Safety and efficacy of a glucagon-like peptide-1 receptor agonist added to basal insulin therapy versus basal insulin with or without a rapid-acting insulin in patients with type 2 diabetes: results of a meta-analysis

Objective: To consolidate the evidence from randomized controlled trials evaluating the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as add-on to basal insulin therapy in type 2 diabetes (T2D) patients.

Research design and methods: We searched the EMBASE® and NCBI PubMed (Medline) databases and relevant congress abstracts for randomized controlled trials evaluating the efficacy and safety of GLP-1 RAs as add-on to basal insulin compared with basal insulin with or without rapid-acting insulin (RAI) through 23 May 2016. The pooled data were analyzed using a random-effects meta-analysis model. A subanalysis was performed for trials investigating basal insulin plus GLP-1 RAs versus basal insulin plus RAI.

Results: Of the 2617 retrieved records, 19 randomized controlled trials enrolling 7,053 patients with T2D were included. Compared with basal insulin ± RAI, reduction in glycated hemoglobin (HbA1c) from baseline (difference in means: –0.48% [95% confidence interval (CI), –0.67 to –0.30]; p < 0.0001) and weight loss (–2.60 kg [95% CI, –3.32 to –1.89]; p < 0.0001) were significantly greater with basal insulin plus GLP-1 RA. The subanalysis similarly showed significant results for change in HbA1c from baseline and for weight loss, as well as a significantly lower risk of symptomatic hypoglycemia in patients treated with basal insulin plus GLP-1 RA versus basal insulin plus RAI (odds ratio, 0.52 [95% CI, 0.42 to 0.64]; p < 0.0001).

Conclusions: Addition of GLP-1 RA to basal insulin provided improved glycemic control, led to weight reduction and similar hypoglycemia rates versus an intensified insulin strategy; however, symptomatic hypoglycemia rates were significantly lower when compared with a basal insulin plus RAI.     

Effects of clozapine administration on body weight, glucose tolerance, blood glucose concentrations, plasma lipids, and insulin in male C57BL/6 mice: A parallel controlled study

Background: Clozapine has been associated with metabolic adverse events (AEs) (eg, elevated body weight, blood glucose concentrations, cholesterol, triglycerides [TG]), all of which have deleterious effects on health and medication compliance. However, little focus has been directed toward finding a suitable experimental model to study the metabolic AEs associated with clozapine.Objective: The aim of this study was to assess the effects of clozapine administration for 28 days on body weight, glucose tolerance, blood glucose concentrations, plasma lipids, and insulin in C57BL/6 mice.Methods: C57BL/6 mice were grouped and treated with clozapine 2 or 10 mg/kg or vehicle intraperitoneally QD for 28 days. Body weight was assessed on days 0 (baseline), 7, 14, 21, and 28, and glucose tolerance, blood glucose concentrations, insulin (calculated by insulin resistance index [IRI]), and plasma lipids (including total cholesterol, TG, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol) were assessed on day 29.Results: Sixty 10-week-old, male C57BL/6 mice were included in the study and were divided into 3 groups (20 mice per group). The body weight significantly decreased in the clozapine 10-mg-treated group on days 14, 21, and 28 compared with the vehicle group (mean [SD] body weight: 21.61 [1.05] vs 22.79 [1.11], 22.53 [1.05] vs 24.17 [1.24], and 22.21 [1.07] vs 24.99 [1.39] g, respectively; all, P < 0.05). In the clozapine 10-mg/kg group, blood glucose concentrations significantly increased 0, 30, 60, and 120 minutes after glucose administration compared with the vehicle group (mean [SD]: 6.67 [1.25], 25.34 [5.85], 12.68 [3.39], and 7.52 [1.45] mmol/L, respectively, vs 4.61 [0.78], 21.54 [6.55], 11.46 [3.46], and 6.55 [1.42] mmol/L, respectively; all P < 0.05). The clozapine 10-mg/kg group also had significant increases in plasma insulin concentrations compared with the vehicle group (12.70 [5.27] vs 7.62 [4.54] μIU/mL; P < 0.05) and IRI (3.01 [1.26] vs 1.51 [0.96]; P < 0.05). Plasma HDL-C concentration also significantly decreased in the clozapine 10-mg/kg group compared with the vehicle group (1.23 [0.25] vs 1.47 [0.16]; P < 0.05).Conclusion: Clozapine 10 mg/kg was associated with significant decreases in body weight and significant increases in fasting blood glucose and glucose tolerance in these male C57BL/6 mice.     

Effectiveness and tolerability of rosiglitazone on insulin resistance and body composition in nondiabetic Thai patients undergoing continuous ambulatory peritoneal dialysis: A 12-week pilot study

Background: Patients with chronic renal insufficiency, especially those undergoing continuous ambulatory peritoneal dialysis (CAPD), normally have insulin resistance due to deficiencies in insulin secretion and degradation, as well as tissue resistance to insulin at both receptor and postreceptor levels.Objective: The aim of this study was to investigate the effectiveness and tolerability of rosiglitazone on insulin resistance and body composition in patients without diabetes mellitus (DM) undergoing CAPD.Methods: This pilot study included a pretest and posttest with a repeated-measure design in a small number of patients. CAPD patients without DM received rosiglitazone 2-mg tablets BID for 12 weeks. Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) and bioelectrical impedance analysis (BIA) were used to assess insulin resistance and body composition, respectively. Tolerability was assessed using laboratory analyses as well as physical examination findings to evaluate peripheral edema. Peripheral edema was assessed by the study investigators.Results: Thirteen Thai patients (mean [SD] age, 54.17 [11.42] years [range, 35-85 years]; body mass index [BMI], >20 to <30 kg/m²; fasting blood glucose [FBG] concentration, <5.39 mmol/L) were included in the study. One patient was withdrawn due to illness unrelated to the study. No significant difference was found in FBG concentration between baseline and posttreatment (after 12 weeks of treatment) (5.45 [0.59] vs 5.24 [0.51] mmol/L), but fasting plasma insulin concentrations (28.50 [23.70] vs 10.15 [4.22] μIU/mL; P = 0.005) and HOMA-IR score (6.70 [5.23] vs 2.40 [1.15]; P = 0.011) were significantly lower. There were no significant changes in weight or BMI from baseline to posttreatment. Seven subjects (58.3%) experienced weight gain at week 4, while 2 patients (16.7%) still had weight gain after 12 weeks of treatment. A significant increase was found between baseline and posttreatment in total body water (38.03 [4.55] vs 42.44 [5.99] L; P = 0.018), extracellular fluid (20.24 [3.75] vs 26.22 [8.69] L; P = 0.005), plasma fluid (4.29 [0.80] vs 5.20 [0.93] L; P = 0.005), and interstitial fluid (14.99 [2.78] vs 17.68 [3.07] L; P = 0.040). Using BIA, no significant changes were observed in intracellular fluid, fat mass, or liver function. After 12 weeks of rosiglitazone administration, 2 patients (16.7%) had mild edema.Conclusions: Rosiglitazone 2 mg BID for 12 weeks was associated with significantly improved insulin resistance in this small group of nondiabetic Thai patients undergoing CAPD. There was a significant increase in total body water and extracellular fluid after administration of rosiglitazone for 12 weeks. There were no significant changes in FBG, weight, or BMI.     

Effects of travoprost in the treatment of open-angle glaucoma or ocular hypertension: A systematic review and meta-analysis

Background: A 2005 meta-analysis suggests that lowering intraocular pressure (IOP) in patients with ocular hypertension (OHT) or open-angle glaucoma (OAG) is beneficial in reducing the risk for visual field loss in the long term.Objective: The aim of this meta-analysis was to compare the efficacy and toler-ability of travoprost and latanoprost in patients with OAG or OHT.Methods: Pertinent studies published from 1996 to 2008 were identified using systematic searches of major literature databases, including the Cochrane Library, MEDLINE, EMBASE, and the Chinese Biomedicine Database. Internet searches of major search engines, professional associations' Web sites, and manufacturers' databases were also performed. Randomized controlled trials (RCTs) comparing the effects of travoprost 0.004% and latanoprost 0.005% in patients with OAG or OHT were selected. The primary efficacy measure was the weighted mean difference (WMD) in the IOP reduction (IOPR). The primary tolerability measure was the relative risk (RR) for adverse events. The pooled effects were calculated using the random-effects model.Results: Seventeen studies (1491 patients) were included in the meta-analysis, 4 of which were of poor quality based on Jadad scoring. Travoprost was associated with significantly greater diurnal mean IOPRs compared with latanoprost at 2 weeks and 2 months (WMDs [95% CI] mm Hg: 2 weeks, 1.47 [0.33 to 2.62]; 2 months, 0.71 [0.04 to 1.38]); these values were not significant at 1 (0.81 [−0.78 to 2.40]), 3 (0.01 [−0.50 to 0.52]), and 6 months (0.27 [−0.40 to 0.95]). When the 4 studies of low quality were excluded, no significant treatment differences in diurnal IOPR were found. IOPR measured at 5 pm was significantly greater with travoprost compared with latanoprost at 2 weeks (WMD [95% CI], 0.87 mm Hg [0.40 to 1.33]); these values were not significant at 1 (WMD [95% CI], 0.60 mm Hg [0.00 to 1.20], 2 (0.65 [−0.69 to 1.99]), 3 (0.04 [−0.51 to 0.59]), 6 (0.00 [−0.68 to 0.68]), and 12 months (0.30 [−0.36 to 0.96]). Travoprost was associated with a significantly greater frequency of hyperemia than was latanoprost (RR = 1.72 [95% CI, 1.33 to 2.23]). Rates of serious ocular adverse events did not differ significantly between travoprost and latanoprost (cystoid macular edema: RR = 0.22 [95% CI, 0.03 to 1.76]; cataract: RR = 2.29 [95% CI, 0.90 to 5.83]).Conclusions: The findings from the present meta-analysis of these 17 RCTs suggest that there were no significant differences between travoprost and latanoprost in IOPR in these patients with OHT or OAG. Both agents were generally well tolerated.     

Effects of vitamins E and C supplementation on hepatic glutathione peroxidase activity and tissue injury associated with ethanol ingestion in malnourished rats

Background: Oxidative stress has been associated with tissue injury in alcoholic liver disease. Although this close association is well known, whether prevention of oxidative stress retards tissue injury has not been thoroughly investigated.Objective: The aim of this study was to determine the effects of supplementation with vitamins E and C on antioxidant enzyme status and histologic changes in hepatic tissue in a rat model of alcoholic liver disease.Methods: This 8-week, blinded, controlled study was conducted at the Department of Internal Medicine, Trakya University, Edirne, Turkey. Weanling albino female protein-deficient Wistar rats weighing ∼200 g were randomly assigned to 1 of 6 groups: (1) liquid diet+ethanol+vitamin E 15 mg/kg PO (LDetvitE); (2) liquid diet+ethanol+vitamin C 10 mg/kg PO (LDetvitC); (3) liquid diet+ethanol+vitamin E 15 mg/kg+vitamin C 10 mg/kg PO (LDetvitEC); (4) liquid diet+ethanol (LDet); (5) liquid diet+isocaloric sucrose (LDS); and (6) normal diet (control). The primary end point of the study was to determine whether antioxidant vitamin E/C combination therapy prevents development of hepatic fibrosis (ie, cirrhosis in a period of 1 year). After being euthanized at week 8, the rats were weighed, and their livers and spleens were weighed. Hepatic tissue specimens were histopathologically assessed according to the Brunt system. Hepatic tissue glutathione peroxidase, superoxide dismutase, and catalase activities were determined. Biochemical tissue collagen concentrations were measured to determine the presence of hepatic fibrosis.Results: Seventy-two rats were included in the study (mean [SE] weight, 205 [21] g) (12 rats per group). Initially planned to last 48 weeks, the study was terminated at 8 weeks due to the death of 3 rats in each group (except the LDS group and control group). The relative liver weight was significantly lower in the LDetvitEC group compared with that in the LDet group (mean [SE], 3.7% [0.5%] vs 4.8% [0.9%]; P<0.01). Mean (SE) hepatic tissue glutathione peroxidase activity was significantly reduced in the LDet-treated rats compared with controls (1.2 [0.2] vs 2.6 [0.3] U/mg protein; P<0.001). The groups that received supplementation with vitamin E, vitamin C, and vitamins E and C combined had significantly more hepatic glutathione peroxidase activity (mean [SE], 2.1 [0.5], 2.5 [0.2], and 2.6 [0.7] U/mg protein, respectively) compared with the LDet group (1.2 [0.2] U/mg protein) (all, P<0.001). No significant between-group differences in hepatic superoxide dismutase or catalase activities were found. Compared with controls (14.5 [1.9] μg collagen/mg protein), the mean (SE) histologic hepatic collagen concentration was significantly higher in all groups (19.2 [1.2], 19.5 [3.3], 18.5 [3.0], 25.9 [3.3], and 21.6 [1.5] μg collagen/mg protein in the LDetvitE, LDetvitC, LDetvitEC, LDet, and LDS groups, respectively; P<0.01, P<0.01, P<0.05, P<0.001, and P<0.001, respectively). Compared with the LDet group, the mean hepatic collagen concentration was significantly lower in the LDetvitE, LDetvitC, and LDetvitEC groups (P<0.01, P<0.05, and P<0.01, respectively). The LDetvitEC group had a significantly lower mean (SE) hepatic inflammatory score compared with the LDet group (0.8 [0.1] vs 1.3 [0.2]; P<0.05). The LDetvitEC group had a significantly lower mean (SE) hepatic necrosis score compared with that in the LDet group (1.5 [0.2] vs 2.4 [0.3]; P<0.05).Conclusions: The results of this study in protein-deficient rats fed with a high-fat liquid diet suggest that supplementation with vitamin E, vitamin C, and a combination of vitamins E and C was associated with decreased ethanol-induced hepatic glutathione peroxidase activity and hepatic fibrosis, and that supplementation with vitamins E and C might have attenuated the development of hepatomegaly and hepatic necroinflammation, whereas this result was not found in the group given a liquid diet and ethanol in this 8-week study. (Curr Ther Res Clin Exp. 2006;67:118-137) Copyright © 2006 Excerpta Medica, Inc.     

Comparison of methimazole/hydrocortisone ointment with oral methimazole in patients with graves disease: A prospective, randomized, open-label, parallel-group, 18-month study

Background: Thionamide antithyroid drugs (ATDs) have certain disadvantages and are associated with some adverse events (AEs). To overcome the problems associated with ATDs, a compound antithyroid ointment (CATO) containing methimazole (MMI) and hydrocortisone has been developed for use as a local thyroid treatment (LTT).Objective: The aim of this study was to assess the clinical effectiveness and tolerability of CATO LTT in patients with Graves disease (GD).Methods: This was a prospective, randomized, open-label, parallel-group clinical trial conducted at the Provincial Hospital Affiliated to Shandong University (Jinan, China). Patients with GD aged 19 to 65 years were randomized to receive either CATO LTT 0.3 g/d or oral MMI 37.5 mg/d (control group) treatment for 18 months, with a 4-year follow-up period. Hyperthyroid symptoms, thyroid function, granulocyte count, liver function, and AEs were assessed at baseline and every 2 weeks until serum thyroid hormone (TH) concentration normalized, at which point patients were assessed monthly. The primary efficacy end points were the duration of treatment required for serum TH concentration to normalize and the remission rate after completing the 18-month treatment regimen.Results: A total of 154 patients (133 women, 21 men; mean [SD] age, 39.6 [11.8] years; all Han Chinese) participated in the study; all patients completed the 18-month treatment period. Compared with the MMI group (n 76), the CATO- treated group (n 78) had a significantly shorter median (range) time to restoration of normal serum thyroid hormone concentration (43 [12-150] vs 22 [7-60] days; P < 0.001), a significantly lower rate of recurrence of hyperthyroidism (309/1520 [20.3%] vs 193/1368 [14.1%] person-time; P < 0.001), a significantly lower drug hypothyroidism rate (185/1520 [12.2%] vs 54/1368 [3.9%] person-time; P < 0.001), and a higher remission rate (year 1:46/69 [66.7%] vs 65/72 [90.3%] patients, P 0.001; year 2:40/69 [58.0%] vs 60/72 [83.3%] patients, P - 0.001; year 3:34/69 [49.3%] vs 57/72 [79.2%] patients, P < 0.001; and year 4:30/69 [43.5%] vs 55/72 [76.4%] patients, P < 0.001). Systemic AEs occurred in 6 patients (7.9%) in the MMI group (drug neutropenia, 2 patients [2.6%]; epistaxis, 1 [1.3%]; hepatopathy, 1 [1.3%]; and other systemic AEs, 2 [2.6%]), while no systemic AEs were observed/reported in the CATO group.Conclusion: This study suggests that CATO LTT was well tolerated and more effective than oral MMI treatment in controlling thyrotoxicosis and promoting remission of GD in these Han Chinese patients.     

Effects of ezetimibe on glucose metabolism in patients with type 2 diabetes: A 12-week, open-label, uncontrolled, pilot study

Background: A potential effect of ezetimibe, a novel cholesterol-absorption inhibitor, on insulin resistance has been reported in an animal model.Objective: The aim of this study was to evaluate the effects of ezetimibe on glucose metabolism in patients with type 2 diabetes mellitus (T2DM).Methods: Between March and June 2008, outpatients with T2DM who were being treated at Yokohama Sakae Kyosai Hospital, Yokohama, Japan, were enrolled in this pilot study if they had not achieved the target lipid levels recommended by the Japan Atherosclerosis Society Guidelines despite diet and exercise or a statin therapy for ≥3 months. At baseline and at 4 and 12 weeks after open-label treatment with ezetimibe 10 mg/d, the levels of lipid parameters, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA_1c), and high-sensitivity C-reactive protein were measured. Adverse effects (AEs) were assessed at each study visit by patient interviews and laboratory testing.Results: A total of 21 consecutive patients (10 men, 11 women; mean [SD] age, 72 [9] years; weight, 63.4 [10.5] kg; body mass index, 25.5 [3.2] kg/m²) were enrolled in this study. The mean (SD) level of LDL-C decreased significantly from 146 (31) to 114 (27) mg/dL (−21%; P < 0.001) after 12 weeks of treatment with ezetimibe. The mean level of remnant-like particle cholesterol also decreased significantly from 6.5 (3.8) to 4.8 (2.2) mg/dL (−15%; P = 0.03). Treatment with ezetimibe was associated with a reduction in FPG level from 127 (31) to 119 (30) mg/dL (P = 0.02), and HbAlc from 6.3% (0.6%) to 6.1% (0.7%) (P = 0.003). No AEs were observed or reported during the study period.Conclusion: In this small, open-label, uncontrolled, pilot study, ezetimibe was associated with a significant decrease in lipid parameters and improvement in glucose metabolism in these patients with T2DM.     

Dexmedetomidine as an adjunct to epidural analgesia after abdominal surgery in elderly intensive care patients: A prospective, double-blind, clinical trial

Background: The ideal postoperative analgesia management of elderly surgical patients in intensive care units (ICUs) is continually being investigated.Objective: The purpose of this study was to assess the effectiveness and tolerability of IV administration of dexmedetomidine as an adjunct to a low-dose epidural bupivacaine infusion for postoperative analgesia after abdominal surgery in elderly patients in the ICU.Methods: ICU patients aged >70 years undergoing abdominal surgery were eligible for the study. A lumbar epidural catheter was inserted at the beginning of the surgery with no medication. On arrival at the ICU, the catheter was loaded with 0.25% bupivacaine 25 mg at the T8 to T10 sensory level, and a continuous infusion of 0.125% bupivacaine was started at 4 to 6 mL/h in combination with patient-controlled epidural analgesia (PCEA) of fentanyl (4 μg/bolus) for pain treatment. Patients in the treatment group received dexmedetomidine as an IV loading dose of 0.6 pg/kg for 30 minutes followed by continuous infusion at 0.2 μg/kg · h^-1. Patients in the control group were not administered dexmedetomidine. The effectiveness of the pain relief was determined using a visual analog scale (VAS) (0 = no pain to 10 = worst pain imaginable) at rest. VAS score, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure, and arterial blood gases were monitored periodically for 24 hours after surgery. If required, tenoxicam (20-mg IV bolus) was used to ensure a VAS score of ≤3. The number of times PCEA and tenoxicam were administered and the occurrence of adverse events (AEs) were also recorded.Results: Sixty patients (34 men, 26 women; mean [SD] age, 75.96 [4.25] years; mean [SD] weight, 74.13 [10.62] kg) were included in the study. VAS scores were significantly lower in the dexmedetomidine group compared with the control group at hours 1, 2, and 12 (VAS [hour 1]: 2.8 [0.4], P < 0.001; VAS [hour 2]: 2.7 [0.5], P < 0.001; and VAS [hour 12]: 0.9 [0.7], P 0.044). The mean number of administrations of fentanyl via PCEA was significantly greater in the control group compared with the dexmedetomidine group (2.20 vs 6.63 times; P < 0.001). The mean number of administrations of tenoxicam was significantly lower in the treatment group than the control group (0.27 vs 1.07 times; P < 0.001). In the control group, the decreases in sedation at 0, 8, 12, 16, and 20 hours were significant compared with baseline (P = 0.024, P = 0.001, P = 0.020, P < 0.001, and P = 0.005, respectively). Mean HR, SBR and AEs (eg, bradycardia [HR <60 beats/min], respiratory depression [respiratory rate <8 breaths/min], hypotension \SBP <90 mm Hg], oversedation, hypoxia, and hypercapnia) decreased significantly in the dexmedetomidine group (all, P < 0.05). Significantly more patients in the dexmedetomidine group rated their satisfaction with postoperative pain control as excellent compared with the control group (12 vs 6 patients; P = 0.014).Conclusion: Intravenous dexmedetomidine was effective and generally well tolerated as an analgesic adjunct to epidural low-dose bupivacaine infusion for pain treatment, with lower need for opioids after abdominal surgery in these elderly intensive care patients than in the control group.     

Effects of gliclazide dose escalation on postprandial hyperglycemia in type 2 diabetes mellitus: A prospective, open-label, case-controlled, dose-escalation study

Objectives: The aims of this study were to determine the effects of increasing doses of gliclazide on postprandial glucose excursions after a standardized breakfast and lunch, and to clarify the relationship between gliclazide dose and glucose response.Methods: This prospective, open-label, case-controlled, dose-escalation study was conducted at the Addington Hospital Diabetes Clinic, eThekwini/Durban, KwaZulu-Natal, South Africa. Male and female patients aged ≥18 years with type 2 diabetes mellitus (DM) and postprandial hyperglycemia (2-hour postprandial blood glucose [PPBG_{2 h}] level, ≥11.1 mmol/L [≥200 mg/dL]) and receiving an oral hypoglycemic agent were eligible. After a 1-week washout period during which patients were asked to discontinue treatment with all oral hypoglycemic agents, baseline glycemic measurements were performed (fasting blood glucose, PPBG_{2 h}, 6-hour postprandial blood glucose [PPBG_{6 h}], mean blood glucose [MBG], plasma insulin, fasting serum fructosamine, and glycosylated hemoglobin). All patients subsequently received 2 weeks of oral treatment with each of 3 doses of gliclazide: 40, 80, and 160 mg/d. Glycemic parameters were measured at the end of each dosing interval. Adverse-effect monitoring included direct reporting of untoward effects to the resident medical practitioner, clinical examination, monitoring of home blood glucose records, hematology, and liver and kidney function tests. Compliance was assessed using pill counts, examination of diary entries, and patient interview.Results: Thirty-three patients were screened; 14 entered the dose-escalation phase. Thirteen patients completed the study (7 women, 6 men; mean [SD] age, 52.0 [11.1] years); 1 was withdrawn because of poor compliance. Dose escalation from 40 to 80 mg/d was associated with a significant change only in MBG (mean [SD], 11.3 [4.2] vs 10.0 [3.9] mmol/L [203.6 (75.7) vs 180.1 (70.3) mg/dL]; P<0.001). Dose escalation from 80 to 160 mg/d was associated with a significant change only in PPBG_{6 h} (9.5 [4.2] vs 10.3 [4.1] mmol/L [171.1 (75.7) vs 185.6 (73.9) mg/dL]; P=0.018). No other significant changes in glycemic parameters between doses were found throughout the treatment period. No adverse effects were reported.Conclusions: In this small study of gliclazide dose escalation in patients with type 2 DM and postprandial hyperglycemia, gliclazide 80 mg/d was associated with a reduction in postprandial hyperglycemia. Dose escalation from 80 to 160 mg/d was not found to be associated with additional clinical benefit. Based on these results, we recommend that gliclazide dose escalation to the maximum dose recommended by the manufacturer be guided by measures of glycemia. All doses were well tolerated.     

Effect of Glucagon-like Peptide-1 Receptor Agonists on Prognosis of Heart Failure and Cardiac Function: A Systematic Review and Meta-analysis of Randomized Controlled Trials

PurposeWhether an antidiabetic drug, glucagon-like peptide-1 receptor agonist (GLP-1RA), could improve the prognosis of heart failure and cardiac function remains controversial. We conducted a systematic review and meta-analysis of randomized controlled trials to explore the influence of GLP-1RAs on heart failure in patients regardless of diabetes diagnosis.MethodsLiterature in English from the PubMed, EMBASE, and Cochrane Library databases was searched from inception to July 2022. The study aim was to identify published, randomized, placebo-controlled trials testing GLP-1RAs in patients with or without diabetes. Outcomes were heart failure hospitalization, cardiac function, and structure measures.FindingsTwenty-two randomized controlled trials involving 61,412 patients are included in the meta-analysis. Overall, compared with the placebo group, GLP-1RA treatment could not significantly decrease heart failure hospitalization in patients with a history of heart failure (hazard ratio [HR], 1.07; 95% CI, 0.91 to 1.25; P = 0.422). Six-minute walking test distances (WMD, 19.08 m; 95% CI, 4.81 to 33.36; P = 0.01), E-wave (SMD, –0.40; 95% CI, –0.60 to –0.20; P < 0.001), early diastolic to late diastolic velocities ratio (WMD, –0.10; 95% CI, –0.18 to –0.02; P = 0.01), mitral inflow E velocity to tissue Doppler e′ ratio (WMD, –0.97; 95% CI, –1.54 to –0.41; P < 0.001), and E-wave deceleration time (WMD, –9.96 milliseconds; 95% CI, –18.52 to –1.41; P = 0.02) increased significantly after administration of GLP-1RAs. However, GLP-1RAs do not significantly influence N-terminal pro–B-type natriuretic peptide levels (WMD, –20.02 pg/mL; 95% CI, –53.12 to 13.08; P = 0.24), Minnesota Living with Heart Failure Questionnaire quality of life scores (WMD, –1.08; 95% CI, –3.99 to 1.84; P = 0.47), or left ventricular ejection fractions (WMD, –0.37%; 95% CI, –1.19 to 0.46; P = 0.38).ImplicationsGLP-1RAs did not reduce heart failure readmissions in patients with a history of heart failure and elevated N-terminal pro–B-type natriuretic peptide levels. Thus, the prognosis of heart failure was not improved, although GLP-1RAs did significantly improve left ventricular diastolic function in patients. PROSPERO identifier: CRD42021226231.     

The Role of Adiponectin as a Compensatory Mediator for the Primary Secretory Defect in Latent Autoimmune Diabetes in Adults

Background

Increased adiposity in patients with newly diagnosed type 2 diabetes mellitus (DM), as well as in patients who do not have DM, affects the regulation of insulin sensitivity and the metabolic effects of adiponectin.

Objective

The goal of this study was to investigate the relationship between plasma adiponectin levels and obesity in patients developing DM mainly due to an early decline in β-cell function.

Methods

We studied 29 patients with latent autoimmune diabetes in adults (LADA), 38 patients with type 1 DM, and 55 healthy volunteers.

Results

Plasma adiponectin levels, adjusted for body mass index (BMI), were higher in patients with type 1 DM than in controls (P < 0.001) and similar to those in patients with LADA (P = 0.464). Plasma adiponectin levels were higher in LADA patients compared with controls (P < 0.001). In LADA patients, plasma adiponectin levels, adjusted for BMI, correlated significantly with insulin resistance (β coefficient, –6.453 [2.772]; P = 0.028). Interestingly, this relationship in LADA patients was significant in more overweight patients (β coefficient, –7.142 [3.249]; P = 0.048) but not in leaner patients (P = 0.571), a finding that was not confirmed through the results in the controls (P = 0.520 and P = 0.992, respectively).

Conclusions

In patients with LADA, increases in plasma adiponectin levels, after adjustment for BMI, could act as a mediator for improvement in insulin sensitivity and thus compensate for the primary secretory defect. This effect seems more profound in more overweight subjects than in leaner subjects.     

Effects of fosinopril on blood pressure, lipid profile, and lipoprotein(a) levels in normotensive patients with type 2 diabetes and microalbuminuria: An open-label, uncontrolled study

Background: Patients with type 2 diabetes mellitus often have other cardiovascular risk factors, and alterations in lipid profile play an important role. The angiotensin-converting enzyme inhibitors are often used in these patients, particularly those with type 2 diabetes and proteinuria.Objective: This study evaluated the effects of fosinopril therapy on fasting plasma glucose (FPG), lipid profile, and lipoprotein(a), or Lp(a), levels in normotensive patients with type 2 diabetes mellitus and microalbuminuria.Methods: Normotensive (systolic blood pressure [SBP] <130 mm Hg and diastolic blood pressure [DBP] <85 mm Hg) patients with type 2 diabetes and microalbuminuria and a normal lipid profile were enrolled. Patients had their diabetes controlled by diet alone or diet plus oral hypoglycemic agents. Fosinopril 10 mg/d was administered for 6 months and then interrupted for 1 month. FPG, glycosylated hemoglobin, SBP, DBP, lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), Lp(a), albumin excretion rate (AER), and creatinine levels were evaluated at baseline; 1, 3, and 6 months after initiation of treatment; and 1 month after interruption of treatment.Results: A total of 120 patients were enrolled (63 men, 57 women; mean age ± SD, 54 ± 10 years; duration of diabetes, 7 ± 2 years). Significant decreases versus baseline were observed in the following parameters at month 6: SBP (122 ± 7 vs 117 ± 9.1 mm Hg, P < 0.01), DBP (80 ± 4.8 vs 74 ± 4.5 mm Hg, P < 0.05), TC (186 ± 11 vs 176 ± 10 mg/dL, P < 0.05), LDL-C (124 ± 10 vs 114 ± 11 mg/dL, P < 0.05), Lp(a) (24 ± 10 vs 19 ± 7.5 mg/dL, P < 0.05), and AER (103 ± 45 vs 48 ± 21 mg/24 hours, P < 0.01). When fosinopril therapy was interrupted for 1 month, the values for all these parameters tended to return to baseline values; SBP, TC, and Lp(a) values were significantly different from month 6 values, whereas DBP, LDL-C, and AER did not change significantly during the washout period.Conclusions: Fosinopril therapy for 6 months resulted in a reduction of microalbuminuria and an improvement in lipid profile and Lp(a) levels in patients with type 2 diabetes. This suggests that fosinopril may improve lipid profile and reduce Lp(a) levels by lowering proteinuria or by other more direct actions on lipid and Lp(a) metabolism. Additional controlled studies are needed to confirm these results.     

Risperidone long-acting injection in the treatment of schizophrenia spectrum illnesses: A retrospective chart review of 19 patients in the Vancouver Community Mental Health Organization (Vancouver, Canada)

Background: Schizophrenia is a chronic debilitating disease that affects ~110,000 Canadians (0.55% lifetime prevalence). Risperidone long-acting injection (RLAI) is the first injectable, long-acting, atypical antipsychotic drug marketed in Canada.Objective: The aim of this study was to assess the clinical effectiveness and hospitalization rates of patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder treated with RLAI in a community mental health care setting.Methods: Data were collected between August 1, 2006 and September 30, 2006 via a retrospective chart review of outpatients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder who received treatment from 1 of the 8 mental health teams within the Vancouver Community Mental Health Organization (VCMHO) in Vancouver, British Columbia, Canada. Collected data included: frequency and duration of institutional care, discharge and relapse rates, demographic variables, diagnosis history, RLAI medication history, and history of other medications. The overall severity of symptoms before and after RLAI treatment and the improvement in symptoms during treatment were evaluated using the Clinical Global Impression Scales for severity (CGI-S)(1 = not ill to 7 = extremely ill) and improvement (CGI-I)(1 = very much improved to 7 = very much worse).Results: Forty-four patients were identified as having received RLAI. The charts of 19 patients (10 men, 9 women; mean [SD] age at time of chart audit, 36.7 [11.7] years; mean [SD] age at primary diagnosis, 23.6 [7.4] years; race: white, 10 [52.6%]; Asian, 6 [31.6%]; American Indian, 1 [5.3%]; black, 1 [5.3%]; other, 1 [5.3%]) were included in the analysis. The majority of patients (78%) had been treated with another antipsychotic drug prior to treatment with RLAI: risperidone (77%), quetiapine (47%), zuclopenthixol (43%), olanzapine (43%), and loxapine (17%). Mean (SD) CGI-S Scale score declined significantly from 5.29 (1.3) before treatment initiation to 3.05 (1.0) posttreatment (P < 0.001). Mean (SD) CGI-I Scale score was 2.58 (0.71) (P < 0.001); 94% of patients had a CGI-I score ≤3. Mean (SD) duration of hospitalization decreased significantly from 15.7 (19.7) days before treatment to 2.4 (6.0) days after treatment (P < 0.05). Mean (SD) number of hospializations also decreased significantly from 2.0 (1.8) before treatment to 0.5 (1.3) after treatment (P < 0.01).Conclusions: The results of this pilot study suggest that use of the atypical-antipsychotic medication RLAI significantly decreased duration and rates of hospitalization, compared with baseline, in these VCMHO patients with schizophrenia spectrum illnesses.     

Effects of atorvastatin 10 mg and fenofibrate 200 mg on the low-density lipoprotein profile in dyslipidemic patients: A 12-week, multicenter, randomized, open-label, parallel-group study

Background: Elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations are highly atherogenic, especially the small, dense LDL (sdLDL) species. Fenofibrate has been reported to shift the LDL profile by decreasing the sdLDL subfraction and increasing larger LDL subclasses. Atorvastatin, anantihyperlipidemic agent, has been reported to reduce plasma total cholesterol (TC) and triglyceride (TG) concentrations and thus could modify the LDL profile.Objective: The aim of this study was to compare the effects of fenofi brate and atorvastatin on standard lipid concentrations and the LDL profile.Methods: In this randomized, open-label, parallel-group study, men and women aged 18 to 79 years with type II primary dyslipidemia, defined as LDL-C ≥160 and TG 150 to 400 mg/dL, after a 4- to 6-week washout period while eating an appropriate diet, were randomized to receive either atorvastatin 10 mg once daily or fenofi-brate 200 mg once daily. Plasma lipid concentrations and cholesterol and apolipoprotein (apo) B (reflecting the LDL particle number) in each LDL subfraction prepared by ultracentrifiigation were determined at baseline and after 12 weeks of treatment. Tolerability was assessed using adverse events (AEs) obtained on laboratory analysis and vital sign measurement. Adherence was assessed by counting unused drug supplies.Results: A total of 165 patients (117 men, 48 women; mean [SD] age, 50.1 [10.7] years; mean TC concentration, 289 mg/dL) were randomized to receive atorvastatin (n = 81) or fenofibrate (n = 84). Compared with fenofibrate, atorvastatin was associated with a significantly greater mean (SD) percentage decrease in TC (27.0% [12.3%] vs 16.5% [12.9%]; P < 0.001), calculated LDL-C (35.4% [15.8%] vs 17.3% [17.2%]; P < 0.001), TC/high-density lipoprotein cholesterol (HDL-C) ratio (29.1% [16.3%] vs 22.9% [15.9%]; P = 0.001), and apoB (30.3% [12.7%] vs 19.6% [15.5%]; P < 0.001). Compared with atorvastatin, fenofibrate was associated with a significantly greater decrease in TG (37.2% [25.9%] vs 20.2% [27.3%]; P < 0.001) and a significantly greater increase in HDL-C concentration (10.4% [15.7%] vs 4.6% [12.1%]; P = 0.017). Fibrinogen concentration was significantly different between the 2 groups (P = 0.002); it was decreased with fenofibrate use (4.6% [23.7%]) and was increased with atorvastatin use (5.7% [23.5%]). Atorvastatin did not markedly affect the LDL distribution; it was associated with a homogeneous decrease in cholesterol and apoB concentrations in all subfractions, whereas fenofibrate was associated with a marked movement toward a normalized LDL profile, shifting the sdLDL subfractions toward larger and less atherogenic particles, particularly in those patients with baseline TG ≥200 mg/dL. No serious AEs related to the study treatments were reported. A total of 5 AEs were observed in 8 patients, including: abdominal pain, 3 patients (2 in the atorvastatin group and 1 in the fenofibrate group); abnormal liver function test results, 1 (fenofibrate); increased creatine Phosphokinase activity, 2 (atorvastatin); gastrointestinal disorders, 1 (fenofibrate); and vertigo, 1 (fenofibrate).Conclusion: In these dyslipidemic patients, fenofibrate treatment was associated with an improved LDL subfraction profile beyond reduction in LDL-C, particularly in patients with elevated TG concentration, whereas atorvastatin was associated with equally reduced concentrations of cholesterol and apoB in all LDL subfractions independent of TG concentrations.     

Effects of a Stimulant-Free Dietary Supplement on Body Weight and Fat Loss in Obese Adults: A Six-Week Exploratory Study

Background: Obesity is a well-established risk factor for cardiovascular disease, diabetes, hyperlipidemia, hypertension, osteoarthritis, and stroke. Stimulants, such as ephedrine and caffeine and their herbal counterparts, have proved effective in facilitating body weight loss, but their use is controversial due to their undesired effects. Other nutraceuticals have shown moderate success in reducing body weight, whereas several other compounds have demonstrated little or no effect. Therefore, a tolerable and effective nutraceutical that can increase energy expenditure and/or decrease caloric intake is desirable for body weight reduction.Objective: The primary purpose of this study was to assess the tolerability and effectiveness of a novel, stimulant-free, dietary supplement containing glucomannan, chitosan, fenugreek, Gymnema sylvestre, and vitamin C on body weight and fat loss and change in body composition in obese adults.Methods: In this single-center, prospective, randomized, double-blind, placebo-controlled study conducted at the University of Guelph (Guelph, Ontario, Canada), obese adults (aged 20-50 years; body mass index [BMI], ≥30 kg/m²) were randomized to the treatment or placebo group. The treatment group received 6 capsules of a dietary supplement containing a proprietary blend of glucomannan, chitosan, fenugreek, G sylvestre, and vitamin C daily for 6 weeks, and the placebo group received 6 capsules of rice flour daily for 6 weeks. Body weight; percentage of body fat; absolute fat mass; lean body mass; BMI; upper abdominal, waist, and hip circumference; and anthropometric measurements were recorded at baseline and at study end. Patients completed daily dietary intake records on days 1 to 3 and days 40 to 42. They also completed weekly activity logs throughout the study.Results: Twenty-four subjects (mean [SD] age, 37.0 [8.2] years [range, 21-48years]; mean [SD] BMI, 35.7 [6.2] kg/m² [range, 28.9-50.9 kg/m²]) were assigned to the treatment group (8 women, 4 men) or the placebo group (9 women,3 men). Two subjects (8.3%; 1 patient [8.3%] from each group) dropped out for personal reasons unrelated to the study. No significant changes in the consumption of total calories; the percentage of calories ingested as carbohydrates, fat, or protein; or activity levels were found in either group throughout the study. Compared with the placebo group, the treatment group lost significantly more body weight (−2.3 kg vs 0.0 kg; P<0.01), percentage of body fat (−1.1% vs 0.2%; P<0.05), and absolute fat mass (−2.0 kg vs 0.2 kg; P<0.001). The treatment group also experienced a significantly greater reduction in upper abdominal circumference (−4.5 cm vs −0.7 cm), waist circumference (−4.1 cm vs 0.1 cm), and hip circumference (−2.9 cm vs 0.6 cm) compared with the placebo group (P<0.05 for all). No significant changes in heart rate or blood pressure were found in either group. Both the treatment and the placebo were well tolerated.Conclusion: Within the context of this study, the novel combination of glucomannan, chitosan, fenugreek, G sylvestre, and vitamin C results in significant body weight and fat loss in obese adults.Disclosure: Derek E. Woodgate, MSc, is president and owner of NxCare Inc., which produces the dietary supplement containing glucomannan, chitosan, fenugreek, Gymnema sylvestre, and vitamin C (trade name Calorie-Care™).     

Quality of life in patients with functional dyspepsia: Short- and long-term effect of Helicobacter pylori eradication with pantoprazole, amoxicillin, and clarithromycin or cisapride therapy: A prospective, parallel-group study

Background:

Quality of life (QOL) is impaired in functional dyspepsia (FD). Little is known about the effects of different therapies on the QOL profile in patients with this condition.

Objectives:

The aims of this study were to measure baseline QOL in patients with FD and to assess changes in QOL over time associated with Helicobacter pylori eradication and prokinetic treatment. The primary and secondary end points were the improvement in QOL 6 weeks and 1 year after successful eradication of the infection or prokinetic therapy.

Methods:

This 1-year, single-center, prospective, open-label, controlled, parallel-group trial was conducted at the Department of Gastroenterology, Ferencvdros Health Centre, Budapest, Hungary. The Functional Digestive Disorder Quality of Life (FDDQoL) Questionnaire (MAPI Research Institute, Lyon, France) was translated and validated previously in Hungarian. Male and female subjects aged 20 to 60 years were enrolled and classified as H pylori positive (HP+), H pylori negative (HP-) with FD, or healthy (control group). The HP+ patients received pantoprazole 40 mg BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID for 7 days, followed by on-demand ranitidine (150-300 mg/d) for 1 year. The HP- patients received the prokinetic cisapride 10 mg TID for 1 month, followed by on-demand cisapride (10-20 mg/d) for 1 year. The FDDQoL questionnaire was completed by all 3 groups on enrollment, at 6 weeks, and 1 year.

Results:

A total of 101 HP+ patients, 98 HP- patients, and 123 healthy controls were included in the study (185 women, 137 men; mean age, 39.0 ears). The mean (SD) baseline QOL scores were significantly lower in the HP+ group (53.3 [9.6]; 95% CI, 54.4-58.2) and the HP- groups (50.0 [9.8]; 95% CI, 58.0-62.0) compared with that in healthy controls (76.2 [8.7]; 95% CI, 74.6-77.8) (both, P < 0.001). Analysis of the short-term domain scores found that the HP+ group had significantly decreased scores in 6 of 8 domains: daily activities (P = 0.005), anxiety level (P = 0.02), diet (P = 0.008), sleep (P < 0.001), discomfort (P = 0.004), and disease control (P = 0.02); the HP- group had significantly decreased scores in 5 of 8 domains: daily activities (P < 0.001), diet (P = 0.004), sleep (P = 0.005), discomfort (P < 0.001), and disease control (P = 0.02). Eradication of the infection was successful in 77/101 (76.2%) of the patients on intent-to-treat analysis and 77/94 (81.9%) on per-protocol analysis. Eradication was associated with an increase in mean (SD) QOL score to 70.8 (10.7) at 6 weeks (95% CI, 63.3-73.2; P < 0.001 vs baseline) and to 75.3 (9.3) at 1 year (95% CI, 73.2-77.5; P= 0.05 vs 6 weeks). In the HP- group, the QOL score increased to 73.3 (9.7) (95% CI, 71.3-75.4; P < 0.001 vs baseline) at 6 weeks of cisapride treatment and to 76.5 (8.5) at 1 year (95% CI, 74.5-78.4; P = 0.06 vs 6 weeks). Most of the impaired domain scores improved significantly after both treatments. The short-term effect size was 1.48 in HP+ and 1.35 in HP− patients. Adverse events (AEs) occurred in 22 (21.8%) patients in the HP+ group (nausea, 8 [7.9%] patients; diarrhea, 5 [5.0%]; loss of appetite, 5 [5.0%]; stomatitis, 5 [5.0%]; abdominal pain, 4 [4.0%]; bloating, 4 [4.0%]; headache, 4 [4.0%]; vomiting, 4 [4.0%]; constipation, 3 [3.0%]; and vaginitis, 3 [3.0%]). In HP− cases, AEs occurred in 9 (9.2%) patients (abdominal cramps, 7 [7.1%]; diarrhea, 4 [4.1%]; and nausea, 3 [3.1%]).

Conclusion:

In this study in patients with FD and healthy controls, eradication of H pylori infection in infected patients and cisapride treatment in uninfected patients reversed low QOL scores during the 1-year follow-up period.