Retrospective cohort study evaluating exenatide twice daily and long-acting insulin analogs in a Veterans Health Administration population with type 2 diabetes.

AIM: This was a retrospective cohort study that evaluated the differences in glycated haemoglobin (HbA1c) and body mass index (BMI) in veterans with type 2 diabetes mellitus (T2DM), prescribed exenatide twice daily (BID) versus long-acting insulin analog (LAIA) two years after initiation in the United States (US) veteran population. MATERIALS AND METHODS: Patients were included if they were ≥ 18 years old with T2DM, and initiated exenatide BID or LAIA at the Veterans Health Administration between January 1, 2006 and December 31, 2010. Multivariate models were used to evaluate the changes in HbA1c and BMI between groups, controlling for potential confounders. Logistic regression was used to evaluate the odds of achieving ≥ 0.5% HbA1c reduction based on baseline HbA1c stratifications: low,<7%; moderate, 7% to<9%; and high,≥ 9%. RESULTS: A total of 446 exenatide BID and 51,531 LAIA patients met inclusion/exclusion criteria. On average, exenatide BID patients were significantly older (64 versus 60 years) with a higher BMI (37.8 versus 32.9 kg/m(2)). Baseline HbA1c was 8.2% and 8.8% for exenatide BID and LAIA patients, respectively (P<0.001); otherwise, patients were similar for all other characteristics. Exenatide BID treatment was significantly associated with a 0.32% (95%CI: 0.18-0.47%) greater reduction in HbA1c at two years compared with LAIA. Similar findings were observed for BMI reduction (0.68 kg/m(2); 95%CI: 0.42-0.95 kg/m(2)). Exenatide BID patients with moderate baseline HbA1c had significantly higher odds of achieving ≥ 0.5% HbA1c reduction compared with LAIA patients (OR=1.5; 95%CI: 1.2-2.0). CONCLUSIONS: Veterans treated with exenatide BID had significantly greater reduction in HbA1c and BMI compared with patients treated with LAIA patients two years after initiation.

A network meta-analysis to compare glycaemic control in patients with type 2 diabetes treated with exenatide once weekly or liraglutide once daily in comparison with insulin glargine, exenatide twice daily or placebo.

AIMS: The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exenatide once weekly (ExQW) and liraglutide once daily (QD) are indicated to improve glycaemic control in patients with type 2 diabetes. Although glycaemic control with ExQW versus liraglutide QD 1.8 mg has been directly compared, no studies have compared ExQW with liraglutide QD 1.2 mg or determined the probable relative efficacies of various injectable therapies for glycaemic control; therefore, a network meta-analysis was performed to address these questions. METHODS: A systematic review identified randomized controlled trials of ≥24 weeks that compared ExQW, liraglutide QD (1.2 mg, 1.8 mg), insulin glargine, exenatide twice daily (ExBID), or placebo. Twenty-two studies evaluating 11 049 patients were included in the network meta-analysis. Mean differences in HbA1c relative to placebo or each other and probability rankings were estimated. RESULTS: Estimated mean differences in HbA1c versus placebo were -1.15% (95% CrI: -1.31 to -1.00) for ExQW, -1.01% (95% CrI: -1.18 to -0.85) for liraglutide 1.2 mg, and -1.18% (95% CrI: -1.32 to -1.04) for liraglutide 1.8 mg. HbA1c differences for ExQW versus liraglutide 1.2 mg and 1.8 mg were -0.14% (95% CrI: -0.34 to 0.06) and 0.03% (95% CrI: -0.14 to 0.18), respectively. The estimated mean difference in HbA1c between liraglutide 1.2 mg and 1.8 mg was 0.17% (95% CrI: 0.02-0.30). Results were consistent when adjusted for background antihyperglycaemic medications and diabetes duration. CONCLUSIONS: This network meta-analysis did not identify meaningful differences in HbA1c lowering between ExQW and both liraglutide doses, suggesting that these GLP-1 RAs have similar glycaemic effects.

The effects of exenatide bid on metabolic control, medication use and hospitalization in patients with type 2 diabetes mellitus in clinical practice: a systematic review.

The objective of this systematic review was to assess the published literature on the effectiveness of exenatide twice daily (exenatide) in clinical practice, specifically its effects on haemoglobin A1c (A1C), fasting glucose (FG), weight, systolic blood pressure (SBP), medication use, hospitalization and cardiovascular disease (CVD) outcomes. A systematic literature search using the MEDLINE database of English language literature published between January 2005 and May 2011 was performed. The review included retrospective or prospective observational studies that included 100 or more patients per treatment group. A total of 15 studies meeting the inclusion criteria were identified. The studies revealed significant reductions of -0.4 to -0.9% in A1C, -10 mg/dl in FG, -2 to -11 kg in body weight and -2 to -11 mmHg in SBP. Statistically significant reductions in the use or dosage of either oral glucose-lowering medications or insulin after initiating exenatide treatment were found in every observational study that assessed medication changes, including reductions in dosage of up to 75% in sulphonylureas dosages, 22% in metformin, 66% in thiazolidinediones (TZD) or TZD combination therapy and 75% in prandial insulin. Exenatide-treated patients experienced significantly lower rates of all-cause and CVD-related hospitalization and CVD events than patients treated with other therapies overall. In this review of observational studies, exenatide initiation was associated with significant reductions in clinically relevant outcomes. Improvements in A1C, FG, weight and SBP in the observational studies in this review were consistent with improvements observed in controlled clinical trials.

Patient perspectives on once-weekly medications for diabetes.

AIM: to examine patient beliefs, preferences and concerns regarding a once-weekly (QW) glucose-lowering medication option. METHODS: a total of 1516 adults with type 2 diabetes drawn from a national Chronic Illness Panel completed an anonymous online survey that assessed perceived attributes of QW therapy, willingness to take an injectable QW medication and patient characteristics that might influence their willingness, such as current perceived glycaemic control and diabetes quality of life (DQOL). RESULTS: positive attitudes regarding QW medication were common, with current injection users significantly more likely than non-injection users to view beneficial aspects: greater convenience, better medication adherence, improved quality of life (QOL) and a less overwhelming sense of treatment (in all cases, p < 0.001). In all, 46.8% reported that they would likely take an injectable QW medication if recommended by their physician, with current injection users more than twice as likely as non-injection users (73.1 vs. 31.5%; p < 0.001). Greater willingness to take QW medications was associated with poorer DQOL [injection users only; odds ratio (OR) = 1.37, p < 0.01] and poorer perceived glycaemic control (non-injection users only; OR = 1.24, p < 0.05). Concerns arose about consistency of dosage over time, potential forgetfulness and cost. CONCLUSIONS: QW glucose-lowering medications are viewed positively by patients with type 2 diabetes, especially if they are current injection users or are dissatisfied with their current treatments or outcomes. Greater convenience, better medication adherence and improved QOL are commonly endorsed attributes. Clinicians may need to review both the positive attributes of QW medications as well as common patient concerns, when considering this option.

Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily.

AIMS: To assess treatment satisfaction and weight-related quality of life (QOL) in subjects with Type 2 diabetes treated with exenatide once weekly (QW) or twice daily (BID). METHODS: In this 52-week randomized, multi-centre, open-label study, 295 subjects managed with diet and exercise and/or oral glucose-lowering medications received either exenatide QW or BID during weeks 1-30; thereafter, subjects receiving exenatide BID were switched to exenatide QW, with 258 total subjects receiving exenatide QW during weeks 30-52. Diabetes Treatment Satisfaction Questionnaire-status (DTSQ-s) and Impact of Weight on Quality of Life-Lite (IWQOL-Lite) were assessed at baseline and weeks 30 and 52. Mean group changes from baseline to week 30 were estimated by ancova; changes from week 30 to week 52 were assessed by Student's t-test. RESULTS: Statistically significant improvements from baseline to week 30 were observed in both treatment groups for DTSQ-s and IWQOL-Lite measures, with significantly greater reduction in perceived frequency of hyperglycaemia and greater satisfaction with continuing treatment in the QW group compared with the BID group. Effect sizes for change in DTSQ-s total scores were 0.84 QW, 0.64 BID; for IWQOL-Lite: 0.96 QW, 0.82 BID. Treatment satisfaction and QOL improved significantly between weeks 30 and 52 for those switching from BID to QW. Occurrence of adverse events did not affect patients' improvements in treatment satisfaction and QOL. CONCLUSIONS: Patients treated with exenatide QW or BID experienced significant and clinically meaningful improvements in treatment satisfaction and QOL. Patients who switched from exenatide BID to exenatide QW administration reported further significant improvements.

Effects of Microcystis cells, cell extracts and lipopolysaccharide on drinking and liver function in rainbow trout Oncorhynchus mykiss Walbaum.

Liver mass (hepatosomatic index, HSI) increased by approximately 18% and water content in the gut by approximately 13 ml kg(-1) in freshwater rainbow trout exposed for 24 h to intact cells of a microcystin-producing cyanobacterium (Microcystis PCC 7813) together with administration of heterotrophic bacterial LPS. Exposure to broken (ultrasonicated) cyanobacterial cells together with administration of bacterial LPS increased HSI by approximately 50% and water content in the gut by almost 30 ml kg(-1). Exposure to broken or unbroken Microcystis cells without administration of bacterial LPS resulted in increased water content of the gut (by approximately 13 ml kg(-1)) with insignificant changes in HIS. Drinking rate increased with increasing dosage of bacterial LPS alone. The increased volume of water in the gut potentially increases the opportunity for uptake of waterborne toxins, including microcystins, and increased liver mass is a symptom consistent with the toxic effects of microcystins. It is concluded that exposure of fish to the cell contents of cyanobacteria (e.g. Microcystis PCC 7813) promotes osmoregulatory imbalance resulting from stimulation of the drinking response, increased volume of fluid in the gut and inability to remove excess water.

Effects of enteric bacterial and cyanobacterial lipopolysaccharides, and of microcystin-LR, on glutathione S-transferase activities in zebra fish (Danio rerio).

Cyanobacteria (blue-green algae) can produce a variety of toxins including hepatotoxins e.g. microcystins, and endotoxins such as lipopolysaccharides (LPS). The combined effects of such toxins on fish are little known. This study examines the activities of microsomal (m) and soluble (s) glutathione S-transferases (GST) from embryos of the zebra fish, Danio rerio at the prim six embryo stage, which had been exposed since fertilisation to LPS from different sources. A further aim was to see how activity was affected by co-exposure to LPS and microcystin-LR (MC-LR). LPS were obtained from Salmonella typhimurium, Escherichia coli, a laboratory culture of Microcystis CYA 43 and natural cyanobacterial blooms of Microcystis and Gloeotrichia. Following in vivo exposure of embryos to each of the LPS preparations, mGST activity was significantly reduced (from 0.50 to between 0.06 and 0.32 nanokatals per milligram (nkat mg(-1)) protein). sGST activity in vivo was significantly reduced (from 1.05 to between 0.19 and 0.22 nkat mg(-1) protein) after exposure of embryos to each of the cyanobacterial LPS preparations, but not in response to S. typhimurium or E. coli LPS. Activities of both m- and sGSTs were reduced after co-exposure to MC-LR and cyanobacterial LPS, but only mGST activity was reduced in the S. typhimurium and E. coli LPS-treated embryos. In vitro preparations of GST from adult and prim six embryo D. rerio showed no significant changes in enzyme activity in response to the LPS preparations with the exception of Gloeotrichia bloom LPS, where mGST was reduced in adult and embryo preparations. The present study represents the first investigations into the effects of cyanobacterial LPS on the phase-II microcystin detoxication mechanism. LPS preparations, whether from axenic cyanobacteria or cyanobacterial blooms, are potentially capable of significantly reducing activity of both the s- and mGSTs, so reducing the capacity of D. rerio to detoxicate microcystins. The results presented here have wide ranging implications for both animal and human health.

Trends in expenditures for Medicare liver transplant recipients.

Liver transplantation, a resource-intensive medical procedure, is under particular scrutiny in the current era of cost containment. There have been significant changes in treatment protocols over the past decade; however, information is limited on how these changes have affected the economics of liver transplantation. This study examines a time series from 1993 to 1999 in Medicare expenditures for liver transplantation. We estimated total first- and second-year expenditures, as well as expenditures 90 days pretransplantation. These expenditures included inpatient, outpatient, physician, home health, and hospice care; immunosuppression expenditures were not estimated. Average first-year expenditures (in year 2000 dollars) for liver transplantation, excluding immunosuppressives, decreased from 201,677 dollars in 1993 to 143,363 dollars in 1998. Inpatient costs accounted for the majority of total expenditures, decreasing from 179,306 dollars in 1993 to 120,445 dollars in 1998. Total days of hospitalization decreased from 56.7 days in 1993 to 42.2 days in 1998. The majority of hospitalization occurred during the first 90 days posttransplantation, but decreased from 44.4 days in 1993 to 29.4 days in 1999. Substantial cost reductions over this period were a result of reduced hospitalization and occurred while survival rates gradually improved.

Incidence and long-term cost of steroid-related side effects after renal transplantation.

Corticosteroids are an essential component of most immunosuppressive regimens currently used in renal transplantation because of their efficacy in reducing acute rejection and improving graft survival. Steroids, however, are associated with numerous side effects that lead to increased patient morbidity and mortality. The incidence and economic cost of steroid-related side effects have not been quantitatively assessed. Thus, based on a systematic review of the published literature, we estimated the incidence of steroid-related hypertension (15%), posttransplantation diabetes mellitus (10%), peripheral fractures (2% per year), avascular necrosis of the hip (8%), and cataracts (22%). In addition, we estimated that approximately 5% of patients who have cataracts or avascular necrosis of the hip require surgery. We used these literature-based estimates in a model to project the costs of treating side effects over a 10-year posttransplantation time frame for a 50-patient cohort that represented an average-sized renal transplant center. Steroid-induced hypertension and its complications were the most expensive side effect ($93,900), followed closely by posttransplantation diabetes ($89,700) and avascular necrosis of the hip ($61,700). Cataracts and peripheral bone fractures were less costly ($16,300 and $4,300, respectively). The cumulative projected 10-year cost of all side effects for the 50-patient cohort was $265, 900, or $5,300 per transplant patient. Steroid-related side effects add to the long-term cost of medical care of renal transplant recipients. These costs provide a rationale for further investigation of steroid-sparing immunosuppression protocols.

Transformation of carbon tetrachloride in an anaerobic packed-bed reactor without addition of another electron donor.

Carbon tetrachloride (52 microM) was biodegraded for more than 72% in an anaerobic packed-bed reactor without addition of an external electron donor. The chloride mass balance demonstrated that all carbon tetrachloride transformed was completely dechlorinated. Chloroform and dichloromethane were sometimes also found as transformation products, but neither accumulated to significant levels in comparison to the amount of carbon tetrachloride transformed. Transformation of carbon tetrachloride in the absence of an added electron donor suggests that carbon tetrachloride itself is the source of energy for the biological reaction observed, and possibly the source of carbon for cell growth. No such mechanism is yet known. The pathway of carbon tetrachloride transformation is not clear; it may be dehalogenated by hydrolytic reduction to carbon monoxide or formic acid which are electron demanding transformations. Carbon monoxide or formic acid may be further utilized and serve as electron donor. Complete dechlorination of carbon tetrachloride according to this pathway is independent of a second electron donor or electron acceptor, as with a fermentation process. Vancomycin, an inhibitor of gram positive eubacteria, severely inhibited carbon tetrachloride transformation in batch incubations with an enrichment culture from the reactor, indicating that gram positive eubacteria were involved in carbon tetrachloride transformation. Batch experiments with bromoethanesulfonic acid, used to inhibit methanogens, and molybdate, an inhibitor of sulfate reduction in sulfate reducing bacteria, demonstrated that neither methanogens nor sulfate reducers were involved in the complete dechlorination of carbon tetrachloride.

Cost-effectiveness of repeat medical procedures: kidney transplantation as an example.

The constraints on medical-care resources can give rise to the question of the cost-effectiveness of permitting repeat medical procedures when some patients may die without undergoing even a first procedure. Using kidney transplantation as an example, this study estimates the cost-effectiveness of patients' having available the option of a repeat medical procedure in the event the first procedure fails. Specifically, the analysis examines the effect on transplant candidates of having the option of kidney retransplantation, if and when retransplantation might be needed. Data sources include the U.S. Renal Data System (USRDS) Case-Mix Severity Study, Health Care Financing Administration (HCFA) data, and a MEDLINE search. Outcome measures include life expectancy, quality-adjusted life expectancy, lifetime costs of medical care, and marginal cost-effectiveness from a societal perspective. By avoiding lifelong dialysis after graft failure, first-transplant candidates gain an average of 47 quality-adjusted days with a retransplantation policy, despite the prolongation of time to first transplant by an average of 30 quality-adjusted days. The lifetime cost of medical care per first-transplant candidate is $1,210 higher with a retransplantation policy compared with the no-retransplantation policy; its societal cost-effectiveness is estimated to be $9,656 per quality-adjusted life-year saved. The retransplantation policy provides the greatest improvement in quality-adjusted life expectancy for younger candidates. In the case of kidney transplantation, the cost-effectiveness of a repeat transplant, on average, compares favorably with those of other medical strategies in common practice. As resources become increasingly constrained, this study demonstrates a framework for considering the cost-effectiveness of repeat medical procedures.

The cost effectiveness of mycophenolate mofetil in the first year after primary cadaveric transplant. U.S. Renal Transplant Mycophenolate Mofetil Study Group.

Mycophenolate mofetil (MMF) has been shown to reduce the incidence of acute graft rejection in three controlled trials of cadaveric renal transplantation. In a U.S. trial using quadruple sequential induction therapy as control, the MMF 2-g treatment group had an acute rejection rate 40.6% lower than control in the first posttransplant year (27.9% MMF-treated versus 47.0% control). The purpose of this analysis is to evaluate the economic implications of these clinical differences. The analysis relies on resource use data from the trial and other sources. Medical costs were estimated using a societal perspective and excluded the cost of the transplant procedure and organ acquisition. The two groups were compared in terms of treatment for acute rejection and opportunistic infection, graft survival, dialysis use, and maintenance immunosuppression. The results suggest that, on average, when compared with standard therapy, patients treated with MMF are likely to have lower rejection-related treatment costs because of a lower incidence of rejection ($6237 versus $3702), lower dialysis and graft failure costs because of improved graft survival ($20,104 versus $16,972), no difference in opportunistic infection treatment costs ($1962 versus $1962), and higher additional immunosuppression costs ($855 versus $5170). Taken together, these results suggest that patients treated with MMF are, on average, likely to have slightly lower first-year costs ($29,158 versus $27,807) compared with control, indicating that MMF treatment is cost-effective in the first year. These results remained stable under sensitivity analyses, with plausible variation in the rates of acute rejection, graft survival, and infection.

Transformation of carbon tetrachloride under sulfate reducing conditions.

The removal of carbon tetrachloride under sulfate reducing conditions was studied in an anaerobic packed-bed reactor. Carbon tetrachloride, up to a concentration of 30 microM, was completely converted. Chloroform and dichloromethane were the main transformation products, but part of the carbon tetrachloride was also completely dechlorinated to unknown products. Gram-positive sulfate-reducing bacteria were involved in the reductive dechlorination of carbon tetrachloride to chloroform and dichloromethane since both molybdate, an inhibitor of sulfate reduction, and vancomycin, an inhibitor of gram-positive bacteria completely inhibited carbon tetrachloride transformation. Carbon tetrachloride transformation by these bacteria was a cometabolic process and depended on the input of an electron donor and electron acceptor (sulfate). The rate of carbon tetrachloride transformation by sulfate reducing bacteria depended on the type of electron donor present. A transformation rate of 5.1 nmol x ml(-1) x h(-1) was found with ethanol as electron donor. At carbon tetrachloride concentrations higher than 18 microM, sulfate reduction and reductive dechlorination of carbon tetrachloride decreased and complete inhibition was observed at a carbon tetrachloride concentration of 56.6 microM. It is not clear what type of microorganisms were involved in the observed partial complete dechlorination of carbon tetrachloride. Sulfate reducing bacteria probably did not play a role since inhibition of these bacteria with molybdate had no effect on the complete dechlorination of carbon tetrachloride.