Forty adolescents between 14 and 18 years of age with a mean BMI of 40 kg/m2 entered the protocol between December 2002 and February 2003. Study subjects stayed overnight in the General Clinical Research Center, during which dietary records were reviewed and lifestyle recommendations were given. The study participants received either orlistat (120 mg orally 3 times a day) or placebo and were assessed monthly for 6 months. At 0, 3, and 6 months, fasting laboratory tests were performed. The primary end point was the change in BMI from baseline to 6 months. Secondary outcomes included changes in weight, lean body mass, and results of blood chemistry studies. RESULTS No statistically significant difference was noted between the 2 study groups for decrease in BMI from baseline to 6 months (P = 0.39). The decrease in BMI within the orlistat group (-1.3 +/- 1.6 kg/m2; P = 0.04) and within the placebo group (-0.8 +/- 3.0 kg/m2; P = 0.02), however, was statistically significant. Laboratory measurements did not differ between the 2 groups. In comparison with the placebo group, the orlistat group had increased adverse events, primarily gastrointestinal symptoms and findings. CONCLUSION In this study of obese adolescents, orlistat did not significantly reduce BMI in comparison with placebo at 6 months.

Insulin Suppresses Its Own Secretion In Vivo

This study addressed the controversial question of whether a negative—insulin-feedback loop exists in vivo. We utilized prehepatic insulin production, calculated by computerized deconvolution analysis of peripheral C-peptide concentration, as a measure of endogenous insulin secretion. Prehepatic insulin production was determined in 10 normal men who randomly underwent a control study and two additional studies involving different insulin infusion rates that achieved circulating insulin concentrations within the physiologic range during euglycemic clamps. The results demonstrate a dose-dependent suppression of prehepatic insulin production from 5.8 ± 1.4 mU/min during the control study to 4.0 ± 1.2 and 3.2 ± 0.9 mU/min during plasma insulin levels of 34 ± 4 and 61 ± 6 μU/ml, respectively (P < .05). Therefore, in contrast to recently reported results in vitro, insulin inhibits its own secretion in humans.

Timing of Antioxidant Vitamin Ingestion Alters Postprandial Proatherogenic Serum Markers

Background This study was designed to determine the optimal timing of vitamins E and C to prevent oxidative stress induced by a high‐fat evening meal in type 2 diabetes. Methods and Results Eleven subjects were admitted on 4 occasions. Euglycemia was maintained for 24 hours by insulin infusion. Participants were fed a high‐fat test supper equivalent to a McDonalds Big Mac Meal. Blood was drawn for measurement of C‐reactive protein (CRP), interleukin 6 (IL‐6), plasminogen activator inhibitor‐1 (PAI‐1), malonyldialdehyde (MDA), and total radical antioxidant parameter (TRAP) before and during the 4 hours after the test meal. Studies were performed in random sequence with vitamin E 800 IU and vitamin C 1 g given either before breakfast or before supper in a double‐blind manner on the day of the test meal. Control studies were performed with no vitamins and no test meal administered. There was a significant rise in CRP and PAI‐1 after the test supper (P<0.05 compared with “no meal”). Either presupper or prebreakfast vitamins E and C prevented the meal‐induced rise in CRP (P=0.03), although presupper vitamins were more effective (P=0.03 compared with prebreakfast vitamins). Only prebreakfast vitamins prevented the meal‐induced rise in PAI‐1 (P=0.006). There were no significant meal‐related changes in the concentrations of IL‐6, MDA, or TRAP. Conclusions The timing of administration of antioxidant vitamins has variable effects on markers of meal‐induced inflammation and fibrinolysis. This observation may be one reason why cardiovascular disease prevention trials using these vitamins have reported conflicting results. (Circulation. 2003;108:24‐31.)

Impact of Subclinical Hypothyroidism on Serum Total Homocysteine Concentrations, the Prevalence of Coronary Heart Disease (CHD), and CHD Risk Factors in the New Mexico Elder Health Survey

The serum/plasma total homocysteine (tHcy) concentration, now recognized as an independent risk factor for accelerated atherosclerotic disease, is increased in overtly hypothyroid patients, and it decreases with thyroid replacement therapy. Whether or not individuals with subclinical hypothyroidism also increase their tHcy concentrations, and whether this elevation might help to explain the increased prevalence of the atherosclerotic diseases observed in this condition, remains unclear. If individuals with subclinical hypothyroidism have higher tHcy concentrations than euthyroid subjects, there would be added incentive to treat this condition earlier. In this cross-sectional study (New Mexico Elder Health Survey) of a randomly selected sample of Medicare recipients (age > or =65 years), no significant difference in serum tHcy concentrations could be detected between the 112 participants with subclinical hypothyroidism (Groups 2 and 3) and the 643 participants with thyrotropin (TSH) values < or =4.6 microU/mL (Group 1) after adjusting for differences in gender, ethnicity, age, and serum concentrations of folate, vitamin B(12), and creatinine. Only those participants with the highest TSH levels (>10 microU/mL) (Group 3) had a significantly higher prevalence of coronary heart disease (CHD) when compared against Group 1 participants (p = 0.007). No consistent significant differences in the prevalences of CHD or in the CHD risk factors examined were observed when all participants with subclinical hypothyroidism (Groups 2 and 3 combined) were compared against Group 1 participants.

The kinetics of peritoneal insulin absorption

This study examined the relationship between the delivery of insulin into the peritoneal space and its absorption into the peripheral circulation. Studies were performed in conscious dogs receiving somatostatin (5.0 microgram/min) to suppress endogenous insulin secretion, and intravenous glucose (50 mg/min) to prevent hypoglycemia. The biologic effectiveness of the absorbed insulin was determined by its hypoglycemic effect. The possibility of direct absorption of insulin into the portal circulation from the peritoneal space in anesthetized, portal vein-catheterized dogs was examined with radiolabeled I125 insulin. Our results suggest that absorption of insulin from the peritoneal space is volume, concentration, and time-dependent. Maximal absorption of insulin was observed at 50 min when 1.92 U of insulin in a volume of 3 ml was infused intraperitoneally over 30 min. More rapid absorption was observed at 30 min when this quantity of insulin was given in a 1-min intraperitoneal bolus, compared to 30 min of intraperitoneal infusion. Least rapid absorption of insulin followed the delivery of 1.92 U of insulin in a volume of 15 ml. Intermediate absorption of insulin was observed at 40 min when the 1.92 U was delivered in a volume of 0.6 ml. Peripheral intravenous insulin delivery of 1.92 U reached a maximal plasma concentration at 20 min, which was more than three times the concentration observed with intraperitoneal insulin. Isotopic tracer studies, in which radioiodinated insulin was placed into the peritoneal space in anesthetized dogs, demonstrated greater radioactivity in the portal vein than in the aorta throughout a 30-min observation period. These studies demonstrate that intraperitoneal administration of insulin results in absorption of insulin which is volume, concentration, and time-dependent. Thus, the peritoneal space may be an appropriate site for insulin delivery through a transcutaneous catheter.

Prevalences of Type 2 Diabetes, the Insulin Resistance Syndrome, and Coronary Heart Disease in an Elderly, Biethnic Population

OBJECTIVE To compare the prevalences of type 2 diabetes, the various cardiovascular risk factors encompassing the insulin resistance syndrome (IRS), and coronary heart disease (CHD) in elderly Hispanics compared with non-Hispanic whites. RESEARCH DESIGN AND METHODS Elderly Hispanics (n = 414) and non-Hispanic whites (n = 469), randomly selected from the Medicare rolls of Bernalillo County (Albuquerque, NM; age ≥ 65 years), underwent a home interview followed by an interview/examination by a nurse-practitioner, nurse, and nutritionist that included an evaluation of glucose tolerance. Prevalences of total and central obesity, dyslipidemia, hypertension, and microalbuminuria also were determined. History of myocardial infarction, recent angina, and/or coronary bypass graft, and electrocardiograms (ECGs) were used to document CHD. RESULTS Elderly Hispanics had twice the prevalence of type 2 diabetes compared with non-Hispanic whites, but the prevalence of impaired glucose tolerance was not increased in Hispanics. Mean serum fasting and 2-h post-glucola insulin concentrations, fasting insulin resistance indexes, and HbA1c were higher in Hispanics. Hispanics were shorter, weighed less, and had more total body and central obesity. The higher prevalences of dyslipidemia in Hispanics could be explained by a higher prevalence of diabetes. The prevalences of hypertension and CHD were not different for the two ethnic groups. CONCLUSIONS Elderly Hispanics had twice the prevalence of diabetes and higher prevalences of cardiovascular risk factors associated with IRS. Prevalences of hypertension and CHD were similar in the two ethnic groups.

A Placebo-Controlled, Randomized Study of Glimepiride in Patients with Type 2 Diabetes Mellitus for Whom Diet Therapy is Unsuccessful

This multicenter, randomized, placebo‐controlled study of glimepiride, a new oral sulfonylurea, was conducted in patients with type 2 diabetes for whom dietary treatment was unsuccessful (fasting plasma glucose [FPG] = 151–300 mg/dL) during a 1‐week screening period. Patients were randomized to receive glimepiride (n = 123) or placebo (n = 126) once daily for a 10‐week dose‐titration period, then maintained on an individually determined optimal dose (1–8 mg of glimepiride or placebo) for 12 weeks. Glimepiride lowered FPG by 46 mg/dL, hemoglobin A1C (HbA1C) by 1.4%, and 2‐hour postprandial glucose by 72 mg/dL more than placebo. Glimepiride improved postprandial insulin and C‐peptide responses without producing clinically meaningful increases in fasting insulin or C‐peptide levels. Good glycemic control (HbA1 ≤ 7.2%) was achieved by 69% of the patients taking glimepiride versus 32% of those taking placebo. The overall incidence of adverse events was similar in both groups. No clinically noteworthy abnormal laboratory values or hypoglycemia (blood glucose < 60 mg/dL) occurred. Glimepiride is safe and effective for treatment of patients with type 2 diabetes for whom diet therapy is unsuccessful.

VITAMIN E IN HUMANS: AN EXPLANATION OF CLINICAL TRIAL FAILURE

OBJECTIVE To describe the potential benefits and hazards of vitamin E supplementation and present a rational basis for understanding the conflicting results among randomized clinical trials, epidemiologic investigations, and animal studies on the use of vitamin E to prevent atherosclerosis. METHODS We conducted a retrospective review of the pertinent literature found in PubMed from 1981 through August 2005. The published data are analyzed and summarized. RESULTS The possible factors implicated for failure of vitamin E therapy include the following: (1) the inclusion of patients without biochemical evidence of increased oxidative stress, (2) the relatively short duration of treatment, (3) the use of suboptimal dosages of vitamin E, (4) the suppression of gamma-tocopherol by alpha-tocopherol, (5) the use of vitamin E supplementation without the concurrent use of vitamin C, (6) the lack of inclusion of biochemical markers of oxidative stress and markers of vascular response, (7) the inappropriate administration of vitamins relative to meal ingestion, and (8) the poor patient compliance and the lack of monitoring of vitamin E levels. CONCLUSION Large, randomized clinical trials have not yet substantiated a beneficial effect of use of vitamin E to reduce atherosclerotic risk in humans, despite demonstration of antioxidant effects in vitro and in animals. Only in subsets of patients at high risk for atherosclerosis has a beneficial effect been suggested. Before additional large, randomized clinical trials of vitamin E are performed, the specific biologic and surrogate marker effects of vitamin E in each target population must be defined more carefully. This approach will save resources, minimize untoward side effects, and identify the patients who will benefit the most.